U.S. patent application number 16/194504 was filed with the patent office on 2019-08-15 for substituted polycyclic carbamoyl pyridone derivative prodrug.
This patent application is currently assigned to Shionogi & Co., Ltd.. The applicant listed for this patent is Shionogi & Co., Ltd.. Invention is credited to Toshiyuki AKIYAMA, Kosuke ANAN, Makoto KAWAI, Hidenori MIKAMIYAMA, Masayoshi MIYAGAWA, Naoyuki SUZUKI, Chika TAKAHASHI, Yoshiyuki TAODA, Kenji TOMITA.
Application Number | 20190248785 16/194504 |
Document ID | / |
Family ID | 45873898 |
Filed Date | 2019-08-15 |
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United States Patent
Application |
20190248785 |
Kind Code |
A1 |
TAKAHASHI; Chika ; et
al. |
August 15, 2019 |
SUBSTITUTED POLYCYCLIC CARBAMOYL PYRIDONE DERIVATIVE PRODRUG
Abstract
The present invention provides a compound having antiviral
effects, particularly having growth inhibitory activity on
influenza viruses, a preferred example of the compound being a
substituted 3-hydroxy-4-pyridone derivative prodrug having
cap-dependent endonuclease inhibitory activity.
Inventors: |
TAKAHASHI; Chika; (Osaka,
JP) ; MIKAMIYAMA; Hidenori; (Osaka, JP) ;
AKIYAMA; Toshiyuki; (Osaka, JP) ; TOMITA; Kenji;
(Osaka, JP) ; TAODA; Yoshiyuki; (Osaka, JP)
; KAWAI; Makoto; (Osaka, JP) ; ANAN; Kosuke;
(Osaka, JP) ; MIYAGAWA; Masayoshi; (Osaka, JP)
; SUZUKI; Naoyuki; (Osaka, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Shionogi & Co., Ltd. |
Osaka |
|
JP |
|
|
Assignee: |
Shionogi & Co., Ltd.
Osaka
JP
|
Family ID: |
45873898 |
Appl. No.: |
16/194504 |
Filed: |
November 19, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15676540 |
Aug 14, 2017 |
10202379 |
|
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16194504 |
|
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14562117 |
Dec 5, 2014 |
9758515 |
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15676540 |
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13824723 |
Mar 18, 2013 |
8987441 |
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PCT/JP2011/071446 |
Sep 21, 2011 |
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14562117 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07F 9/65616 20130101;
C07F 9/6561 20130101; C07D 471/04 20130101; A61P 31/16 20180101;
A61K 31/4738 20130101; A61P 31/00 20180101; C07D 471/14 20130101;
A61P 43/00 20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07F 9/6561 20060101 C07F009/6561; A61K 31/4738
20060101 A61K031/4738; C07D 471/14 20060101 C07D471/14 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 24, 2010 |
JP |
2010-213012 |
Claims
1-24. (canceled)
25. A compound of formula (I''): ##STR01340## or a pharmaceutically
acceptable salt or solvate thereof, wherein: "Ring" is a 5- to
7-membered ring that may be substituted by one, two or more same or
different substituents selected from substituent group D; P.sup.R
is a group selected from the group consisting of: b)
--C(.dbd.O)--P.sup.R1, c) --C(.dbd.O)-L-P.sup.R1, d)
--C(.dbd.O)-L-O--P.sup.R1, e) --C(.dbd.O)-L-O-L-O--P.sup.R1, f)
--C(.dbd.O)-L-O--C(.dbd.O)--P.sup.R1, g) --C(.dbd.O)--O--P.sup.R2,
h) --C(.dbd.O)--N(P.sup.R2).sub.2, i) --C(.dbd.O)--O-L-O--P.sup.R2,
j) --CH.sub.2--O--P.sup.R3, k) --CH.sub.2--O-L-O--P.sup.R3, l)
--CH.sub.2--O--C(.dbd.O)--P.sup.R3, m)
--CH.sub.2--O--C(.dbd.O)--O--P.sup.R3, n)
--CH(--CH.sub.3)--O--C(.dbd.O)--O--P.sup.R3, o)
--CH.sub.2--O--C(.dbd.O)--N(--K)--P.sup.R3, p)
--CH.sub.2--O--C(.dbd.O)--O-L-O--P.sup.R3, q)
--CH.sub.2--O--C(.dbd.O)--O-L-N(P.sup.R3).sub.2, r)
--CH.sub.2--O--C(.dbd.O)--N(--K)-L-O--P.sup.R3, s)
--CH.sub.2--O--C(.dbd.O)--N(--K)-L-N(P.sup.R3).sub.2, t)
--CH.sub.2--O--C(.dbd.O)--O-L-O-L-O--P.sup.R3, u)
--CH.sub.2--O--C(.dbd.O)--O-L-N(--K)--C(.dbd.O)--P.sup.R3, v)
--CH.sub.2--O--P(.dbd.O)(--OH).sub.2, w)
--CH.sub.2--O--P(.dbd.O)(--OBn).sub.2, and x) --CH.sub.2--P.sup.R4,
wherein: L is straight or branched lower alkylene, K is hydrogen,
or straight or branched lower alkyl, P.sup.R1 is carbocyclic group
optionally substituted by substituent group F, heterocyclic group
optionally substituted by substituent group F, lower alkyl amino
optionally substituted by substituent group F, or lower alkylthio
optionally substituted by substituent group F, P.sup.R2 is lower
alkyl optionally substituted by substituent group F, carbocyclic
group optionally substituted by substituent group F, or
heterocyclic group optionally substituted by substituent group F,
P.sup.R3 is lower alkyl optionally substituted by substituent group
F, carbocyclic group optionally substituted by substituent group F,
heterocyclic group optionally substituted by substituent group F,
lower alkyl amino optionally substituted by substituent group F,
carbocycle lower alkyl optionally substituted by substituent group
F, heterocycle lower alkyl optionally substituted by substituent
group F, or lower alkylsilyl, and P.sup.R4 is carbocyclic group
optionally substituted by substituent group F, or heterocyclic
group optionally substituted by substituent group F; R.sup.1a is
hydrogen; R.sup.2a is hydrogen; R.sup.5a and R.sup.7a are each
independently selected from a substituent group consisting of
hydrogen, benzhydryl, benzyl, indolylmethyl, cyclohexylmethyl,
phenethyl, 3,5-dimethylisoxazolyl, 5-chloro-3-ethylbenzothiophenyl,
biphenylmethyl, 4-fluorobenzyl, methylthiazolylmethyl,
cyclopentylmethyl, 4-methoxybenzyl, 3-fluorobenzyl, naphthylmethyl,
methyl, 3-trifluoromethylbenzyl, pyridylmethyl,
4-methylcarbonylaminobenzyl, pyrimidinyl, and the following groups:
##STR01341## wherein R.sup.E6 is selected from substituent group C;
m is an integer 0 or 1 or more; substituent group C is selected
from the group consisting of halogen, cyano, hydroxy, carboxy,
formyl, amino, oxo, nitro, lower alkyl, lower alkenyl, lower
alkynyl, halogeno lower alkyl, lower alkyloxy, lower alkynyloxy,
lower alkylthio, hydroxy lower alkyl, carbocyclic group,
heterocyclic group, heterocyclic group substituted by oxo,
carbocycle lower alkyloxy, carbocycleoxy lower alkyl, carbocycle
lower alkyloxy lower alkyl, heterocycle lower alkyloxy,
heterocycleoxy lower alkyl, heterocycle lower alkyloxy lower alkyl,
halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy
lower alkyloxy, lower alkylcarbonyl, lower alkylcarbonyloxy, lower
alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino,
halogeno lower alkyl carbonylamino, lower alkylaminocarbonyl, lower
alkylsulfonyl, lower alkylsulfinyl, and lower alkylsulfonylamino;
substituent group D is selected from the group consisting of
halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower
alkyl, halogeno lower alkyl, lower alkyloxy, carbocycle lower
alkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy,
lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower
alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower
alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl,
lower alkylsulfonylamino, carbocyclic group optionally substituted
by substituent group C, heterocyclic group optionally substituted
by substituent group C, carbocycle lower alkyl optionally
substituted by substituent group C, and heterocycle lower alkyl
optionally substituted by substituent group C; and substituent
group F is selected from the group consisting of oxo, lower alkyl,
hydroxy lower alkyl, amino, lower alkylamino, carbocycle lower
alkyl, lower alkylcarbonyl, halogen, hydroxy, carboxy, lower
alkylcarbonylamino, lower alkylcarbonyloxy, lower alkyloxycarbonyl,
lower alkyloxy, cyano, and nitro.
26. The compound according to claim 25, or a pharmaceutically
acceptable salt or solvate thereof, wherein P.sup.R is selected
from the group consisting of: b) --C(.dbd.O)--P.sup.R1, l)
--CH.sub.2--O--C(.dbd.O)--P.sup.R3, m)
--CH.sub.2--O--C(.dbd.O)--O--P.sup.R3, and n)
--CH(--CH.sub.3)--O--C(.dbd.O)--O--P.sup.R3.
27. The compound according to claim 25, or a pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.7a is the
following group: ##STR01342##
28. The compound according to claim 27, or a pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.E6 is selected
from the group consisting of fluorine atom, chlorine atom, bromine
atom, methyl, methoxy, and trifluoromethyl.
29. The compound according to claim 28, or a pharmaceutically
acceptable salt or solvate thereof, wherein m is an integer of 0 to
2.
30. A compound of formula (III'''): ##STR01343## or a
pharmaceutically acceptable salt or solvate thereof, wherein:
P.sup.R is --CH.sub.2--O--C(.dbd.O)--O--P.sup.R3, P.sup.R3 is lower
alkyl optionally substituted by substituent group F, carbocyclic
group optionally substituted by substituent group F, heterocyclic
group optionally substituted by substituent group F, lower alkyl
amino optionally substituted by substituent group F, carbocycle
lower alkyl optionally substituted by substituent group F,
heterocycle lower alkyl optionally substituted by substituent group
F, or lower alkylsilyl; R.sup.1a is hydrogen; R.sup.2a is hydrogen;
R.sup.5a is hydrogen; R.sup.7a is a heterocyclic group optionally
substituted by substituent group C; substituent group C is selected
from the group consisting of halogen, cyano, hydroxyl, carboxy,
formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower
alkyloxy, carbocyclic group, heterocyclic group, carbocycle lower
alkyloxy, heterocycle lower alkyloxy, halogeno lower alkyloxy,
lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower
alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower
alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl,
and lower alkylsulfonylamino; and substituent group F is selected
from the group consisting of oxo, lower alkyl, hydroxy lower alkyl,
amino, lower alkylamino, carbocycle lower alkyl, lower
alkylcarbonyl, halogen, hydroxy, carboxy, lower alkylcarbonylamino,
lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkyloxy,
cyano, and nitro.
31. The compound according to claim 30, or the pharmaceutically
acceptable salt thereof or the solvate thereof, wherein P.sup.R is
##STR01344##
32. A pharmaceutical composition containing a compound according to
claim 25, or a pharmaceutically acceptable salt or solvate thereof,
and at least one pharmaceutically acceptable carrier or
diluent.
33. A method for treating infectious disease characterized in
administering a compound according to claim 25, or a
pharmaceutically acceptable salt or solvate thereof, to a subject
in need thereof.
34. A pharmaceutical composition containing a compound according to
claim 30, or a pharmaceutically acceptable salt or solvate thereof,
and at least one pharmaceutically acceptable carrier or
diluent.
35. A method for treating infectious disease characterized in
administering a compound according to claim 30, or a
pharmaceutically acceptable salt or solvate thereof, to a subject
in need thereof.
Description
TECHNICAL FIELD
[0001] This invention relates to substituted polycyclic
carbamoylpyridone derivatives having cap-dependent endonuclease
inhibitory activity, prodrugs thereof, and pharmaceutical
compositions including thereof.
BACKGROUND ART
[0002] Influenza is an acute respiratory infectious disease caused
by infection with an influenza virus. In Japan, there is a report
of millions of influenza-like patients every winter, and influenza
is accompanied with high morbidity and mortality. Influenza is a
particularly important disease in a high risk population such as
baby and elderly, a complication rate with pneumonia is high in
elderly, and death with influenza is occupied with elderly in many
cases.
[0003] As anti-influenza drugs, Symmetrel (trade name: Amantadine)
and Flumadine (trade name: Rimantadine) which inhibit the
denucleation process of a virus, and Oseltamivir (trade name:
Tamiflu) and Zanamivir (trade name: Relenza) which are
neuraminidase inhibitors suppressing virus budding and release from
a cell are known. However, since problems of appearances of
resistant strains and side effects, and worldwide epidemic of a
new-type influenza virus having high pathogenicity and mortality
are feared, development of an anti-influenza drug having a novel
mechanism has been desired.
[0004] Since a cap-dependent endonuclease which is an influenza
virus-derived enzyme is essential for virus proliferation, and has
the virus-specific enzymatic activity which is not possessed by a
host, it is believed that the endonuclease is suitable for a target
of an anti-influenza drug. The cap-dependent endonuclease has a
host mRNA precursor as a substrate, and has the endonuclease
activity of producing a fragment of 9 to 13 bases including a cap
structure (not including the number of bases of the cap structure).
This fragment functions as a primer of a virus RNA polymerase, and
is used in synthesizing mRNA encoding a virus protein. That is, it
is believed that a substance which inhibits the cap-dependent
endonuclease inhibits synthesis of a virus protein by inhibiting
synthesis of virus mRNA and, as a result, inhibits virus
proliferation.
[0005] As the substance which inhibits the cap-dependent
endonuclease, flutimide (Patent Document 1 and Non-Patent Documents
1 and 2) and 4-substituted 2,4-dioxobutanoic acid (Non-Patent
Documents 3 to 5) and the like have been reported, but they have
not yet led to clinical use as anti-influenza drugs. In addition,
Patent Documents 2 to 16 and Non-Patent Document 6 describe
compounds having a similar structure to that of this invention as a
compound having integrase inhibitory activity, however, the
documents do not describe cap-dependent endonuclease. In addition,
Patent Document 17 describes an invention relating to "substituted
polycyclic carbamoylpyridone derivative" having cap-dependent
endonuclease inhibitory activity, that has been filed by the
applicants, but does not describe the prodrug relating to the
present invention.
PRIOR ART DOCUMENTS
Patent Documents
[0006] [Patent Document 1] GB No. 2280435 specification [0007]
[Patent Document 2] International Publication No. 2007/049675
pamphlet [0008] [Patent Document 3] International Publication No.
2006/088173 pamphlet [0009] [Patent Document 4] International
Publication No. 2006/066414 pamphlet [0010] [Patent Document 5]
International Publication No. 2005/092099 pamphlet [0011] [Patent
Document 6] International Publication No. 2005/087766 pamphlet
[0012] [Patent Document 7] International Publication No.
2005/016927 pamphlet [0013] [Patent Document 8] International
Publication No. 2004/024078 pamphlet [0014] [Patent Document 9]
International Publication No. 2006/116764 pamphlet [0015] [Patent
Document 10] International Publication No. 2010/011818 pamphlet
[0016] [Patent Document 11] International Publication No.
2010/011816 pamphlet [0017] [Patent Document 12] International
Publication No. 2010/011819 pamphlet [0018] [Patent Document 13]
International Publication No. 2010/011815 pamphlet [0019] [Patent
Document 14] International Publication No. 2010/011814 pamphlet
[0020] [Patent Document 15] International Publication No.
2010/011812 pamphlet [0021] [Patent Document 16] International
Publication No. 2011/011483 pamphlet [0022] [Patent Document 17]
International Publication No. 2010/147068 pamphlet
Non-Patent Documents
[0022] [0023] [NON-PATENT DOCUMENT 1] Tetrahedron Lett 1995, 36
(12), 2005 [0024] [NON-PATENT DOCUMENT 2] Tetrahedron Lett 1995, 36
(12), 2009 [0025] [NON-PATENT DOCUMENT 3] Antimicrobial Agents And
Chemotherapy, December 1994, p. 2827-2837 [0026] [NON-PATENT
DOCUMENT 4] Antimicrobial Agents And Chemotherapy, May 1996, p.
1304-1307 [0027] [NON-PATENT DOCUMENT 5] J. Med. Chem. 2003, 46,
1153-1164 [0028] [NON-PATENT DOCUMENT 6] Bioorganic & Medicinal
Chemistry Letters 17 (2007) 5595-5599
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0029] An object of the present invention is to provide compounds
having antiviral activities, especially inhibiting growth activity
of influenza virus. Another object of the present invention is to
provide compounds being efficiently absorbed into the body after
administration and showing high pharmacological effect by
converting into a prodrug a compound used for in vivo
administration (for example, oral administration). More preferably,
this invention provides compounds and medicament containing the
same which inhibit increase of influenza virus by exhibiting
cap-dependent endonuclease inhibitory activity after in vivo
administration.
Means for Solving the Problems
[0030] The present invention provides inventions shown below.
(Item 1)
[0031] A compound represented by formula (I):
##STR00001##
[0032] a pharmaceutically acceptable salt, or a solvate
thereof:
[0033] (wherein
[0034] P.sup.R is a group to form a prodrug (preferably, except for
a benzyl group and methoxy group);
[0035] R.sup.1a is hydrogen, halogen, hydroxy, carboxy, cyano,
formyl, lower alkyl optionally substituted by substituent group C,
lower alkenyl optionally substituted by substituent group C, lower
alkynyl optionally substituted by substituent group C, lower
alkyloxy optionally substituted by substituent group C, lower
alkenyloxy optionally substituted by substituent group C, lower
alkylcarbonyl optionally substituted by substituent group C, lower
alkyloxycarbonyl optionally substituted by substituent group C,
carbocyclic group optionally substituted by substituent group C,
carbocycle lower alkyl optionally substituted by substituent group
C, carbocycleoxy optionally substituted by substituent group C,
carbocycleoxycarbonyl optionally substituted by substituent group
C, heterocyclic group optionally substituted by substituent group
C, heterocycle lower alkyl optionally substituted by substituent
group C, heterocycleoxy optionally substituted by substituent group
C, heterocycleoxycarbonyl optionally substituted by substituent
group C,
[0036] --Z--N(R.sup.A1)(R.sup.A2),
[0037] --Z--N(R.sup.A3)--S.sub.2--(R.sup.A4),
[0038] --Z--C(.dbd.O)--N(R.sup.A5)--SO.sub.2--(R.sup.A6),
[0039] --Z--N(R.sup.A7)--C(.dbd.O)--R.sup.A8,
[0040] --Z--S--R.sup.A9,
[0041] --Z--SO.sub.2--R.sup.A10,
[0042] --Z--S(.dbd.O)--R.sup.A11,
[0043] --Z--N(R.sup.A12)--C(.dbd.O)--O--R.sup.A13,
[0044] --Z--N(R.sup.A14)--C(.dbd.O)--N(R.sup.A15)(R.sup.A16),
[0045]
--Z--C(.dbd.O)--N(R.sup.A17)--C(.dbd.O)--N(R.sup.A18)(R.sup.A19),
[0046] --Z--N(R.sup.A20)--C(.dbd.O)C((.dbd.O)--R.sup.A21, or
[0047] --Z--B(--OR.sup.A22)(--OR.sup.A2)
[0048] (wherein R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A5, R.sup.A7,
R.sup.A8, R.sup.A9, R.sup.A12, R.sup.A13, R.sup.A14, R.sup.A15,
R.sup.A16, R.sup.A17, R.sup.A18, R.sup.A19, R.sup.A20, and
R.sup.A21 are each independently selected from a substituent group
consisting of hydrogen, lower alkyl optionally substituted by
substituent group C, lower alkenyl optionally substituted by
substituent group C, lower alkynyl optionally substituted by
substituent group C, carbocyclic group optionally substituted by
substituent group C, heterocyclic group optionally substituted by
substituent group C, carbocycle lower alkyl optionally substituted
by substituent group C, and heterocycle lower alkyl optionally
substituted by substituent group C,
[0049] R.sup.A4, R.sup.A6, R.sup.A10, and R.sup.A11 are each
independently selected from a substituent group consisting of lower
alkyl optionally substituted by substituent group C, lower alkenyl
optionally substituted by substituent group C, lower alkynyl
optionally substituted by substituent group C, carbocyclic group
optionally substituted by substituent group C, heterocyclic group
optionally substituted by substituent group C, carbocycle lower
alkyl optionally substituted by substituent group C, and
heterocycle lower alkyl optionally substituted by substituent group
C,
[0050] R.sup.A1 and R.sup.A2, R.sup.A15 and R.sup.A16, and
R.sup.A18 and R.sup.A19, each may be taken together with an
adjacent atom to form heterocycle,
[0051] R.sup.A22 and R.sup.A23 are each independently an hydrogen
atom, lower alkyl optionally substituted by substituent group C, or
R.sup.A22 and R.sup.A23 may be taken together with an adjacent atom
to form heterocycle, and
[0052] Z is a single bond or straight or branched lower
alkylene);
[0053] R.sup.2a is hydrogen, halogen, carboxy, cyano, formyl, lower
alkyl optionally substituted by substituent group C, lower alkenyl
optionally substituted by substituent group C, lower alkynyl
optionally substituted by substituent group C, lower alkyloxy
optionally substituted by substituent group C, lower alkenyloxy
optionally substituted by substituent group C, lower alkylcarbonyl
optionally substituted by substituent group C, lower
alkyloxycarbonyl optionally substituted by substituent group C,
carbocyclic group optionally substituted by substituent group C,
carbocycle lower alkyl optionally substituted by substituent group
C, carbocyclecarbonyl optionally substituted by substituent group
C, carbocycleoxy optionally substituted by substituent group C,
carbocycleoxycarbonyl optionally substituted by substituent group
C, heterocyclic group optionally substituted by substituent group
C, heterocycle lower alkyl optionally substituted by substituent
group C, heterocyclecarbonyl optionally substituted by substituent
group C, heterocycleoxy optionally substituted by substituent group
C, heterocycleoxycarbonyl optionally substituted by substituent
group C,
[0054] --Z--N(R.sup.B1)--SO.sub.2--R.sup.B2,
[0055] --Z--N(R.sup.B3)--C(.dbd.O)--R.sup.B4,
[0056] --Z--N(R.sup.B5)--C(.dbd.O)--O--R.sup.B6,
[0057] --Z--C(.dbd.O)--N(R.sup.B7)(R.sup.B8),
[0058] --Z--N(R.sup.B9)(R.sup.B10), or
[0059] --Z--SO.sub.2--R.sup.B11
[0060] (wherein R.sup.B1, R.sup.B3, R.sup.B4, R.sup.B5, R.sup.B6,
R.sup.B7, R.sup.B8, R.sup.B9, and R.sup.B10 are each independently
selected from a substituent group consisting of hydrogen, lower
alkyl optionally substituted by substituent group C, lower alkenyl
optionally substituted by substituent group C, lower alkynyl
optionally substituted by substituent group C, carbocyclic group
optionally substituted by substituent group C, heterocyclic group
optionally substituted by substituent group C, carbocycle lower
alkyl optionally substituted by substituent group C, and
heterocycle lower alkyl optionally substituted by substituent group
C,
[0061] R.sup.B2 and R.sup.B11 are each independently selected from
a substituent group consisting of lower alkyl optionally
substituted by substituent group C, lower alkenyl optionally
substituted by substituent group C, lower alkynyl optionally
substituted by substituent group C, carbocyclic group optionally
substituted by substituent group C, heterocyclic group optionally
substituted by substituent group C, carbocycle lower alkyl
optionally substituted by substituent group C, and heterocycle
lower alkyl optionally substituted by substituent group C,
[0062] R.sup.B7 and R.sup.B8, and R.sup.B9 and R.sup.B10 may be
taken together with an adjacent atom to form heterocycle and
[0063] Z is a single bond or straight or branched lower
alkylene);
[0064] R.sup.3a is hydrogen, halogen, hydroxy, carboxy, cyano,
formyl, lower alkyl optionally substituted by substituent group C,
lower alkenyl optionally substituted by substituent group C, lower
alkynyl optionally substituted by substituent group C, lower
alkyloxy optionally substituted by substituent group C, lower
alkenyloxy optionally substituted by substituent group C, lower
alkylcarbonyl optionally substituted by substituent group C, lower
alkyloxycarbonyl optionally substituted by substituent group C,
carbocyclic group optionally substituted by substituent group C,
carbocycle lower alkyl optionally substituted by substituent group
C, carbocycleoxy lower alkyl optionally substituted by substituent
group C, carbocyclecarbonyl optionally substituted by substituent
group C, carbocycleoxy optionally substituted by substituent group
C, carbocycleoxycarbonyl optionally substituted by substituent
group C, heterocyclic group optionally substituted by substituent
group C, heterocycle lower alkyl optionally substituted by
substituent group C, heterocycleoxy lower alkyl optionally
substituted by substituent group C, heterocyclecarbonyl optionally
substituted by substituent group C, heterocycleoxy optionally
substituted by substituent group C, heterocycleoxycarbonyl
optionally substituted by substituent group C,
[0065] --Z--N(R.sup.C1)--SO.sub.2--R.sup.C2,
[0066] --Z--N(R.sup.C3)--C(.dbd.O)--R.sup.C4,
[0067] --Z--N(R.sup.C5)--C(.dbd.O)--O--R.sup.C6,
[0068] --Z--C(.dbd.O)--N(R.sup.C7)(R.sup.C8),
[0069] --Z--N(R.sup.C9)(R.sup.C10),
[0070] --Z--SO.sub.2--R.sup.C11, or
[0071] --Z--N(R.sup.C12)--O--C(.dbd.O)--R.sup.C13
[0072] (wherein R.sup.C1, R.sup.C3, R.sup.C4, R.sup.C5, R.sup.C6,
R.sup.C7, R.sup.C8, R.sup.C9, R.sup.C10, R.sup.C12, and R.sup.C13
are each independently selected from a substituent group consisting
of hydrogen, lower alkyl optionally substituted by substituent
group C, lower alkenyl optionally substituted by substituent group
C, lower alkynyl optionally substituted by substituent group C,
carbocyclic group optionally substituted by substituent group C,
heterocyclic group optionally substituted by substituent group C,
carbocycle lower alkyl optionally substituted by substituent group
C, and heterocycle lower alkyl optionally substituted by
substituent group C,
[0073] R.sup.C2 and R.sup.C11 are each independently selected from
a substituent group consisting of lower alkyl optionally
substituted by substituent group C, lower alkenyl optionally
substituted by substituent group C, lower alkynyl optionally
substituted by substituent group C, carbocyclic group optionally
substituted by substituent group C, heterocyclic group optionally
substituted by substituent group C, carbocycle lower alkyl
optionally substituted by substituent group C, and heterocycle
lower alkyl optionally substituted by substituent group C,
[0074] R.sup.C7 and R.sup.C8, and R.sup.C9 and R.sup.C10 each may
be taken together with an adjacent atom to form heterocycle,
and
[0075] Z is a single bond or straight or branched lower alkylene)
and;
[0076] a) either B.sup.1 or B.sup.2 is CR.sup.5aR.sup.6a, and the
other is NR.sup.7a, or
[0077] b) B.sup.1 is CR.sup.8aR.sup.9a, and B.sup.2 is
CR.sup.10aR.sup.11a,
[0078] R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a, R.sup.9a, R.sup.10a,
and R.sup.11a are each independently selected from a substituent
group consisting of hydrogen, carboxy, cyano, lower alkyl
optionally substituted by substituent group C, lower alkenyl
optionally substituted by substituent group C, lower alkynyl
optionally substituted by substituent group C, lower alkyl carbonyl
optionally substituted by substituent group C, lower alkyl
oxycarbonyl optionally substituted by substituent group C,
carbocyclic group optionally substituted by substituent group C,
carbocycle lower alkyl optionally substituted by substituent group
C, carbocycleoxy lower alkyl optionally substituted by substituent
group C, carbocyclecarbonyl optionally substituted by substituent
group C, carbocycleoxycarbonyl optionally substituted by
substituent group C, heterocyclic group optionally substituted by
substituent group C, heterocycle lower alkyl optionally substituted
by substituent group C, heterocycleoxy lower alkyl optionally
substituted by substituent group C, heterocyclecarbonyl optionally
substituted by substituent group C, heterocycleoxycarbonyl
optionally substituted by substituent group C,
[0079] --Y--S--R.sup.D1,
[0080] --Z--S(.dbd.O)--R.sup.D2,
[0081] --Z--SO.sub.2--R.sup.D3,
[0082] --C(.dbd.O)--C(.dbd.O)--R.sup.D4,
[0083] --C(.dbd.O)--N(R.sup.D5)(R.sup.D6),
[0084] --Z--C(R.sup.D7)(R.sup.D8)(R.sup.D9),
[0085] --Z--CH.sub.2--R.sup.D10,
[0086] --Z--N(R.sup.D11)--C(.dbd.O)--O--R.sup.D12, or
[0087] --Z--N(R.sup.D13)--C(.dbd.O)--R.sup.D14, or
[0088] R.sup.5a and R.sup.6a may be taken together to form
heterocyclic group optionally substituted by substituent group
C
[0089] (wherein R.sup.D1, R.sup.D4, R.sup.D5, R.sup.D6, R.sup.D9,
R.sup.D11, R.sup.D12, R.sup.D13, and R.sup.D14 are each
independently selected from a substituent group consisting of
hydrogen, lower alkyl optionally substituted by substituent group
C, lower alkenyl optionally substituted by substituent group C,
lower alkynyl optionally substituted by substituent group C,
carbocyclic group optionally substituted by substituent group C,
heterocyclic group optionally substituted by substituent group C,
carbocycle lower alkyl optionally substituted by substituent group
C, and heterocycle lower alkyl optionally substituted by
substituent group C,
[0090] R.sup.D2 and R.sup.D3 are each independently selected from a
substituent group consisting of lower alkyl optionally substituted
by substituent group C, lower alkenyl optionally substituted by
substituent group C, lower alkynyl optionally substituted by
substituent group C, carbocyclic group optionally substituted by
substituent group C, heterocyclic group optionally substituted by
substituent group C, carbocycle lower alkyl optionally substituted
by substituent group C, and heterocycle lower alkyl optionally
substituted by substituent group C,
[0091] R.sup.D7, R.sup.D8, and R.sup.D10 are each independently
carbocyclic group optionally substituted by substituent group C, or
heterocyclic group optionally substituted by substituent group
C,
[0092] R.sup.D5 and R.sup.D6 may be taken together with an adjacent
atom to form heterocycle,
[0093] Y is straight or branched lower alkylene, and
[0094] Z is a single bond or straight or branched lower alkylene),
and
[0095] R.sup.D5 and R.sup.D6 may be taken together with an adjacent
atom to form carbocycle;
[0096] 1) when B.sup.1 is CR.sup.5aR.sup.6a and B.sup.2 is
NR.sup.7a,
[0097] R.sup.3a and R.sup.7a may be taken together with an adjacent
atom to form heterocycle optionally substituted by substituent
group D,
[0098] 2) when B.sup.1 is NR.sup.7a and B.sup.2 is
CR.sup.5aR.sup.6a,
[0099] R.sup.3a and R.sup.6a may be taken together with an adjacent
atom to form heterocycle optionally substituted by substituent
group D, or
[0100] 3) when B.sup.1 is CR.sup.8aR.sup.9a, and B.sup.2 is
CR.sup.10aR.sup.11a,
[0101] R.sup.8a and R.sup.10a may be taken together with an
adjacent atom to form carbocycle or heterocycle optionally
substituted by substituent group D, or
[0102] R.sup.3a and R.sup.11a may be taken together with an
adjacent atom to form heterocycle optionally substituted by
substituent group D;
[0103] wherein
[0104] when B.sup.1 is CR.sup.8aR.sup.9a, and B.sup.2 is
CR.sup.10aR.sup.11a, and R.sup.9a is hydrogen, and R.sup.11a is
hydrogen,
[0105] i) either R.sup.8a or R.sup.10a is
[0106] --Z--C(R.sup.E1)(R.sup.E2)(R.sup.E3),
[0107] --Y--S--R.sup.E4,
[0108] --Z--CH.sub.2--R.sup.E5, or
[0109] a group shown below:
##STR00002##
[0110] (wherein R.sup.E1 and R.sup.E2 are each independently,
selected from a substituent group consisting of carbocyclic group
optionally substituted by substituent group C, and heterocyclic
group optionally substituted by substituent group C,
[0111] R.sup.E3 is selected from a substituent group consisting of
hydrogen, lower alkyl optionally substituted by substituent group
C, lower alkenyl optionally substituted by substituent group C,
lower alkynyl optionally substituted by substituent group C,
carbocyclic group optionally substituted by substituent group C,
heterocyclic group optionally substituted by substituent group C,
carbocycle lower alkyl optionally substituted by substituent group
C, and heterocycle lower alkyl optionally substituted by
substituent group C,
[0112] R.sup.E4 is selected from a substituent group consisting of
carbocycle lower alkyl optionally substituted by substituent group
C, and heterocycle lower alkyl optionally substituted by
substituent group C,
[0113] R.sup.E5 is aromatic heterocyclic group optionally
substituted by substituent group C,
[0114] R.sup.E6 is selected from a substituent group C,
[0115] m is an integer of 0 or 1 or more, provided that
[0116] m of R.sup.E6s is same or different groups selected from
substituent group C,
[0117] Y is straight or branched lower alkylene, and
[0118] Z is a single bond or straight or branched lower alkylene);
and
[0119] ii) the other of R.sup.8a or R.sup.10a is
[0120] hydrogen, carboxy, cyano, lower alkyl optionally substituted
by substituent group C, lower alkenyl optionally substituted by
substituent group C, lower alkynyl optionally substituted by
substituent group C, lower alkylcarbonyl optionally substituted by
substituent group C, lower alkyloxycarbonyl optionally substituted
by substituent group C, carbocyclic group optionally substituted by
substituent group C, carbocycle lower alkyl optionally substituted
by substituent group C, carbocycleoxy lower alkyl optionally
substituted by substituent group C, carbocyclecarbonyl optionally
substituted by substituent group C, carbocycleoxycarbonyl
optionally substituted by substituent group C, heterocyclic group
optionally substituted by substituent group C, heterocycle lower
alkyl optionally substituted by substituent group C, heterocycleoxy
lower alkyl optionally substituted by substituent group C,
heterocyclecarbonyl optionally substituted by substituent group C,
heterocycleoxycarbonyl optionally substituted by substituent group
C,
[0121] --Y--S--R.sup.F1,
[0122] --C(.dbd.O)--C(.dbd.O)--R.sup.F2, or
[0123] --C(.dbd.O)--N(R.sup.F3)(R.sup.F4)
[0124] (wherein R.sup.F1, R.sup.F2, R.sup.F3, and R.sup.F4 are each
independently selected from a substituent group consisting of
hydrogen, lower alkyl optionally substituted by substituent group
C, lower alkenyl optionally substituted by substituent group C,
lower alkynyl optionally substituted by substituent group C,
carbocyclic group optionally substituted by substituent group C,
heterocyclic group optionally substituted by substituent group C,
carbocycle lower alkyl optionally substituted by substituent group
C, and heterocycle lower alkyl optionally substituted by
substituent group C, and
[0125] Y is straight or branched lower alkylene);
[0126] with a proviso that the following c) and d) are excluded
[0127] c) R.sup.5a, R.sup.6a, and R.sup.7a are all hydrogens.
[0128] d) R.sup.8a, R.sup.9a, R.sup.10a, and R.sup.11a are all
hydrogens;
[0129] Substituent group C: halogen, cyano, hydroxy, carboxy,
formyl, amino, oxo, nitro, lower alkyl, lower alkenyl, lower
alkynyl, halogeno lower alkyl, lower alkyloxy, lower alkynyloxy,
lower alkylthio, hydroxy lower alkyl, carbocyclic group,
heterocyclic group, heterocyclic group substituted by oxo,
carbocycle lower alkyloxy, carbocycleoxy lower alkyl, carbocycle
lower alkyloxy lower alkyl, heterocycle lower alkyloxy,
heterocycleoxy lower alkyl, heterocycle lower alkyloxy lower alkyl,
halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy
lower alkyloxy, lower alkylcarbonyl, lower alkylcarbonyloxy, lower
alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino,
halogeno lower alkyl carbonylamino, lower alkylaminocarbonyl, lower
alkylsulfonyl, lower alkylsulfinyl, and lower
alkylsulfonylamino;
[0130] Substituent group D: halogen, cyano, hydroxy, carboxy,
formyl, amino, oxo, nitro, lower alkyl, halogeno lower alkyl, lower
alkyloxy, carbocycle lower alkyloxy, heterocycle lower alkyloxy,
halogeno lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy
lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower
alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl,
lower alkylsulfonyl, lower alkylsulfonylamino, carbocyclic group
optionally substituted by substituent group C, heterocyclic group
optionally substituted by substituent group C, carbocycle lower
alkyl optionally substituted by substituent group C, and
heterocycle lower alkyl optionally substituted by substituent group
C).
(Item 2)
[0131] The compound according to item 1, or the pharmaceutically
acceptable salt thereof or the solvate thereof,
[0132] wherein R.sup.1a is hydrogen, halogen, hydroxy, carboxy,
cyano, formyl, lower alkyl optionally substituted by substituent
group C, lower alkenyl optionally substituted by substituent group
C, lower alkynyl optionally substituted by substituent group C,
lower alkyloxy optionally substituted by substituent group C, lower
alkenyloxy optionally substituted by substituent group C, lower
alkylcarbonyl optionally substituted by substituent group C, lower
alkyloxycarbonyl optionally substituted by substituent group C,
carbocyclic group optionally substituted by substituent group C,
carbocycle lower alkyl optionally substituted by substituent group
C, carbocycleoxy optionally substituted by substituent group C,
carbocycleoxycarbonyl optionally substituted by substituent group
C, heterocyclic group optionally substituted by substituent group
C, heterocycle lower alkyl optionally substituted by substituent
group C, heterocycleoxy optionally substituted by substituent group
C, heterocycleoxycarbonyl optionally substituted by substituent
group C,
[0133] --Z--N(R.sup.A1)(R.sup.A2),
[0134] --Z--N(R.sup.A3)--SO.sub.2--(R.sup.A4),
[0135] --Z--N(R.sup.A7)--C(.dbd.O)--R.sup.A8,
[0136] --Z--S--R.sup.A9,
[0137] --Z--SO.sub.2--R.sup.A10,
[0138] --Z--N(R.sup.A12)--C(.dbd.O)--O--R.sup.A13,
[0139] --Z--N(R.sup.A20)--C(.dbd.O)C(.dbd.O)--C(.dbd.O)--R.sup.A21,
or
[0140] --Z--B(--OR.sup.A22)(--OR.sup.A23)
[0141] (substituent group C, R.sup.A1, R.sup.A2, R.sup.A3,
R.sup.A4, R.sup.A7, R.sup.A8, R.sup.A9, R.sup.A10, R.sup.A12,
R.sup.A13, R.sup.A20, R.sup.A21, R.sup.A22, R.sup.A23, and Z are
same as those of item 1).
(Item 3)
[0142] The compound according to item 1, or the pharmaceutically
acceptable salt thereof or the solvate thereof,
[0143] wherein R.sup.1a is hydrogen, halogen, hydroxy, carboxy,
lower alkyl optionally substituted by substituent group C, lower
alkenyl optionally substituted by substituent group C, lower
alkyloxy optionally substituted by substituent group C, lower
alkylcarbonyl optionally substituted by substituent group C, lower
alkyloxycarbonyl optionally substituted by substituent group C,
heterocyclic group optionally substituted by substituent group
C,
[0144] --Z--N(R.sup.A1)(R.sup.A2),
[0145] --Z--N(R.sup.A7)--C(.dbd.O)--R.sup.A8,
[0146] --Z--N(R.sup.A12)--C(.dbd.O)--O--R.sup.A13, or
[0147] --Z--B(--OR.sup.A22)(--OR.sup.A23)
[0148] (substituent group C, R.sup.A1, R.sup.A2, R.sup.A7,
R.sup.A8, R.sup.A2, R.sup.A3, R.sup.A22, R.sup.A23, and Z are same
as those of item 1).
(Item 4)
[0149] The compound according to item 1, or the pharmaceutically
acceptable salt thereof or the solvate thereof,
[0150] wherein R.sup.1a is hydrogen, halogen, hydroxy, carboxy,
lower alkyl optionally substituted by substituent group C, lower
alkenyl optionally substituted by substituent group C, lower
alkyloxy optionally substituted by substituent group C, lower
alkylcarbonyl optionally substituted by substituent group C, lower
alkyloxycarbonyl optionally substituted by substituent group C,
heterocyclic group optionally substituted by substituent group C,
or
[0151] --Z--N(R.sup.A1)(R.sup.A2)
[0152] (substituent group C, R.sup.A1, R.sup.A2, and Z are same as
those of item 1).
(Item 5)
[0153] The compound according to item 1, or the pharmaceutically
acceptable salt thereof or the solvate thereof, wherein R.sup.1a is
hydrogen, or carboxy.
(Item 6)
[0154] The compound according to any one of items 1 to 5, or the
pharmaceutically acceptable salt thereof or the solvate
thereof,
[0155] wherein R.sup.2a is hydrogen, lower alkyl optionally
substituted by substituent group C, carbocycle lower alkyl
optionally substituted by substituent group C, heterocycle lower
alkyl optionally substituted by substituent group C, or
[0156] --Z--N(R.sup.B9)(R.sup.B10)
[0157] (substituent group C, R.sup.B9, R.sup.B10, and Z are same as
those of item 1).
(Item 7)
[0158] The compound according to any one of items 1 to 5, or the
pharmaceutically acceptable salt thereof or the solvate
thereof,
[0159] wherein R.sup.2a is hydrogen or lower alkyl optionally
substituted by substituent group C
[0160] (substituent group C is same as that of item 1).
(Item 8)
[0161] The compound according to any one of items 1 to 7, or the
pharmaceutically acceptable salt thereof or the solvate
thereof,
[0162] wherein R.sup.3a is hydrogen, lower alkyl optionally
substituted by substituent group C, lower alkenyl optionally
substituted by substituent group C, lower alkynyl optionally
substituted by substituent group C, carbocyclic group optionally
substituted by substituent group C, carbocycle lower alkyl
optionally substituted by substituent group C, carbocycleoxy lower
alkyl optionally substituted by substituent group C, heterocycle
lower alkyl optionally substituted by substituent group C,
[0163] --Z--N(R.sup.C1)--SO.sub.2--R.sup.C2,
[0164] --Z--N(R.sup.C3)--C(.dbd.O)--R.sup.C4,
[0165] --Z--N(R.sup.C5)--C(.dbd.O)--O--R.sup.C6,
[0166] --Z--C(.dbd.O)--N(R.sup.C7)(R.sup.C8), or
[0167] --Z--N(R.sup.C9)(R.sup.C10)
[0168] (substituent group C, R.sup.C1, R.sup.C2, R.sup.C3,
R.sup.C4, R.sup.C5, R.sup.C6, R.sup.C7, R.sup.C8, R.sup.C9,
R.sup.C10, and Z are same as those of item 1).
(Item 9)
[0169] The compound according to any one of items 1 to 7, or the
pharmaceutically acceptable salt thereof or the solvate
thereof,
[0170] wherein R.sup.3a is hydrogen, lower alkyl optionally
substituted by substituent group C, carbocyclic group optionally
substituted by substituent group C, heterocyclic group optionally
substituted by substituent group C, carbocycle lower alkyl
optionally substituted by substituent group C,
[0171] (substituent group C is same as that of item 1).
(Item 10)
[0172] The compound according to any one of items 1 to 9, or the
pharmaceutically acceptable salt thereof or the solvate
thereof,
[0173] wherein B.sup.1 is NR.sup.7a, and B.sup.2 is
CR.sup.5aR.sup.6a, and
[0174] R.sup.5a, R.sup.6a and R.sup.7a are each independently
hydrogen, carboxy, cyano, lower alkyl optionally substituted by
substituent group C, lower alkenyl optionally substituted by
substituent group C, lower alkynyl optionally substituted by
substituent group C, lower alkyl carbonyl optionally substituted by
substituent group C, lower alkyl oxycarbonyl optionally substituted
by substituent group C, carbocyclic group optionally substituted by
substituent group C, carbocycle lower alkyl optionally substituted
by substituent group C, carbocycleoxy lower alkyl optionally
substituted by substituent group C, carbocyclecarbonyl optionally
substituted by substituent group C, carbocycleoxycarbonyl
optionally substituted by substituent group C, heterocyclic group
optionally substituted by substituent group C, heterocycle lower
alkyl optionally substituted by substituent group C, heterocycleoxy
lower alkyl optionally substituted by substituent group C,
heterocyclecarbonyl optionally substituted by substituent group C,
heterocycleoxycarbonyl optionally substituted by substituent group
C,
[0175] --Y--S--R.sup.D1,
[0176] --Z--S(.dbd.O)--R.sup.D2,
[0177] --Z--SO.sub.2--R.sup.D3,
[0178] --C(.dbd.O)--C(.dbd.O)--R.sup.D4,
[0179] --C(.dbd.O)--N(R.sup.D5)(R.sup.D6),
[0180] --Z--C(R.sup.D7)(R.sup.D8)(R.sup.D9),
[0181] --Z--N(R.sup.D11)--C(.dbd.O)--O--R.sup.D12, or
[0182] --Z--N(R.sup.D13)--C(.dbd.O)--R.sup.D14
[0183] (substituent group C, R.sup.D1, R.sup.D2, R.sup.D3,
R.sup.D4, R.sup.D5, R.sup.D6, R.sup.D7, R.sup.D8, R.sup.D9,
R.sup.D11, R.sup.D12, R.sup.D13, R.sup.D14, Y, and Z are same as
those of item 1).
(Item 11)
[0184] The compound according to any one of items 1 to 9, or the
pharmaceutically acceptable salt thereof or the solvate
thereof,
[0185] wherein B.sup.1 is NR.sup.7a, and B.sup.2 is
CR.sup.5aR.sup.6a,
[0186] R.sup.5a is hydrogen,
[0187] R.sup.6a is hydrogen, or lower alkyl optionally substituted
by substituent group C, and
[0188] R.sup.7a is lower alkyl optionally substituted by
substituent group C, carbocyclic group optionally substituted by
substituent group C, carbocycleoxy lower alkyl optionally
substituted by substituent group C, heterocyclic group optionally
substituted by substituent group C, carbocycle lower alkyl
optionally substituted by substituent group C, heterocycle lower
alkyl optionally substituted by substituent group C, or
[0189] --Z--C(R.sup.D7)(R.sup.D8)(R.sup.D9)
[0190] (substituent group C, R.sup.D7, R.sup.D8, R.sup.D9, and Z
are same as those of item 1).
(Item 12)
[0191] The compound according to any one of items 1 to 9, or the
pharmaceutically acceptable salt thereof or the solvate
thereof,
[0192] wherein B.sup.1 is CR.sup.5aR.sup.6a, and B.sup.2 is
NR.sup.7a,
[0193] R.sup.5a is hydrogen,
[0194] R.sup.6a is hydrogen, or lower alkyl optionally substituted
by substituent group C, and
[0195] R.sup.7a is lower alkyl optionally substituted by
substituent group C, carbocyclic group optionally substituted by
substituent group C, carbocycleoxy lower alkyl optionally
substituted by substituent group C, heterocyclic group optionally
substituted by substituent group C, carbocycle lower alkyl
optionally substituted by substituent group C, heterocycle lower
alkyl optionally substituted by substituent group C, or
[0196] --Z--C(R.sup.D7)(R.sup.D8)(R.sup.D9)
[0197] (substituent group C, R.sup.D7, R.sup.D8, R.sup.D9, and Z
are same as those of item 1).
(Item 13)
[0198] The compound according to items 11 or 12, or the
pharmaceutically acceptable salt thereof or the solvate
thereof,
[0199] wherein R.sup.7a is a group shown below:
##STR00003##
[0200] (wherein R.sup.E6 and m are same as those of item 1).
(Item 14)
[0201] The compound according to item 1, or the pharmaceutically
acceptable salt thereof or the solvate thereof,
[0202] wherein R.sup.1a is hydrogen, or carboxy,
[0203] R.sup.2a is hydrogen,
[0204] R.sup.3a is lower alkyl optionally substituted by
substituent group C,
[0205] B.sup.1 is NR.sup.7a, and B.sup.2 is CH.sub.2, and
[0206] R.sup.7a is a group shown below:
##STR00004##
[0207] (wherein substituent group C, R.sup.E6, and m are same as
those of item 1).
(Item 15)
[0208] The compound according to any one of items 1 to 9, or the
pharmaceutically acceptable salt thereof or the solvate
thereof,
[0209] wherein B.sup.1 is CR.sup.8aR.sup.9a, and B.sup.2 is
CR.sup.10aR.sup.11a,
[0210] R.sup.9a is hydrogen, and R.sup.11a is hydrogen, and
[0211] i) either R.sup.8a or R.sup.10a is
[0212] a group shown below:
##STR00005##
[0213] (wherein R.sup.E6 and m are same as those of item 1);
and
[0214] ii) the other of R.sup.8a or R.sup.10a is
[0215] hydrogen, or lower alkyl optionally substituted by
substituent group C
[0216] (substituent group C is same as that of item 1).
(Item 16)
[0217] The compound according to any one of items 1 to 7, or the
pharmaceutically acceptable salt thereof or the solvate
thereof,
[0218] wherein B.sup.1 is CR.sup.5aR.sup.6a, and B.sup.2 is
NR.sup.7a,
[0219] R.sup.6a is hydrogen,
[0220] R.sup.3a and R.sup.7a are taken together with an adjacent
atom to form heterocycle optionally substituted by substituent
group D, and
[0221] R.sup.5a is hydrogen, lower alkyl optionally substituted by
substituent group C, carbocyclic group optionally substituted by
substituent group C, carbocycle lower alkyl optionally substituted
by substituent group C, carbocycleoxy lower alkyl optionally
substituted by substituent group C, heterocyclic group optionally
substituted by substituent group C, heterocycle lower alkyl
optionally substituted by substituent group C, heterocycleoxy lower
alkyl optionally substituted by substituent group C,
[0222] --Y--S--R.sup.D1,
[0223] --C(.dbd.O)--C(.dbd.O)--R.sup.D2, or
[0224] --C(.dbd.O)--N(R.sup.D3)(R.sup.D4)
[0225] (wherein R.sup.D1, R.sup.D2, R.sup.D3, R.sup.D4, Y,
substituent group C and substituent group D are same as those of
item 1).
(Item 17)
[0226] The compound according to item 16, or the pharmaceutically
acceptable salt thereof or the solvate thereof,
[0227] wherein R.sup.5a is hydrogen, carbocyclic group optionally
substituted by substituent group C, carbocycle lower alkyl
optionally substituted by substituent group C, heterocyclic group
optionally substituted by substituent group C, or heterocycle lower
alkyl optionally substituted by substituent group C
[0228] (wherein substituent group C is same as that of item 1).
(Item 18)
[0229] The compound according to any one of items 1 to 7, or the
pharmaceutically acceptable salt thereof or the solvate
thereof,
[0230] wherein B.sup.1 is CR.sup.8aR.sup.9a, and B.sup.2 is
CR.sup.10aR.sup.11a,
[0231] R.sup.9a is hydrogen, and R.sup.10a is hydrogen,
[0232] R.sup.3a and R.sup.11a are taken together with an adjacent
atom to form heterocycle optionally substituted by substituent
group D, and
[0233] R.sup.8a is hydrogen, lower alkyl optionally substituted by
substituent group C, carbocyclic group optionally substituted by
substituent group C, carbocycle lower alkyl optionally substituted
by substituent group C, carbocycleoxy lower alkyl optionally
substituted by substituent group C, heterocyclic group optionally
substituted by substituent group C, heterocycle lower alkyl
optionally substituted by substituent group C, heterocycleoxy lower
alkyl optionally substituted by substituent group C,
[0234] --Y--S--R.sup.D1,
[0235] --C(.dbd.O)--C(.dbd.O)--R.sup.D2, or
[0236] --C(.dbd.O)--N(R.sup.D3)(R.sup.D4)
[0237] (wherein R.sup.D1, R.sup.D2, R.sup.D3, R.sup.D4, Y,
substituent group C and substituent group D are same as those of
item 1).
(Item 19)
[0238] The compound according to item 18, or the pharmaceutically
acceptable salt thereof or the solvate thereof,
[0239] wherein R.sup.8a is hydrogen, carbocyclic group optionally
substituted by substituent group C, carbocycle lower alkyl
optionally substituted by substituent group C, heterocyclic group
optionally substituted by substituent group C, or heterocycle lower
alkyl optionally substituted by substituent group C
[0240] (wherein substituent group C is same as that of item 1).
(Item 20)
[0241] The compound according to any one of items 16 to 19, or the
pharmaceutically acceptable salt thereof or the solvate
thereof,
[0242] wherein substituent group D is carbocyclic group optionally
substituted by substituent group C, heterocyclic group optionally
substituted by substituent group C, carbocycle lower alkyl
optionally substituted by substituent group C, or heterocycle lower
alkyl optionally substituted by substituent group C
[0243] (wherein substituent group C is same as that of item 1).
(Item 21)
[0244] The compound according to any one of items 1 to 20, or the
pharmaceutically acceptable salt thereof or the solvate
thereof,
[0245] wherein P.sup.R is a group selected from the following
formulae a) to y):
[0246] a) --C(.dbd.O)--P.sup.R0,
[0247] b) --C(.dbd.O)--P.sup.R1,
[0248] c) --C(.dbd.O)-L-P.sup.R1,
[0249] d) --C(.dbd.O)-L-O--P.sup.R1,
[0250] e) --C(.dbd.O)-L-O-L-O--P.sup.R1,
[0251] f) --C(.dbd.O)-L-O--C(.dbd.O)--P.sup.R1,
[0252] g) --C(.dbd.O)--O--P.sup.R2,
[0253] h) --C(.dbd.O)--N(P.sup.R2).sub.2,
[0254] i) --C(.dbd.O)--O-L-O--P.sup.R2,
[0255] j) --CH.sub.2--O--P.sup.R3,
[0256] k) --CH.sub.2--O-L-O--P.sup.R3,
[0257] l) --CH.sub.2--O--C(.dbd.O)--P.sup.R3,
[0258] m) --CH.sub.2--O--C(.dbd.O)--O--P.sup.R3,
[0259] n) --CH(--CH.sub.3)--O--C(.dbd.O)--O--P.sup.R3,
[0260] o) --CH.sub.2--O--C(.dbd.O)--N(--K)--P.sup.R3,
[0261] p) --CH.sub.2--O--C(.dbd.O)--O-L-O--P.sup.R3,
[0262] q) --CH.sub.2--O--C(.dbd.O)--O-L-N(P.sup.R3).sub.2,
[0263] r) --CH.sub.2--O--C(.dbd.O)--N(--K)-L-O--P.sup.R3,
[0264] s) --CH.sub.2--O--C(.dbd.O)--N(--K)-L-N(P.sup.R3).sub.2,
[0265] t) --CH.sub.2--O--C(.dbd.O)--O-L-O-L-O--P.sup.R3,
[0266] u)
--CH.sub.2--O--C(.dbd.O)--O-L-N(--K)--C(.dbd.O)--P.sup.R3,
[0267] v) --CH.sub.2--O--P(.dbd.O)(--OH).sub.2,
[0268] w) --CH.sub.2--O--P(.dbd.O)(--OBn).sub.2,
[0269] x) --CH.sub.2--P.sup.R4 (except for a benzyl group)
[0270] y) --C(.dbd.N.sup.+P.sup.R5.sub.2)(--NP.sup.R5.sub.2)
[0271] (wherein L is straight or branched lower alkylene, or
straight or branched lower alkenylene,
[0272] K is hydrogen, or straight or branched lower alkylene,
[0273] P.sup.R0 is lower alkyl optionally substituted by
substituent group F, or lower alkenyl optionally substituted by
substituent group F,
[0274] P.sup.R1 is carbocyclic group optionally substituted by
substituent group F, heterocyclic group optionally substituted by
substituent group F, lower alkyl amino optionally substituted by
substituent group F, or lower alkylthio optionally substituted by
substituent group F,
[0275] P.sup.R2 is lower alkyl optionally substituted by
substituent group F, carbocyclic group optionally substituted by
substituent group F, or heterocyclic group optionally substituted
by substituent group F,
[0276] P.sup.R3 is lower alkyl optionally substituted by
substituent group F, carbocyclic group optionally substituted by
substituent group F, heterocyclic group optionally substituted by
substituent group F, lower alkyl amino optionally substituted by
substituent group F, carbocycle lower alkyl optionally substituted
by substituent group F, heterocycle lower alkyl optionally
substituted by substituent group F, or lower alkylsilyl,
[0277] P.sup.R4 is carbocyclic group optionally substituted by
substituent group F, or heterocyclic group optionally substituted
by substituent group F, and
[0278] P.sup.R5 is lower alkyl optionally substituted by
substituent group F.
[0279] Substituent group F; oxo, lower alkyl, hydroxy lower alkyl,
amino, lower alkylamino, carbocycle lower alkyl, lower
alkylcarbonyl, halogen, hydroxy, carboxy, lower alkylcarbonylamino,
lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkyloxy,
cyano, and nitro).
(Item 22)
[0280] A pharmaceutical composition containing a compound according
to any one of items 1 to 21, or a pharmaceutically acceptable salt
thereof or a solvate thereof.
(Item 23)
[0281] The pharmaceutical composition according to item 22 which
exhibits anti influenza activity.
(Item 24)
[0282] The pharmaceutical composition according to item 22 which
exhibits cap-dependent endonuclease inhibitory activity.
(Item 25)
[0283] The pharmaceutical composition according to item 22 for
treating and/or preventing influenza infectious disease.
(Item 26)
[0284] A cap-dependent endonuclease inhibitor containing a compound
according to any one of items 1 to 21, or a pharmaceutically
acceptable salt thereof or a solvate thereof.
[0285] The present invention further provides a method for treating
or preventing influenza infectious disease using the prodrug
compound and the compound which exhibits anti influenza activity.
The present invention further provides a parent compound of the
prodrug compound. The parent compound is effective as an
anti-influenza agent or an intermediate of the prodrug
compound.
Effect of the Invention
[0286] The compound according to the present invention has an
inhibitory activity on cap-dependent endonuclease. More preferred
compound is a prodrug, and the prodrug becomes a parent compound
having an inhibitory activity on cap-dependent endonuclease in vivo
after administration, thus is effective as a therapeutic agent
and/or preventive agent for influenza infectious disease.
BRIEF DESCRIPTION OF DRAWINGS
[0287] FIG. 1 is a result of measuring changes in the plasma
concentration of Reference example 301, for compound of Example 114
obtained by converting into a prodrug compound of Reference example
301 that is a parent compound, after oral administration to rat
under non-fasting conditions.
[0288] FIG. 2 is a graph showing an average of the changes in the
plasma concentration when the measurement shown in FIG. 1 is
performed three times.
[0289] FIG. 3 is a result of measuring changes in the plasma
concentration of Reference example 301, for compound of Example 204
obtained by converting into a prodrug compound of Reference example
301 that is a parent compound, after oral administration to rat
under non-fasting conditions.
[0290] FIG. 4 is a graph showing an average of the changes in the
plasma concentration when the measurement shown in FIG. 3 is
performed three times.
BEST MODE FOR CARRYING OUT THE INVENTION
[0291] The meaning of each term used in the present description is
explained below. Each term is used in a unified sense, and is used
in the same sense when used alone, or when used in combination of
other term.
[0292] "Optionally substituted by substituent group C" means that
an arbitrary position may be substituted by one, two or more same
or different substituents selected from substituent group C.
[0293] "Optionally substituted by substituent group D", and
"optionally substituted by substituent group F" are also as
described above.
[0294] "Prodrug" in the present description refers to a compound
represented by formula (I) in the following reaction formula:
##STR00006##
[0295] (wherein each symbol is same as that of item 1)
[0296] or a pharmaceutically acceptable salt thereof or a solvate
thereof, and means a compound showing cap-dependant endonuclease
(CEN) inhibitory activity and/or CPE inhibitory effect by being
converted into a compound represented by formula (II) by a
decomposition reaction caused by drug-metabolizing enzymes,
hydrolases, gastric acids, enterobacteria, etc. under physiological
conditions in vivo.
[0297] The prodrug more preferably means a compound in which
bioavailability and/or AUC (area under the blood concentration
curve) in in vivo administration is improved more than those of the
compound represented by formula (II).
[0298] Therefore, the prodrug is efficiently absorbed into the body
in the stomach and/or intestines after in vivo administration (for
example, oral administration), then converted into the compound
represented by formula (II). Thus, the prodrug preferably shows an
effect of treating and/or preventing influenza higher than the
compound represented by formula (II).
[0299] "Group to form a prodrug" in the present description refers
to a "P.sup.R" group in the formula (I), in the following reaction
formula:
##STR00007##
[0300] (wherein each symbol is same as that of item 1)
[0301] and --OP.sup.R group is converted into --OH group in the
formula (II) by a decomposition reaction caused by
drug-metabolizing enzymes, hydrolases, gastric acids,
enterobacteria, etc. under physiological conditions in vivo. The
"group to form a prodrug" more preferably means a group that
improves bioavailability and/or AUC (area under the blood
concentration curve) of the compound represented by formula (II) by
being added to the compound represented by formula (II).
[0302] Examples of the group to form a prodrug include the groups
described in Prog. Med. 5: 2157-2161 (1985) and Supplied by The
British Library--"The world's Knowledge".
[0303] The "P.sup.R" group in --OP.sup.R group in the formula (I)
may be a group converted into --OH group in vivo. Preferably the
groups selected from various substituted carbonyl groups,
substituted lower alkyl oxy groups (e.g., substituted oxymethyl),
optionally substituted cyclic group lower alkyl (e.g., optionally
substituted cyclic methyl group), and optionally substituted imino
lower alkyl (e.g., optionally substituted imino methyl) are
exemplified, and examples preferably include a group selected from
the following formulae a) to y).
[0304] a) --C(.dbd.O)--P.sup.R0,
[0305] b) --C(.dbd.O)--P.sup.R1,
[0306] c) --C(.dbd.O)-L-P.sup.R1,
[0307] d) --C(.dbd.O)-L-O--P.sup.R1,
[0308] e) --C(.dbd.O)-L-O-L-O--P.sup.R1,
[0309] f) --C(.dbd.O)-L-O--C(.dbd.O)--P.sup.R1,
[0310] g) --C(.dbd.O)--O--P.sup.R2,
[0311] h) --C(.dbd.O)--N(P.sup.R2).sub.2,
[0312] i) --C(.dbd.O)--O-L-O--P.sup.R2,
[0313] j) --CH.sub.2--O--P.sup.R3,
[0314] k) --CH.sub.2--O-L-O--P.sup.R3,
[0315] l) --CH.sub.2--O--C(.dbd.O)--P.sup.R3,
[0316] m) --CH.sub.2--O--C(.dbd.O)--O--P.sup.R3,
[0317] n) --CH(--CH.sub.3)--O--C(.dbd.O)--O--P.sup.R3,
[0318] o) --CH.sub.2--O--C(.dbd.O)--N(--K)--P.sup.R3,
[0319] p) --CH.sub.2--O--C(.dbd.O)--O-L-O--P.sup.R3,
[0320] q) --CH.sub.2--O--C(.dbd.O)--O-L-N(P.sup.R3).sub.2,
[0321] r) --CH.sub.2--O--C(.dbd.O)--N(--K)-L-O--P.sup.R3,
[0322] s) --CH.sub.2--O--C(.dbd.O)--N(--K)-L-N(P.sup.R3).sub.2,
[0323] t) --CH.sub.2--O--C(.dbd.O)--O-L-O-L-O--P.sup.R3,
[0324] u)
--CH.sub.2--O--C(.dbd.O)--O-L-N(--K)--C(.dbd.O)--P.sup.R3,
[0325] v) --CH.sub.2--O--P(.dbd.O)(--OH).sub.2,
[0326] w) --CH.sub.2--O--P(.dbd.O)(--OBn).sub.2,
[0327] x) --CH.sub.2--P.sup.R4
[0328] y) --C(.dbd.N.sup.+P.sup.R5.sub.2)(--NP.sup.R5.sub.2)
[0329] (wherein L is straight or branched lower alkylene,
[0330] K is hydrogen, or straight or branched lower alkylene, or
straight or branched lower alkenylene,
[0331] P.sup.R0 is lower alkyl optionally substituted by
substituent group F, or lower alkenyl optionally substituted by
substituent group F,
[0332] P.sup.R1 is carbocyclic group optionally substituted by
substituent group F, heterocyclic group optionally substituted by
substituent group F, lower alkyl amino optionally substituted by
substituent group F, or lower alkylthio optionally substituted by
substituent group F,
[0333] P.sup.R2 is lower alkyl optionally substituted by
substituent group F, carbocyclic group optionally substituted by
substituent group F, or heterocyclic group optionally substituted
by substituent group F,
[0334] P.sup.R3 is lower alkyl optionally substituted by
substituent group F, carbocyclic group optionally substituted by
substituent group F, heterocyclic group optionally substituted by
substituent group F, lower alkyl amino optionally substituted by
substituent group F, carbocycle lower alkyl optionally substituted
by substituent group F, heterocycle lower alkyl optionally
substituted by substituent group F, or lower alkylsilyl,
[0335] P.sup.R4 is carbocyclic group optionally substituted by
substituent group F, or heterocyclic group optionally substituted
by substituent group F, and
[0336] P.sup.R5 is lower alkyl optionally substituted by
substituent group F.
[0337] Substituent group F; oxo, lower alkyl, hydroxy lower alkyl,
amino, lower alkylamino, carbocycle lower alkyl, lower
alkylcarbonyl, halogen, hydroxy, carboxy, lower alkylcarbonylamino,
lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkyloxy,
cyano, and nitro)
[0338] As the group to form a prodrug, the "P.sup.R" group in
--OP.sup.R group in the formula (I) is preferably a group selected
from the following b), k), l), and m).
[0339] b) --C(.dbd.O)--P.sup.R1,
[0340] l) --CH.sub.2--O--C(.dbd.O)--P.sup.R3,
[0341] m) --CH.sub.2--O--C(.dbd.O)--O--P.sup.R3,
[0342] n) --CH(--CH.sub.3)--O--C(.dbd.O)--O--P.sup.R3,
[0343] (wherein each symbol is same as above)
[0344] "Converted into a prodrug" in the present description means
that, as shown in the following reaction formula:
##STR00008##
[0345] (wherein each symbol is same as that of item 1)
[0346] a hydroxy group in the formula (II) or pharmaceutically
acceptable salt thereof or a solvate thereof is converted into
--OP.sup.R group.
[0347] "Parent compound" in the present description means a
compound to be a source before synthesizing the "prodrug" and/or a
compound released from the "prodrug" by the reaction by enzymes, a
gastric acid, and the like under physiological conditions in vivo,
and specifically means a compound shown by the formula (II), or
pharmaceutically acceptable salt thereof or a solvate thereof.
[0348] "Halogen" includes fluorine, chlorine, bromine and iodine.
Preferable is fluorine, chlorine and bromine.
[0349] "Lower alkyl" includes straight or branched alkyl of a
carbon number of 1 to 15, preferably a carbon number of 1 to 10,
more preferably a carbon number of 1 to 6, further preferably a
carbon number of 1 to 4, and examples include methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl,
isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl etc. Examples of
a preferable embodiment of "lower alkyl" include methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and
n-pentyl. Examples of a further preferable embodiment include
methyl, ethyl, n-propyl, isopropyl, and tert-butyl.
[0350] "Lower alkenyl" includes straight or branched alkenyl of a
carbon number of 2 to 15, preferably a carbon number of 2 to 10,
more preferably a carbon number of 2 to 6, further preferably a
carbon number of 2 to 4, having one or more double bonds at an
arbitrary position. Specifically, lower alkenyl includes vinyl,
allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl,
butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl,
isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl,
undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl etc.
Examples of a preferable embodiment of "lower alkenyl" include
vinyl, allyl, propenyl, isopropenyl, and butenyl.
[0351] "Lower alkynyl" includes straight or branched alkynyl of a
carbon number of 2 to 10, preferably a carbon number of 2 to 8,
further preferably a carbon number of 3 to 6, having one or more
triple bonds at an arbitrary position. Specifically, lower alkynyl
includes ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl,
octynyl, nonynyl, decynyl etc. These may further have a double bond
at an arbitrary position. Examples of a preferable embodiment of
"lower alkynyl" include ethynyl, propynyl, butynyl, and
pentynyl.
[0352] A lower alkyl part of "lower alkyloxy", "lower
alkylcarbonyl", "lower alkyloxycarbonyl", "carbocycle lower alkyl",
"heterocycle lower alkyl", "carbocycleoxy lower alkyl",
"heterocycleoxy lower alkyl", "halogeno lower alkyl", "carbocycle
lower alkyloxy", "heterocycle lower alkyloxy", "halogeno lower
alkyloxy", "lower alkyloxy lower alkyl", "lower alkyloxy lower
alkyloxy", "lower alkylcarbonyl", "lower alkyloxycarbonyl", "lower
alkylamino", "lower alkylcarbonylamino", "lower
alkylaminocarbonyl", "lower alkylsulfonyl", "lower
alkylsulfonylamino", "lower alkylthio", "hydroxy lower alkyl",
"carbocycle lower alkyloxy lower alkyl", "heterocycle lower
alkyloxy lower alkyl", "lower alkylcarbonyloxy", "halogeno lower
alkylcarbonylamino", and "lower alkylsulfinyl" is the same as the
"lower alkyl" as described above.
[0353] A lower alkenyl part of "lower alkenyloxy" is the same as
the "lower alkenyl" as described above.
[0354] A halogen part of "halogeno lower alkyl", "halogeno lower
alkyloxy", and "halogeno lower alkylcarbonylamino" is the same as
the "halogen". Herein, an arbitrary position on an alkyl group of
"lower alkyl", "lower alkyloxy", and "lower alkylcarbonylamino" may
be substituted by same or different one or plural halogen atoms,
respectively.
[0355] "Carbocyclic group" or "carbocycle" means carbocyclic group
of a carbon number of 3 to 20, preferably a carbon number of 3 to
16, more preferably a carbon number of 4 to 12, and includes
cycloalkyl, cycloalkenyl, aryl and a non-aromatic condensed
carbocyclic group, etc.
[0356] Specifically, "cycloalkyl" is carbocyclic group of a carbon
number of 3 to 16, preferably a carbon number of 3 to 12, more
preferably a carbon number of 4 to 8, and examples include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclononyl and cyclodecyl, etc.
[0357] Specifically, "cycloalkenyl" includes cycloalkenyl having
one or more double bonds at an arbitrary position in the cycloalkyl
ring, and examples include cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl and
cyclohexadienyl, etc.
[0358] Specifically, "aryl" means an aromatic carbocyclic group,
and includes phenyl, naphthyl, anthryl and phenanthryl, etc. and,
particularly, phenyl is preferable.
[0359] Specifically, "non-aromatic condensed carbocyclic group"
includes a group in which two or more cyclic groups selected from
the "cycloalkyl", the "cycloalkenyl" and the "aryl" are condensed,
and examples include indanyl, indenyl, tetrahydronaphthyl,
fluorenyl, adamantyl, and groups shown below
##STR00009##
[0360] etc.
[0361] Examples of a preferable embodiment of "carbocyclic group"
or "carbocycle" include cycloalkyl, aryl and a non-aromatic
condensed carbocyclic group, specifically examples include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
phenyl, naphthyl, and groups shown below
##STR00010##
[0362] etc.
[0363] A carbocyclic part of "carbocycle lower alkyl", "carbocycle
lower alkyloxy", "carbocycleoxy lower alkyl", "carbocyclecarbonyl",
"carbocycleoxy", "carbocycleoxycarbonyl" and "carbocycle lower
alkyloxy lower alkyl" is the same as the "carbocyclic group" or the
"carbocycle" as described above.
[0364] "Heterocyclic group" or "heterocycle" includes heterocyclic
group such as heteroaryl, a non-aromatic heterocyclic group, a
bicyclic condensed heterocyclic group, a tricyclic condensed
heterocyclic group, a tetracyclic condensed heterocyclic group,
etc., having one or more same or different hetero atoms arbitrarily
selected from O, S and N in a ring.
[0365] Specifically, "heteroaryl" includes a 5- to 6-membered
aromatic cyclic group such as pyrrolyl, imidazolyl, pyrazolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl,
tetrazolyl, furyl, thienyl, isooxazolyl, oxazolyl, oxadiazolyl,
isothiazolyl, thiazolyl, thiadiazolyl, etc.
[0366] Specifically, "non-aromatic heterocyclic group" includes a
4- to 8-membered non-aromatic heterocyclic group such as dioxanyl,
thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl,
thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,
imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl,
morpholinyl, morpholino, thiomorpholinyl, thiomorpholino,
dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl,
tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl,
tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl,
tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl,
dioxolanyl, dioxolyl, oxabicycloheptanyl, etc.
[0367] Specifically, "bicyclic condensed heterocyclic group"
includes a cyclic group including at least one 4- to 8-membered
aromatic or non-aromatic heterocyclic group such as indolyl,
isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl,
quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,
naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl,
benzimidazolyl, benzotriazolyl, benzisooxazolyl, benzoxazolyl,
benzoxadiazolyl, benzisothiazolyl, benzothiazolyl,
benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl,
benzotriazolyl, thienopyridyl, thienopyrrolyl, thienopyrazolyl,
thienopyrazinyl, furopyrrolyl, thienothienyl, imidazopyridyl,
pyrazolopyridyl, thiazolopyridyl, pyrazolopyrimidinyl,
pyrazolotrianizyl, pyridazolopyridyl, triazolopyridyl,
imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl,
isoquinolyl, naphthyridinyl, dihydrothiazolopyrimidinyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzofuryl,
dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothienyl,
tetrahydrobenzofuryl, benzodioxolyl, benzodioxonyl, chromanyl,
chromenyl, octahydrochromenyl, dihydrobenzodioxynyl,
dihydrobenzooxezinyl, dihydrobenzodioxepinyl,
dihydrothienodioxynyl, etc.
[0368] Specifically, "tricyclic condensed heterocyclic group"
includes a cyclic group including at least one 4- to 8-membered
aromatic or non-aromatic heterocyclic group such as carbazolyl,
acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
dibenzofuryl, imidazoquinolyl, tetrahydrocarbazolyl, and groups
shown below
##STR00011##
[0369] etc.
[0370] Examples of a preferable embodiment of "heterocyclic group"
include 5- to 6-membered heteroaryl, a non-aromatic heterocyclic
group and a tricyclic condensed heterocyclic group.
[0371] A heterocyclic part of "heterocycle lower alkyl",
"heterocycle lower alkyloxy", "carbocycleoxy lower alkyl",
"heterocyclecarbonyl", "heterocycleoxy", "heterocycleoxycarbonyl",
and "heterocycle lower alkyloxy lower alkyl" is the same as the
"heterocyclic group" or the "heterocycle" as described above.
[0372] "Heterocyclic group substituted by oxo" means the
"heterocyclic group" as described above, substituted by oxo as
shown below. Groups shown below
##STR00012##
[0373] are exemplified.
[0374] "Straight or branched lower alkylene" is divalent "lower
alkyl" as described above, and includes, for example, methylene,
ethylene, propylene, butylene, isobutylene, pentylene, heptylene,
dimethylmethylene, ethylmethylmethylene, 1,2-dimethylethylene,
etc.
[0375] Examples of "lower alkyloxy" include methoxy, ethoxy,
propyloxy, isopropyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy,
pentyloxy, isopentyloxy, hexyloxy, etc. Examples of a preferable
embodiment include methoxy, ethoxy, propyloxy, isopropyloxy, and
tert-butyloxy.
[0376] Examples of "lower alkylcarbonyl" include methylcarbonyl,
ethylcarbonyl, propylcarbonyl, isopropylcarbonyl,
tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl,
pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl, etc. Examples of
a preferable embodiment include methylcarbonyl, ethylcarbonyl, and
propylcarbonyl.
[0377] Examples of "lower alkyloxycarbonyl" include
methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl,
isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl,
sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl,
hexyloxycarbonyl, etc. Examples of a preferable embodiment include
methyloxycarbonyl, ethyloxycarbonyl, and propyloxycarbonyl.
[0378] "Carbocycle lower alkyl" represents lower alkyl substituted
by one, two or more carbocyclic groups, and examples of "carbocycle
lower alkyl" include benzyl, phenethyl, phenylpropynyl, benzhydryl,
trityl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, naphthylmethyl, a group shown below
##STR00013##
[0379] etc.
[0380] Examples of a preferable embodiment include benzyl,
phenethyl, and benzhydryl.
[0381] "Heterocycle lower alkyl" represents lower alkyl substituted
by one, two or more heterocyclic groups, and also includes
heterocycle lower alkyl in which an alkyl part is substituted by
carbocyclic group. Examples of "heterocycle lower alkyl" include
pyridylmethyl, tetrahydropyranylmethyl, furanylmethyl,
morpholinylethyl, imidazolylmethyl, indolylmethyl,
benzothiophenylmethyl, oxazolylmethyl, isooxazolylmethyl,
thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl,
isopyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl,
piperidinylmethyl, piperazinylmethyl, groups shown below
##STR00014##
[0382] etc.
[0383] Examples of a preferable embodiment include pyridylmethyl,
tetrahydropyranylmethyl, furanylmethyl, and morpholinylethyl.
[0384] Examples of "carbocycleoxy lower alkyl" include
phenyloxymethyl, phenyloxyethyl, cyclopropyloxymethyl,
cyclopropyloxyethyl, cyclobutyloxymethyl, cyclobutyloxyethyl,
cyclohexyloxymethyl, cyclohexyloxyethyl, etc. Examples of a
preferable embodiment include phenyloxymethyl, and
phenyloxyethyl.
[0385] Examples of "heterocycleoxy lower alkyl" include
pyridyloxymethyl, pyridyloxyethyl, morpholinyloxymethyl,
morpholinyloxyethyl, benzoxazolyloxymethyl, etc. Examples of a
preferable embodiment include pyridyloxymethyl,
morpholinyloxymethyl, etc.
[0386] "Carbocycle lower alkyloxy" represents lower alkyloxy in
which an alkyl part is substituted by one, two or more carbocyclic
groups, and examples of "carbocycle lower alkyloxy" include
phenylmethyloxy, phenylethyloxy, cyclopropylmethyloxy,
cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy,
etc. Examples of a preferable embodiment include phenylmethyloxy,
cyclopropylmethyloxy, etc.
[0387] "Heterocycle lower alkyloxy" represents lower alkyloxy in
which an alkyl part is substituted by one, two or more heterocyclic
groups, and also includes heterocycle lower alkyloxy in which an
alkyl part is substituted by carbocyclic group. Examples of
"heterocycle lower alkyloxy" include pyridylmethyloxy,
pyridylethyloxy, imidazolylmethyloxy, imidazolylethyloxy,
benzoxazolylmethyloxy, benzoxazolylethyloxy, etc.
[0388] Examples of "lower alkyloxy lower alkyl" include
methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl,
methoxypropyl, methoxybutyl, ethoxypropyl, ethoxybutyl,
isopropyloxymethyl, tert-butyloxymethyl, etc. Examples of a
preferable embodiment include methoxymethyl, methoxyethyl,
ethoxymethyl, and ethoxyethyl.
[0389] Examples of "lower alkyloxy lower alkyloxy" include
methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy,
methoxypropyloxy, methoxybutyloxy, ethoxypropyloxy, ethoxybutyloxy,
isopropyloxymethyloxy, tert-butyloxymethyloxy, etc. Examples of a
preferable embodiment include methoxymethoxy, methoxyethoxy,
ethoxymethoxy, and ethoxyethoxy.
[0390] Examples of "lower alkylamino" include methylamino,
dimethylamino, ethylamino, diethylamino, isopropylamino,
N,N-diisopropylamino, N-methyl-N-ethylamino,
N-isopropyl-N-ethylamino, etc. Examples of a preferable embodiment
include methylamino, dimethylamino, ethylamino, and
diethylamino.
[0391] Examples of "lower alkylcarbonylamino" include
methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino,
isopropylcarbonylamino, tert-butylcarbonylamino,
isobutylcarbonylamino, sec-butylcarbonylamino, etc. Examples of a
preferable embodiment include methylcarbonylamino, and
ethylcarbonylamino.
[0392] Examples of "lower alkylaminocarbonyl" include
methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl,
diethylaminocarbonyl, isopropylaminocarbonyl,
N,N-diisopropylaminocarbonyl, N-methyl-N-ethylaminocarbonyl,
N-isopropyl-N-ethylaminocarbonyl, etc. Examples of a preferable
embodiment include methylaminocarbonyl, dimethylaminocarbonyl,
ethylaminocarbonyl, and diethylaminocarbonyl.
[0393] Examples of "lower alkylsulfonyl" include methylsulfonyl,
ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,
tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, etc.
Examples of a preferable embodiment include methylsulfonyl, and
ethylsulfonyl.
[0394] Examples of "lower alkylsulfonylamino" include
methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino,
isopropylsulfonylamino, tert-butylsulfonylamino,
isobutylsulfonylamino, sec-butylsulfonylamino, etc. Examples of a
preferable embodiment include methylsulfonylamino, and
ethylsulfonylamino.
[0395] Examples of "lower alkenyloxy" include ethylenyloxy,
1-propylenyloxy, 2-propylenyloxy, 1-butylenyloxy, 2-butylenyloxy,
3-butylenyloxy, etc.
[0396] Examples of "halogeno lower alkyl" include monofluoromethyl,
monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl,
monochloromethyl, trifluoromethyl, trichloromethyl,
2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,2-dibromoethyl,
1,1,1-trifluoropropan-2-yl, etc. Examples of a preferable
embodiment include trifluoromethyl, trichloromethyl,
1,1,1-trifluoropropan-2-yl.
[0397] Examples of "halogeno lower alkyloxy" include
monofluoromethoxy, monofluoroethoxy, trifluoromethoxy,
trichloromethoxy, trifluoroethoxy, trichloroethoxy, etc. Examples
of a preferable embodiment include trifluoromethoxy, and
trichloromethoxy.
[0398] Examples of "lower alkylthio" include methylthio, ethylthio,
propylthio, etc.
[0399] Examples of "hydroxy lower alkyl" include hydroxymethyl,
hydroxyethyl, hydroxypropyl, etc.
[0400] Examples of "carbocycle lower alkyloxy lower alkyl" include
benzyloxymethyl, benzyloxyethyl, benzhydryloxymethyl, etc.
[0401] Examples of "heterocycle lower alkyloxy lower alkyl" include
pyridylmethyloxymethyl, pyridylmethyloxyethyl, etc.
[0402] Examples of "lower alkylcarbonyloxy" include
methylcarbonyloxy, ethylcarbonyloxy, etc.
[0403] Examples of "halogeno lower alkylcarbonylamino" include
trifluoromethylcarbonylamino,
2,2,3,3,3-pentafluoropropylcarbonylamino, etc.
[0404] Examples of "lower alkylsulfinyl" include methylsulfinyl,
ethylsulfinyl, etc.
[0405] Examples of "carbocyclecarbonyl" include phenylcarbonyl,
naphthylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl,
cyclopentylcarbonyl, cyclohexylcarbonyl, etc.
[0406] Examples of "carbocycleoxy" include phenyloxy, naphthyloxy,
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,
etc.
[0407] Examples of "carbocycleoxycarbonyl" include
phenyloxycarbonyl, naphthyloxycarbonyl, cyclopropyloxycarbonyl,
cyclobutyloxycarbonyl, cyclopentyloxycarbonyl,
cyclohexyloxycarbonyl, etc.
[0408] Examples of "heterocyclecarbonyl" include pyridylcarbonyl,
benzoxazolylcarbonyl, morpholinylcarbonyl,
tetrahydropyranylcarbonyl, etc.
[0409] Examples of "heterocycleoxy" include pyridyloxy,
benzoxazolyloxy, morpholinyloxy, tetrahydropyranyloxy, etc.
[0410] Examples of "heterocycleoxycarbonyl" include
pyridyloxycarbonyl, benzoxazolyloxycarbonyl,
morpholinyloxycarbonyl, tetrahydropyranyloxycarbonyl, etc.
[0411] The terms:
[0412] "R.sup.A1 and R.sup.A2, R.sup.A15 and R.sup.A16, as well as
R.sup.A19 and R.sup.A20, each may be taken together with an
adjacent atom to form a heterocycle",
[0413] "R.sup.B7 and R.sup.B8, as well as R.sup.B9 and R.sup.B10,
each may be taken together with an adjacent atom to form a
heterocycle",
[0414] "R.sup.C7 and R.sup.C8, as well as R.sup.C9 and R.sup.C10,
each may be taken together with an adjacent atom to form a
heterocycle", and
[0415] "R.sup.D5 and R.sup.D6 may be taken together with an
adjacent atom to form a heterocycle" in item 1
[0416] mean a heterocycle having N atom, and include, for example,
groups shown below
##STR00015##
[0417] etc.
[0418] In the present description, (R.sup.E6)m in the formulae
shown below
##STR00016## ##STR00017##
[0419] means that an arbitrary carbon atom or nitrogen atom which
can chemically have a substituent on a ring is substituted by m of
R.sup.E6s which are same or different.
[0420] For example, in the formula below
##STR00018##
[0421] as shown by a substituent below
##STR00019##
[0422] (wherein ma+mb+mc=m, and R.sup.E6 is same as above),
[0423] it is meant that any hydrogen atom on two benzene rings and
a 7-membered ring containing a sulfur atom may be substituted by
R.sup.E6, and respective R.sup.E6s may be the same or
different.
[0424] And, ma is preferably an integer of 0 to 3, mb is preferably
an integer of 0 to 3, and me is preferably an integer of 0 or 1.
And, ma is more preferably an integer of 0 or 1, mb is more
preferably an integer of 0 or 1, and me is more preferably 0.
[0425] For example, in the formula below
##STR00020##
[0426] substituents shown below
##STR00021##
[0427] (wherein R.sup.E6, and m are same as those of item 1)
[0428] etc. are included.
[0429] "B.sup.1 is CR.sup.5aR.sup.6a, and B.sup.2 is NR.sup.7a,
R.sup.3a and R.sup.7a may be taken together with an adjacent atom
to form a heterocycle optionally substituted by substituent group
D" in the formula (I) in item 1 represents the formula (I') shown
below:
##STR00022##
[0430] (wherein P.sup.R, R.sup.1a, R.sup.2a, R.sup.5a and R.sup.6a
are same as those of item 1), and indicates that a part of a ring
may be substituted by one, two or more same or different
substituents selected from substituent group D at an arbitrary
position. The heterocycle is preferably a 5- to 7-membered ring. In
addition, "the heterocycle may form a condensed ring" indicates
that the ring in the formula (I') may be further condensed with a
ring, and indicates that substituent group D may be bound to any of
the ring in the formula (I') or the ring which is condensed with a
ring.
[0431] Examples of the formula (I') include compounds shown by the
following formulae
##STR00023##
[0432] (wherein R.sup.x, and R.sup.y are a substituent selected
from substituent group D, and P.sup.R, R.sup.1a, R.sup.2a,
R.sup.5a, and R.sup.6a are same as those of item 1) etc.
[0433] "When form a heterocyle" in "B.sup.1 is NR.sup.7a, and
B.sup.2 is CR.sup.5aR.sup.6a, R.sup.3a and R.sup.6a may be taken
together with an adjacent atom to form a heterocycle optionally
substituted by substituent group D" in the formula (I) in item 1
represents the formula (I'') shown below:
##STR00024##
[0434] (wherein P.sup.R, R.sup.1a, R.sup.2a, R.sup.5a and R.sup.7a
are same as those of item 1), and indicates that "Ring" may be
substituted by one, two or more same or different substituents
selected from substituent group D at an arbitrary position. The
heterocycle is preferably a 5- to 7-membered ring. In addition,
"the heterocycle may form a condensed ring" indicates that the ring
in the formula (I'') may be further condensed with a ring, and
indicates that one, two or more of substituent group D may be bound
to any of the ring in the formula (I'') or the ring which is
condensed with a ring. Examples of the formula (I'') include
compounds shown by the following formulae
##STR00025##
[0435] (wherein R.sup.x, and R.sup.y are a substituent selected
from substituent group D, and P.sup.R, R.sup.1a, R.sup.2a,
R.sup.5a, and R.sup.7a are same as those of item 1) etc.
[0436] "When form a carbocycle or heterocyle" in "R.sup.8a and
R.sup.10a may be taken together with an adjacent atom to form a
carbocycle or heterocycle optionally substituted by substituent
group D" in the formula (I) in item 1 represents the formula
(I'''') shown below:
##STR00026##
[0437] (wherein P.sup.R, R.sup.1a, R.sup.2a, R.sup.3a, R.sup.9a,
and R.sup.11a are same as those of item 1), and indicates that
"Ring" may be substituted by one, two or more same or different
substituents selected from substituent group D at an arbitrary
position. The carbocycle or the heterocycle is preferably a 5- to
7-membered ring. Examples of the formula (I'''') include compounds
shown by the following formula
##STR00027##
[0438] (wherein R.sup.x is a substituent selected from substituent
group D, and P.sup.R, R.sup.1a, R.sup.2a, R.sup.3a, R.sup.9a, and
R.sup.11a are same as those of item 1) etc.
[0439] Further, "R.sup.3a and R.sup.11a may be taken together with
an adjacent atom to form a heterocycle optionally substituted by
substituent group D, and the heterocycle may form a condensed ring"
represents the formula (I''''') shown below:
##STR00028##
[0440] (wherein P.sup.R, R.sup.1a, R.sup.2a, R.sup.8a, R.sup.9a,
and R.sup.10a are same as those of item 1), and indicates that
"Ring" may further form a condensed ring, and the same or different
substituents selected from substituent group D may be bound to any
of the ring in the formula (I''''') or the ring which is condensed
with a ring at an arbitrary position. The heterocycle is preferably
a 5- to 7-membered ring. Examples of the formula (I''''') include
compounds shown by the following formulae
##STR00029##
[0441] (wherein R.sup.x, and R.sup.y are a substituent selected
from substituent group D, and P.sup.R, R.sup.1a, R.sup.2a,
R.sup.8a, R.sup.9a, and R.sup.10a are same as those of item 1)
etc.
[0442] "Solvate" includes, for example, a solvate with an organic
solvent, a hydrate, etc. Preferred embodiment is a hydrate or
alcoholate, and more preferred embodiment is a hydrate. When a
hydrate is formed, the compound may be coordinated with an
arbitrary number of water molecules. Examples include hemihydrate
(1 water molecule is coordinated to 2 molecules of the present
compound), monohydrate (1 water molecule is coordinated to 1
molecule of the present compound), dihydrate (2 water molecules are
coordinated to 1 molecule of the present compound), trihydrate (3
water molecules are coordinated to 1 molecule of the present
compound), etc. The same shall apply when an alcoholate is formed.
Examples of alcohol when an alcoholate is formed include methanol,
ethanol, isopropanol, etc.
[0443] The compound of the present invention includes a
pharmaceutically acceptable salt. Examples include salts with an
alkali metal (lithium, sodium or potassium, etc.), an alkaline
earth metal (magnesium or calcium, etc.), ammonium, an organic base
and an amino acid, or salts with an inorganic acid (hydrochloric
acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid
or hydroiodic acid, etc.), and an organic acid (acetic acid,
trifluoroacetic acid, citric acid, lactic acid, tartaric acid,
oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric
acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic
acid, p-toluenesulfonic acid, methanesulfonic acid or
ethanesulfonic acid, etc.). These salts can be formed by the method
which is usually performed.
[0444] Examples of preferred salt of the formula (I) in the present
invention include hydrochloride, hydrobromate, acetate, sulfate,
etc.
[0445] In addition, the compound of the present invention is not
limited to a particular isomer, but includes all possible isomers
(keto-enol isomer, imine-enamine isomer, diastereoisomer, optical
isomer and rotation isomer, etc.) and racemic bodies.
[0446] The formula (I) in the present invention is not limited to a
particular isomer, but includes all possible isomers and racemic
bodies. For example, they also contain a tautomer and a steric
isomer as shown below.
##STR00030##
(wherein each symbol is same as above)
##STR00031##
[0447] (wherein each symbol is same as above)
[0448] Further, one or more hydrogen atoms, carbon atoms or other
atoms of the compound of the formula (I) can be substituted by an
isotope of a hydrogen atom, a carbon atom or other atoms,
respectively.
[0449] In addition, the compound of the formula (I) includes all
radioactive labeled bodies thereof. Such the "radioactive labeling"
and "radioactive labeled form" of the compound of the formula (I)
are included in the present invention, respectively, and are useful
as a study and/or diagnostic tool in metabolized drug dynamic state
study and binding assay.
[0450] Examples of an isotope which can be incorporated into the
compound of the formula (I) of the present invention include a
hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a
phosphorus atom, a sulfur atom, a fluorine atom and a chlorine
atom, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and
.sup.36Cl. A particularly preferable example of an isotope which
can be incorporated into the compound of the formula (I) of the
present invention is .sup.2H (i.e. heavy hydrogen atom), and can be
prepared by the method shown in Reference examples of the present
description, or the method well-known in the art. In addition, a
heavy hydrogen atom is expressed as "D" in Reference examples of
the present description. Compound of the formula (I) of the present
invention in which a hydrogen atom has been converted into a heavy
hydrogen atom are excellent in respect of bioavailability,
metabolism safety, drug efficacy, and toxicity as compared with
unconverted forms, in some cases, and can be useful as
medicaments.
[0451] Examples of "lower alkyl optionally substituted by
substituent group C" include methyl, ethyl, propyl, isopropyl,
butyl, tert-butyl, sec-butyl, pentan-2-yl, hydroxymethyl,
hydroxyethyl, carboxymethyl, carboxyethyl, carboxypropyl,
ethoxycarbonylpropyl, cyanomethyl, cyanoethyl, fluoromethyl,
fluoroethyl, fluoropropyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl,
ethyloxycarbonylethyl, methoxymethyl, dimethoxymethyl,
methoxyethyl, methoxypropyl, ethoxyethyl, 1-methyl-1-methoxymethyl,
propyloxymethyl, aminopropyl, dimethylaminomethyl, aminomethyl,
aminoethyl, dimethylaminoethyl, diethylaminomethyl,
diethylaminoethyl, dimethylaminopropyl, cyclopropylmethyloxymethyl,
methylsulfonylaminomethyl, methylaminocarbonylethyl,
1,1,1-trifluoropropan-2-yl, 1,1-difluoroethyl,
1,1,1-trifluoroethyl, 1,1,1-trifluoropropyl,
trifluoromethyloxyethyl, trifluoromethylcarbonylaminomethyl,
methylsulfonylethyl, methylcarbonyloxyethyl, and groups shown
below
##STR00032##
[0452] etc.
[0453] Examples of "lower alkyl optionally substituted by
substituent group F" include hydroxyethyl, methyl, ethyl, propyl,
isopropyl, butyl, tert-butyl, iso-butyl, sec-butyl, pentan-2-yl,
hydroxymethyl, hydroxyethyl, carboxymethyl, carboxyethyl,
carboxypropyl, ethoxycarbonylpropyl, and groups shown below
##STR00033##
[0454] etc.
[0455] Examples of "lower alkenyl optionally substituted by
substituent group C" include ethylenyl, 3-methylbuten-2-yl,
carboxyethylenyl, hydroxyethylenyl, difluoroethylenyl,
1-propen-2-yl, etc.
[0456] Examples of "lower alkynyl optionally substituted by
substituent group C" include 1-propynyl, 1-butynyl,
3,3,3-trifluoromethylpropynyl, 3-hydroxy-propynyl, etc.
[0457] Examples of "lower alkyloxy optionally substituted by
substituent group C" include methyloxy, ethyloxy,
trifluoromethyloxy, trichloromethyloxy, hydroxymethyloxy,
hydroxyethyloxy, carboxymethyloxy, carboxyethyloxy, etc.
[0458] Examples of "lower alkenyloxy optionally substituted by
substituent group C" include 3-fluoro-1-propenyloxy, ethylenyl,
carboxyethylenyl, hydroxyethylenyloxy, difluoroethylenyloxy,
etc.
[0459] Examples of "lower alkylcarbonyl optionally substituted by
substituent group C" include methylcarbonyl, ethylcarbonyl,
propylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl,
hydroxyethylcarbonyl, trifluoromethylcarbonyl,
2,2,2-trifluoromethylcarbonyl, carboxymethylcarbonyl, etc.
[0460] Examples of "lower alkyloxycarbonyl optionally substituted
by substituent group C" include methyloxycarbonyl,
ethyloxycarbonyl, trifluoromethyl oxycarbonyl,
trichloromethyloxycarbonyl, hydroxymethyloxycarbonyl,
hydroxyethyloxycarbonyl, carboxymethyloxycarbonyl, etc.
[0461] Examples of "carbocyclic group optionally substituted by
substituent group C" include phenyl, naphthyl, anthracenyl,
phenanthracenyl, adamantyl, 1-hydroxyadamantyl, 2-hydroxyadamantyl,
3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl,
3-hydroxyphenyl, 4-hydroxyphenyl, 4-chlorophenyl, 4-fluorophenyl,
2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, fluorocyclopropyl,
difluorocyclobutanyl, difluorocyclohexyl, and groups shown
below
##STR00034##
[0462] (wherein R.sup.E6 represents a group selected from
substituent group C, and m of R.sup.E6s may be the same or
different) etc.
[0463] Examples of "carbocyclic group optionally substituted by
substituent group F" include phenyl, naphthyl, 3-methylphenyl,
4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 4-chlorophenyl, 4-fluorophenyl,
1,5-difluorophenyl, etc.
[0464] Examples of "carbocycle lower alkyl optionally substituted
by substituent group C" include cyclopropylmethyl, 4-hydroxybenzyl,
cyclopentylmethyl, benzyl, 2-aminobenzyl, 2-cyanobenzyl,
2-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl,
1,3,5-trifluorobenzyl, 3,4,5-trifluorobenzyl, 4-methoxybenzyl,
2,4-difluorobenzyl, 2-fluoro-3-chlorobenzyl, benzhydryl,
4-phenylbenzyl, phenethyl, phenylpropyl,
4-methylcarbonylaminobenzyl, 3,4-dichlorobenzyl,
4-chloro-2-fluorobenzyl, 3,5-dihydroxybenzyl, and groups shown
below
##STR00035## ##STR00036## ##STR00037##
[0465] etc.
[0466] Examples of "carbocycle lower alkyl optionally substituted
by substituent group F" include cyclopropylmethyl, 4-hydroxybenzyl,
cyclopentylmethyl, benzyl, 2-aminobenzyl, 2-cyanobenzyl,
2-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl,
1,3,5-trifluorobenzyl, 3,4,5-trifluorobenzyl, 4-methoxybenzyl,
2,4-difluorobenzyl, 2-fluoro-3-chlorobenzyl, benzhydryl,
4-phenylbenzyl, phenethyl, phenylpropyl,
4-methylcarbonylaminobenzyl, 3,4-dichlorobenzyl,
4-chloro-2-fluorobenzyl, 3,5-dihydroxybenzyl, etc.
[0467] Examples of "carbocycleoxy lower alkyl optionally
substituted by substituent group C" include
4-hydroxyphenyloxymethyl, 4-hydroxyphenyloxyethyl,
cyclopropyloxymethyl, cyclopentyloxymethyl,
4-fluorophenyloxymethyl, 4-fluorophenyloxyethyl,
4-trifluoromethylphenyloxymethyl, 4-trifluoromethylphenyloxyethyl,
4-methoxyphenyloxymethyl, 4-methoxyphenyloxyethyl, etc.
[0468] Examples of "carbocyclecarbonyl optionally substituted by
substituent group C" include phenylcarbonyl,
4-fluorophenylcarbonyl, 4-trifluoromethylphenylcarbonyl,
4-methoxyphenylcarbonyl, cyclopropylcarbonyl, etc.
[0469] Examples of "carbocycleoxy optionally substituted by
substituent group C" include phenyloxy, cyclopropyloxy,
cyclopentyloxy, 4-fluorophenyloxy, 4-trifluoromethylphenyloxy,
4-methoxyphenyloxy, etc.
[0470] Examples of "carbocycleoxycarbonyl optionally substituted by
substituent group C" include phenyloxycarbonyl,
cyclopropyloxycarbonyl, cyclopentyloxycarbonyl,
4-fluorophenyloxycarbonyl, 4-trifluoromethylphenyloxycarbonyl,
4-methoxyphenyloxycarbonyl, etc.
[0471] Examples of "heterocyclic group optionally substituted by
substituent group C" include pyrimidinyl, pyridyl, benzoxazolyl,
morpholinyl, tetrahydropyranyl, furyl, thiophenyl, oxazolyl,
thiazolyl, pyrazolyl, methylpyrrolidinyl, isopropylpyrrolidinyl,
methylsulfonylpyrrolidinyl, hydroxyethylpyrrolidinyl,
methylpiperidinyl, methylpiperazinyl, tetrahydrofuryl, and groups
shown below
##STR00038##
[0472] (wherein R.sup.E6 represents a group selected from
substituent group C, and m of R.sup.E6s may be the same or
different) etc.
[0473] Examples of "heterocyclic group optionally substituted by
substituent group F" include morpholinyl, pyridyl,
methyl-1,3-dioxol-2-one, trimethyl-2-oxabicyclo[2.2.1]heptan-3-one,
pyrrolidinyl, methyl-pyrrolidine-2-carboxylate, tetrahydropyranyl,
hydroxymethylpyrrolidinyl, etc.
[0474] Examples of "heterocycle lower alkyl optionally substituted
by substituent group C" include tetrahydropyranylmethyl,
pyridylmethyl, isoxazolylmethyl, 5-methyl-isoxazolylmethyl,
3-methyl-oxadiazolylmethyl, indolylmethyl, benzothiophenylmethyl,
5-chlorobenzothiophenylmethyl, thiazolylmethyl,
2-methylthiazolylmethyl, pyrazolylmethyl, 2-methylpyrazolylmethyl,
dithiophenylmethyl, tetrazolylmethyl, quinazolylmethyl,
morpholinylmethyl, and groups shown below
##STR00039##
[0475] etc.
[0476] Examples of "heterocycle lower alkyl optionally substituted
by substituent group F" include tetrahydropyranylmethyl,
pyridylmethyl, isoxazolylmethyl, 5-methyl-isoxazolylmethyl,
3-methyl-oxadiazolylmethyl, indolylmethyl, benzothiophenylmethyl,
5-chlorobenzothiophenylmethyl, thiazolylmethyl,
2-methylthiazolylmethyl, pyrazolylmethyl, 2-methylpyrazolylmethyl,
dithiophenylmethyl, tetrazolylmethyl, quinazolylmethyl,
morpholinylmethyl, etc.
[0477] Examples of "heterocycleoxy lower alkyl optionally
substituted by a substituent group C" include
tetrahydropyranyloxymethyl, pyridyloxymethyl, isoxazolyloxymethyl,
5-methyl-isoxazolyloxymethyl, indolyloxymethyl,
benzothiophenyloxymethyl, 5-chlorobenzothiophenyloxymethyl,
thiazolyloxymethyl, 2-methylthiazolyloxymethyl, pyrazolyloxymethyl,
2-methylpyrazolyloxymethyl, etc.
[0478] Examples of "heterocyclecarbonyl optionally substituted by
substituent group C" include tetrahydropyranylcarbonyl,
pyridylcarbonyl, isoxazolylcarbonyl, 5-methyl-isoxazolylcarbonyl,
indolylcarbonyl, benzothiophenylcarbonyl,
5-chlorobenzothiophenylcarbonyl, thiazolylcarbonyl,
2-methylthiazolylcarbonyl, pyrazolylcarbonyl,
2-methylpyrazolylcarbonyl, etc.
[0479] Examples of "heterocycleoxy optionally substituted by
substituent C" include tetrahydropyranyloxy, pyridyloxy,
isoxazolyloxy, 5-methyl-isoxazolyloxy, indolyloxy,
benzothiophenyloxy, 5-chlorobenzothiophenyloxy, thiazolyloxy,
2-methylthiazolyloxy, pyrazolyloxy, 2-methylpyrazolyloxy, etc.
[0480] Examples of "heterocycleoxycarbonyl optionally substituted
by substituent group C" include tetrahydropyranyloxycarbonyl,
pyridyloxycarbonyl, isoxazolyloxycarbonyl,
5-methyl-isoxazolyloxycarbonyl, indolyloxycarbonyl,
benzothiophenyloxycarbonyl, 5-chlorobenzothiophenyloxycarbonyl,
thiazolyloxycarbonyl, 2-methylthiazolyloxycarbonyl,
pyrazolyloxycarbonyl, 2-methylpyrazolyloxycarbonyl, etc.
[0481] Examples of "lower alkylamino optionally substituted by
substituent group F" include methylamino, dimethylamino,
ethylamino, diethylamino, etc.
[0482] Examples of "lower alkylthio optionally substituted by
substituent group F" include methylthio, ethylthio, etc.
[0483] Examples of "lower alkylsilyl optionally substituted by
substituent group F" include trimethylsilyl, triethylsilyl,
tert-butyldimethylsilyl, etc.
[0484] P.sup.R in --OP.sup.R group is preferably a group converted
into --OH group by action of drug-metabolizing enzymes, hydrolases,
gastric acids, and/or enterobacteria, after in vivo administration
(for example, oral administration).
[0485] Examples of more preferred embodiment of P.sup.R include a
group selected from the following formulae b) to x).
b) --C(.dbd.O)--P.sup.R1,
c) --C(.dbd.O)-L-P.sup.R1,
d) --C(.dbd.O)-L-O--P.sup.R1,
e) --C(.dbd.O)-L-O-L-O--P.sup.R1,
f) --C(.dbd.O)-L-O--C(.dbd.O)--P.sup.R1,
g) --C(.dbd.O)--O--P.sup.R2,
[0486] h) --C(.dbd.O)--N(P.sup.R2).sub.2,
i) --C(.dbd.O)--O-L-O--P.sup.R2,
[0487] j) --CH.sub.2--O--P.sup.R3, k) --CH.sub.2--O-L-O--P.sup.R3,
l) --CH.sub.2--O--C(.dbd.O)--P.sup.R3, m)
--CH.sub.2--O--C(.dbd.O)--O--P.sup.R3, n)
--CH(--CH.sub.3)--O--C(.dbd.O)--O--P.sup.R3, o)
--CH.sub.2--O--C(.dbd.O)--N(--K)--P.sup.R3, p)
--CH.sub.2--O--C(.dbd.O)--O-L-O--P.sup.R3, q)
--CH.sub.2--O--C(.dbd.O)--O-L-N(P.sup.R3).sub.2, r)
--CH.sub.2--O--C(.dbd.O)--N(--K)-L-O--P.sup.R3, s)
--CH.sub.2--O--C(.dbd.O)--N(--K)-L-N(P.sup.R3).sub.2, t)
--CH.sub.2--O--C(.dbd.O)--O-L-O-L-O--P.sup.R3, u)
--CH.sub.2--O--C(.dbd.O)--O-L-N(--K)--C(.dbd.O)--P.sup.R3, v)
--CH.sub.2--O--P(.dbd.O)(--OH).sub.2, w)
--CH.sub.2--O--P(.dbd.O)(--OBn).sub.2, x) --CH.sub.2--P.sup.R4
(wherein L is straight or branched lower alkylene,
[0488] K is hydrogen, or straight or branched lower alkylene, or
straight or branched lower alkenylene,
[0489] P.sup.R1 is carbocyclic group optionally substituted by
substituent group F, heterocyclic group optionally substituted by
substituent group F, lower alkyl amino optionally substituted by
substituent group F, or lower alkylthio optionally substituted by
substituent group F,
[0490] P.sup.R2 is lower alkyl optionally substituted by
substituent group F, carbocyclic group optionally substituted by
substituent group F, or heterocyclic group optionally substituted
by substituent group F,
[0491] P.sup.R3 is lower alkyl optionally substituted by
substituent group F, carbocyclic group optionally substituted by
substituent group F, heterocyclic group optionally substituted by
substituent group F, lower alkyl amino optionally substituted by
substituent group F, carbocycle lower alkyl optionally substituted
by substituent group F, heterocycle lower alkyl optionally
substituted by substituent group F, or lower alkylsilyl,
[0492] P.sup.R4 is carbocyclic group optionally substituted by
substituent group F, or heterocyclic group optionally substituted
by substituent group F, and
[0493] substituent group F; oxo, lower alkyl, hydroxy lower alkyl,
amino, lower alkylamino, carbocycle lower alkyl, lower
alkylcarbonyl, halogen, hydroxy, carboxy, lower alkylcarbonylamino,
lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkyloxy,
cyano, and nitro)
[0494] Examples of further preferred embodiment of P.sup.R include
following b), k), l), and m).
b) --C(.dbd.O)--P.sup.R1,
[0495] l) --CH.sub.2--O--C(.dbd.O)--P.sup.R3, n)
--CH.sub.2--O--C(.dbd.O)--O--P.sup.R3, n)
--CH(--CH.sub.3)--O--C(.dbd.O)--O--P.sup.R3, (wherein each symbol
is same as above)
[0496] Examples of another embodiment of a preferable substituent
of P.sup.R include groups of P-1 to P-83 in the following Tables 1
to 9.
TABLE-US-00001 TABLE 1 ##STR00040## P-1 ##STR00041## P-2
##STR00042## P-3 ##STR00043## P-4 ##STR00044## P-5 ##STR00045## P-6
##STR00046## P-7 ##STR00047## P-8 ##STR00048## P-9 ##STR00049##
P-10 ##STR00050##
TABLE-US-00002 TABLE 2 ##STR00051## P-11 ##STR00052## P-12
##STR00053## P-13 ##STR00054## P-14 ##STR00055## P-15 ##STR00056##
P-16 ##STR00057## P-17 ##STR00058## P-18 ##STR00059## P-19
##STR00060## P-20 ##STR00061##
TABLE-US-00003 TABLE 3 ##STR00062## P-21 ##STR00063## P-22
##STR00064## P-23 ##STR00065## P-24 ##STR00066## P-25 ##STR00067##
P-26 ##STR00068## P-27 ##STR00069## P-28 ##STR00070## P-29
##STR00071## P-30 ##STR00072##
TABLE-US-00004 TABLE 4 ##STR00073## P-31 ##STR00074## P-32
##STR00075## P-33 ##STR00076## P-34 ##STR00077## P-35 ##STR00078##
P-36 ##STR00079## P-37 ##STR00080## P-38 ##STR00081## P-39
##STR00082## P-40 ##STR00083##
TABLE-US-00005 TABLE 5 ##STR00084## P-41 ##STR00085## P-42
##STR00086## P-43 ##STR00087## P-44 ##STR00088## P-45 ##STR00089##
P-46 ##STR00090## P-47 ##STR00091## P-48 ##STR00092## P-49
##STR00093## P-50 ##STR00094##
TABLE-US-00006 TABLE 6 ##STR00095## P-51 ##STR00096## P-52
##STR00097## P-53 ##STR00098## P-54 ##STR00099## P-55 ##STR00100##
P-56 ##STR00101## P-57 ##STR00102## P-58 ##STR00103## P-59
##STR00104## P-60 ##STR00105##
TABLE-US-00007 TABLE 7 ##STR00106## P-61 ##STR00107## P-62
##STR00108## P-63 ##STR00109## P-64 ##STR00110## P-65 ##STR00111##
P-66 ##STR00112## P-67 ##STR00113## P-68 ##STR00114## P-69
##STR00115## P-70 ##STR00116##
TABLE-US-00008 TABLE 8 ##STR00117## P-71 ##STR00118## P-72
##STR00119## P-73 ##STR00120## P-74 ##STR00121## P-75 ##STR00122##
P-76 ##STR00123## P-77 ##STR00124##
TABLE-US-00009 TABLE 9 ##STR00125## P-78 ##STR00126## P-79
##STR00127## P-80 ##STR00128## P-81 ##STR00129## P-82 ##STR00130##
P-83 ##STR00131##
[0497] Examples of another embodiment of a particularly preferable
substituent of P.sup.R include following groups.
##STR00132##
[0498] Examples of a preferable substituent in R.sup.1a include
hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower alkyl
optionally substituted by substituent group C, lower alkenyl
optionally substituted by substituent group C, lower alkynyl
optionally substituted by substituent group C, lower alkyloxy
optionally substituted by substituent group C, lower alkenyloxy
optionally substituted by substituent group C, lower alkylcarbonyl
optionally substituted by substituent group C, lower
alkyloxycarbonyl optionally substituted by substituent group C,
carbocyclic group optionally substituted by substituent group C,
carbocycle lower alkyl optionally substituted by substituent group
C, carbocyclecarbonyl optionally substituted by substituent group
C, carbocycleoxy optionally substituted by substituent group C,
carbocycleoxycarbonyl optionally substituted by substituent group
C, heterocyclic group optionally substituted by substituent group
C, heterocycle lower alkyl optionally substituted by substituent
group C, heterocyclecarbonyl optionally substituted by substituent
group C, heterocycleoxy optionally substituted by substituent group
C, heterocycleoxycarbonyl optionally substituted by substituent
group C,
--Z--N(R.sup.A1)(R.sup.A2), --Z--N(R.sup.A3)--SO.sub.2--(R.sup.A4),
--Z--C(.dbd.O)--N(R.sup.A5)--SO.sub.2--(R.sup.A6),
--Z--N(R.sup.A7)--C(.dbd.O)--R.sup.A8,
--Z--S--R.sup.A9,
[0499] --Z--SO.sub.2--R.sup.A10,
--Z--S(.dbd.O)--R.sup.A11,
[0500] --Z--N(R.sup.A12)--C(.dbd.O)--O--R.sup.A13,
--Z--N(R.sup.A14)--C(.dbd.O)--N(R.sup.A15)(R.sup.A6),
--Z--C(.dbd.O)--N(R.sup.A17)--C(.dbd.O)--N(R.sup.A18)(R.sup.A19),
--Z--N(R.sup.A2)--C(.dbd.O)C(.dbd.O)--C(.dbd.O)--R.sup.A21, or
--Z--B(--OR.sup.A22)(--OR.sup.A23) (substituent group C, R.sup.A1,
R.sup.A2, R.sup.A3, R.sup.A5, R.sup.A7, R.sup.A8, R.sup.A9,
R.sup.A10, R.sup.A11, R.sup.A12, R.sup.A13, R.sup.A14, R.sup.A15,
R.sup.A16, R.sup.A17, R.sup.A18, R.sup.A19, R.sup.A20, R.sup.A21,
R.sup.A22, R.sup.A23, and Z are same as those of item 1).
[0501] Examples of a more preferable substituent in R.sup.1a
include hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally
substituted by substituent group C, lower alkenyl optionally
substituted by substituent group C, lower alkyloxy optionally
substituted by substituent group C, lower alkylcarbonyl optionally
substituted by substituent group C, lower alkyloxycarbonyl
optionally substituted by substituent group C, heterocyclic group
optionally substituted by substituent group C,
--Z--N(R.sup.A1)(R.sup.A2), --Z--N(R.sup.A7)--C(.dbd.O)--R.sup.A8,
--Z--N(R.sup.A12)--C(.dbd.O)--O--R.sup.A3, or
--Z--B(--OR.sup.A22)(--OR.sup.A23) (substituent group C, R.sup.A1,
R.sup.A2, R.sup.A7, R.sup.A8, R.sup.A12, R.sup.A3, R.sup.A22,
R.sup.A23, and Z are same as those of item 1).
[0502] Examples of a preferable substituent in R.sup.1a include
hydrogen, halogen, hydroxy, carboxy, lower alkyl optionally
substituted by substituent group C, lower alkenyl optionally
substituted by substituent group C, lower alkyloxy optionally
substituted by substituent group C, lower alkylcarbonyl optionally
substituted by substituent group C, lower alkyloxycarbonyl
optionally substituted by substituent group C, heterocyclic group
optionally substituted by substituent group C, or
--Z--N(R.sup.A1)(R.sup.A2) (substituent group C, R.sup.A1,
R.sup.A2, and Z are same as those of item 1).
[0503] Examples of another embodiment of a preferable substituent
in R.sup.1a include hydrogen, carboxy, hydroxymethyl, methoxy,
chlorine atom, bromine atom, ethoxymethyl, dimethylamino, hydroxy,
--C(.dbd.O)--NH--S(.dbd.O).sub.2-Me, amino, methylamino,
methylaminomethyl, --NH--C(.dbd.O)--CF.sub.3, pyrazolyl,
--NH--C(.dbd.O)-Me, --C(.dbd.O)N-Me.sub.2, tetrazolyl,
--NH--C(.dbd.O)-Ph, --C(.dbd.O)NH-Me, --C(.dbd.O)NH-Et,
--C(.dbd.O)NH-cyclopropyl, methoxycarbonyl, methyl, propenyl,
propyl, isopropyl, fluoromethyl, difluoromethyl, cyano,
--C(.dbd.O)-Me, --CH(--OH)-Me, --B(--OH).sub.2,
##STR00133##
(Me represents a methyl group, Ph represents a phenyl group, and Et
represents an ethyl group) etc.
[0504] Examples of another embodiment of a more preferable
substituent in R.sup.1a include hydrogen, carboxy, hydroxymethyl,
methoxy, bromine atom, ethoxymethyl, dimethylamino, hydroxy,
--C(.dbd.O)--NH--S(.dbd.O).sub.2-Me, amino, methylamino, methyl,
propenyl, --C(.dbd.O)-Me, --B(--OH).sub.2
(Me represents a methyl group) etc.
[0505] Examples of another embodiment of a further preferable
substituent in R.sup.1a include hydrogen, carboxy, and
--C(.dbd.O)-Me.
[0506] Examples of a most preferable substituent in R.sup.1a
include hydrogen.
[0507] Examples of a preferable substituent in R.sup.2a is
hydrogen, halogen, carboxy, cyano, formyl, lower alkyl optionally
substituted by substituent group C, lower alkenyl optionally
substituted by substituent group C, lower alkynyl optionally
substituted by substituent group C, lower alkyloxy optionally
substituted by substituent group C, lower alkenyloxy optionally
substituted by substituent group C, lower alkylcarbonyl optionally
substituted by substituent group C, lower alkyloxycarbonyl
optionally substituted by substituent group C, carbocyclic group
optionally substituted by substituent group C, carbocycle lower
alkyl optionally substituted by substituent group C,
carbocyclecarbonyl optionally substituted by substituent group C,
carbocycleoxy optionally substituted by substituent group C,
carbocycleoxycarbonyl optionally substituted by substituent group
C, heterocyclic group optionally substituted by substituent group
C, heterocycle lower alkyl optionally substituted by substituent
group C, heterocyclecarbonyl optionally substituted by substituent
group C, heterocycleoxy optionally substituted by substituent group
C, heterocycleoxycarbonyl optionally substituted by substituent
group C,
--Z--N(R.sup.B1)--SO.sub.2--R.sup.B2,
--Z--N(R.sup.B3)--C(.dbd.O)--R.sup.B4,
--Z--N(R.sup.5B)--C(.dbd.O)--O--R.sup.B6,
--Z--C(.dbd.O)--N(R.sup.B7)(R.sup.8B), --Z--N(R.sup.B9)(R.sup.B10),
or --Z--SO.sub.2--R.sup.B11 (substituent group C, R.sup.B1,
R.sup.B2, R.sup.B3, R.sup.B4, R.sup.B5, R.sup.B6, R.sup.B7,
R.sup.B8, R.sup.B9, R.sup.B10, R.sup.B11, and Z are same as those
of item 1).
[0508] Examples of a more preferable substituent in R.sup.2a is
hydrogen, lower alkyl optionally substituted by substituent group
C, carbocycle lower alkyl optionally substituted by substituent
group C, heterocycle lower alkyl optionally substituted by
substituent group C, or
--Z--N(R.sup.B9)(R.sup.B10) (substituent group C, R.sup.B9,
R.sup.B10, and Z are same as those of item 1).
[0509] Examples of a further preferable substituent in R.sup.2a
include hydrogen, or lower alkyl optionally substituted by
substituent group C, heterocycle lower alkyl optionally substituted
by substituent group C
(substituent group C is same as that of item 1).
[0510] Examples of another embodiment of a preferable substituent
in R.sup.2a include hydrogen, hydroxymethyl, amino, methoxymethyl,
methoxymethylcyclopropylmethyloxymethyl, cyanomethyl, aminomethyl,
propyloxymethyl, --CH.sub.2--NH--C(.dbd.O)-Me, methylaminomethyl,
imidazolyl, dimethylaminomethyl, pyrrolidinyl, fluoromethyl,
--CH.sub.2--NH--C(.dbd.O)H
(Me represents a methyl group) etc.
[0511] Examples of another embodiment of a more preferable
substituent in R.sup.2a include hydrogen, hydroxymethyl,
methoxymethylcyclopropylmethyloxymethyl, aminomethyl,
propyloxymethyl, etc.
[0512] Examples of another embodiment of a further preferable
substituent in R.sup.2a include hydrogen.
[0513] Examples of a preferable substituent in R.sup.3a include
[0514] hydrogen, halogen, hydroxy, carboxy, cyano, formyl, lower
alkyl optionally substituted by substituent group C, lower alkenyl
optionally substituted by substituent group C, lower alkynyl
optionally substituted by substituent group C, lower alkyloxy
optionally substituted by substituent group C, lower alkenyloxy
optionally substituted by substituent group C, lower alkylcarbonyl
optionally substituted by substituent group C, lower
alkyloxycarbonyl optionally substituted by substituent group C,
carbocyclic group optionally substituted by substituent group C,
carbocycle lower alkyl optionally substituted by substituent group
C, carbocycleoxy lower alkyl optionally substituted by substituent
group C, carbocyclecarbonyl optionally substituted by substituent
group C, carbocycleoxy optionally substituted by substituent group
C, carbocycleoxycarbonyl optionally substituted by substituent
group C, heterocyclic group optionally substituted by substituent
group C, heterocycle lower alkyl optionally substituted by
substituent group C, heterocycleoxy lower alkyl optionally
substituted by substituent group C, heterocyclecarbonyl optionally
substituted by substituent group C, heterocycleoxy optionally
substituted by substituent group C, heterocycleoxycarbonyl
optionally substituted by substituent group C,
--Z--N(R.sup.C1)--SO.sub.2--R.sup.C2,
--Z--N(R.sup.C3)--C(.dbd.O)--R.sup.C4,
--Z--N(R.sup.C5)--C(.dbd.O)--O--R.sup.C6,
--Z--C(.dbd.O)--N(R.sup.C7)(R.sup.C8), --Z--N(R.sup.C9)(R.sup.C10),
or --Z--SO.sub.2--R.sup.C11 (substituent group C, R.sup.C1,
R.sup.C2, R.sup.C3, R.sup.C4, R.sup.C5, R.sup.C6, R.sup.C7,
R.sup.C8, R.sup.C9, R.sup.C10, R.sup.C11, and Z are same as those
of item 1).
[0515] Examples of a more preferable substituent in R.sup.3a is
hydrogen, lower alkyl optionally substituted by substituent group
C, lower alkenyl optionally substituted by substituent group C,
lower alkynyl optionally substituted by substituent group C,
carbocyclic group optionally substituted by substituent group C,
carbocycle lower alkyl optionally substituted by substituent group
C, carbocycleoxy lower alkyl optionally substituted by substituent
group C,
--Z--N(R.sup.C1)--SO.sub.2--R.sup.C2,
--Z--N(R.sup.C3)--C(.dbd.O)--R.sup.C4,
--Z--N(R.sup.C5)--C(.dbd.O)--O--R.sup.C6,
--Z--C(.dbd.O)--N(R.sup.C7)(R.sup.C8), or
--Z--N(R.sup.C9)(R.sup.C10) (substituent group C, R.sup.C1,
R.sup.C2, R.sup.C3, R.sup.C4, R.sup.C5, R.sup.C6, R.sup.C7,
R.sup.C8, R.sup.C9, R.sup.C10, and Z are same as those of item
1).
[0516] Examples of a further preferable substituent in R.sup.3a
include hydrogen, lower alkyl optionally substituted by substituent
group C, lower alkynyl optionally substituted by substituent group
C, carbocyclic group optionally substituted by substituent group C,
or carbocycle lower alkyl optionally substituted by substituent
group C
(substituent group C is same as that of item 1).
[0517] Examples of another embodiment of a preferable substituent
in R.sup.3a include hydrogen, ethoxyethyl, methyl, ethyl, propyl,
2,4-difluorobenzyl, methoxyethyl, cyanomethyl, cyanoethyl,
3-chloro-2-fluorobenzyl, 1-methoxypropyl, pyridylmethyl, isopropyl,
tetrahydropyranylmethyl, cyclopropylmethyl, benzyl,
methylisoxazolylmethyl, methyloxadiazolyl, isopropyloxyethyl,
hydroxyethyl, 4-fluorobenzyl, cyclopropyl, ethoxycarbonylethyl,
--CH(Me)CH.sub.2OMe, carboxyethyl,
--CH.sub.2CH.sub.2C(.dbd.O)--N(Me).sub.2,
--CH.sub.2CH.sub.2N(Me)-S(.dbd.O).sub.2-Ph,
--CH.sub.2CH.sub.2--N(Me)-S(.dbd.O).sub.2-Me,
--CH.sub.2CH.sub.2--NHC(.dbd.O)-Ph, --CH(Me)-CH.sub.2--OMe,
--CH.sub.2CH.sub.2--NH--S(.dbd.O).sub.2-Ph,
--CH.sub.2CH.sub.2--NH--C(.dbd.O)--O--CH(Me).sub.2,
--CH.sub.2CH.sub.2--C(.dbd.O)--NH-Ph,
--CH.sub.2CH.sub.2--N(Me)C(.dbd.O)-Ph,
--CH.sub.2CH.sub.2--NH--C(.dbd.O)-Me,
--CH.sub.2CH.sub.2--NH--S(.dbd.O).sub.2-Me, aminoethyl,
--CH.sub.2CH.sub.2--N(Me)-C(.dbd.O)-Me,
--CH.sub.2CH.sub.2--C(.dbd.O)--N(Me)-Ph,
--CH.sub.2CH.sub.2--NH--C(.dbd.O)--O-tBu, piperidinylcarbonylethyl,
dimethylaminoethyl, cyclopropylmethyl, methylaminoethyl,
furanylmethyl, morpholinylcarbonylethyl, sec-butyl, pentan-2-yl,
carboxypropyl, ethoxycarbonylpropyl, phenylpropyl, propyloxyethyl,
aminopropyl, dimethylaminomethyl, dimethylaminoethyl,
diethylaminomethyl, diethylaminoethyl, dimethylaminopropyl,
methylaminocarbonylethyl, 1,1,1-trifluoropropan-2-yl,
1,1-difluoroethyl, 1,1,1-trifluoroethyl, 1,1,1-trifluoropropyl,
trifluoromethyloxyethyl, trifluoromethylcarbonylaminomethyl,
methylsulfonylethyl, methylcarbonyloxyethyl,
methylcarbonyloxypropyl, 1-fluoropropyl, fluorocyclopropyl,
difluorocyclopropyl, 3,3-dimethylbutan-2-yl, 1-fluoroethyl,
1-methoxypropan-2-yl, amino, thiazolylmethyl, methylsulfonylethyl,
4-fluorophenyloxyethyl, pyridyl, pentan-2-yl, butan-2-yl,
3-methylbuten-2-yl, as well as groups shown below
##STR00134## ##STR00135##
(Me represents a methyl group, Ph represents a phenyl group, and
tBu represents a tert-butyl group) etc.
[0518] Examples of another embodiment of a more preferable
substituent in R.sup.3a include ethoxyethyl, methyl, ethyl,
2,4-difluorobenzyl, methoxyethyl, cyanomethyl,
3-chloro-2-fluorobenzyl, methoxypropyl, pyridylmethyl, isopropyl,
tetrahydropyranylmethyl, cyclopropylmethyl, benzyl,
methylisoxazolylmethyl, 4-fluorobenzyl, cyclopropyl,
ethoxycarbonylethyl, --CH(Me)CH.sub.2OMe, carboxyethyl,
--CH.sub.2CH.sub.2C(.dbd.O)--N(Me).sub.2,
--CH.sub.2CH.sub.2N(Me)-S(.dbd.O).sub.2-Ph,
--CH.sub.2CH.sub.2--N(Me)-S(.dbd.O).sub.2-Me,
--CH.sub.2CH.sub.2--NHC(.dbd.O)-Ph, --CH(Me)-CH.sub.2--OMe,
--CH.sub.2CH.sub.2--NH--S(.dbd.O).sub.2-Ph,
--CH.sub.2CH.sub.2--NH--C(.dbd.O)--O--CH(Me).sub.2,
--CH.sub.2CH.sub.2--C(.dbd.O)--NH-Ph,
--CH.sub.2CH.sub.2--N(Me)C(.dbd.O)-Ph,
--CH.sub.2CH.sub.2--NH--C(.dbd.O)-Me,
--CH.sub.2CH.sub.2--NH--S(.dbd.O).sub.2-Me, aminoethyl,
1,1,1-trifluoropropan-2-yl, propyl, methylthiomethyl, hydrogen,
fluorocyclopropyl, trifluoromethoxyethyl, 1-fluoropropyl,
1-fluoroethyl, methylcarbonyloxymethyl, 1,1-difluoromethyl, and
groups shown below
##STR00136##
(Me represents methyl group, and Ph represents phenyl group)
etc.
[0519] Examples of another embodiment of a further preferable
substituent in R.sup.3a include ethoxyethyl, methyl, ethyl,
2,4-difluorobenzyl, methoxyethyl, cyanomethyl,
3-chloro-2-fluorobenzyl, methoxypropyl, pyridylmethyl, isopropyl,
tetrahydropyranylmethyl, cyclopropylmethyl, benzyl, 4-fluorobenzyl,
cyclopropyl, ethoxycarbonylethyl, --CH(Me)CH.sub.2OMe,
carboxyethyl, 1,1,1-trifluoropropan-2-yl, hydroxyethyl,
1-fluoroethyl
(Me represents methyl group) etc.
[0520] Examples of another embodiment of a most preferable
substituent in R.sup.3a include 1,1,1-trifluoropropan-2-yl.
[0521] Examples of a preferable substituent in R.sup.5a, R.sup.6a,
R.sup.7a, R.sup.8a, R.sup.9a, R.sup.10a, and R.sup.11a include
hydrogen, carboxy, cyano, lower alkyl optionally substituted by
substituent group C, lower alkenyl optionally substituted by
substituent group C, lower alkynyl optionally substituted by
substituent group C, lower alkylcarbonyl optionally substituted by
substituent group C, lower alkyloxycarbonyl optionally substituted
by substituent group C, carbocyclic group optionally substituted by
substituent group C, carbocycle lower alkyl optionally substituted
by substituent group C, carbocycleoxy lower alkyl optionally
substituted by substituent group C, carbocyclecarbonyl optionally
substituted by substituent group C, carbocycleoxycarbonyl
optionally substituted by substituent group C, heterocyclic group
optionally substituted by substituent group C, heterocycle lower
alkyl optionally substituted by substituent group C, heterocycleoxy
lower alkyl optionally substituted by substituent group C,
heterocyclecarbonyl optionally substituted by substituent group C,
heterocycleoxycarbonyl optionally substituted by substituent group
C,
--Y--S--R.sup.D1,
--Z--S(.dbd.O)--R.sup.D2,
[0522] --Z--SO.sub.2--R.sup.D3,
--C(.dbd.O)--C(.dbd.O)--R.sup.D4,
[0523] --C(.dbd.O)--N(R.sup.D5)(R.sup.D6),
--Z--C(R.sup.D7)(R.sup.D8)(R.sup.D9), or --Z--CH.sub.2--R.sup.D10
(substituent group C, R.sup.D1, R.sup.D2, R.sup.D3, R.sup.D4,
R.sup.D5, R.sup.D6, R.sup.D7, R.sup.D8, R.sup.D9, R.sup.D10, and Z
are same as those of item 1).
[0524] Examples of a more preferable substituent in R.sup.5a,
R.sup.6a, R.sup.7a, R.sup.8a, R.sup.9a, R.sup.10a, and R.sup.11a
include hydrogen, lower alkyl optionally substituted by substituent
group C, carbocyclic group optionally substituted by substituent
group C, carbocycleoxy lower alkyl optionally substituted by
substituent group C, heterocyclic group optionally substituted by
substituent group C, tricyclic condensed heterocyclic group
optionally substituted by substituent group C, heterocycleoxy lower
alkyl optionally substituted by substituent group C,
--Y--S--R.sup.D1, or
[0525] --Z--C(R.sup.D7)(R.sup.D8)(R.sup.D9) (substituent group C,
R.sup.D1, R.sup.D7, R.sup.D8, R.sup.D9, Y, and Z are same as those
of item 1).
[0526] Examples of another embodiment of a preferable substituent
in R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a, R.sup.9a, R.sup.10a, and
R.sup.11a include hydrogen, benzhydryl, benzyl, indolylmethyl,
cyclohexylmethyl, phenethyl, benzylthiomethyl,
3,5-dimethylisoxazolyl, 5-chloro-3-ethylbenzothiophenyl,
4-fluorobenzyl, methylthiazolylmethyl, cyclopentylmethyl,
4-methoxybenzyl, 3-fluorobenzyl, naphthylmethyl, methyl,
3-trifluoromethylbenzyl, pyridylmethyl,
4-methylcarbonylaminobenzyl, pyrimidinyl, isobutyl, phenoxyethyl,
methoxypropyl, phenylpropyl, as well as tricyclic or tetracyclic
condensed heterocyclic group optionally substituted by substituent
group C such as the following groups
##STR00137## ##STR00138## ##STR00139## ##STR00140##
##STR00141##
(wherein R.sup.E6 represents a group selected from substituent
group C, and m of R.sup.E6s may be the same or different) etc.
[0527] Examples of another embodiment of a more preferable
substituent in R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a, R.sup.9a,
R.sup.10a, and R.sup.11a include hydrogen, benzhydryl, benzyl,
indolylmethyl, cyclohexylmethyl, phenethyl, 3,5-dimethylisoxazolyl,
5-chloro-3-ethylbenzothiophenyl, biphenylmethyl, 4-fluorobenzyl,
methylthiazolylmethyl, cyclopentylmethyl, 4-methoxybenzyl,
3-fluorobenzyl, naphthylmethyl, methyl, 3-trifluoromethylbenzyl,
pyridylmethyl, 4-methylcarbonylaminobenzyl, pyrimidinyl, and the
following groups
##STR00142##
(wherein R.sup.E6 represents a group selected from substituent
group C, and m of R.sup.E6s may be the same or different), etc.
[0528] , etc.
[0529] 1) Examples of a preferable embodiment when B.sup.1 is
CR.sup.5aR.sup.6a, and B.sup.2 is NR.sup.7a include
[0530] the case where R.sup.3a and R.sup.7a are taken together with
an adjacent atom to form a heterocycle optionally substituted by
substituent group D.
[0531] 2) Examples of a preferable embodiment when B.sup.1 is
NR.sup.7a, and B.sup.2 is CR.sup.5aR.sup.6a include
[0532] the case where R.sup.3a and R.sup.6a are taken together with
an adjacent atom to form a heterocycle optionally substituted by
substituent group D.
[0533] 3) Examples of a preferable embodiment when B.sup.1 is
CR.sup.8aR.sup.9a, and B.sup.2 is CR.sup.10aR.sup.11a include
[0534] the case where R.sup.8a and R.sup.10a are taken together
with an adjacent atom to form a carbocycle or a heterocycle
optionally substituted by substituent group D.
[0535] 4) Examples of another preferable embodiment when B.sup.1 is
CR.sup.8aR.sup.9a, and B.sup.2 is CR.sup.10aR.sup.11a include
[0536] the case where R.sup.3a and R.sup.11a are taken together
with an adjacent atom to form a heterocycle optionally substituted
by substituent group D.
[0537] When one of B.sup.1 and B.sup.2 is CR.sup.5aR.sup.6a and the
other is NR.sup.7a,
[0538] the case where B.sup.1 is NR.sup.7a and B.sup.2 is
CR.sup.5aR.sup.6a is more preferable.
[0539] When one of B.sup.1 and B.sup.2 is CR.sup.5aR.sup.6a and the
other is NR.sup.7a,
[0540] it is preferable that at least one of R.sup.5a or R.sup.6a
is hydrogen. A more preferable embodiment is such that R.sup.5a is
hydrogen and R.sup.6a is hydrogen. In this case, R.sup.7a is not a
hydrogen atom.
[0541] A particularly preferable embodiment of B.sup.1 and B.sup.2
is such that B.sup.1 is NR.sup.7a and B.sup.2 is
CR.sup.5aR.sup.6a.
[0542] A most preferable embodiment of B.sup.1 and B.sup.2 is such
that B.sup.1 is NR.sup.7a and B.sup.2 is CH.sub.2.
[0543] A preferable embodiment of R.sup.7a is carbocyclic group
optionally substituted by substituent group C, carbocycle lower
alkyl optionally substituted by substituent group C, heterocyclic
group optionally substituted by substituent group C, and
heterocycle lower alkyl optionally substituted by substituent group
C.
[0544] A more preferable embodiment of R.sup.7a is cycloalkyl,
cycloalkenyl, aryl, non-aromatic condensed carbocyclic group,
heteroaryl, non-aromatic heterocyclic group, bicyclic condensed
heterocyclic group, tricyclic condensed heterocyclic group, lower
alkyl substituted by one or two carbocyclic groups, and lower alkyl
substituted by one or two heterocyclic groups.
[0545] A further preferable embodiment of R.sup.7a is benzyl,
benzhydryl, 4-fluorobenzyl, p-methoxybenzyl, and the following
groups
##STR00143##
(wherein R.sup.E6, and m are same as those of item 1).
[0546] A particularly preferable embodiment of R.sup.7a is the
following groups
##STR00144##
(wherein R.sup.E6, and m are same as those of item 1).
[0547] A most preferable embodiment of R.sup.7a is the following
groups
##STR00145##
(wherein R.sup.E6, and m are same as those of item 1).
[0548] When B.sup.1 is CR.sup.8aR.sup.9a, and B.sup.2 is
CR.sup.10aR.sup.11a, it is preferable that R.sup.9a and R.sup.11a
are hydrogen. A preferable embodiment of R.sup.8a and R.sup.10a is
such that any one of them is hydrogen.
[0549] When R.sup.9a and R.sup.11a are hydrogen, and any one of
R.sup.8a and R.sup.10a is hydrogen, a preferable embodiment of the
other of R.sup.8a and R.sup.10a is the following groups
--Z--C(R.sup.E1)(R.sup.E2)(R.sup.E3) or
##STR00146##
(wherein Z, R.sup.E1, R.sup.E2, R.sup.E3, R.sup.E6, and m are same
as those of item 1).
[0550] When R.sup.9a and R.sup.11a are hydrogen, and any one of
R.sup.8a and R.sup.10a is hydrogen, a further preferable embodiment
of the other of R.sup.8a and R.sup.10a is the following groups
##STR00147##
(wherein R.sup.E6, and m are same as those of item 1).
[0551] When R.sup.9a and R.sup.11a are hydrogen, and any one of
R.sup.8a and R.sup.10a is hydrogen, a most preferable embodiment of
the other of R.sup.8a and R.sup.10a is the following groups
##STR00148##
(wherein R.sup.E6, and m are same as those of item 1).
[0552] Examples of a preferable substituent in substituent group D
include carbocyclic group optionally substituted by substituent
group C, heterocyclic group optionally substituted by substituent
group C, carbocycle lower alkyl optionally substituted by
substituent group C, and heterocycle lower alkyl optionally
substituted by substituent group C.
[0553] Examples of another embodiment of a preferable substituent
in substituent group D include benzyl, benzhydryl, 4-fluorobenzyl,
p-methoxybenzyl,
##STR00149##
(wherein R.sup.E6 represents a group selected from substituent
group C, and m of R.sup.E6s may be the same or different) etc.
[0554] Examples of a preferable substituent of R.sup.E6 include
halogen, cyano, hydroxy, carboxy, formyl, amino, oxo, nitro, lower
alkyl, lower alkynyl, halogeno lower alkyl, lower alkyloxy, lower
alkyl amino, halogeno lower alkyloxy, carbocyclic group, etc.
[0555] Examples of a more preferable substituent of R.sup.E6
include fluorine atom, chlorine atom, bromine atom, cyano, hydroxy,
methyl, ethyl, ethynyl, hydroxymethyl, isopropyl, methoxy, ethoxy,
methoxymethyl, cyclopropyl, dimethylamino, trifluoromethyl, oxo,
carboxy, etc.
[0556] Examples of a particularly preferable substituent of
R.sup.E6 include fluorine atom, chlorine atom, bromine atom,
methyl, methoxy, and trifluoromethyl.
[0557] A preferable embodiment of m is an integer of 0 to 6,
further preferably an integer of 0 to 3, and most preferably an
integer of 0 to 2.
[0558] One of characteristics of the compound in the present
invention is in that a prodrug of a polycyclic carbamoylpyridone
derivative, in which two or more rings are condensed, such as shown
in the formula (I) in item 1 and/or a composition including them,
has high inhibitory activity on cap-dependent endonuclease, and has
an effect of treating and/or preventing influenza infectious
disease.
[0559] The characteristic of the compound in the present invention
is that cap-dependent endonuclease inhibitory activity was
improved, by applying a functional group as shown below to R.sup.1a
in the formula (I).
[0560] Functional group: hydrogen, halogen, hydroxy, carboxy,
cyano, formyl, lower alkyl optionally substituted by substituent
group C, lower alkenyl optionally substituted by substituent group
C, lower alkynyl optionally substituted by substituent group C,
lower alkyloxy optionally substituted by substituent group C, lower
alkenyloxy optionally substituted by substituent group C, lower
alkylcarbonyl optionally substituted by substituent group C, lower
alkyloxycarbonyl optionally substituted by substituent group C,
carbocyclic group optionally substituted by substituent group C,
carbocycle lower alkyl optionally substituted by substituent group
C, carbocyclecarbonyl optionally substituted by substituent group
C, carbocycleoxy optionally substituted by substituent group C,
carbocycleoxycarbonyl optionally substituted by substituent group
C, heterocyclic group optionally substituted by substituent group
C, heterocycle lower alkyl optionally substituted by substituent
group C, heterocyclecarbonyl optionally substituted by substituent
group C, heterocycleoxy optionally substituted by substituent group
C, heterocycleoxycarbonyl optionally substituted by substituent
group C,
--Z--N(R.sup.A1)(R.sup.A2), --Z--N(R.sup.A3)--SO.sub.2--(R.sup.A4),
--Z--C(.dbd.O)--N(R.sup.A5)--SO.sub.2--(R.sup.A6),
--Z--N(R.sup.A7)--C(.dbd.O)--R.sup.A8,
--Z--S--R.sup.A9,
[0561] --Z--SO.sub.2--R.sup.A10,
--Z--S(.dbd.O)--R.sup.A11,
[0562] --Z--N(R.sup.A12)--C(.dbd.O)--O--R.sup.A13,
--Z--N(R.sup.A14)--C(.dbd.O)--N(R.sup.A15)(R.sup.A16),
--Z--C(.dbd.O)--N(R.sup.A17)--C(.dbd.O)--N(R.sup.A18)(R.sup.A19),
or --Z--N(R.sup.A20)--C(.dbd.O)--C(.dbd.O)--R.sup.A21 (substituent
group C, R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A5, R.sup.A7,
R.sup.A8, R.sup.A9, R.sup.A12, R.sup.A13, R.sup.A14, R.sup.A15,
R.sup.A16, R.sup.A7, R.sup.A18, R.sup.A19, R.sup.A20, and R.sup.A21
are same as those of item 1)
[0563] The characteristic of a more preferable compound in the
present invention is that cap-dependent endonuclease inhibitory
activity was improved, by applying a functional group as shown
below to R.sup.1a in the formula (I).
[0564] Functional group: hydrogen, halogen, hydroxy, carboxy, lower
alkyl optionally substituted by substituent group C, lower alkenyl
optionally substituted by substituent group C, lower alkyloxy
optionally substituted by substituent group C, lower alkylcarbonyl
optionally substituted by substituent group C, lower
alkyloxycarbonyl optionally substituted by substituent group C,
heterocyclic group optionally substituted by substituent group
C,
--Z--N(R.sup.A1)(R.sup.A2), --Z--N(R.sup.A7)--C(.dbd.O)--R.sup.A8,
or --Z--N(R.sup.A12)--C(.dbd.O)--O--R.sup.A13 (substituent group C,
R.sup.A1, R.sup.A2, R.sup.A7, R.sup.A8, R.sup.A12, R.sup.A13, and Z
are same as those of item 1).
[0565] The characteristic of a further preferable compound in the
present invention is that cap-dependent endonuclease inhibitory
activity was improved, by applying a functional group as shown
below to R.sup.1a in the formula (I).
[0566] Functional group: hydrogen, halogen, hydroxy, carboxy, lower
alkyl optionally substituted by substituent group C, lower alkenyl
optionally substituted by substituent group C, lower alkyloxy
optionally substituted by substituent group C, lower alkylcarbonyl
optionally substituted by substituent group C, lower
alkyloxycarbonyl optionally substituted by substituent group C,
heterocyclic group optionally substituted by substituent group C,
or
--Z--N(R.sup.A1)(R.sup.A2) (substituent group C, R.sup.A1,
R.sup.A2, and Z are same as those of item 1).
[0567] The characteristic of a particularly preferable compound in
the present invention is that cap-dependent endonuclease inhibitory
activity was improved, by applying a functional group as shown
below to R.sup.1a in the formula (I). Functional group: hydrogen,
acetyl, or carboxy
[0568] Another characteristic of the compound in the present
invention is that cap-dependent endonuclease inhibitory activity
was improved, by introducing one, two or more of lipid-soluble
functional groups shown below on carbon atom or on nitrogen atom of
B.sup.1 and/or B.sup.2 in the formula (I).
[0569] Lipid-soluble functional group: carbocyclic group optionally
substituted by substituent group C, carbocycle lower alkyl
optionally substituted by substituent group C, carbocycleoxy lower
alkyl optionally substituted by substituent group C,
carbocycleoxycarbonyl optionally substituted by substituent group
C, heterocyclic group optionally substituted by substituent group
C, heterocycle lower alkyl optionally substituted by substituent
group C, heterocycleoxy lower alkyl optionally substituted by
substituent group C, heterocycleoxycarbonyl optionally substituted
by substituent group C
(substituent group C is same as that of item 1).
[0570] Another characteristic of a more preferable compound in the
present invention is that cap-dependent endonuclease inhibitory
activity is improved, by introducing one lipid-soluble functional
group shown below on carbon atom or on nitrogen atom of B.sup.1 or
B.sup.2 in the formula (I).
[0571] Lipid-soluble functional group: carbocyclic group optionally
substituted by substituent group C, carbocycle lower alkyl
optionally substituted by substituent group C, carbocycleoxy lower
alkyl optionally substituted by substituent group C, heterocyclic
group optionally substituted by substituent group C, heterocycle
lower alkyl optionally substituted by substituent group C
(substituent group C is same as that of item 1).
[0572] Another characteristic of a particularly preferable compound
in the present invention is that cap-dependent endonuclease
inhibitory activity is improved, by introducing one lipid-soluble
functional group shown below on carbon atom or on nitrogen atom of
B.sup.1 or B.sup.2 in the formula (I).
[0573] Lipid-soluble functional group: carbocyclic group optionally
substituted by substituent group C, heterocyclic group optionally
substituted by substituent group C
(substituent group C is same as that of item 1).
[0574] Other characteristic of a preferable compound in the present
invention is that the compound is efficiently absorbed into the
body after in vivo administration (for example, oral
administration) and shows high drug efficacy by introducing a group
to form a prodrug into a P.sup.R part in the formula (I).
[0575] Other characteristic of a more preferable compound in the
present invention is that the compound is efficiently absorbed into
the body after administration and shows high drug efficacy by
introducing a group selected from the following formulae a) to v)
into a P.sup.R part in the formula (I).
a) --C(.dbd.O)--P.sup.R0,
b) --C(.dbd.O)--P.sup.R1,
c) --C(.dbd.O)-L-O--P.sup.R1,
d) --C(.dbd.O)-L-O-L-O--P.sup.R1,
e) --C(.dbd.O)-L-O--C(.dbd.O)--P.sup.R1,
f) --C(.dbd.O)--O--P.sup.R2,
[0576] g) --C(.dbd.O)--N(P.sup.R2).sub.2,
h) --C(.dbd.O)--O-L-O--P.sup.R2,
[0577] i) --CH.sub.2--O--P.sup.R3, j) --CH.sub.2--O-L-O--P.sup.R3,
k) --CH.sub.2--O--C(.dbd.O)--P.sup.R3, l)
--CH.sub.2--O--C(.dbd.O)--O--P.sup.R3, m)
--CH(--CH.sub.3)--O--C(.dbd.O)--O--P.sup.R3, n)
--CH.sub.2--O--C(.dbd.O)--N(--K)--P.sup.R3, o)
--CH.sub.2--O--C(.dbd.O)--O-L-O--P.sup.R3, p)
--CH.sub.2--O--C(.dbd.O)--O-L-N(P.sup.R3).sub.2, q)
--CH.sub.2--O--C(.dbd.O)--N(--K)-L-O--P.sup.R3, r)
--CH.sub.2--O--C(.dbd.O)--N(--K)-L-N(P.sup.R3).sub.2, s)
--CH.sub.2--O--C(.dbd.O)--O-L-O-L-O--P.sup.R3, t)
--CH.sub.2--O--P(.dbd.O)(--OH).sub.2, u)
--CH.sub.2--O--P(.dbd.O)(--OBn).sub.2, v) --CH.sub.2--P.sup.R4
(wherein L is straight or branched lower alkylene,
[0578] K is hydrogen, or straight or branched lower alkylene,
[0579] P.sup.R0 is lower alkyl optionally substituted by
substituent group F,
[0580] P.sup.R1 is carbocyclic group optionally substituted by
substituent group F, heterocyclic group optionally substituted by
substituent group F, lower alkyl amino optionally substituted by
substituent group F, or lower alkylthio optionally substituted by
substituent group F,
[0581] P.sup.R2 is lower alkyl optionally substituted by
substituent group F, carbocyclic group optionally substituted by
substituent group F, or heterocyclic group optionally substituted
by substituent group F,
[0582] P.sup.R3 is lower alkyl optionally substituted by
substituent group F, carbocyclic group optionally substituted by
substituent group F, heterocyclic group optionally substituted by
substituent group F, lower alkyl amino optionally substituted by
substituent group F, carbocycle lower alkyl optionally substituted
by substituent group F, heterocycle lower alkyl optionally
substituted by substituent group F, or lower alkylsilyl,
[0583] P.sup.R4 is carbocyclic group optionally substituted by
substituent group F, or heterocyclic group optionally substituted
by substituent group F.
[0584] Substituent group F; oxo, lower alkyl, hydroxyl lower alkyl,
amino, lower alkylamino, carbocycle lower alkyl, lower
alkylcarbonyl, halogen, hydroxy, carboxy, lower alkylcarbonylamino,
lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkyloxy,
cyano, and nitro)
[0585] Other characteristic of a more preferable compound in the
present invention is that the compound is efficiently absorbed into
the body after administration and shows high drug efficacy by
introducing groups of P-1 to P-77 in Tables 1 to 8 into a P.sup.R
part in the formula (I).
[0586] A preferable embodiment of the present invention will be
exemplified below. In the formula (III), the formula (III'), the
formula (III''), the formula (III'''), the formula (III''''), the
formula (III'''''):
##STR00150##
[0587] 1)
[0588] a compound in which R.sup.1a is hydrogen (hereinafter,
R.sup.1a is R1-1),
[0589] a compound in which R.sup.1a is carboxy (hereinafter,
R.sup.1a is R1-2),
[0590] a compound in which R.sup.1a is halogen (hereinafter
R.sup.1a is R1-3),
[0591] a compound in which R.sup.1a is hydroxy (hereinafter,
R.sup.1a is R1-4),
[0592] a compound in which R.sup.1a is lower alkyl optionally
substituted by substituent group C (hereinafter, R.sup.1a is
R1-5),
[0593] a compound in which R.sup.1a is lower alkylcarbonyl
optionally substituted by substituent group C (hereinafter,
R.sup.1a is R1-6),
[0594] a compound in which R.sup.1a is lower alkyloxycarbonyl
optionally substituted by substituent group C (hereinafter,
R.sup.1a is R1-7),
[0595] a compound in which R.sup.1a is amino (hereinafter, R.sup.1a
is R1-8),
[0596] 2)
[0597] a compound in which R.sup.2a is hydrogen (hereinafter,
R.sup.2a is R2-1),
[0598] a compound in which R.sup.2a is lower alkyl optionally
substituted by substituent group C (hereinafter, R.sup.2a is
R2-2),
[0599] 3)
[0600] a compound in which R.sup.3a is lower alkyl optionally
substituted by substituent group C (hereinafter, R.sup.3a is
R3-1),
[0601] a compound in which R.sup.3a is carbocycle lower alkyl
optionally substituted by substituent group C (hereinafter,
R.sup.3a is R3-2),
[0602] a compound in which R.sup.3a is heterocycle lower alkyl
optionally substituted by substituent group C (hereinafter,
R.sup.3a is R3-3),
[0603] a compound in which R.sup.3a is carbocyclic group optionally
substituted by substituent group C (hereinafter, R.sup.3a is
R3-4),
[0604] a compound in which R.sup.3a is heterocyclic group
optionally substituted by substituent group C (hereinafter,
R.sup.3a is R3-5),
[0605] 4)
[0606] a compound in which P.sup.R is --C(.dbd.O)--P.sup.R1
(hereinafter, P.sup.R is Pr-1),
[0607] a compound in which P.sup.R is
--CH.sub.2--O--C(.dbd.O)--P.sup.R3 (hereinafter, P.sup.R is
Pr-2),
[0608] a compound in which P.sup.R is
--CH.sub.2--O--C(.dbd.O)--O--P.sup.R3 (hereinafter, P.sup.R is
Pr-3),
[0609] a compound in which P.sup.R is
--CH(--CH.sub.3)--O--C(.dbd.O)--O--P.sup.R3 (hereinafter, P.sup.R
is Pr-4),
[0610] (wherein each symbol is same as above)
[0611] in the formula (III'),
[0612] a compound in which R.sup.7a is carbocyclic group optionally
substituted by substituent group C, and R.sup.5a and R.sup.6a are
hydrogen (hereinafter, R7-1),
[0613] a compound in which R.sup.7a is heterocyclic group
optionally substituted by substituent group C, and R.sup.5a and
R.sup.6a are hydrogen (hereinafter, R7-2),
[0614] a compound in which R.sup.7a is carbocycle lower alkyl
optionally substituted by substituent group C, and R.sup.5a and
R.sup.6a are hydrogen (hereinafter, R7-3),
[0615] in the formula (III),
[0616] a compound in which R.sup.9a is carbocyclic group optionally
substituted by substituent group C, and R.sup.8a, R.sup.10a and
R.sup.11a are hydrogen (hereinafter, R9-1),
[0617] a compound in which R.sup.9a is heterocyclic group
optionally substituted by substituent group C, and R.sup.8a,
R.sup.10a and R.sup.11a are hydrogen (hereinafter, R9-2),
[0618] a compound in which R.sup.9a is carbocycle lower alkyl
optionally substituted by substituent group C, and R.sup.8a,
R.sup.10a, and R.sup.11a are hydrogen (hereinafter, R9-3)
[0619] Herein, the substituent group C is at least one selected
from a substituent group consisting of halogen, cyano, hydroxy,
carboxy, formyl, amino, oxo, nitro, lower alkyl, halogeno lower
alkyl, lower alkyloxy, carbocyclic group, heterocyclic group,
carbocycle lower alkyloxy, heterocycle lower alkyloxy, halogeno
lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower
alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower
alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl,
lower alkylsulfonyl, and lower alkylsulfonylamino.
[0620] Compounds in which, in the formula (III'), a combination of
R.sup.1a, R.sup.2a, R.sup.3a, P.sup.R, as well as (R.sup.5a,
R.sup.6a, and R.sup.7a) is as follows.
(R1-1, R2-1, R3-1, Pr-1, R7-1), (R1-1, R2-1, R3-1, Pr-1, R7-2),
(R1-1, R2-1, R3-1, Pr-1, R7-3), (R1-1, R2-1, R3-1, Pr-2, R7-1),
(R1-1, R2-1, R3-1, Pr-2, R7-2), (R1-1, R2-1, R3-1, Pr-2, R7-3),
(R1-1, R2-1, R3-1, Pr-3, R7-1), (R1-1, R2-1, R3-1, Pr-3, R7-2),
(R1-1, R2-1, R3-1, Pr-3, R7-3), (R1-1, R2-1, R3-1, Pr-4, R7-1),
(R1-1, R2-1, R3-1, Pr-4, R7-2), (R1-1, R2-1, R3-1, Pr-4, R7-3),
(R1-1, R2-1, R3-2, Pr-1, R7-1), (R1-1, R2-1, R3-2, Pr-1, R7-2),
(R1-1, R2-1, R3-2, Pr-1, R7-3), (R1-1, R2-1, R3-2, Pr-2, R7-1),
(R1-1, R2-1, R3-2, Pr-2, R7-2), (R1-1, R2-1, R3-2, Pr-2, R7-3),
(R1-1, R2-1, R3-2, Pr-3, R7-1), (R1-1, R2-1, R3-2, Pr-3, R7-2),
(R1-1, R2-1, R3-2, Pr-3, R7-3), (R1-1, R2-1, R3-2, Pr-4, R7-1),
(R1-1, R2-1, R3-2, Pr-4, R7-2), (R1-1, R2-1, R3-2, Pr-4, R7-3),
(R1-1, R2-1, R3-3, Pr-1, R7-1), (R1-1, R2-1, R3-3, Pr-1, R7-2),
(R1-1, R2-1, R3-3, Pr-1, R7-3), (R1-1, R2-1, R3-3, Pr-2, R7-1),
(R1-1, R2-1, R3-3, Pr-2, R7-2), (R1-1, R2-1, R3-3, Pr-2, R7-3),
(R1-1, R2-1, R3-3, Pr-3, R7-1), (R1-1, R2-1, R3-3, Pr-3, R7-2),
(R1-1, R2-1, R3-3, Pr-3, R7-3), (R1-1, R2-1, R3-3, Pr-4, R7-1),
(R1-1, R2-1, R3-3, Pr-4, R7-2), (R1-1, R2-1, R3-3, Pr-4, R7-3),
(R1-1, R2-1, R3-4, Pr-1, R7-1), (R1-1, R2-1, R3-4, Pr-1, R7-2),
(R1-1, R2-1, R3-4, Pr-1, R7-3), (R1-1, R2-1, R3-4, Pr-2, R7-1),
(R1-1, R2-1, R3-4, Pr-2, R7-2), (R1-1, R2-1, R3-4, Pr-2, R7-3),
(R1-1, R2-1, R3-4, Pr-3, R7-1), (R1-1, R2-1, R3-4, Pr-3, R7-2),
(R1-1, R2-1, R3-4, Pr-3, R7-3), (R1-1, R2-1, R3-4, Pr-4, R7-1),
(R1-1, R2-1, R3-4, Pr-4, R7-2), (R1-1, R2-1, R3-4, Pr-4, R7-3),
(R1-1, R2-1, R3-5, Pr-1, R7-1), (R1-1, R2-1, R3-5, Pr-1, R7-2),
(R1-1, R2-1, R3-5, Pr-1, R7-3), (R1-1, R2-1, R3-5, Pr-2, R7-1),
(R1-1, R2-1, R3-5, Pr-2, R7-2), (R1-1, R2-1, R3-5, Pr-2, R7-3),
(R1-1, R2-1, R3-5, Pr-3, R7-1), (R1-1, R2-1, R3-5, Pr-3, R7-2),
(R1-1, R2-1, R3-5, Pr-3, R7-3), (R1-1, R2-1, R3-5, Pr-4, R7-1),
(R1-1, R2-1, R3-5, Pr-4, R7-2), (R1-1, R2-1, R3-5, Pr-4, R7-3),
(R1-1, R2-2, R3-1, Pr-1, R7-1), (R1-1, R2-2, R3-1, Pr-1, R7-2),
(R1-1, R2-2, R3-1, Pr-1, R7-3), (R1-1, R2-2, R3-1, Pr-2, R7-1),
(R1-1, R2-2, R3-1, Pr-2, R7-2), (R1-1, R2-2, R3-1, Pr-2, R7-3),
(R1-1, R2-2, R3-1, Pr-3, R7-1), (R1-1, R2-2, R3-1, Pr-3, R7-2),
(R1-1, R2-2, R3-1, Pr-3, R7-3), (R1-1, R2-2, R3-1, Pr-4, R7-1),
(R1-1, R2-2, R3-1, Pr-4, R7-2), (R1-1, R2-2, R3-1, Pr-4, R7-3),
(R1-1, R2-2, R3-2, Pr-1, R7-1), (R1-1, R2-2, R3-2, Pr-1, R7-2),
(R1-1, R2-2, R3-2, Pr-1, R7-3), (R1-1, R2-2, R3-2, Pr-2, R7-1),
(R1-1, R2-2, R3-2, Pr-2, R7-2), (R1-1, R2-2, R3-2, Pr-2, R7-3),
(R1-1, R2-2, R3-2, Pr-3, R7-1), (R1-1, R2-2, R3-2, Pr-3, R7-2),
(R1-1, R2-2, R3-2, Pr-3, R7-3), (R1-1, R2-2, R3-2, Pr-4, R7-1),
(R1-1, R2-2, R3-2, Pr-4, R7-2), (R1-1, R2-2, R3-2, Pr-4, R7-3),
(R1-1, R2-2, R3-3, Pr-1, R7-1), (R1-1, R2-2, R3-3, Pr-1, R7-2),
(R1-1, R2-2, R3-3, Pr-1, R7-3), (R1-1, R2-2, R3-3, Pr-2, R7-1),
(R1-1, R2-2, R3-3, Pr-2, R7-2), (R1-1, R2-2, R3-3, Pr-2, R7-3),
(R1-1, R2-2, R3-3, Pr-3, R7-1), (R1-1, R2-2, R3-3, Pr-3, R7-2),
(R1-1, R2-2, R3-3, Pr-3, R7-3), (R1-1, R2-2, R3-3, Pr-4, R7-1),
(R1-1, R2-2, R3-3, Pr-4, R7-2), (R1-1, R2-2, R3-3, Pr-4, R7-3),
(R1-1, R2-2, R3-4, Pr-1, R7-1), (R1-1, R2-2, R3-4, Pr-1, R7-2),
(R1-1, R2-2, R3-4, Pr-1, R7-3), (R1-1, R2-2, R3-4, Pr-2, R7-1),
(R1-1, R2-2, R3-4, Pr-2, R7-2), (R1-1, R2-2, R3-4, Pr-2, R7-3),
(R1-1, R2-2, R3-4, Pr-3, R7-1), (R1-1, R2-2, R3-4, Pr-3, R7-2),
(R1-1, R2-2, R3-4, Pr-3, R7-3), (R1-1, R2-2, R3-4, Pr-4, R7-1),
(R1-1, R2-2, R3-4, Pr-4, R7-2), (R1-1, R2-2, R3-4, Pr-4, R7-3),
(R1-1, R2-2, R3-5, Pr-1, R7-1), (R1-1, R2-2, R3-5, Pr-1, R7-2),
(R1-1, R2-2, R3-5, Pr-1, R7-3), (R1-1, R2-2, R3-5, Pr-2, R7-1),
(R1-1, R2-2, R3-5, Pr-2, R7-2), (R1-1, R2-2, R3-5, Pr-2, R7-3),
(R1-1, R2-2, R3-5, Pr-3, R7-1), (R1-1, R2-2, R3-5, Pr-3, R7-2),
(R1-1, R2-2, R3-5, Pr-3, R7-3), (R1-1, R2-2, R3-5, Pr-4, R7-1),
(R1-1, R2-2, R3-5, Pr-4, R7-2), (R1-1, R2-2, R3-5, Pr-4, R7-3),
[0621] (R1-2, R2-1, R3-1, Pr-1, R7-1), (R1-2, R2-1, R3-1, Pr-1,
R7-2), (R1-2, R2-1, R3-1, Pr-1, R7-3), (R1-2, R2-1, R3-1, Pr-2,
R7-1), (R1-2, R2-1, R3-1, Pr-2, R7-2), (R1-2, R2-1, R3-1, Pr-2,
R7-3), (R1-2, R2-1, R3-1, Pr-3, R7-1), (R1-2, R2-1, R3-1, Pr-3, R7-
2), (R1-2, R2-1, R3-1, Pr-3, R7-3), (R1-2, R2-1, R3-1, Pr-4, R7-1),
(R1-2, R2-1, R3-1, Pr-4, R7-2), (R1-2, R2-1, R3-1, Pr-4, R7-3),
(R1-2, R2-1, R3-2, Pr-1, R7-1), (R1-2, R2-1, R3-2, Pr-1, R7-2),
(R1-2, R2-1, R3-2, Pr-1, R7-3), (R1-2, R2-1, R3-2, Pr-2, R7-1),
(R1-2, R2-1, R3-2, Pr-2, R7-2), (R1-2, R2-1, R3-2, Pr-2, R7-3),
(R1-2, R2-1, R3-2, Pr-3, R7-1), (R1-2, R2-1, R3-2, Pr-3, R7-2),
(R1-2, R2-1, R3-2, Pr-3, R7-3), (R1-2, R2-1, R3-2, Pr-4, R7-1),
(R1-2, R2-1, R3-2, Pr-4, R7-2), (R1-2, R2-1, R3-2, Pr-4, R7-3),
(R1-2, R2-1, R3-3, Pr-1, R7-1), (R1-2, R2-1, R3-3, Pr-1, R7-2),
(R1-2, R2-1, R3-3, Pr-1, R7-3), (R1-2, R2-1, R3-3, Pr-2, R7-1),
(R1-2, R2-1, R3-3, Pr-2, R7-2), (R1-2, R2-1, R3-3, Pr-2, R7-3),
(R1-2, R2-1, R3-3, Pr-3, R7-1), (R1-2, R2-1, R3-3, Pr-3, R7-2),
(R1-2, R2-1, R3-3, Pr-3, R7-3), (R1-2, R2-1, R3-3, Pr-4, R7-1),
(R1-2, R2-1, R3-3, Pr-4, R7-2), (R1-2, R2-1, R3-3, Pr-4, R7-3),
(R1-2, R2-1, R3-4, Pr-1, R7-1), (R1-2, R2-1, R3-4, Pr-1, R7-2),
(R1-2, R2-1, R3-4, Pr-1, R7-3), (R1-2, R2-1, R3-4, Pr-2, R7-1),
(R1-2, R2-1, R3-4, Pr-2, R7-2), (R1-2, R2-1, R3-4, Pr-2, R7-3),
(R1-2, R2-1, R3-4, Pr-3, R7-1), (R1-2, R2-1, R3-4, Pr-3, R7-2),
(R1-2, R2-1, R3-4, Pr-3, R7-3), (R1-2, R2-1, R3-4, Pr-4, R7-1),
(R1-2, R2-1, R3-4, Pr-4, R7-2), (R1-2, R2-1, R3-4, Pr-4, R7-3),
(R1-2, R2-1, R3-5, Pr-1, R7-1), (R1-2, R2-1, R3-5, Pr-1, R7-2),
(R1-2, R2-1, R3-5, Pr-1, R7-3), (R1-2, R2-1, R3-5, Pr-2, R7-1),
(R1-2, R2-1, R3-5, Pr-2, R7-2), (R1-2, R2-1, R3-5, Pr-2, R7-3),
(R1-2, R2-1, R3-5, Pr-3, R7-1), (R1-2, R2-1, R3-5, Pr-3, R7-2),
(R1-2, R2-1, R3-5, Pr-3, R7-3), (R1-2, R2-1, R3-5, Pr-4, R7-1),
(R1-2, R2-1, R3-5, Pr-4, R7-2), (R1-2, R2-1, R3-5, Pr-4, R7-3),
(R1-2, R2-2, R3-1, Pr-1, R7-1), (R1-2, R2-2, R3-1, Pr-1, R7-2),
(R1-2, R2-2, R3-1, Pr-1, R7-3), (R1-2, R2-2, R3-1, Pr-2, R7-1),
(R1-2, R2-2, R3-1, Pr-2, R7-2), (R1-2, R2-2, R3-1, Pr-2, R7-3),
(R1-2, R2-2, R3-1, Pr-3, R7-1), (R1-2, R2-2, R3-1, Pr-3, R7-2),
(R1-2, R2-2, R3-1, Pr-3, R7-3), (R1-2, R2-2, R3-1, Pr-4, R7-1),
(R1-2, R2-2, R3-1, Pr-4, R7-2), (R1-2, R2-2, R3-1, Pr-4, R7-3),
(R1-2, R2-2, R3-2, Pr-1, R7-1), (R1-2, R2-2, R3-2, Pr-1, R7-2),
(R1-2, R2-2, R3-2, Pr-1, R7-3), (R1-2, R2-2, R3-2, Pr-2, R7-1),
(R1-2, R2-2, R3-2, Pr-2, R7-2), (R1-2, R2-2, R3-2, Pr-2, R7-3),
(R1-2, R2-2, R3-2, Pr-3, R7-1), (R1-2, R2-2, R3-2, Pr-3, R7-2),
(R1-2, R2-2, R3-2, Pr-3, R7-3), (R1-2, R2-2, R3-2, Pr-4, R7-1),
(R1-2, R2-2, R3-2, Pr-4, R7-2), (R1-2, R2-2, R3-2, Pr-4, R7-3),
(R1-2, R2-2, R3-3, Pr-1, R7-1), (R1-2, R2-2, R3-3, Pr-1, R7-2),
(R1-2, R2-2, R3-3, Pr-1, R7-3), (R1-2, R2-2, R3-3, Pr-2, R7-1),
(R1-2, R2-2, R3-3, Pr-2, R7-2), (R1-2, R2-2, R3-3, Pr-2, R7-3),
(R1-2, R2-2, R3-3, Pr-3, R7-1), (R1-2, R2-2, R3-3, Pr-3, R7-2),
(R1-2, R2-2, R3-3, Pr-3, R7-3), (R1-2, R2-2, R3-3, Pr-4, R7-1),
(R1-2, R2-2, R3-3, Pr-4, R7-2), (R1-2, R2-2, R3-3, Pr-4, R7-3),
(R1-2, R2-2, R3-4, Pr-1, R7-1), (R1-2, R2-2, R3-4, Pr-1, R7-2),
(R1-2, R2-2, R3-4, Pr-1, R7-3), (R1-2, R2-2, R3-4, Pr-2, R7-1),
(R1-2, R2-2, R3-4, Pr-2, R7-2), (R1-2, R2-2, R3-4, Pr-2, R7-3),
(R1-2, R2-2, R3-4, Pr-3, R7-1), (R1-2, R2-2, R3-4, Pr-3, R7-2),
(R1-2, R2-2, R3-4, Pr-3, R7-3), (R1-2, R2-2, R3-4, Pr-4, R7-1),
(R1-2, R2-2, R3-4, Pr-4, R7-2), (R1-2, R2-2, R3-4, Pr-4, R7-3),
(R1-2, R2-2, R3-5, Pr-1, R7-1), (R1-2, R2-2, R3-5, Pr-1, R7-2),
(R1-2, R2-2, R3-5, Pr-1, R7-3), (R1-2, R2-2, R3-5, Pr-2, R7-1),
(R1-2, R2-2, R3-5, Pr-2, R7-2), (R1-2, R2-2, R3-5, Pr-2, R7-3),
(R1-2, R2-2, R3-5, Pr-3, R7-1), (R1-2, R2-2, R3-5, Pr-3, R7-2),
(R1-2, R2-2, R3-5, Pr-3, R7-3), (R1-2, R2-2, R3-5, Pr-4, R7-1),
(R1-2, R2-2, R3-5, Pr-4, R7-2), (R1-2, R2-2, R3-5, Pr-4, R7-3),
[0622] (R1-3, R2-1, R3-1, Pr-1, R7-1), (R1-3, R2-1, R3-1, Pr-1,
R7-2), (R1-3, R2-1, R3-1, Pr-1, R7-3), (R1-3, R2-1, R3-1, Pr-2,
R7-1), (R1-3, R2-1, R3-1, Pr-2, R7-2), (R1-3, R2-1, R3-1, Pr-2,
R7-3), (R1-3, R2-1, R3-1, Pr-3, R7-1), (R1-3, R2-1, R3-1, Pr-3, R7-
2), (R1-3, R2-1, R3-1, Pr-3, R7-3), (R1-3, R2-1, R3-1, Pr-4, R7-1),
(R1-3, R2-1, R3-1, Pr-4, R7-2), (R1-3, R2-1, R3-1, Pr-4, R7-3),
(R1-3, R2-1, R3-2, Pr-1, R7-1), (R1-3, R2-1, R3-2, Pr-1, R7-2),
(R1-3, R2-1, R3-2, Pr-1, R7-3), (R1-3, R2-1, R3-2, Pr-2, R7-1),
(R1-3, R2-1, R3-2, Pr-2, R7-2), (R1-3, R2-1, R3-2, Pr-2, R7-3),
(R1-3, R2-1, R3-2, Pr-3, R7-1), (R1-3, R2-1, R3-2, Pr-3, R7-2),
(R1-3, R2-1, R3-2, Pr-3, R7-3), (R1-3, R2-1, R3-2, Pr-4, R7-1),
(R1-3, R2-1, R3-2, Pr-4, R7-2), (R1-3, R2-1, R3-2, Pr-4, R7-3),
(R1-3, R2-1, R3-3, Pr-1, R7-1), (R1-3, R2-1, R3-3, Pr-1, R7-2),
(R1-3, R2-1, R3-3, Pr-1, R7-3), (R1-3, R2-1, R3-3, Pr-2, R7-1),
(R1-3, R2-1, R3-3, Pr-2, R7-2), (R1-3, R2-1, R3-3, Pr-2, R7-3),
(R1-3, R2-1, R3-3, Pr-3, R7-1), (R1-3, R2-1, R3-3, Pr-3, R7-2),
(R1-3, R2-1, R3-3, Pr-3, R7-3), (R1-3, R2-1, R3-3, Pr-4, R7-1),
(R1-3, R2-1, R3-3, Pr-4, R7-2), (R1-3, R2-1, R3-3, Pr-4, R7-3),
(R1-3, R2-1, R3-4, Pr-1, R7-1), (R1-3, R2-1, R3-4, Pr-1, R7-2),
(R1-3, R2-1, R3-4, Pr-1, R7-3), (R1-3, R2-1, R3-4, Pr-2, R7-1),
(R1-3, R2-1, R3-4, Pr-2, R7-2), (R1-3, R2-1, R3-4, Pr-2, R7-3),
(R1-3, R2-1, R3-4, Pr-3, R7-1), (R1-3, R2-1, R3-4, Pr-3, R7-2),
(R1-3, R2-1, R3-4, Pr-3, R7-3), (R1-3, R2-1, R3-4, Pr-4, R7-1),
(R1-3, R2-1, R3-4, Pr-4, R7-2), (R1-3, R2-1, R3-4, Pr-4, R7-3),
(R1-3, R2-1, R3-5, Pr-1, R7-1), (R1-3, R2-1, R3-5, Pr-1, R7-2),
(R1-3, R2-1, R3-5, Pr-1, R7-3), (R1-3, R2-1, R3-5, Pr-2, R7-1),
(R1-3, R2-1, R3-5, Pr-2, R7-2), (R1-3, R2-1, R3-5, Pr-2, R7-3),
(R1-3, R2-1, R3-5, Pr-3, R7-1), (R1-3, R2-1, R3-5, Pr-3, R7-2),
(R1-3, R2-1, R3-5, Pr-3, R7-3), (R1-3, R2-1, R3-5, Pr-4, R7-1),
(R1-3, R2-1, R3-5, Pr-4, R7-2), (R1-3, R2-1, R3-5, Pr-4, R7-3),
(R1-3, R2-2, R3-1, Pr-1, R7-1), (R1-3, R2-2, R3-1, Pr-1, R7-2),
(R1-3, R2-2, R3-1, Pr-1, R7-3), (R1-3, R2-2, R3-1, Pr-2, R7-1),
(R1-3, R2-2, R3-1, Pr-2, R7-2), (R1-3, R2-2, R3-1, Pr-2, R7-3),
(R1-3, R2-2, R3-1, Pr-3, R7-1), (R1-3, R2-2, R3-1, Pr-3, R7-2),
(R1-3, R2-2, R3-1, Pr-3, R7-3), (R1-3, R2-2, R3-1, Pr-4, R7-1),
(R1-3, R2-2, R3-1, Pr-4, R7-2), (R1-3, R2-2, R3-1, Pr-4, R7-3),
(R1-3, R2-2, R3-2, Pr-1, R7-1), (R1-3, R2-2, R3-2, Pr-1, R7-2),
(R1-3, R2-2, R3-2, Pr-1, R7-3), (R1-3, R2-2, R3-2, Pr-2, R7-1),
(R1-3, R2-2, R3-2, Pr-2, R7-2), (R1-3, R2-2, R3-2, Pr-2, R7-3),
(R1-3, R2-2, R3-2, Pr-3, R7-1), (R1-3, R2-2, R3-2, Pr-3, R7-2),
(R1-3, R2-2, R3-2, Pr-3, R7-3), (R1-3, R2-2, R3-2, Pr-4, R7-1),
(R1-3, R2-2, R3-2, Pr-4, R7-2), (R1-3, R2-2, R3-2, Pr-4, R7-3),
(R1-3, R2-2, R3-3, Pr-1, R7-1), (R1-3, R2-2, R3-3, Pr-1, R7-2),
(R1-3, R2-2, R3-3, Pr-1, R7-3), (R1-3, R2-2, R3-3, Pr-2, R7-1),
(R1-3, R2-2, R3-3, Pr-2, R7-2), (R1-3, R2-2, R3-3, Pr-2, R7-3),
(R1-3, R2-2, R3-3, Pr-3, R7-1), (R1-3, R2-2, R3-3, Pr-3, R7-2),
(R1-3, R2-2, R3-3, Pr-3, R7-3), (R1-3, R2-2, R3-3, Pr-4, R7-1),
(R1-3, R2-2, R3-3, Pr-4, R7-2), (R1-3, R2-2, R3-3, Pr-4, R7-3),
(R1-3, R2-2, R3-4, Pr-1, R7-1), (R1-3, R2-2, R3-4, Pr-1, R7-2),
(R1-3, R2-2, R3-4, Pr-1, R7-3), (R1-3, R2-2, R3-4, Pr-2, R7-1),
(R1-3, R2-2, R3-4, Pr-2, R7-2), (R1-3, R2-2, R3-4, Pr-2, R7-3),
(R1-3, R2-2, R3-4, Pr-3, R7-1), (R1-3, R2-2, R3-4, Pr-3, R7-2),
(R1-3, R2-2, R3-4, Pr-3, R7-3), (R1-3, R2-2, R3-4, Pr-4, R7-1),
(R1-3, R2-2, R3-4, Pr-4, R7-2), (R1-3, R2-2, R3-4, Pr-4, R7-3),
(R1-3, R2-2, R3-5, Pr-1, R7-1), (R1-3, R2-2, R3-5, Pr-1, R7-2),
(R1-3, R2-2, R3-5, Pr-1, R7-3), (R1-3, R2-2, R3-5, Pr-2, R7-1),
(R1-3, R2-2, R3-5, Pr-2, R7-2), (R1-3, R2-2, R3-5, Pr-2, R7-3),
(R1-3, R2-2, R3-5, Pr-3, R7-1), (R1-3, R2-2, R3-5, Pr-3, R7-2),
(R1-3, R2-2, R3-5, Pr-3, R7-3), (R1-3, R2-2, R3-5, Pr-4, R7-1),
(R1-3, R2-2, R3-5, Pr-4, R7-2), (R1-3, R2-2, R3-5, Pr-4, R7-3),
[0623] (R1-4, R2-1, R3-1, Pr-1, R7-1), (R1-4, R2-1, R3-1, Pr-1,
R7-2), (R1-4, R2-1, R3-1, Pr-1, R7-3), (R1-4, R2-1, R3-1, Pr-2,
R7-1), (R1-4, R2-1, R3-1, Pr-2, R7-2), (R1-4, R2-1, R3-1, Pr-2,
R7-3), (R1-4, R2-1, R3-1, Pr-3, R7-1), (R1-4, R2-1, R3-1, Pr-3, R7-
2), (R1-4, R2-1, R3-1, Pr-3, R7-3), (R1-4, R2-1, R3-1, Pr-4, R7-1),
(R1-4, R2-1, R3-1, Pr-4, R7-2), (R1-4, R2-1, R3-1, Pr-4, R7-3),
(R1-4, R2-1, R3-2, Pr-1, R7-1), (R1-4, R2-1, R3-2, Pr-1, R7-2),
(R1-4, R2-1, R3-2, Pr-1, R7-3), (R1-4, R2-1, R3-2, Pr-2, R7-1),
(R1-4, R2-1, R3-2, Pr-2, R7-2), (R1-4, R2-1, R3-2, Pr-2, R7-3),
(R1-4, R2-1, R3-2, Pr-3, R7-1), (R1-4, R2-1, R3-2, Pr-3, R7-2),
(R1-4, R2-1, R3-2, Pr-3, R7-3), (R1-4, R2-1, R3-2, Pr-4, R7-1),
(R1-4, R2-1, R3-2, Pr-4, R7-2), (R1-4, R2-1, R3-2, Pr-4, R7-3),
(R1-4, R2-1, R3-3, Pr-1, R7-1), (R1-4, R2-1, R3-3, Pr-1, R7-2),
(R1-4, R2-1, R3-3, Pr-1, R7-3), (R1-4, R2-1, R3-3, Pr-2, R7-1),
(R1-4, R2-1, R3-3, Pr-2, R7-2), (R1-4, R2-1, R3-3, Pr-2, R7-3),
(R1-4, R2-1, R3-3, Pr-3, R7-1), (R1-4, R2-1, R3-3, Pr-3, R7-2),
(R1-4, R2-1, R3-3, Pr-3, R7-3), (R1-4, R2-1, R3-3, Pr-4, R7-1),
(R1-4, R2-1, R3-3, Pr-4, R7-2), (R1-4, R2-1, R3-3, Pr-4, R7-3),
(R1-4, R2-1, R3-4, Pr-1, R7-1), (R1-4, R2-1, R3-4, Pr-1, R7-2),
(R1-4, R2-1, R3-4, Pr-1, R7-3), (R1-4, R2-1, R3-4, Pr-2, R7-1),
(R1-4, R2-1, R3-4, Pr-2, R7-2), (R1-4, R2-1, R3-4, Pr-2, R7-3),
(R1-4, R2-1, R3-4, Pr-3, R7-1), (R1-4, R2-1, R3-4, Pr-3, R7-2),
(R1-4, R2-1, R3-4, Pr-3, R7-3), (R1-4, R2-1, R3-4, Pr-4, R7-1),
(R1-4, R2-1, R3-4, Pr-4, R7-2), (R1-4, R2-1, R3-4, Pr-4, R7-3),
(R1-4, R2-1, R3-5, Pr-1, R7-1), (R1-4, R2-1, R3-5, Pr-1, R7-2),
(R1-4, R2-1, R3-5, Pr-1, R7-3), (R1-4, R2-1, R3-5, Pr-2, R7-1),
(R1-4, R2-1, R3-5, Pr-2, R7-2), (R1-4, R2-1, R3-5, Pr-2, R7-3),
(R1-4, R2-1, R3-5, Pr-3, R7-1), (R1-4, R2-1, R3-5, Pr-3, R7-2),
(R1-4, R2-1, R3-5, Pr-3, R7-3), (R1-4, R2-1, R3-5, Pr-4, R7-1),
(R1-4, R2-1, R3-5, Pr-4, R7-2), (R1-4, R2-1, R3-5, Pr-4, R7-3),
(R1-4, R2-2, R3-1, Pr-1, R7-1), (R1-4, R2-2, R3-1, Pr-1, R7-2),
(R1-4, R2-2, R3-1, Pr-1, R7-3), (R1-4, R2-2, R3-1, Pr-2, R7-1),
(R1-4, R2-2, R3-1, Pr-2, R7-2), (R1-4, R2-2, R3-1, Pr-2, R7-3),
(R1-4, R2-2, R3-1, Pr-3, R7-1), (R1-4, R2-2, R3-1, Pr-3, R7-2),
(R1-4, R2-2, R3-1, Pr-3, R7-3), (R1-4, R2-2, R3-1, Pr-4, R7-1),
(R1-4, R2-2, R3-1, Pr-4, R7-2), (R1-4, R2-2, R3-1, Pr-4, R7-3),
(R1-4, R2-2, R3-2, Pr-1, R7-1), (R1-4, R2-2, R3-2, Pr-1, R7-2),
(R1-4, R2-2, R3-2, Pr-1, R7-3), (R1-4, R2-2, R3-2, Pr-2, R7-1),
(R1-4, R2-2, R3-2, Pr-2, R7-2), (R1-4, R2-2, R3-2, Pr-2, R7-3),
(R1-4, R2-2, R3-2, Pr-3, R7-1), (R1-4, R2-2, R3-2, Pr-3, R7-2),
(R1-4, R2-2, R3-2, Pr-3, R7-3), (R1-4, R2-2, R3-2, Pr-4, R7-1),
(R1-4, R2-2, R3-2, Pr-4, R7-2), (R1-4, R2-2, R3-2, Pr-4, R7-3),
(R1-4, R2-2, R3-3, Pr-1, R7-1), (R1-4, R2-2, R3-3, Pr-1, R7-2),
(R1-4, R2-2, R3-3, Pr-1, R7-3), (R1-4, R2-2, R3-3, Pr-2, R7-1),
(R1-4, R2-2, R3-3, Pr-2, R7-2), (R1-4, R2-2, R3-3, Pr-2, R7-3),
(R1-4, R2-2, R3-3, Pr-3, R7-1), (R1-4, R2-2, R3-3, Pr-3, R7-2),
(R1-4, R2-2, R3-3, Pr-3, R7-3), (R1-4, R2-2, R3-3, Pr-4, R7-1),
(R1-4, R2-2, R3-3, Pr-4, R7-2), (R1-4, R2-2, R3-3, Pr-4, R7-3),
(R1-4, R2-2, R3-4, Pr-1, R7-1), (R1-4, R2-2, R3-4, Pr-1, R7-2),
(R1-4, R2-2, R3-4, Pr-1, R7-3), (R1-4, R2-2, R3-4, Pr-2, R7-1),
(R1-4, R2-2, R3-4, Pr-2, R7-2), (R1-4, R2-2, R3-4, Pr-2, R7-3),
(R1-4, R2-2, R3-4, Pr-3, R7-1), (R1-4, R2-2, R3-4, Pr-3, R7-2),
(R1-4, R2-2, R3-4, Pr-3, R7-3), (R1-4, R2-2, R3-4, Pr-4, R7-1),
(R1-4, R2-2, R3-4, Pr-4, R7-2), (R1-4, R2-2, R3-4, Pr-4, R7-3),
(R1-4, R2-2, R3-5, Pr-1, R7-1), (R1-4, R2-2, R3-5, Pr-1, R7-2),
(R1-4, R2-2, R3-5, Pr-1, R7-3), (R1-4, R2-2, R3-5, Pr-2, R7-1),
(R1-4, R2-2, R3-5, Pr-2, R7-2), (R1-4, R2-2, R3-5, Pr-2, R7-3),
(R1-4, R2-2, R3-5, Pr-3, R7-1), (R1-4, R2-2, R3-5, Pr-3, R7-2),
(R1-4, R2-2, R3-5, Pr-3, R7-3), (R1-4, R2-2, R3-5, Pr-4, R7-1),
(R1-4, R2-2, R3-5, Pr-4, R7-2), (R1-4, R2-2, R3-5, Pr-4, R7-3),
[0624] (R1-5, R2-1, R3-1, Pr-1, R7-1), (R1-5, R2-1, R3-1, Pr-1,
R7-2), (R1-5, R2-1, R3-1, Pr-1, R7-3), (R1-5, R2-1, R3-1, Pr-2,
R7-1), (R1-5, R2-1, R3-1, Pr-2, R7-2), (R1-5, R2-1, R3-1, Pr-2,
R7-3), (R1-5, R2-1, R3-1, Pr-3, R7-1), (R1-5, R2-1, R3-1, Pr-3, R7-
2), (R1-5, R2-1, R3-1, Pr-3, R7-3), (R1-5, R2-1, R3-1, Pr-4, R7-1),
(R1-5, R2-1, R3-1, Pr-4, R7-2), (R1-5, R2-1, R3-1, Pr-4, R7-3),
(R1-5, R2-1, R3-2, Pr-1, R7-1), (R1-5, R2-1, R3-2, Pr-1, R7-2),
(R1-5, R2-1, R3-2, Pr-1, R7-3), (R1-5, R2-1, R3-2, Pr-2, R7-1),
(R1-5, R2-1, R3-2, Pr-2, R7-2), (R1-5, R2-1, R3-2, Pr-2, R7-3),
(R1-5, R2-1, R3-2, Pr-3, R7-1), (R1-5, R2-1, R3-2, Pr-3, R7-2),
(R1-5, R2-1, R3-2, Pr-3, R7-3), (R1-5, R2-1, R3-2, Pr-4, R7-1),
(R1-5, R2-1, R3-2, Pr-4, R7-2), (R1-5, R2-1, R3-2, Pr-4, R7-3),
(R1-5, R2-1, R3-3, Pr-1, R7-1), (R1-5, R2-1, R3-3, Pr-1, R7-2),
(R1-5, R2-1, R3-3, Pr-1, R7-3), (R1-5, R2-1, R3-3, Pr-2, R7-1),
(R1-5, R2-1, R3-3, Pr-2, R7-2), (R1-5, R2-1, R3-3, Pr-2, R7-3),
(R1-5, R2-1, R3-3, Pr-3, R7-1), (R1-5, R2-1, R3-3, Pr-3, R7-2),
(R1-5, R2-1, R3-3, Pr-3, R7-3), (R1-5, R2-1, R3-3, Pr-4, R7-1),
(R1-5, R2-1, R3-3, Pr-4, R7-2), (R1-5, R2-1, R3-3, Pr-4, R7-3),
(R1-5, R2-1, R3-4, Pr-1, R7-1), (R1-5, R2-1, R3-4, Pr-1, R7-2),
(R1-5, R2-1, R3-4, Pr-1, R7-3), (R1-5, R2-1, R3-4, Pr-2, R7-1),
(R1-5, R2-1, R3-4, Pr-2, R7-2), (R1-5, R2-1, R3-4, Pr-2, R7-3),
(R1-5, R2-1, R3-4, Pr-3, R7-1), (R1-5, R2-1, R3-4, Pr-3, R7-2),
(R1-5, R2-1, R3-4, Pr-3, R7-3), (R1-5, R2-1, R3-4, Pr-4, R7-1),
(R1-5, R2-1, R3-4, Pr-4, R7-2), (R1-5, R2-1, R3-4, Pr-4, R7-3),
(R1-5, R2-1, R3-5, Pr-1, R7-1), (R1-5, R2-1, R3-5, Pr-1, R7-2),
(R1-5, R2-1, R3-5, Pr-1, R7-3), (R1-5, R2-1, R3-5, Pr-2, R7-1),
(R1-5, R2-1, R3-5, Pr-2, R7-2), (R1-5, R2-1, R3-5, Pr-2, R7-3),
(R1-5, R2-1, R3-5, Pr-3, R7-1), (R1-5, R2-1, R3-5, Pr-3, R7-2),
(R1-5, R2-1, R3-5, Pr-3, R7-3), (R1-5, R2-1, R3-5, Pr-4, R7-1),
(R1-5, R2-1, R3-5, Pr-4, R7-2), (R1-5, R2-1, R3-5, Pr-4, R7-3),
(R1-5, R2-2, R3-1, Pr-1, R7-1), (R1-5, R2-2, R3-1, Pr-1, R7-2),
(R1-5, R2-2, R3-1, Pr-1, R7-3), (R1-5, R2-2, R3-1, Pr-2, R7-1),
(R1-5, R2-2, R3-1, Pr-2, R7-2), (R1-5, R2-2, R3-1, Pr-2, R7-3),
(R1-5, R2-2, R3-1, Pr-3, R7-1), (R1-5, R2-2, R3-1, Pr-3, R7-2),
(R1-5, R2-2, R3-1, Pr-3, R7-3), (R1-5, R2-2, R3-1, Pr-4, R7-1),
(R1-5, R2-2, R3-1, Pr-4, R7-2), (R1-5, R2-2, R3-1, Pr-4, R7-3),
(R1-5, R2-2, R3-2, Pr-1, R7-1), (R1-5, R2-2, R3-2, Pr-1, R7-2),
(R1-5, R2-2, R3-2, Pr-1, R7-3), (R1-5, R2-2, R3-2, Pr-2, R7-1),
(R1-5, R2-2, R3-2, Pr-2, R7-2), (R1-5, R2-2, R3-2, Pr-2, R7-3),
(R1-5, R2-2, R3-2, Pr-3, R7-1), (R1-5, R2-2, R3-2, Pr-3, R7-2),
(R1-5, R2-2, R3-2, Pr-3, R7-3), (R1-5, R2-2, R3-2, Pr-4, R7-1),
(R1-5, R2-2, R3-2, Pr-4, R7-2), (R1-5, R2-2, R3-2, Pr-4, R7-3),
(R1-5, R2-2, R3-3, Pr-1, R7-1), (R1-5, R2-2, R3-3, Pr-1, R7-2),
(R1-5, R2-2, R3-3, Pr-1, R7-3), (R1-5, R2-2, R3-3, Pr-2, R7-1),
(R1-5, R2-2, R3-3, Pr-2, R7-2), (R1-5, R2-2, R3-3, Pr-2, R7-3),
(R1-5, R2-2, R3-3, Pr-3, R7-1), (R1-5, R2-2, R3-3, Pr-3, R7-2),
(R1-5, R2-2, R3-3, Pr-3, R7-3), (R1-5, R2-2, R3-3, Pr-4, R7-1),
(R1-5, R2-2, R3-3, Pr-4, R7-2), (R1-5, R2-2, R3-3, Pr-4, R7-3),
(R1-5, R2-2, R3-4, Pr-1, R7-1), (R1-5, R2-2, R3-4, Pr-1, R7-2),
(R1-5, R2-2, R3-4, Pr-1, R7-3), (R1-5, R2-2, R3-4, Pr-2, R7-1),
(R1-5, R2-2, R3-4, Pr-2, R7-2), (R1-5, R2-2, R3-4, Pr-2, R7-3),
(R1-5, R2-2, R3-4, Pr-3, R7-1), (R1-5, R2-2, R3-4, Pr-3, R7-2),
(R1-5, R2-2, R3-4, Pr-3, R7-3), (R1-5, R2-2, R3-4, Pr-4, R7-1),
(R1-5, R2-2, R3-4, Pr-4, R7-2), (R1-5, R2-2, R3-4, Pr-4, R7-3),
(R1-5, R2-2, R3-5, Pr-1, R7-1), (R1-5, R2-2, R3-5, Pr-1, R7-2),
(R1-5, R2-2, R3-5, Pr-1, R7-3), (R1-5, R2-2, R3-5, Pr-2, R7-1),
(R1-5, R2-2, R3-5, Pr-2, R7-2), (R1-5, R2-2, R3-5, Pr-2, R7-3),
(R1-5, R2-2, R3-5, Pr-3, R7-1), (R1-5, R2-2, R3-5, Pr-3, R7-2),
(R1-5, R2-2, R3-5, Pr-3, R7-3), (R1-5, R2-2, R3-5, Pr-4, R7-1),
(R1-5, R2-2, R3-5, Pr-4, R7-2), (R1-5, R2-2, R3-5, Pr-4, R7-3),
[0625] (R1-6, R2-1, R3-1, Pr-1, R7-1), (R1-6, R2-1, R3-1, Pr-1,
R7-2), (R1-6, R2-1, R3-1, Pr-1, R7-3), (R1-6, R2-1, R3-1, Pr-2,
R7-1), (R1-6, R2-1, R3-1, Pr-2, R7-2), (R1-6, R2-1, R3-1, Pr-2,
R7-3), (R1-6, R2-1, R3-1, Pr-3, R7-1), (R1-6, R2-1, R3-1, Pr-3, R7-
2), (R1-6, R2-1, R3-1, Pr-3, R7-3), (R1-6, R2-1, R3-1, Pr-4, R7-1),
(R1-6, R2-1, R3-1, Pr-4, R7-2), (R1-6, R2-1, R3-1, Pr-4, R7-3),
(R1-6, R2-1, R3-2, Pr-1, R7-1), (R1-6, R2-1, R3-2, Pr-1, R7-2),
(R1-6, R2-1, R3-2, Pr-1, R7-3), (R1-6, R2-1, R3-2, Pr-2, R7-1),
(R1-6, R2-1, R3-2, Pr-2, R7-2), (R1-6, R2-1, R3-2, Pr-2, R7-3),
(R1-6, R2-1, R3-2, Pr-3, R7-1), (R1-6, R2-1, R3-2, Pr-3, R7-2),
(R1-6, R2-1, R3-2, Pr-3, R7-3), (R1-6, R2-1, R3-2, Pr-4, R7-1),
(R1-6, R2-1, R3-2, Pr-4, R7-2), (R1-6, R2-1, R3-2, Pr-4, R7-3),
(R1-6, R2-1, R3-3, Pr-1, R7-1), (R1-6, R2-1, R3-3, Pr-1, R7-2),
(R1-6, R2-1, R3-3, Pr-1, R7-3), (R1-6, R2-1, R3-3, Pr-2, R7-1),
(R1-6, R2-1, R3-3, Pr-2, R7-2), (R1-6, R2-1, R3-3, Pr-2, R7-3),
(R1-6, R2-1, R3-3, Pr-3, R7-1), (R1-6, R2-1, R3-3, Pr-3, R7-2),
(R1-6, R2-1, R3-3, Pr-3, R7-3), (R1-6, R2-1, R3-3, Pr-4, R7-1),
(R1-6, R2-1, R3-3, Pr-4, R7-2), (R1-6, R2-1, R3-3, Pr-4, R7-3),
(R1-6, R2-1, R3-4, Pr-1, R7-1), (R1-6, R2-1, R3-4, Pr-1, R7-2),
(R1-6, R2-1, R3-4, Pr-1, R7-3), (R1-6, R2-1, R3-4, Pr-2, R7-1),
(R1-6, R2-1, R3-4, Pr-2, R7-2), (R1-6, R2-1, R3-4, Pr-2, R7-3),
(R1-6, R2-1, R3-4, Pr-3, R7-1), (R1-6, R2-1, R3-4, Pr-3, R7-2),
(R1-6, R2-1, R3-4, Pr-3, R7-3), (R1-6, R2-1, R3-4, Pr-4, R7-1),
(R1-6, R2-1, R3-4, Pr-4, R7-2), (R1-6, R2-1, R3-4, Pr-4, R7-3),
(R1-6, R2-1, R3-5, Pr-1, R7-1), (R1-6, R2-1, R3-5, Pr-1, R7-2),
(R1-6, R2-1, R3-5, Pr-1, R7-3), (R1-6, R2-1, R3-5, Pr-2, R7-1),
(R1-6, R2-1, R3-5, Pr-2, R7-2), (R1-6, R2-1, R3-5, Pr-2, R7-3),
(R1-6, R2-1, R3-5, Pr-3, R7-1), (R1-6, R2-1, R3-5, Pr-3, R7-2),
(R1-6, R2-1, R3-5, Pr-3, R7-3), (R1-6, R2-1, R3-5, Pr-4, R7-1),
(R1-6, R2-1, R3-5, Pr-4, R7-2), (R1-6, R2-1, R3-5, Pr-4, R7-3),
(R1-6, R2-2, R3-1, Pr-1, R7-1), (R1-6, R2-2, R3-1, Pr-1, R7-2),
(R1-6, R2-2, R3-1, Pr-1, R7-3), (R1-6, R2-2, R3-1, Pr-2, R7-1),
(R1-6, R2-2, R3-1, Pr-2, R7-2), (R1-6, R2-2, R3-1, Pr-2, R7-3),
(R1-6, R2-2, R3-1, Pr-3, R7-1), (R1-6, R2-2, R3-1, Pr-3, R7-2),
(R1-6, R2-2, R3-1, Pr-3, R7-3), (R1-6, R2-2, R3-1, Pr-4, R7-1),
(R1-6, R2-2, R3-1, Pr-4, R7-2), (R1-6, R2-2, R3-1, Pr-4, R7-3),
(R1-6, R2-2, R3-2, Pr-1, R7-1), (R1-6, R2-2, R3-2, Pr-1, R7-2),
(R1-6, R2-2, R3-2, Pr-1, R7-3), (R1-6, R2-2, R3-2, Pr-2, R7-1),
(R1-6, R2-2, R3-2, Pr-2, R7-2), (R1-6, R2-2, R3-2, Pr-2, R7-3),
(R1-6, R2-2, R3-2, Pr-3, R7-1), (R1-6, R2-2, R3-2, Pr-3, R7-2),
(R1-6, R2-2, R3-2, Pr-3, R7-3), (R1-6, R2-2, R3-2, Pr-4, R7-1),
(R1-6, R2-2, R3-2, Pr-4, R7-2), (R1-6, R2-2, R3-2, Pr-4, R7-3),
(R1-6, R2-2, R3-3, Pr-1, R7-1), (R1-6, R2-2, R3-3, Pr-1, R7-2),
(R1-6, R2-2, R3-3, Pr-1, R7-3), (R1-6, R2-2, R3-3, Pr-2, R7-1),
(R1-6, R2-2, R3-3, Pr-2, R7-2), (R1-6, R2-2, R3-3, Pr-2, R7-3),
(R1-6, R2-2, R3-3, Pr-3, R7-1), (R1-6, R2-2, R3-3, Pr-3, R7-2),
(R1-6, R2-2, R3-3, Pr-3, R7-3), (R1-6, R2-2, R3-3, Pr-4, R7-1),
(R1-6, R2-2, R3-3, Pr-4, R7-2), (R1-6, R2-2, R3-3, Pr-4, R7-3),
(R1-6, R2-2, R3-4, Pr-1, R7-1), (R1-6, R2-2, R3-4, Pr-1, R7-2),
(R1-6, R2-2, R3-4, Pr-1, R7-3), (R1-6, R2-2, R3-4, Pr-2, R7-1),
(R1-6, R2-2, R3-4, Pr-2, R7-2), (R1-6, R2-2, R3-4, Pr-2, R7-3),
(R1-6, R2-2, R3-4, Pr-3, R7-1), (R1-6, R2-2, R3-4, Pr-3, R7-2),
(R1-6, R2-2, R3-4, Pr-3, R7-3), (R1-6, R2-2, R3-4, Pr-4, R7-1),
(R1-6, R2-2, R3-4, Pr-4, R7-2), (R1-6, R2-2, R3-4, Pr-4, R7-3),
(R1-6, R2-2, R3-5, Pr-1, R7-1), (R1-6, R2-2, R3-5, Pr-1, R7-2),
(R1-6, R2-2, R3-5, Pr-1, R7-3), (R1-6, R2-2, R3-5, Pr-2, R7-1),
(R1-6, R2-2, R3-5, Pr-2, R7-2), (R1-6, R2-2, R3-5, Pr-2, R7-3),
(R1-6, R2-2, R3-5, Pr-3, R7-1), (R1-6, R2-2, R3-5, Pr-3, R7-2),
(R1-6, R2-2, R3-5, Pr-3, R7-3), (R1-6, R2-2, R3-5, Pr-4, R7-1),
(R1-6, R2-2, R3-5, Pr-4, R7-2), (R1-6, R2-2, R3-5, Pr-4, R7-3),
[0626] (R1-7, R2-1, R3-1, Pr-1, R7-1), (R1-7, R2-1, R3-1, Pr-1,
R7-2), (R1-7, R2-1, R3-1, Pr-1, R7-3), (R1-7, R2-1, R3-1, Pr-2,
R7-1), (R1-7, R2-1, R3-1, Pr-2, R7-2), (R1-7, R2-1, R3-1, Pr-2,
R7-3), (R1-7, R2-1, R3-1, Pr-3, R7-1), (R1-7, R2-1, R3-1, Pr-3, R7-
2), (R1-7, R2-1, R3-1, Pr-3, R7-3), (R1-7, R2-1, R3-1, Pr-4, R7-1),
(R1-7, R2-1, R3-1, Pr-4, R7-2), (R1-7, R2-1, R3-1, Pr-4, R7-3),
(R1-7, R2-1, R3-2, Pr-1, R7-1), (R1-7, R2-1, R3-2, Pr-1, R7-2),
(R1-7, R2-1, R3-2, Pr-1, R7-3), (R1-7, R2-1, R3-2, Pr-2, R7-1),
(R1-7, R2-1, R3-2, Pr-2, R7-2), (R1-7, R2-1, R3-2, Pr-2, R7-3),
(R1-7, R2-1, R3-2, Pr-3, R7-1), (R1-7, R2-1, R3-2, Pr-3, R7-2),
(R1-7, R2-1, R3-2, Pr-3, R7-3), (R1-7, R2-1, R3-2, Pr-4, R7-1),
(R1-7, R2-1, R3-2, Pr-4, R7-2), (R1-7, R2-1, R3-2, Pr-4, R7-3),
(R1-7, R2-1, R3-3, Pr-1, R7-1), (R1-7, R2-1, R3-3, Pr-1, R7-2),
(R1-7, R2-1, R3-3, Pr-1, R7-3), (R1-7, R2-1, R3-3, Pr-2, R7-1),
(R1-7, R2-1, R3-3, Pr-2, R7-2), (R1-7, R2-1, R3-3, Pr-2, R7-3),
(R1-7, R2-1, R3-3, Pr-3, R7-1), (R1-7, R2-1, R3-3, Pr-3, R7-2),
(R1-7, R2-1, R3-3, Pr-3, R7-3), (R1-7, R2-1, R3-3, Pr-4, R7-1),
(R1-7, R2-1, R3-3, Pr-4, R7-2), (R1-7, R2-1, R3-3, Pr-4, R7-3),
(R1-7, R2-1, R3-4, Pr-1, R7-1), (R1-7, R2-1, R3-4, Pr-1, R7-2),
(R1-7, R2-1, R3-4, Pr-1, R7-3), (R1-7, R2-1, R3-4, Pr-2, R7-1),
(R1-7, R2-1, R3-4, Pr-2, R7-2), (R1-7, R2-1, R3-4, Pr-2, R7-3),
(R1-7, R2-1, R3-4, Pr-3, R7-1), (R1-7, R2-1, R3-4, Pr-3, R7-2),
(R1-7, R2-1, R3-4, Pr-3, R7-3), (R1-7, R2-1, R3-4, Pr-4, R7-1),
(R1-7, R2-1, R3-4, Pr-4, R7-2), (R1-7, R2-1, R3-4, Pr-4, R7-3),
(R1-7, R2-1, R3-5, Pr-1, R7-1), (R1-7, R2-1, R3-5, Pr-1, R7-2),
(R1-7, R2-1, R3-5, Pr-1, R7-3), (R1-7, R2-1, R3-5, Pr-2, R7-1),
(R1-7, R2-1, R3-5, Pr-2, R7-2), (R1-7, R2-1, R3-5, Pr-2, R7-3),
(R1-7, R2-1, R3-5, Pr-3, R7-1), (R1-7, R2-1, R3-5, Pr-3, R7-2),
(R1-7, R2-1, R3-5, Pr-3, R7-3), (R1-7, R2-1, R3-5, Pr-4, R7-1),
(R1-7, R2-1, R3-5, Pr-4, R7-2), (R1-7, R2-1, R3-5, Pr-4, R7-3),
(R1-7, R2-2, R3-1, Pr-1, R7-1), (R1-7, R2-2, R3-1, Pr-1, R7-2),
(R1-7, R2-2, R3-1, Pr-1, R7-3), (R1-7, R2-2, R3-1, Pr-2, R7-1),
(R1-7, R2-2, R3-1, Pr-2, R7-2), (R1-7, R2-2, R3-1, Pr-2, R7-3),
(R1-7, R2-2, R3-1, Pr-3, R7-1), (R1-7, R2-2, R3-1, Pr-3, R7-2),
(R1-7, R2-2, R3-1, Pr-3, R7-3), (R1-7, R2-2, R3-1, Pr-4, R7-1),
(R1-7, R2-2, R3-1, Pr-4, R7-2), (R1-7, R2-2, R3-1, Pr-4, R7-3),
(R1-7, R2-2, R3-2, Pr-1, R7-1), (R1-7, R2-2, R3-2, Pr-1, R7-2),
(R1-7, R2-2, R3-2, Pr-1, R7-3), (R1-7, R2-2, R3-2, Pr-2, R7-1),
(R1-7, R2-2, R3-2, Pr-2, R7-2), (R1-7, R2-2, R3-2, Pr-2, R7-3),
(R1-7, R2-2, R3-2, Pr-3, R7-1), (R1-7, R2-2, R3-2, Pr-3, R7-2),
(R1-7, R2-2, R3-2, Pr-3, R7-3), (R1-7, R2-2, R3-2, Pr-4, R7-1),
(R1-7, R2-2, R3-2, Pr-4, R7-2), (R1-7, R2-2, R3-2, Pr-4, R7-3),
(R1-7, R2-2, R3-3, Pr-1, R7-1), (R1-7, R2-2, R3-3, Pr-1, R7-2),
(R1-7, R2-2, R3-3, Pr-1, R7-3), (R1-7, R2-2, R3-3, Pr-2, R7-1),
(R1-7, R2-2, R3-3, Pr-2, R7-2), (R1-7, R2-2, R3-3, Pr-2, R7-3),
(R1-7, R2-2, R3-3, Pr-3, R7-1), (R1-7, R2-2, R3-3, Pr-3, R7-2),
(R1-7, R2-2, R3-3, Pr-3, R7-3), (R1-7, R2-2, R3-3, Pr-4, R7-1),
(R1-7, R2-2, R3-3, Pr-4, R7-2), (R1-7, R2-2, R3-3, Pr-4, R7-3),
(R1-7, R2-2, R3-4, Pr-1, R7-1), (R1-7, R2-2, R3-4, Pr-1, R7-2),
(R1-7, R2-2, R3-4, Pr-1, R7-3), (R1-7, R2-2, R3-4, Pr-2, R7-1),
(R1-7, R2-2, R3-4, Pr-2, R7-2), (R1-7, R2-2, R3-4, Pr-2, R7-3),
(R1-7, R2-2, R3-4, Pr-3, R7-1), (R1-7, R2-2, R3-4, Pr-3, R7-2),
(R1-7, R2-2, R3-4, Pr-3, R7-3), (R1-7, R2-2, R3-4, Pr-4, R7-1),
(R1-7, R2-2, R3-4, Pr-4, R7-2), (R1-7, R2-2, R3-4, Pr-4, R7-3),
(R1-7, R2-2, R3-5, Pr-1, R7-1), (R1-7, R2-2, R3-5, Pr-1, R7-2),
(R1-7, R2-2, R3-5, Pr-1, R7-3), (R1-7, R2-2, R3-5, Pr-2, R7-1),
(R1-7, R2-2, R3-5, Pr-2, R7-2), (R1-7, R2-2, R3-5, Pr-2, R7-3),
(R1-7, R2-2, R3-5, Pr-3, R7-1), (R1-7, R2-2, R3-5, Pr-3, R7-2),
(R1-7, R2-2, R3-5, Pr-3, R7-3), (R1-7, R2-2, R3-5, Pr-4, R7-1),
(R1-7, R2-2, R3-5, Pr-4, R7-2), (R1-7, R2-2, R3-5, Pr-4, R7-3),
[0627] (R1-8, R2-1, R3-1, Pr-1, R7-1), (R1-8, R2-1, R3-1, Pr-1,
R7-2), (R1-8, R2-1, R3-1, Pr-1, R7-3), (R1-8, R2-1, R3-1, Pr-2,
R7-1), (R1-8, R2-1, R3-1, Pr-2, R7-2), (R1-8, R2-1, R3-1, Pr-2,
R7-3), (R1-8, R2-1, R3-1, Pr-3, R7-1), (R1-8, R2-1, R3-1, Pr-3, R7-
2), (R1-8, R2-1, R3-1, Pr-3, R7-3), (R1-8, R2-1, R3-1, Pr-4, R7-1),
(R1-8, R2-1, R3-1, Pr-4, R7-2), (R1-8, R2-1, R3-1, Pr-4, R7-3),
(R1-8, R2-1, R3-2, Pr-1, R7-1), (R1-8, R2-1, R3-2, Pr-1, R7-2),
(R1-8, R2-1, R3-2, Pr-1, R7-3), (R1-8, R2-1, R3-2, Pr-2, R7-1),
(R1-8, R2-1, R3-2, Pr-2, R7-2), (R1-8, R2-1, R3-2, Pr-2, R7-3),
(R1-8, R2-1, R3-2, Pr-3, R7-1), (R1-8, R2-1, R3-2, Pr-3, R7-2),
(R1-8, R2-1, R3-2, Pr-3, R7-3), (R1-8, R2-1, R3-2, Pr-4, R7-1),
(R1-8, R2-1, R3-2, Pr-4, R7-2), (R1-8, R2-1, R3-2, Pr-4, R7-3),
(R1-8, R2-1, R3-3, Pr-1, R7-1), (R1-8, R2-1, R3-3, Pr-1, R7-2),
(R1-8, R2-1, R3-3, Pr-1, R7-3), (R1-8, R2-1, R3-3, Pr-2, R7-1),
(R1-8, R2-1, R3-3, Pr-2, R7-2), (R1-8, R2-1, R3-3, Pr-2, R7-3),
(R1-8, R2-1, R3-3, Pr-3, R7-1), (R1-8, R2-1, R3-3, Pr-3, R7-2),
(R1-8, R2-1, R3-3, Pr-3, R7-3), (R1-8, R2-1, R3-3, Pr-4, R7-1),
(R1-8, R2-1, R3-3, Pr-4, R7-2), (R1-8, R2-1, R3-3, Pr-4, R7-3),
(R1-8, R2-1, R3-4, Pr-1, R7-1), (R1-8, R2-1, R3-4, Pr-1, R7-2),
(R1-8, R2-1, R3-4, Pr-1, R7-3), (R1-8, R2-1, R3-4, Pr-2, R7-1),
(R1-8, R2-1, R3-4, Pr-2, R7-2), (R1-8, R2-1, R3-4, Pr-2, R7-3),
(R1-8, R2-1, R3-4, Pr-3, R7-1), (R1-8, R2-1, R3-4, Pr-3, R7-2),
(R1-8, R2-1, R3-4, Pr-3, R7-3), (R1-8, R2-1, R3-4, Pr-4, R7-1),
(R1-8, R2-1, R3-4, Pr-4, R7-2), (R1-8, R2-1, R3-4, Pr-4, R7-3),
(R1-8, R2-1, R3-5, Pr-1, R7-1), (R1-8, R2-1, R3-5, Pr-1, R7-2),
(R1-8, R2-1, R3-5, Pr-1, R7-3), (R1-8, R2-1, R3-5, Pr-2, R7-1),
(R1-8, R2-1, R3-5, Pr-2, R7-2), (R1-8, R2-1, R3-5, Pr-2, R7-3),
(R1-8, R2-1, R3-5, Pr-3, R7-1), (R1-8, R2-1, R3-5, Pr-3, R7-2),
(R1-8, R2-1, R3-5, Pr-3, R7-3), (R1-8, R2-1, R3-5, Pr-4, R7-1),
(R1-8, R2-1, R3-5, Pr-4, R7-2), (R1-8, R2-1, R3-5, Pr-4, R7-3),
(R1-8, R2-2, R3-1, Pr-1, R7-1), (R1-8, R2-2, R3-1, Pr-1, R7-2),
(R1-8, R2-2, R3-1, Pr-1, R7-3), (R1-8, R2-2, R3-1, Pr-2, R7-1),
(R1-8, R2-2, R3-1, Pr-2, R7-2), (R1-8, R2-2, R3-1, Pr-2, R7-3),
(R1-8, R2-2, R3-1, Pr-3, R7-1), (R1-8, R2-2, R3-1, Pr-3, R7-2),
(R1-8, R2-2, R3-1, Pr-3, R7-3), (R1-8, R2-2, R3-1, Pr-4, R7-1),
(R1-8, R2-2, R3-1, Pr-4, R7-2), (R1-8, R2-2, R3-1, Pr-4, R7-3),
(R1-8, R2-2, R3-2, Pr-1, R7-1), (R1-8, R2-2, R3-2, Pr-1, R7-2),
(R1-8, R2-2, R3-2, Pr-1, R7-3), (R1-8, R2-2, R3-2, Pr-2, R7-1),
(R1-8, R2-2, R3-2, Pr-2, R7-2), (R1-8, R2-2, R3-2, Pr-2, R7-3),
(R1-8, R2-2, R3-2, Pr-3, R7-1), (R1-8, R2-2, R3-2, Pr-3, R7-2),
(R1-8, R2-2, R3-2, Pr-3, R7-3), (R1-8, R2-2, R3-2, Pr-4, R7-1),
(R1-8, R2-2, R3-2, Pr-4, R7-2), (R1-8, R2-2, R3-2, Pr-4, R7-3),
(R1-8, R2-2, R3-3, Pr-1, R7-1), (R1-8, R2-2, R3-3, Pr-1, R7-2),
(R1-8, R2-2, R3-3, Pr-1, R7-3), (R1-8, R2-2, R3-3, Pr-2, R7-1),
(R1-8, R2-2, R3-3, Pr-2, R7-2), (R1-8, R2-2, R3-3, Pr-2, R7-3),
(R1-8, R2-2, R3-3, Pr-3, R7-1), (R1-8, R2-2, R3-3, Pr-3, R7-2),
(R1-8, R2-2, R3-3, Pr-3, R7-3), (R1-8, R2-2, R3-3, Pr-4, R7-1),
(R1-8, R2-2, R3-3, Pr-4, R7-2), (R1-8, R2-2, R3-3, Pr-4, R7-3),
(R1-8, R2-2, R3-4, Pr-1, R7-1), (R1-8, R2-2, R3-4, Pr-1, R7-2),
(R1-8, R2-2, R3-4, Pr-1, R7-3), (R1-8, R2-2, R3-4, Pr-2, R7-1),
(R1-8, R2-2, R3-4, Pr-2, R7-2), (R1-8, R2-2, R3-4, Pr-2, R7-3),
(R1-8, R2-2, R3-4, Pr-3, R7-1), (R1-8, R2-2, R3-4, Pr-3, R7-2),
(R1-8, R2-2, R3-4, Pr-3, R7-3), (R1-8, R2-2, R3-4, Pr-4, R7-1),
(R1-8, R2-2, R3-4, Pr-4, R7-2), (R1-8, R2-2, R3-4, Pr-4, R7-3),
(R1-8, R2-2, R3-5, Pr-1, R7-1), (R1-8, R2-2, R3-5, Pr-1, R7-2),
(R1-8, R2-2, R3-5, Pr-1, R7-3), (R1-8, R2-2, R3-5, Pr-2, R7-1),
(R1-8, R2-2, R3-5, Pr-2, R7-2), (R1-8, R2-2, R3-5, Pr-2, R7-3),
(R1-8, R2-2, R3-5, Pr-3, R7-1), (R1-8, R2-2, R3-5, Pr-3, R7-2),
(R1-8, R2-2, R3-5, Pr-3, R7-3), (R1-8, R2-2, R3-5, Pr-4, R7-1),
(R1-8, R2-2, R3-5, Pr-4, R7-2), (R1-8, R2-2, R3-5, Pr-4, R7-3).
[0628] Compounds in which, in the formula (III), a combination of
R.sup.1a, R.sup.2a, R.sup.3a, P.sup.R, as well as (R.sup.8a,
R.sup.9a, R.sup.10a, and R.sup.11a) is as follows.
(R1-1, R2-1, R3-1, Pr-1, R9-1), (R1-1, R2-1, R3-1, Pr-1, R9-2),
(R1-1, R2-1, R3-1, Pr-1, R9-3), (R1-1, R2-1, R3-1, Pr-2, R9-1),
(R1-1, R2-1, R3-1, Pr-2, R9-2), (R1-1, R2-1, R3-1, Pr-2, R9-3),
(R1-1, R2-1, R3-1, Pr-3, R9-1), (R1-1, R2-1, R3-1, Pr-3, R9-2),
(R1-1, R2-1, R3-1, Pr-3, R9-3), (R1-1, R2-1, R3-1, Pr-4, R9-1),
(R1-1, R2-1, R3-1, Pr-4, R9-2), (R1-1, R2-1, R3-1, Pr-4, R9-3),
(R1-1, R2-1, R3-2, Pr-1, R9-1), (R1-1, R2-1, R3-2, Pr-1, R9-2),
(R1-1, R2-1, R3-2, Pr-1, R9-3), (R1-1, R2-1, R3-2, Pr-2, R9-1),
(R1-1, R2-1, R3-2, Pr-2, R9-2), (R1-1, R2-1, R3-2, Pr-2, R9-3),
(R1-1, R2-1, R3-2, Pr-3, R9-1), (R1-1, R2-1, R3-2, Pr-3, R9-2),
(R1-1, R2-1, R3-2, Pr-3, R9-3), (R1-1, R2-1, R3-2, Pr-4, R9-1),
(R1-1, R2-1, R3-2, Pr-4, R9-2), (R1-1, R2-1, R3-2, Pr-4, R9-3),
(R1-1, R2-1, R3-3, Pr-1, R9-1), (R1-1, R2-1, R3-3, Pr-1, R9-2),
(R1-1, R2-1, R3-3, Pr-1, R9-3), (R1-1, R2-1, R3-3, Pr-2, R9-1),
(R1-1, R2-1, R3-3, Pr-2, R9-2), (R1-1, R2-1, R3-3, Pr-2, R9-3),
(R1-1, R2-1, R3-3, Pr-3, R9-1), (R1-1, R2-1, R3-3, Pr-3, R9-2),
(R1-1, R2-1, R3-3, Pr-3, R9-3), (R1-1, R2-1, R3-3, Pr-4, R9-1),
(R1-1, R2-1, R3-3, Pr-4, R9-2), (R1-1, R2-1, R3-3, Pr-4, R9-3),
(R1-1, R2-1, R3-4, Pr-1, R9-1), (R1-1, R2-1, R3-4, Pr-1, R9-2),
(R1-1, R2-1, R3-4, Pr-1, R9-3), (R1-1, R2-1, R3-4, Pr-2, R9-1),
(R1-1, R2-1, R3-4, Pr-2, R9-2), (R1-1, R2-1, R3-4, Pr-2, R9-3),
(R1-1, R2-1, R3-4, Pr-3, R9-1), (R1-1, R2-1, R3-4, Pr-3, R9-2),
(R1-1, R2-1, R3-4, Pr-3, R9-3), (R1-1, R2-1, R3-4, Pr-4, R9-1),
(R1-1, R2-1, R3-4, Pr-4, R9-2), (R1-1, R2-1, R3-4, Pr-4, R9-3),
(R1-1, R2-1, R3-5, Pr-1, R9-1), (R1-1, R2-1, R3-5, Pr-1, R9-2),
(R1-1, R2-1, R3-5, Pr-1, R9-3), (R1-1, R2-1, R3-5, Pr-2, R9-1),
(R1-1, R2-1, R3-5, Pr-2, R9-2), (R1-1, R2-1, R3-5, Pr-2, R9-3),
(R1-1, R2-1, R3-5, Pr-3, R9-1), (R1-1, R2-1, R3-5, Pr-3, R9-2),
(R1-1, R2-1, R3-5, Pr-3, R9-3), (R1-1, R2-1, R3-5, Pr-4, R9-1),
(R1-1, R2-1, R3-5, Pr-4, R9-2), (R1-1, R2-1, R3-5, Pr-4, R9-3),
(R1-1, R2-2, R3-1, Pr-1, R9-1), (R1-1, R2-2, R3-1, Pr-1, R9-2),
(R1-1, R2-2, R3-1, Pr-1, R9-3), (R1-1, R2-2, R3-1, Pr-2, R9-1),
(R1-1, R2-2, R3-1, Pr-2, R9-2), (R1-1, R2-2, R3-1, Pr-2, R9-3),
(R1-1, R2-2, R3-1, Pr-3, R9-1), (R1-1, R2-2, R3-1, Pr-3, R9-2),
(R1-1, R2-2, R3-1, Pr-3, R9-3), (R1-1, R2-2, R3-1, Pr-4, R9-1),
(R1-1, R2-2, R3-1, Pr-4, R9-2), (R1-1, R2-2, R3-1, Pr-4, R9-3),
(R1-1, R2-2, R3-2, Pr-1, R9-1), (R1-1, R2-2, R3-2, Pr-1, R9-2),
(R1-1, R2-2, R3-2, Pr-1, R9-3), (R1-1, R2-2, R3-2, Pr-2, R9-1),
(R1-1, R2-2, R3-2, Pr-2, R9-2), (R1-1, R2-2, R3-2, Pr-2, R9-3),
(R1-1, R2-2, R3-2, Pr-3, R9-1), (R1-1, R2-2, R3-2, Pr-3, R9-2),
(R1-1, R2-2, R3-2, Pr-3, R9-3), (R1-1, R2-2, R3-2, Pr-4, R9-1),
(R1-1, R2-2, R3-2, Pr-4, R9-2), (R1-1, R2-2, R3-2, Pr-4, R9-3),
(R1-1, R2-2, R3-3, Pr-1, R9-1), (R1-1, R2-2, R3-3, Pr-1, R9-2),
(R1-1, R2-2, R3-3, Pr-1, R9-3), (R1-1, R2-2, R3-3, Pr-2, R9-1),
(R1-1, R2-2, R3-3, Pr-2, R9-2), (R1-1, R2-2, R3-3, Pr-2, R9-3),
(R1-1, R2-2, R3-3, Pr-3, R9-1), (R1-1, R2-2, R3-3, Pr-3, R9-2),
(R1-1, R2-2, R3-3, Pr-3, R9-3), (R1-1, R2-2, R3-3, Pr-4, R9-1),
(R1-1, R2-2, R3-3, Pr-4, R9-2), (R1-1, R2-2, R3-3, Pr-4, R9-3),
(R1-1, R2-2, R3-4, Pr-1, R9-1), (R1-1, R2-2, R3-4, Pr-1, R9-2),
(R1-1, R2-2, R3-4, Pr-1, R9-3), (R1-1, R2-2, R3-4, Pr-2, R9-1),
(R1-1, R2-2, R3-4, Pr-2, R9-2), (R1-1, R2-2, R3-4, Pr-2, R9-3),
(R1-1, R2-2, R3-4, Pr-3, R9-1), (R1-1, R2-2, R3-4, Pr-3, R9-2),
(R1-1, R2-2, R3-4, Pr-3, R9-3), (R1-1, R2-2, R3-4, Pr-4, R9-1),
(R1-1, R2-2, R3-4, Pr-4, R9-2), (R1-1, R2-2, R3-4, Pr-4, R9-3),
(R1-1, R2-2, R3-5, Pr-1, R9-1), (R1-1, R2-2, R3-5, Pr-1, R9-2),
(R1-1, R2-2, R3-5, Pr-1, R9-3), (R1-1, R2-2, R3-5, Pr-2, R9-1),
(R1-1, R2-2, R3-5, Pr-2, R9-2), (R1-1, R2-2, R3-5, Pr-2, R9-3),
(R1-1, R2-2, R3-5, Pr-3, R9-1), (R1-1, R2-2, R3-5, Pr-3, R9-2),
(R1-1, R2-2, R3-5, Pr-3, R9-3), (R1-1, R2-2, R3-5, Pr-4, R9-1),
(R1-1, R2-2, R3-5, Pr-4, R9-2), (R1-1, R2-2, R3-5, Pr-4, R9-3),
[0629] (R1-2, R2-1, R3-1, Pr-1, R9-1), (R1-2, R2-1, R3-1, Pr-1,
R9-2), (R1-2, R2-1, R3-1, Pr-1, R9-3), (R1-2, R2-1, R3-1, Pr-2,
R9-1), (R1-2, R2-1, R3-1, Pr-2, R9-2), (R1-2, R2-1, R3-1, Pr-2,
R9-3), (R1-2, R2-1, R3-1, Pr-3, R9-1), (R1-2, R2-1, R3-1, Pr-3, R9-
2), (R1-2, R2-1, R3-1, Pr-3, R9-3), (R1-2, R2-1, R3-1, Pr-4, R9-1),
(R1-2, R2-1, R3-1, Pr-4, R9-2), (R1-2, R2-1, R3-1, Pr-4, R9-3),
(R1-2, R2-1, R3-2, Pr-1, R9-1), (R1-2, R2-1, R3-2, Pr-1, R9-2),
(R1-2, R2-1, R3-2, Pr-1, R9-3), (R1-2, R2-1, R3-2, Pr-2, R9-1),
(R1-2, R2-1, R3-2, Pr-2, R9-2), (R1-2, R2-1, R3-2, Pr-2, R9-3),
(R1-2, R2-1, R3-2, Pr-3, R9-1), (R1-2, R2-1, R3-2, Pr-3, R9-2),
(R1-2, R2-1, R3-2, Pr-3, R9-3), (R1-2, R2-1, R3-2, Pr-4, R9-1),
(R1-2, R2-1, R3-2, Pr-4, R9-2), (R1-2, R2-1, R3-2, Pr-4, R9-3),
(R1-2, R2-1, R3-3, Pr-1, R9-1), (R1-2, R2-1, R3-3, Pr-1, R9-2),
(R1-2, R2-1, R3-3, Pr-1, R9-3), (R1-2, R2-1, R3-3, Pr-2, R9-1),
(R1-2, R2-1, R3-3, Pr-2, R9-2), (R1-2, R2-1, R3-3, Pr-2, R9-3),
(R1-2, R2-1, R3-3, Pr-3, R9-1), (R1-2, R2-1, R3-3, Pr-3, R9-2),
(R1-2, R2-1, R3-3, Pr-3, R9-3), (R1-2, R2-1, R3-3, Pr-4, R9-1),
(R1-2, R2-1, R3-3, Pr-4, R9-2), (R1-2, R2-1, R3-3, Pr-4, R9-3),
(R1-2, R2-1, R3-4, Pr-1, R9-1), (R1-2, R2-1, R3-4, Pr-1, R9-2),
(R1-2, R2-1, R3-4, Pr-1, R9-3), (R1-2, R2-1, R3-4, Pr-2, R9-1),
(R1-2, R2-1, R3-4, Pr-2, R9-2), (R1-2, R2-1, R3-4, Pr-2, R9-3),
(R1-2, R2-1, R3-4, Pr-3, R9-1), (R1-2, R2-1, R3-4, Pr-3, R9-2),
(R1-2, R2-1, R3-4, Pr-3, R9-3), (R1-2, R2-1, R3-4, Pr-4, R9-1),
(R1-2, R2-1, R3-4, Pr-4, R9-2), (R1-2, R2-1, R3-4, Pr-4, R9-3),
(R1-2, R2-1, R3-5, Pr-1, R9-1), (R1-2, R2-1, R3-5, Pr-1, R9-2),
(R1-2, R2-1, R3-5, Pr-1, R9-3), (R1-2, R2-1, R3-5, Pr-2, R9-1),
(R1-2, R2-1, R3-5, Pr-2, R9-2), (R1-2, R2-1, R3-5, Pr-2, R9-3),
(R1-2, R2-1, R3-5, Pr-3, R9-1), (R1-2, R2-1, R3-5, Pr-3, R9-2),
(R1-2, R2-1, R3-5, Pr-3, R9-3), (R1-2, R2-1, R3-5, Pr-4, R9-1),
(R1-2, R2-1, R3-5, Pr-4, R9-2), (R1-2, R2-1, R3-5, Pr-4, R9-3),
(R1-2, R2-2, R3-1, Pr-1, R9-1), (R1-2, R2-2, R3-1, Pr-1, R9-2),
(R1-2, R2-2, R3-1, Pr-1, R9-3), (R1-2, R2-2, R3-1, Pr-2, R9-1),
(R1-2, R2-2, R3-1, Pr-2, R9-2), (R1-2, R2-2, R3-1, Pr-2, R9-3),
(R1-2, R2-2, R3-1, Pr-3, R9-1), (R1-2, R2-2, R3-1, Pr-3, R9-2),
(R1-2, R2-2, R3-1, Pr-3, R9-3), (R1-2, R2-2, R3-1, Pr-4, R9-1),
(R1-2, R2-2, R3-1, Pr-4, R9-2), (R1-2, R2-2, R3-1, Pr-4, R9-3),
(R1-2, R2-2, R3-2, Pr-1, R9-1), (R1-2, R2-2, R3-2, Pr-1, R9-2),
(R1-2, R2-2, R3-2, Pr-1, R9-3), (R1-2, R2-2, R3-2, Pr-2, R9-1),
(R1-2, R2-2, R3-2, Pr-2, R9-2), (R1-2, R2-2, R3-2, Pr-2, R9-3),
(R1-2, R2-2, R3-2, Pr-3, R9-1), (R1-2, R2-2, R3-2, Pr-3, R9-2),
(R1-2, R2-2, R3-2, Pr-3, R9-3), (R1-2, R2-2, R3-2, Pr-4, R9-1),
(R1-2, R2-2, R3-2, Pr-4, R9-2), (R1-2, R2-2, R3-2, Pr-4, R9-3),
(R1-2, R2-2, R3-3, Pr-1, R9-1), (R1-2, R2-2, R3-3, Pr-1, R9-2),
(R1-2, R2-2, R3-3, Pr-1, R9-3), (R1-2, R2-2, R3-3, Pr-2, R9-1),
(R1-2, R2-2, R3-3, Pr-2, R9-2), (R1-2, R2-2, R3-3, Pr-2, R9-3),
(R1-2, R2-2, R3-3, Pr-3, R9-1), (R1-2, R2-2, R3-3, Pr-3, R9-2),
(R1-2, R2-2, R3-3, Pr-3, R9-3), (R1-2, R2-2, R3-3, Pr-4, R9-1),
(R1-2, R2-2, R3-3, Pr-4, R9-2), (R1-2, R2-2, R3-3, Pr-4, R9-3),
(R1-2, R2-2, R3-4, Pr-1, R9-1), (R1-2, R2-2, R3-4, Pr-1, R9-2),
(R1-2, R2-2, R3-4, Pr-1, R9-3), (R1-2, R2-2, R3-4, Pr-2, R9-1),
(R1-2, R2-2, R3-4, Pr-2, R9-2), (R1-2, R2-2, R3-4, Pr-2, R9-3),
(R1-2, R2-2, R3-4, Pr-3, R9-1), (R1-2, R2-2, R3-4, Pr-3, R9-2),
(R1-2, R2-2, R3-4, Pr-3, R9-3), (R1-2, R2-2, R3-4, Pr-4, R9-1),
(R1-2, R2-2, R3-4, Pr-4, R9-2), (R1-2, R2-2, R3-4, Pr-4, R9-3),
(R1-2, R2-2, R3-5, Pr-1, R9-1), (R1-2, R2-2, R3-5, Pr-1, R9-2),
(R1-2, R2-2, R3-5, Pr-1, R9-3), (R1-2, R2-2, R3-5, Pr-2, R9-1),
(R1-2, R2-2, R3-5, Pr-2, R9-2), (R1-2, R2-2, R3-5, Pr-2, R9-3),
(R1-2, R2-2, R3-5, Pr-3, R9-1), (R1-2, R2-2, R3-5, Pr-3, R9-2),
(R1-2, R2-2, R3-5, Pr-3, R9-3), (R1-2, R2-2, R3-5, Pr-4, R9-1),
(R1-2, R2-2, R3-5, Pr-4, R9-2), (R1-2, R2-2, R3-5, Pr-4, R9-3),
[0630] (R1-3, R2-1, R3-1, Pr-1, R9-1), (R1-3, R2-1, R3-1, Pr-1,
R9-2), (R1-3, R2-1, R3-1, Pr-1, R9-3), (R1-3, R2-1, R3-1, Pr-2,
R9-1), (R1-3, R2-1, R3-1, Pr-2, R9-2), (R1-3, R2-1, R3-1, Pr-2,
R9-3), (R1-3, R2-1, R3-1, Pr-3, R9-1), (R1-3, R2-1, R3-1, Pr-3, R9-
2), (R1-3, R2-1, R3-1, Pr-3, R9-3), (R1-3, R2-1, R3-1, Pr-4, R9-1),
(R1-3, R2-1, R3-1, Pr-4, R9-2), (R1-3, R2-1, R3-1, Pr-4, R9-3),
(R1-3, R2-1, R3-2, Pr-1, R9-1), (R1-3, R2-1, R3-2, Pr-1, R9-2),
(R1-3, R2-1, R3-2, Pr-1, R9-3), (R1-3, R2-1, R3-2, Pr-2, R9-1),
(R1-3, R2-1, R3-2, Pr-2, R9-2), (R1-3, R2-1, R3-2, Pr-2, R9-3),
(R1-3, R2-1, R3-2, Pr-3, R9-1), (R1-3, R2-1, R3-2, Pr-3, R9-2),
(R1-3, R2-1, R3-2, Pr-3, R9-3), (R1-3, R2-1, R3-2, Pr-4, R9-1),
(R1-3, R2-1, R3-2, Pr-4, R9-2), (R1-3, R2-1, R3-2, Pr-4, R9-3),
(R1-3, R2-1, R3-3, Pr-1, R9-1), (R1-3, R2-1, R3-3, Pr-1, R9-2),
(R1-3, R2-1, R3-3, Pr-1, R9-3), (R1-3, R2-1, R3-3, Pr-2, R9-1),
(R1-3, R2-1, R3-3, Pr-2, R9-2), (R1-3, R2-1, R3-3, Pr-2, R9-3),
(R1-3, R2-1, R3-3, Pr-3, R9-1), (R1-3, R2-1, R3-3, Pr-3, R9-2),
(R1-3, R2-1, R3-3, Pr-3, R9-3), (R1-3, R2-1, R3-3, Pr-4, R9-1),
(R1-3, R2-1, R3-3, Pr-4, R9-2), (R1-3, R2-1, R3-3, Pr-4, R9-3),
(R1-3, R2-1, R3-4, Pr-1, R9-1), (R1-3, R2-1, R3-4, Pr-1, R9-2),
(R1-3, R2-1, R3-4, Pr-1, R9-3), (R1-3, R2-1, R3-4, Pr-2, R9-1),
(R1-3, R2-1, R3-4, Pr-2, R9-2), (R1-3, R2-1, R3-4, Pr-2, R9-3),
(R1-3, R2-1, R3-4, Pr-3, R9-1), (R1-3, R2-1, R3-4, Pr-3, R9-2),
(R1-3, R2-1, R3-4, Pr-3, R9-3), (R1-3, R2-1, R3-4, Pr-4, R9-1),
(R1-3, R2-1, R3-4, Pr-4, R9-2), (R1-3, R2-1, R3-4, Pr-4, R9-3),
(R1-3, R2-1, R3-5, Pr-1, R9-1), (R1-3, R2-1, R3-5, Pr-1, R9-2),
(R1-3, R2-1, R3-5, Pr-1, R9-3), (R1-3, R2-1, R3-5, Pr-2, R9-1),
(R1-3, R2-1, R3-5, Pr-2, R9-2), (R1-3, R2-1, R3-5, Pr-2, R9-3),
(R1-3, R2-1, R3-5, Pr-3, R9-1), (R1-3, R2-1, R3-5, Pr-3, R9-2),
(R1-3, R2-1, R3-5, Pr-3, R9-3), (R1-3, R2-1, R3-5, Pr-4, R9-1),
(R1-3, R2-1, R3-5, Pr-4, R9-2), (R1-3, R2-1, R3-5, Pr-4, R9-3),
(R1-3, R2-2, R3-1, Pr-1, R9-1), (R1-3, R2-2, R3-1, Pr-1, R9-2),
(R1-3, R2-2, R3-1, Pr-1, R9-3), (R1-3, R2-2, R3-1, Pr-2, R9-1),
(R1-3, R2-2, R3-1, Pr-2, R9-2), (R1-3, R2-2, R3-1, Pr-2, R9-3),
(R1-3, R2-2, R3-1, Pr-3, R9-1), (R1-3, R2-2, R3-1, Pr-3, R9-2),
(R1-3, R2-2, R3-1, Pr-3, R9-3), (R1-3, R2-2, R3-1, Pr-4, R9-1),
(R1-3, R2-2, R3-1, Pr-4, R9-2), (R1-3, R2-2, R3-1, Pr-4, R9-3),
(R1-3, R2-2, R3-2, Pr-1, R9-1), (R1-3, R2-2, R3-2, Pr-1, R9-2),
(R1-3, R2-2, R3-2, Pr-1, R9-3), (R1-3, R2-2, R3-2, Pr-2, R9-1),
(R1-3, R2-2, R3-2, Pr-2, R9-2), (R1-3, R2-2, R3-2, Pr-2, R9-3),
(R1-3, R2-2, R3-2, Pr-3, R9-1), (R1-3, R2-2, R3-2, Pr-3, R9-2),
(R1-3, R2-2, R3-2, Pr-3, R9-3), (R1-3, R2-2, R3-2, Pr-4, R9-1),
(R1-3, R2-2, R3-2, Pr-4, R9-2), (R1-3, R2-2, R3-2, Pr-4, R9-3),
(R1-3, R2-2, R3-3, Pr-1, R9-1), (R1-3, R2-2, R3-3, Pr-1, R9-2),
(R1-3, R2-2, R3-3, Pr-1, R9-3), (R1-3, R2-2, R3-3, Pr-2, R9-1),
(R1-3, R2-2, R3-3, Pr-2, R9-2), (R1-3, R2-2, R3-3, Pr-2, R9-3),
(R1-3, R2-2, R3-3, Pr-3, R9-1), (R1-3, R2-2, R3-3, Pr-3, R9-2),
(R1-3, R2-2, R3-3, Pr-3, R9-3), (R1-3, R2-2, R3-3, Pr-4, R9-1),
(R1-3, R2-2, R3-3, Pr-4, R9-2), (R1-3, R2-2, R3-3, Pr-4, R9-3),
(R1-3, R2-2, R3-4, Pr-1, R9-1), (R1-3, R2-2, R3-4, Pr-1, R9-2),
(R1-3, R2-2, R3-4, Pr-1, R9-3), (R1-3, R2-2, R3-4, Pr-2, R9-1),
(R1-3, R2-2, R3-4, Pr-2, R9-2), (R1-3, R2-2, R3-4, Pr-2, R9-3),
(R1-3, R2-2, R3-4, Pr-3, R9-1), (R1-3, R2-2, R3-4, Pr-3, R9-2),
(R1-3, R2-2, R3-4, Pr-3, R9-3), (R1-3, R2-2, R3-4, Pr-4, R9-1),
(R1-3, R2-2, R3-4, Pr-4, R9-2), (R1-3, R2-2, R3-4, Pr-4, R9-3),
(R1-3, R2-2, R3-5, Pr-1, R9-1), (R1-3, R2-2, R3-5, Pr-1, R9-2),
(R1-3, R2-2, R3-5, Pr-1, R9-3), (R1-3, R2-2, R3-5, Pr-2, R9-1),
(R1-3, R2-2, R3-5, Pr-2, R9-2), (R1-3, R2-2, R3-5, Pr-2, R9-3),
(R1-3, R2-2, R3-5, Pr-3, R9-1), (R1-3, R2-2, R3-5, Pr-3, R9-2),
(R1-3, R2-2, R3-5, Pr-3, R9-3), (R1-3, R2-2, R3-5, Pr-4, R9-1),
(R1-3, R2-2, R3-5, Pr-4, R9-2), (R1-3, R2-2, R3-5, Pr-4, R9-3),
[0631] (R1-4, R2-1, R3-1, Pr-1, R9-1), (R1-4, R2-1, R3-1, Pr-1,
R9-2), (R1-4, R2-1, R3-1, Pr-1, R9-3), (R1-4, R2-1, R3-1, Pr-2,
R9-1), (R1-4, R2-1, R3-1, Pr-2, R9-2), (R1-4, R2-1, R3-1, Pr-2,
R9-3), (R1-4, R2-1, R3-1, Pr-3, R9-1), (R1-4, R2-1, R3-1, Pr-3, R9-
2), (R1-4, R2-1, R3-1, Pr-3, R9-3), (R1-4, R2-1, R3-1, Pr-4, R9-1),
(R1-4, R2-1, R3-1, Pr-4, R9-2), (R1-4, R2-1, R3-1, Pr-4, R9-3),
(R1-4, R2-1, R3-2, Pr-1, R9-1), (R1-4, R2-1, R3-2, Pr-1, R9-2),
(R1-4, R2-1, R3-2, Pr-1, R9-3), (R1-4, R2-1, R3-2, Pr-2, R9-1),
(R1-4, R2-1, R3-2, Pr-2, R9-2), (R1-4, R2-1, R3-2, Pr-2, R9-3),
(R1-4, R2-1, R3-2, Pr-3, R9-1), (R1-4, R2-1, R3-2, Pr-3, R9-2),
(R1-4, R2-1, R3-2, Pr-3, R9-3), (R1-4, R2-1, R3-2, Pr-4, R9-1),
(R1-4, R2-1, R3-2, Pr-4, R9-2), (R1-4, R2-1, R3-2, Pr-4, R9-3),
(R1-4, R2-1, R3-3, Pr-1, R9-1), (R1-4, R2-1, R3-3, Pr-1, R9-2),
(R1-4, R2-1, R3-3, Pr-1, R9-3), (R1-4, R2-1, R3-3, Pr-2, R9-1),
(R1-4, R2-1, R3-3, Pr-2, R9-2), (R1-4, R2-1, R3-3, Pr-2, R9-3),
(R1-4, R2-1, R3-3, Pr-3, R9-1), (R1-4, R2-1, R3-3, Pr-3, R9-2),
(R1-4, R2-1, R3-3, Pr-3, R9-3), (R1-4, R2-1, R3-3, Pr-4, R9-1),
(R1-4, R2-1, R3-3, Pr-4, R9-2), (R1-4, R2-1, R3-3, Pr-4, R9-3),
(R1-4, R2-1, R3-4, Pr-1, R9-1), (R1-4, R2-1, R3-4, Pr-1, R9-2),
(R1-4, R2-1, R3-4, Pr-1, R9-3), (R1-4, R2-1, R3-4, Pr-2, R9-1),
(R1-4, R2-1, R3-4, Pr-2, R9-2), (R1-4, R2-1, R3-4, Pr-2, R9-3),
(R1-4, R2-1, R3-4, Pr-3, R9-1), (R1-4, R2-1, R3-4, Pr-3, R9-2),
(R1-4, R2-1, R3-4, Pr-3, R9-3), (R1-4, R2-1, R3-4, Pr-4, R9-1),
(R1-4, R2-1, R3-4, Pr-4, R9-2), (R1-4, R2-1, R3-4, Pr-4, R9-3),
(R1-4, R2-1, R3-5, Pr-1, R9-1), (R1-4, R2-1, R3-5, Pr-1, R9-2),
(R1-4, R2-1, R3-5, Pr-1, R9-3), (R1-4, R2-1, R3-5, Pr-2, R9-1),
(R1-4, R2-1, R3-5, Pr-2, R9-2), (R1-4, R2-1, R3-5, Pr-2, R9-3),
(R1-4, R2-1, R3-5, Pr-3, R9-1), (R1-4, R2-1, R3-5, Pr-3, R9-2),
(R1-4, R2-1, R3-5, Pr-3, R9-3), (R1-4, R2-1, R3-5, Pr-4, R9-1),
(R1-4, R2-1, R3-5, Pr-4, R9-2), (R1-4, R2-1, R3-5, Pr-4, R9-3),
(R1-4, R2-2, R3-1, Pr-1, R9-1), (R1-4, R2-2, R3-1, Pr-1, R9-2),
(R1-4, R2-2, R3-1, Pr-1, R9-3), (R1-4, R2-2, R3-1, Pr-2, R9-1),
(R1-4, R2-2, R3-1, Pr-2, R9-2), (R1-4, R2-2, R3-1, Pr-2, R9-3),
(R1-4, R2-2, R3-1, Pr-3, R9-1), (R1-4, R2-2, R3-1, Pr-3, R9-2),
(R1-4, R2-2, R3-1, Pr-3, R9-3), (R1-4, R2-2, R3-1, Pr-4, R9-1),
(R1-4, R2-2, R3-1, Pr-4, R9-2), (R1-4, R2-2, R3-1, Pr-4, R9-3),
(R1-4, R2-2, R3-2, Pr-1, R9-1), (R1-4, R2-2, R3-2, Pr-1, R9-2),
(R1-4, R2-2, R3-2, Pr-1, R9-3), (R1-4, R2-2, R3-2, Pr-2, R9-1),
(R1-4, R2-2, R3-2, Pr-2, R9-2), (R1-4, R2-2, R3-2, Pr-2, R9-3),
(R1-4, R2-2, R3-2, Pr-3, R9-1), (R1-4, R2-2, R3-2, Pr-3, R9-2),
(R1-4, R2-2, R3-2, Pr-3, R9-3), (R1-4, R2-2, R3-2, Pr-4, R9-1),
(R1-4, R2-2, R3-2, Pr-4, R9-2), (R1-4, R2-2, R3-2, Pr-4, R9-3),
(R1-4, R2-2, R3-3, Pr-1, R9-1), (R1-4, R2-2, R3-3, Pr-1, R9-2),
(R1-4, R2-2, R3-3, Pr-1, R9-3), (R1-4, R2-2, R3-3, Pr-2, R9-1),
(R1-4, R2-2, R3-3, Pr-2, R9-2), (R1-4, R2-2, R3-3, Pr-2, R9-3),
(R1-4, R2-2, R3-3, Pr-3, R9-1), (R1-4, R2-2, R3-3, Pr-3, R9-2),
(R1-4, R2-2, R3-3, Pr-3, R9-3), (R1-4, R2-2, R3-3, Pr-4, R9-1),
(R1-4, R2-2, R3-3, Pr-4, R9-2), (R1-4, R2-2, R3-3, Pr-4, R9-3),
(R1-4, R2-2, R3-4, Pr-1, R9-1), (R1-4, R2-2, R3-4, Pr-1, R9-2),
(R1-4, R2-2, R3-4, Pr-1, R9-3), (R1-4, R2-2, R3-4, Pr-2, R9-1),
(R1-4, R2-2, R3-4, Pr-2, R9-2), (R1-4, R2-2, R3-4, Pr-2, R9-3),
(R1-4, R2-2, R3-4, Pr-3, R9-1), (R1-4, R2-2, R3-4, Pr-3, R9-2),
(R1-4, R2-2, R3-4, Pr-3, R9-3), (R1-4, R2-2, R3-4, Pr-4, R9-1),
(R1-4, R2-2, R3-4, Pr-4, R9-2), (R1-4, R2-2, R3-4, Pr-4, R9-3),
(R1-4, R2-2, R3-5, Pr-1, R9-1), (R1-4, R2-2, R3-5, Pr-1, R9-2),
(R1-4, R2-2, R3-5, Pr-1, R9-3), (R1-4, R2-2, R3-5, Pr-2, R9-1),
(R1-4, R2-2, R3-5, Pr-2, R9-2), (R1-4, R2-2, R3-5, Pr-2, R9-3),
(R1-4, R2-2, R3-5, Pr-3, R9-1), (R1-4, R2-2, R3-5, Pr-3, R9-2),
(R1-4, R2-2, R3-5, Pr-3, R9-3), (R1-4, R2-2, R3-5, Pr-4, R9-1),
(R1-4, R2-2, R3-5, Pr-4, R9-2), (R1-4, R2-2, R3-5, Pr-4, R9-3),
[0632] (R1-5, R2-1, R3-1, Pr-1, R9-1), (R1-5, R2-1, R3-1, Pr-1,
R9-2), (R1-5, R2-1, R3-1, Pr-1, R9-3), (R1-5, R2-1, R3-1, Pr-2,
R9-1), (R1-5, R2-1, R3-1, Pr-2, R9-2), (R1-5, R2-1, R3-1, Pr-2,
R9-3), (R1-5, R2-1, R3-1, Pr-3, R9-1), (R1-5, R2-1, R3-1, Pr-3, R9-
2), (R1-5, R2-1, R3-1, Pr-3, R9-3), (R1-5, R2-1, R3-1, Pr-4, R9-1),
(R1-5, R2-1, R3-1, Pr-4, R9-2), (R1-5, R2-1, R3-1, Pr-4, R9-3),
(R1-5, R2-1, R3-2, Pr-1, R9-1), (R1-5, R2-1, R3-2, Pr-1, R9-2),
(R1-5, R2-1, R3-2, Pr-1, R9-3), (R1-5, R2-1, R3-2, Pr-2, R9-1),
(R1-5, R2-1, R3-2, Pr-2, R9-2), (R1-5, R2-1, R3-2, Pr-2, R9-3),
(R1-5, R2-1, R3-2, Pr-3, R9-1), (R1-5, R2-1, R3-2, Pr-3, R9-2),
(R1-5, R2-1, R3-2, Pr-3, R9-3), (R1-5, R2-1, R3-2, Pr-4, R9-1),
(R1-5, R2-1, R3-2, Pr-4, R9-2), (R1-5, R2-1, R3-2, Pr-4, R9-3),
(R1-5, R2-1, R3-3, Pr-1, R9-1), (R1-5, R2-1, R3-3, Pr-1, R9-2),
(R1-5, R2-1, R3-3, Pr-1, R9-3), (R1-5, R2-1, R3-3, Pr-2, R9-1),
(R1-5, R2-1, R3-3, Pr-2, R9-2), (R1-5, R2-1, R3-3, Pr-2, R9-3),
(R1-5, R2-1, R3-3, Pr-3, R9-1), (R1-5, R2-1, R3-3, Pr-3, R9-2),
(R1-5, R2-1, R3-3, Pr-3, R9-3), (R1-5, R2-1, R3-3, Pr-4, R9-1),
(R1-5, R2-1, R3-3, Pr-4, R9-2), (R1-5, R2-1, R3-3, Pr-4, R9-3),
(R1-5, R2-1, R3-4, Pr-1, R9-1), (R1-5, R2-1, R3-4, Pr-1, R9-2),
(R1-5, R2-1, R3-4, Pr-1, R9-3), (R1-5, R2-1, R3-4, Pr-2, R9-1),
(R1-5, R2-1, R3-4, Pr-2, R9-2), (R1-5, R2-1, R3-4, Pr-2, R9-3),
(R1-5, R2-1, R3-4, Pr-3, R9-1), (R1-5, R2-1, R3-4, Pr-3, R9-2),
(R1-5, R2-1, R3-4, Pr-3, R9-3), (R1-5, R2-1, R3-4, Pr-4, R9-1),
(R1-5, R2-1, R3-4, Pr-4, R9-2), (R1-5, R2-1, R3-4, Pr-4, R9-3),
(R1-5, R2-1, R3-5, Pr-1, R9-1), (R1-5, R2-1, R3-5, Pr-1, R9-2),
(R1-5, R2-1, R3-5, Pr-1, R9-3), (R1-5, R2-1, R3-5, Pr-2, R9-1),
(R1-5, R2-1, R3-5, Pr-2, R9-2), (R1-5, R2-1, R3-5, Pr-2, R9-3),
(R1-5, R2-1, R3-5, Pr-3, R9-1), (R1-5, R2-1, R3-5, Pr-3, R9-2),
(R1-5, R2-1, R3-5, Pr-3, R9-3), (R1-5, R2-1, R3-5, Pr-4, R9-1),
(R1-5, R2-1, R3-5, Pr-4, R9-2), (R1-5, R2-1, R3-5, Pr-4, R9-3),
(R1-5, R2-2, R3-1, Pr-1, R9-1), (R1-5, R2-2, R3-1, Pr-1, R9-2),
(R1-5, R2-2, R3-1, Pr-1, R9-3), (R1-5, R2-2, R3-1, Pr-2, R9-1),
(R1-5, R2-2, R3-1, Pr-2, R9-2), (R1-5, R2-2, R3-1, Pr-2, R9-3),
(R1-5, R2-2, R3-1, Pr-3, R9-1), (R1-5, R2-2, R3-1, Pr-3, R9-2),
(R1-5, R2-2, R3-1, Pr-3, R9-3), (R1-5, R2-2, R3-1, Pr-4, R9-1),
(R1-5, R2-2, R3-1, Pr-4, R9-2), (R1-5, R2-2, R3-1, Pr-4, R9-3),
(R1-5, R2-2, R3-2, Pr-1, R9-1), (R1-5, R2-2, R3-2, Pr-1, R9-2),
(R1-5, R2-2, R3-2, Pr-1, R9-3), (R1-5, R2-2, R3-2, Pr-2, R9-1),
(R1-5, R2-2, R3-2, Pr-2, R9-2), (R1-5, R2-2, R3-2, Pr-2, R9-3),
(R1-5, R2-2, R3-2, Pr-3, R9-1), (R1-5, R2-2, R3-2, Pr-3, R9-2),
(R1-5, R2-2, R3-2, Pr-3, R9-3), (R1-5, R2-2, R3-2, Pr-4, R9-1),
(R1-5, R2-2, R3-2, Pr-4, R9-2), (R1-5, R2-2, R3-2, Pr-4, R9-3),
(R1-5, R2-2, R3-3, Pr-1, R9-1), (R1-5, R2-2, R3-3, Pr-1, R9-2),
(R1-5, R2-2, R3-3, Pr-1, R9-3), (R1-5, R2-2, R3-3, Pr-2, R9-1),
(R1-5, R2-2, R3-3, Pr-2, R9-2), (R1-5, R2-2, R3-3, Pr-2, R9-3),
(R1-5, R2-2, R3-3, Pr-3, R9-1), (R1-5, R2-2, R3-3, Pr-3, R9-2),
(R1-5, R2-2, R3-3, Pr-3, R9-3), (R1-5, R2-2, R3-3, Pr-4, R9-1),
(R1-5, R2-2, R3-3, Pr-4, R9-2), (R1-5, R2-2, R3-3, Pr-4, R9-3),
(R1-5, R2-2, R3-4, Pr-1, R9-1), (R1-5, R2-2, R3-4, Pr-1, R9-2),
(R1-5, R2-2, R3-4, Pr-1, R9-3), (R1-5, R2-2, R3-4, Pr-2, R9-1),
(R1-5, R2-2, R3-4, Pr-2, R9-2), (R1-5, R2-2, R3-4, Pr-2, R9-3),
(R1-5, R2-2, R3-4, Pr-3, R9-1), (R1-5, R2-2, R3-4, Pr-3, R9-2),
(R1-5, R2-2, R3-4, Pr-3, R9-3), (R1-5, R2-2, R3-4, Pr-4, R9-1),
(R1-5, R2-2, R3-4, Pr-4, R9-2), (R1-5, R2-2, R3-4, Pr-4, R9-3),
(R1-5, R2-2, R3-5, Pr-1, R9-1), (R1-5, R2-2, R3-5, Pr-1, R9-2),
(R1-5, R2-2, R3-5, Pr-1, R9-3), (R1-5, R2-2, R3-5, Pr-2, R9-1),
(R1-5, R2-2, R3-5, Pr-2, R9-2), (R1-5, R2-2, R3-5, Pr-2, R9-3),
(R1-5, R2-2, R3-5, Pr-3, R9-1), (R1-5, R2-2, R3-5, Pr-3, R9-2),
(R1-5, R2-2, R3-5, Pr-3, R9-3), (R1-5, R2-2, R3-5, Pr-4, R9-1),
(R1-5, R2-2, R3-5, Pr-4, R9-2), (R1-5, R2-2, R3-5, Pr-4, R9-3),
[0633] (R1-6, R2-1, R3-1, Pr-1, R9-1), (R1-6, R2-1, R3-1, Pr-1,
R9-2), (R1-6, R2-1, R3-1, Pr-1, R9-3), (R1-6, R2-1, R3-1, Pr-2,
R9-1), (R1-6, R2-1, R3-1, Pr-2, R9-2), (R1-6, R2-1, R3-1, Pr-2,
R9-3), (R1-6, R2-1, R3-1, Pr-3, R9-1), (R1-6, R2-1, R3-1, Pr-3, R9-
2), (R1-6, R2-1, R3-1, Pr-3, R9-3), (R1-6, R2-1, R3-1, Pr-4, R9-1),
(R1-6, R2-1, R3-1, Pr-4, R9-2), (R1-6, R2-1, R3-1, Pr-4, R9-3),
(R1-6, R2-1, R3-2, Pr-1, R9-1), (R1-6, R2-1, R3-2, Pr-1, R9-2),
(R1-6, R2-1, R3-2, Pr-1, R9-3), (R1-6, R2-1, R3-2, Pr-2, R9-1),
(R1-6, R2-1, R3-2, Pr-2, R9-2), (R1-6, R2-1, R3-2, Pr-2, R9-3),
(R1-6, R2-1, R3-2, Pr-3, R9-1), (R1-6, R2-1, R3-2, Pr-3, R9-2),
(R1-6, R2-1, R3-2, Pr-3, R9-3), (R1-6, R2-1, R3-2, Pr-4, R9-1),
(R1-6, R2-1, R3-2, Pr-4, R9-2), (R1-6, R2-1, R3-2, Pr-4, R9-3),
(R1-6, R2-1, R3-3, Pr-1, R9-1), (R1-6, R2-1, R3-3, Pr-1, R9-2),
(R1-6, R2-1, R3-3, Pr-1, R9-3), (R1-6, R2-1, R3-3, Pr-2, R9-1),
(R1-6, R2-1, R3-3, Pr-2, R9-2), (R1-6, R2-1, R3-3, Pr-2, R9-3),
(R1-6, R2-1, R3-3, Pr-3, R9-1), (R1-6, R2-1, R3-3, Pr-3, R9-2),
(R1-6, R2-1, R3-3, Pr-3, R9-3), (R1-6, R2-1, R3-3, Pr-4, R9-1),
(R1-6, R2-1, R3-3, Pr-4, R9-2), (R1-6, R2-1, R3-3, Pr-4, R9-3),
(R1-6, R2-1, R3-4, Pr-1, R9-1), (R1-6, R2-1, R3-4, Pr-1, R9-2),
(R1-6, R2-1, R3-4, Pr-1, R9-3), (R1-6, R2-1, R3-4, Pr-2, R9-1),
(R1-6, R2-1, R3-4, Pr-2, R9-2), (R1-6, R2-1, R3-4, Pr-2, R9-3),
(R1-6, R2-1, R3-4, Pr-3, R9-1), (R1-6, R2-1, R3-4, Pr-3, R9-2),
(R1-6, R2-1, R3-4, Pr-3, R9-3), (R1-6, R2-1, R3-4, Pr-4, R9-1),
(R1-6, R2-1, R3-4, Pr-4, R9-2), (R1-6, R2-1, R3-4, Pr-4, R9-3),
(R1-6, R2-1, R3-5, Pr-1, R9-1), (R1-6, R2-1, R3-5, Pr-1, R9-2),
(R1-6, R2-1, R3-5, Pr-1, R9-3), (R1-6, R2-1, R3-5, Pr-2, R9-1),
(R1-6, R2-1, R3-5, Pr-2, R9-2), (R1-6, R2-1, R3-5, Pr-2, R9-3),
(R1-6, R2-1, R3-5, Pr-3, R9-1), (R1-6, R2-1, R3-5, Pr-3, R9-2),
(R1-6, R2-1, R3-5, Pr-3, R9-3), (R1-6, R2-1, R3-5, Pr-4, R9-1),
(R1-6, R2-1, R3-5, Pr-4, R9-2), (R1-6, R2-1, R3-5, Pr-4, R9-3),
(R1-6, R2-2, R3-1, Pr-1, R9-1), (R1-6, R2-2, R3-1, Pr-1, R9-2),
(R1-6, R2-2, R3-1, Pr-1, R9-3), (R1-6, R2-2, R3-1, Pr-2, R9-1),
(R1-6, R2-2, R3-1, Pr-2, R9-2), (R1-6, R2-2, R3-1, Pr-2, R9-3),
(R1-6, R2-2, R3-1, Pr-3, R9-1), (R1-6, R2-2, R3-1, Pr-3, R9-2),
(R1-6, R2-2, R3-1, Pr-3, R9-3), (R1-6, R2-2, R3-1, Pr-4, R9-1),
(R1-6, R2-2, R3-1, Pr-4, R9-2), (R1-6, R2-2, R3-1, Pr-4, R9-3),
(R1-6, R2-2, R3-2, Pr-1, R9-1), (R1-6, R2-2, R3-2, Pr-1, R9-2),
(R1-6, R2-2, R3-2, Pr-1, R9-3), (R1-6, R2-2, R3-2, Pr-2, R9-1),
(R1-6, R2-2, R3-2, Pr-2, R9-2), (R1-6, R2-2, R3-2, Pr-2, R9-3),
(R1-6, R2-2, R3-2, Pr-3, R9-1), (R1-6, R2-2, R3-2, Pr-3, R9-2),
(R1-6, R2-2, R3-2, Pr-3, R9-3), (R1-6, R2-2, R3-2, Pr-4, R9-1),
(R1-6, R2-2, R3-2, Pr-4, R9-2), (R1-6, R2-2, R3-2, Pr-4, R9-3),
(R1-6, R2-2, R3-3, Pr-1, R9-1), (R1-6, R2-2, R3-3, Pr-1, R9-2),
(R1-6, R2-2, R3-3, Pr-1, R9-3), (R1-6, R2-2, R3-3, Pr-2, R9-1),
(R1-6, R2-2, R3-3, Pr-2, R9-2), (R1-6, R2-2, R3-3, Pr-2, R9-3),
(R1-6, R2-2, R3-3, Pr-3, R9-1), (R1-6, R2-2, R3-3, Pr-3, R9-2),
(R1-6, R2-2, R3-3, Pr-3, R9-3), (R1-6, R2-2, R3-3, Pr-4, R9-1),
(R1-6, R2-2, R3-3, Pr-4, R9-2), (R1-6, R2-2, R3-3, Pr-4, R9-3),
(R1-6, R2-2, R3-4, Pr-1, R9-1), (R1-6, R2-2, R3-4, Pr-1, R9-2),
(R1-6, R2-2, R3-4, Pr-1, R9-3), (R1-6, R2-2, R3-4, Pr-2, R9-1),
(R1-6, R2-2, R3-4, Pr-2, R9-2), (R1-6, R2-2, R3-4, Pr-2, R9-3),
(R1-6, R2-2, R3-4, Pr-3, R9-1), (R1-6, R2-2, R3-4, Pr-3, R9-2),
(R1-6, R2-2, R3-4, Pr-3, R9-3), (R1-6, R2-2, R3-4, Pr-4, R9-1),
(R1-6, R2-2, R3-4, Pr-4, R9-2), (R1-6, R2-2, R3-4, Pr-4, R9-3),
(R1-6, R2-2, R3-5, Pr-1, R9-1), (R1-6, R2-2, R3-5, Pr-1, R9-2),
(R1-6, R2-2, R3-5, Pr-1, R9-3), (R1-6, R2-2, R3-5, Pr-2, R9-1),
(R1-6, R2-2, R3-5, Pr-2, R9-2), (R1-6, R2-2, R3-5, Pr-2, R9-3),
(R1-6, R2-2, R3-5, Pr-3, R9-1), (R1-6, R2-2, R3-5, Pr-3, R9-2),
(R1-6, R2-2, R3-5, Pr-3, R9-3), (R1-6, R2-2, R3-5, Pr-4, R9-1),
(R1-6, R2-2, R3-5, Pr-4, R9-2), (R1-6, R2-2, R3-5, Pr-4, R9-3),
[0634] (R1-7, R2-1, R3-1, Pr-1, R9-1), (R1-7, R2-1, R3-1, Pr-1,
R9-2), (R1-7, R2-1, R3-1, Pr-1, R9-3), (R1-7, R2-1, R3-1, Pr-2,
R9-1), (R1-7, R2-1, R3-1, Pr-2, R9-2), (R1-7, R2-1, R3-1, Pr-2,
R9-3), (R1-7, R2-1, R3-1, Pr-3, R9-1), (R1-7, R2-1, R3-1, Pr-3, R9-
2), (R1-7, R2-1, R3-1, Pr-3, R9-3), (R1-7, R2-1, R3-1, Pr-4, R9-1),
(R1-7, R2-1, R3-1, Pr-4, R9-2), (R1-7, R2-1, R3-1, Pr-4, R9-3),
(R1-7, R2-1, R3-2, Pr-1, R9-1), (R1-7, R2-1, R3-2, Pr-1, R9-2),
(R1-7, R2-1, R3-2, Pr-1, R9-3), (R1-7, R2-1, R3-2, Pr-2, R9-1),
(R1-7, R2-1, R3-2, Pr-2, R9-2), (R1-7, R2-1, R3-2, Pr-2, R9-3),
(R1-7, R2-1, R3-2, Pr-3, R9-1), (R1-7, R2-1, R3-2, Pr-3, R9-2),
(R1-7, R2-1, R3-2, Pr-3, R9-3), (R1-7, R2-1, R3-2, Pr-4, R9-1),
(R1-7, R2-1, R3-2, Pr-4, R9-2), (R1-7, R2-1, R3-2, Pr-4, R9-3),
(R1-7, R2-1, R3-3, Pr-1, R9-1), (R1-7, R2-1, R3-3, Pr-1, R9-2),
(R1-7, R2-1, R3-3, Pr-1, R9-3), (R1-7, R2-1, R3-3, Pr-2, R9-1),
(R1-7, R2-1, R3-3, Pr-2, R9-2), (R1-7, R2-1, R3-3, Pr-2, R9-3),
(R1-7, R2-1, R3-3, Pr-3, R9-1), (R1-7, R2-1, R3-3, Pr-3, R9-2),
(R1-7, R2-1, R3-3, Pr-3, R9-3), (R1-7, R2-1, R3-3, Pr-4, R9-1),
(R1-7, R2-1, R3-3, Pr-4, R9-2), (R1-7, R2-1, R3-3, Pr-4, R9-3),
(R1-7, R2-1, R3-4, Pr-1, R9-1), (R1-7, R2-1, R3-4, Pr-1, R9-2),
(R1-7, R2-1, R3-4, Pr-1, R9-3), (R1-7, R2-1, R3-4, Pr-2, R9-1),
(R1-7, R2-1, R3-4, Pr-2, R9-2), (R1-7, R2-1, R3-4, Pr-2, R9-3),
(R1-7, R2-1, R3-4, Pr-3, R9-1), (R1-7, R2-1, R3-4, Pr-3, R9-2),
(R1-7, R2-1, R3-4, Pr-3, R9-3), (R1-7, R2-1, R3-4, Pr-4, R9-1),
(R1-7, R2-1, R3-4, Pr-4, R9-2), (R1-7, R2-1, R3-4, Pr-4, R9-3),
(R1-7, R2-1, R3-5, Pr-1, R9-1), (R1-7, R2-1, R3-5, Pr-1, R9-2),
(R1-7, R2-1, R3-5, Pr-1, R9-3), (R1-7, R2-1, R3-5, Pr-2, R9-1),
(R1-7, R2-1, R3-5, Pr-2, R9-2), (R1-7, R2-1, R3-5, Pr-2, R9-3),
(R1-7, R2-1, R3-5, Pr-3, R9-1), (R1-7, R2-1, R3-5, Pr-3, R9-2),
(R1-7, R2-1, R3-5, Pr-3, R9-3), (R1-7, R2-1, R3-5, Pr-4, R9-1),
(R1-7, R2-1, R3-5, Pr-4, R9-2), (R1-7, R2-1, R3-5, Pr-4, R9-3),
(R1-7, R2-2, R3-1, Pr-1, R9-1), (R1-7, R2-2, R3-1, Pr-1, R9-2),
(R1-7, R2-2, R3-1, Pr-1, R9-3), (R1-7, R2-2, R3-1, Pr-2, R9-1),
(R1-7, R2-2, R3-1, Pr-2, R9-2), (R1-7, R2-2, R3-1, Pr-2, R9-3),
(R1-7, R2-2, R3-1, Pr-3, R9-1), (R1-7, R2-2, R3-1, Pr-3, R9-2),
(R1-7, R2-2, R3-1, Pr-3, R9-3), (R1-7, R2-2, R3-1, Pr-4, R9-1),
(R1-7, R2-2, R3-1, Pr-4, R9-2), (R1-7, R2-2, R3-1, Pr-4, R9-3),
(R1-7, R2-2, R3-2, Pr-1, R9-1), (R1-7, R2-2, R3-2, Pr-1, R9-2),
(R1-7, R2-2, R3-2, Pr-1, R9-3), (R1-7, R2-2, R3-2, Pr-2, R9-1),
(R1-7, R2-2, R3-2, Pr-2, R9-2), (R1-7, R2-2, R3-2, Pr-2, R9-3),
(R1-7, R2-2, R3-2, Pr-3, R9-1), (R1-7, R2-2, R3-2, Pr-3, R9-2),
(R1-7, R2-2, R3-2, Pr-3, R9-3), (R1-7, R2-2, R3-2, Pr-4, R9-1),
(R1-7, R2-2, R3-2, Pr-4, R9-2), (R1-7, R2-2, R3-2, Pr-4, R9-3),
(R1-7, R2-2, R3-3, Pr-1, R9-1), (R1-7, R2-2, R3-3, Pr-1, R9-2),
(R1-7, R2-2, R3-3, Pr-1, R9-3), (R1-7, R2-2, R3-3, Pr-2, R9-1),
(R1-7, R2-2, R3-3, Pr-2, R9-2), (R1-7, R2-2, R3-3, Pr-2, R9-3),
(R1-7, R2-2, R3-3, Pr-3, R9-1), (R1-7, R2-2, R3-3, Pr-3, R9-2),
(R1-7, R2-2, R3-3, Pr-3, R9-3), (R1-7, R2-2, R3-3, Pr-4, R9-1),
(R1-7, R2-2, R3-3, Pr-4, R9-2), (R1-7, R2-2, R3-3, Pr-4, R9-3),
(R1-7, R2-2, R3-4, Pr-1, R9-1), (R1-7, R2-2, R3-4, Pr-1, R9-2),
(R1-7, R2-2, R3-4, Pr-1, R9-3), (R1-7, R2-2, R3-4, Pr-2, R9-1),
(R1-7, R2-2, R3-4, Pr-2, R9-2), (R1-7, R2-2, R3-4, Pr-2, R9-3),
(R1-7, R2-2, R3-4, Pr-3, R9-1), (R1-7, R2-2, R3-4, Pr-3, R9-2),
(R1-7, R2-2, R3-4, Pr-3, R9-3), (R1-7, R2-2, R3-4, Pr-4, R9-1),
(R1-7, R2-2, R3-4, Pr-4, R9-2), (R1-7, R2-2, R3-4, Pr-4, R9-3),
(R1-7, R2-2, R3-5, Pr-1, R9-1), (R1-7, R2-2, R3-5, Pr-1, R9-2),
(R1-7, R2-2, R3-5, Pr-1, R9-3), (R1-7, R2-2, R3-5, Pr-2, R9-1),
(R1-7, R2-2, R3-5, Pr-2, R9-2), (R1-7, R2-2, R3-5, Pr-2, R9-3),
(R1-7, R2-2, R3-5, Pr-3, R9-1), (R1-7, R2-2, R3-5, Pr-3, R9-2),
(R1-7, R2-2, R3-5, Pr-3, R9-3), (R1-7, R2-2, R3-5, Pr-4, R9-1),
(R1-7, R2-2, R3-5, Pr-4, R9-2), (R1-7, R2-2, R3-5, Pr-4, R9-3),
[0635] (R1-8, R2-1, R3-1, Pr-1, R9-1), (R1-8, R2-1, R3-1, Pr-1,
R9-2), (R1-8, R2-1, R3-1, Pr-1, R9-3), (R1-8, R2-1, R3-1, Pr-2,
R9-1), (R1-8, R2-1, R3-1, Pr-2, R9-2), (R1-8, R2-1, R3-1, Pr-2,
R9-3), (R1-8, R2-1, R3-1, Pr-3, R9-1), (R1-8, R2-1, R3-1, Pr-3, R9-
2), (R1-8, R2-1, R3-1, Pr-3, R9-3), (R1-8, R2-1, R3-1, Pr-4, R9-1),
(R1-8, R2-1, R3-1, Pr-4, R9-2), (R1-8, R2-1, R3-1, Pr-4, R9-3),
(R1-8, R2-1, R3-2, Pr-1, R9-1), (R1-8, R2-1, R3-2, Pr-1, R9-2),
(R1-8, R2-1, R3-2, Pr-1, R9-3), (R1-8, R2-1, R3-2, Pr-2, R9-1),
(R1-8, R2-1, R3-2, Pr-2, R9-2), (R1-8, R2-1, R3-2, Pr-2, R9-3),
(R1-8, R2-1, R3-2, Pr-3, R9-1), (R1-8, R2-1, R3-2, Pr-3, R9-2),
(R1-8, R2-1, R3-2, Pr-3, R9-3), (R1-8, R2-1, R3-2, Pr-4, R9-1),
(R1-8, R2-1, R3-2, Pr-4, R9-2), (R1-8, R2-1, R3-2, Pr-4, R9-3),
(R1-8, R2-1, R3-3, Pr-1, R9-1), (R1-8, R2-1, R3-3, Pr-1, R9-2),
(R1-8, R2-1, R3-3, Pr-1, R9-3), (R1-8, R2-1, R3-3, Pr-2, R9-1),
(R1-8, R2-1, R3-3, Pr-2, R9-2), (R1-8, R2-1, R3-3, Pr-2, R9-3),
(R1-8, R2-1, R3-3, Pr-3, R9-1), (R1-8, R2-1, R3-3, Pr-3, R9-2),
(R1-8, R2-1, R3-3, Pr-3, R9-3), (R1-8, R2-1, R3-3, Pr-4, R9-1),
(R1-8, R2-1, R3-3, Pr-4, R9-2), (R1-8, R2-1, R3-3, Pr-4, R9-3),
(R1-8, R2-1, R3-4, Pr-1, R9-1), (R1-8, R2-1, R3-4, Pr-1, R9-2),
(R1-8, R2-1, R3-4, Pr-1, R9-3), (R1-8, R2-1, R3-4, Pr-2, R9-1),
(R1-8, R2-1, R3-4, Pr-2, R9-2), (R1-8, R2-1, R3-4, Pr-2, R9-3),
(R1-8, R2-1, R3-4, Pr-3, R9-1), (R1-8, R2-1, R3-4, Pr-3, R9-2),
(R1-8, R2-1, R3-4, Pr-3, R9-3), (R1-8, R2-1, R3-4, Pr-4, R9-1),
(R1-8, R2-1, R3-4, Pr-4, R9-2), (R1-8, R2-1, R3-4, Pr-4, R9-3),
(R1-8, R2-1, R3-5, Pr-1, R9-1), (R1-8, R2-1, R3-5, Pr-1, R9-2),
(R1-8, R2-1, R3-5, Pr-1, R9-3), (R1-8, R2-1, R3-5, Pr-2, R9-1),
(R1-8, R2-1, R3-5, Pr-2, R9-2), (R1-8, R2-1, R3-5, Pr-2, R9-3),
(R1-8, R2-1, R3-5, Pr-3, R9-1), (R1-8, R2-1, R3-5, Pr-3, R9-2),
(R1-8, R2-1, R3-5, Pr-3, R9-3), (R1-8, R2-1, R3-5, Pr-4, R9-1),
(R1-8, R2-1, R3-5, Pr-4, R9-2), (R1-8, R2-1, R3-5, Pr-4, R9-3),
(R1-8, R2-2, R3-1, Pr-1, R9-1), (R1-8, R2-2, R3-1, Pr-1, R9-2),
(R1-8, R2-2, R3-1, Pr-1, R9-3), (R1-8, R2-2, R3-1, Pr-2, R9-1),
(R1-8, R2-2, R3-1, Pr-2, R9-2), (R1-8, R2-2, R3-1, Pr-2, R9-3),
(R1-8, R2-2, R3-1, Pr-3, R9-1), (R1-8, R2-2, R3-1, Pr-3, R9-2),
(R1-8, R2-2, R3-1, Pr-3, R9-3), (R1-8, R2-2, R3-1, Pr-4, R9-1),
(R1-8, R2-2, R3-1, Pr-4, R9-2), (R1-8, R2-2, R3-1, Pr-4, R9-3),
(R1-8, R2-2, R3-2, Pr-1, R9-1), (R1-8, R2-2, R3-2, Pr-1, R9-2),
(R1-8, R2-2, R3-2, Pr-1, R9-3), (R1-8, R2-2, R3-2, Pr-2, R9-1),
(R1-8, R2-2, R3-2, Pr-2, R9-2), (R1-8, R2-2, R3-2, Pr-2, R9-3),
(R1-8, R2-2, R3-2, Pr-3, R9-1), (R1-8, R2-2, R3-2, Pr-3, R9-2),
(R1-8, R2-2, R3-2, Pr-3, R9-3), (R1-8, R2-2, R3-2, Pr-4, R9-1),
(R1-8, R2-2, R3-2, Pr-4, R9-2), (R1-8, R2-2, R3-2, Pr-4, R9-3),
(R1-8, R2-2, R3-3, Pr-1, R9-1), (R1-8, R2-2, R3-3, Pr-1, R9-2),
(R1-8, R2-2, R3-3, Pr-1, R9-3), (R1-8, R2-2, R3-3, Pr-2, R9-1),
(R1-8, R2-2, R3-3, Pr-2, R9-2), (R1-8, R2-2, R3-3, Pr-2, R9-3),
(R1-8, R2-2, R3-3, Pr-3, R9-1), (R1-8, R2-2, R3-3, Pr-3, R9-2),
(R1-8, R2-2, R3-3, Pr-3, R9-3), (R1-8, R2-2, R3-3, Pr-4, R9-1),
(R1-8, R2-2, R3-3, Pr-4, R9-2), (R1-8, R2-2, R3-3, Pr-4, R9-3),
(R1-8, R2-2, R3-4, Pr-1, R9-1), (R1-8, R2-2, R3-4, Pr-1, R9-2),
(R1-8, R2-2, R3-4, Pr-1, R9-3), (R1-8, R2-2, R3-4, Pr-2, R9-1),
(R1-8, R2-2, R3-4, Pr-2, R9-2), (R1-8, R2-2, R3-4, Pr-2, R9-3),
(R1-8, R2-2, R3-4, Pr-3, R9-1), (R1-8, R2-2, R3-4, Pr-3, R9-2),
(R1-8, R2-2, R3-4, Pr-3, R9-3), (R1-8, R2-2, R3-4, Pr-4, R9-1),
(R1-8, R2-2, R3-4, Pr-4, R9-2), (R1-8, R2-2, R3-4, Pr-4, R9-3),
(R1-8, R2-2, R3-5, Pr-1, R9-1), (R1-8, R2-2, R3-5, Pr-1, R9-2),
(R1-8, R2-2, R3-5, Pr-1, R9-3), (R1-8, R2-2, R3-5, Pr-2, R9-1),
(R1-8, R2-2, R3-5, Pr-2, R9-2), (R1-8, R2-2, R3-5, Pr-2, R9-3),
(R1-8, R2-2, R3-5, Pr-3, R9-1), (R1-8, R2-2, R3-5, Pr-3, R9-2),
(R1-8, R2-2, R3-5, Pr-3, R9-3), (R1-8, R2-2, R3-5, Pr-4, R9-1),
(R1-8, R2-2, R3-5, Pr-4, R9-2), (R1-8, R2-2, R3-5, Pr-4, R9-3).
[0636] (Method for Producing Compound of the Present Invention)
[0637] A general method for producing the compound of the present
invention will be exemplified below. And, as extraction and
purification, treatment which is performed in a normal experiment
of organic chemistry may be conducted.
[0638] Synthesis of the compound of the present invention can be
carried out referring to the procedures known in the art.
[0639] As a raw material compound, commercially available
compounds, compounds described in the present description,
compounds described in the references cited in the present
description, and other known compounds can be utilized.
[0640] Among the compounds of the present invention, there are
compounds in which a tautomer can be present, and the present
invention includes all possible isomers and a mixture thereof,
including them.
[0641] When one wants to obtain a salt of the compound of the
present invention, in the case where the compound of the present
invention is obtained in a form of a salt, it may be purified as it
is and, in the case where the compound of the present invention is
obtained in a free form, a salt may be formed by a normal method by
dissolving or suspending the compound in a suitable organic
solvent, and adding an acid or a base.
[0642] In addition, the compound of the present invention and a
pharmaceutically acceptable salt thereof are present in a form of
adducts with water or various solvents (hydrate or solvate) in some
cases, and these adducts are included in the present invention.
[0643] In a general synthesis method as well as Reference examples,
Examples, and Intermediate Synthesis Examples, the meaning of each
abbreviation is as follows.
DMF: N,N-dimethylformamide
DMA: N,N-dimethylacetamide,
NMP: N-methylpyrrolidone
[0644] DMI: dimethylimidazolidinone THF: tetrahydrofuran Ms:
methanesulfonyl Ts: paratoluenesulfonyl Boc: tert-butoxycarbonyl
DIBALH: diisobutylaluminum hydride WSC or EDCI:
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide HOBt:
1-hydroxybenzotriazole HATU:
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate
NBS: N-bromosuccinimide
NCS: N-chlorosuccinimide
[0645] TEMPO: 2,2,6,6-tetramethylpiperidine-1-oxyl radical PDC:
pyridinium dichloromate DEAD: diethyl azodicarboxylate DIAD:
diisopropyl azodicarboxylate DMAP: 4-dimethylaminopyridine mCPBA:
m-chloroperbenzoic acid DBU: 1,8-diazabicyclo[5.4.0]-7-undecene
DIPEA: diisopropylethylamine TBAF: tetrabutylammonium fluoride IBX:
2-iodoxybenzoic acid DMSO: dimethyl sulfoxide NaHMDS: sodium
hexamethyldisilazide TFA: trifluoroacetic acid Ac: acetyl TBS:
tert-butyldimethylsilyl PEPPSI.TM.-IPr:
(1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II)
dichloride BEMP:
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine
Synthesis of Compound aj of Reference Example (See: Reference
Example 1)
##STR00151## ##STR00152##
[0647] (wherein R is carboxy protective group, P.sup.1 is hydroxyl
protective group, R.sup.2, R.sup.3, R.sup.8, R.sup.9, R.sup.10 and
R.sup.11 are same as R.sup.2a, R.sup.3a, R.sup.8a, R.sup.9a,
R.sup.10a and R.sup.11a in item 1, respectively, R and P.sup.1 may
be a group which can be protected and/or deprotected by the method
described in Protective Groups in Organic Synthesis, Theodora W
Green (John Wiley & Sons) etc. and, for example, R is lower
alkyl etc., and P.sup.1 is arylalkyl etc.)
First Step
[0648] A compound ab can be obtained by reacting a compound aa
which is commercially available or can be prepared by the known
method at -20.degree. C. to 30.degree. C., preferably 0.degree. C.
to 20.degree. C. for 0.1 hours to 24 hours, preferably 0.5 hours to
12 hours in a solvent such as dichloromethane, toluene, THF etc. or
a mixed solvent thereof, by adding dropwise tertiary amine such as
pyridine, trimethylamine, N-methylmorpholine,
4-dimethylaminopyridine etc. and benzyloxyacetyl chloride.
Second Step
[0649] A compound ac can be obtained by adding an organometallic
base such as lithium hexamethyldisilazane, lithium
diisopropylamide, butyllithium, tert-butyllithium etc. to the
compound ab in a solvent such as ether, dichloromethane, THF etc.
or a mixed solvent thereof, in the presence of cinnamoyl chloride,
and performing a reaction at -80.degree. C. to 0.degree. C.,
preferably -80.degree. C. to -40.degree. C. for 1 minute to 2
hours, preferably 10 minutes to 1 hour.
Third Step
[0650] A compound ad can be obtained by adding a catalytic amount
of an oxidizing agent such as ruthenium chloride and sodium
periodate, TEMPO, manganese dioxide, as well as PDC etc. to the
compound ac in a solvent such as ether, dichloromethane, THF,
acetonitrile etc. or a mixed solvent thereof, and performing a
reaction at -40.degree. C. to 80.degree. C., preferably 0.degree.
C. to 40.degree. C. for 0.1 hours to 24 hours, preferably 0.2 hours
to 3 hours.
Fourth Step
[0651] Concentrated sulfuric acid and an aqueous solution of
amidosululic acid are added to the compound ad at 0.degree. C. to
60.degree. C., preferably 10.degree. C. to 40.degree. C. in the
presence of a solvent such as ether, dichloromethane, THF,
acetonitrile, acetone, water etc. or in a mixed solvent thereof. An
aqueous sodium chlorite solution is added dropwise thereto at the
same temperature to perform a reaction for 1 minute to 3 hours,
preferably 5 minutes to 1 hour, thereby, a compound ae can be
obtained.
Fifth Step
[0652] A compound af can be obtained by adding a compound
R.sup.3--NH.sub.2 having a substituent corresponding to an
objective compound to the compound ae in a solvent such as DMF,
THF, dichloromethane, acetonitrile etc. in the presence of a
dehydration-condensation agent such as dicyclohexylcarbodiimide,
carbonyldiimidazole,
dicyclohexylcarbodiimido-N-hydroxybenzotriazole,
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,
hexafluorophosphoric acid
2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl,
HATU etc., and performing a reaction at -20.degree. C. to
60.degree. C., preferably -10.degree. C. to 40.degree. C. for 0.1
hours to 24 hours, preferably 1 hour to 12 hours.
Sixth Step
[0653] A compound ah can be obtained by adding a compound ag to the
compound af in the presence of a solvent such as toluene, xylene,
THF, dioxane etc. or in a mixed solvent thereof, and performing a
reaction for 0.1 hours to 12 hours, preferably 0.2 hours to 6 hours
under the heat-refluxing condition.
Seventh Step
[0654] A compound ai can be obtained by adding triphenylphosphine
and a condensation agent such as DEAD, DIAD etc. to the compound ah
in the presence of a solvent such as THF, dioxane, ethyl acetate,
acetonitrile etc. or in a mixed solvent thereof, and performing a
reaction at 0.degree. C. to 60.degree. C., preferably 10.degree. C.
to 40.degree. C. for 0.1 hours to 12 hours, preferably 0.2 hours to
6 hours.
Eighth Step
[0655] By subjecting the compound ai to the known general
deprotecting reaction of a carboxyl protective group and a hydroxyl
protective group, a compound aj can be obtained.
Synthesis of Compound bk of Reference Example (See: Reference
Example 12)
##STR00153## ##STR00154##
[0657] (wherein P.sup.2 is amino protective group, P.sup.2 may be a
group which can be protected and/or deprotected by the method
described in Protective Groups in Organic Synthesis, Theodora W
Green (John Wiley & Sons) etc. and, for example, P.sup.2 is
arylalkyloxycarbonyl, lower alkyloxycarbonyl, etc. Other each
symbol is same as above.)
First Step
[0658] A compound bb can be obtained by adding a base such as
potassium carbonate, sodium carbonate, cesium carbonate etc. and a
compound P.sup.2-L (wherein L is a leaving group such as halogen,
OMs etc.) having a substituent corresponding to an objective
compound to a compound ba in the presence of a solvent such as DMF,
THF, dioxane, acetonitrile etc. or in a mixed solvent thereof, and
performing a reaction at -20.degree. C. to 80.degree. C.,
preferably 0.degree. C. to 50.degree. C. for 0.1 hours to 6 hours,
preferably 0.2 hours to 6 hours.
Second Step
[0659] A compound bc can be obtained by adding triphenylphosphine
and phthalimide to the compound bb in the presence of a solvent
such as DMF, THF, dioxane, acetonitrile etc. or in a mixed solvent
thereof, adding a dehydration-condensation reagent such as DIAD,
DEAD etc., and performing a reaction at -10.degree. C. to
60.degree. C., preferably 0.degree. C. to 50.degree. C. for 0.1
hours to 24 hours, preferably 0.2 hours to 12 hours.
Third Step
[0660] A compound bd can be obtained by adding hydrazine hydrate or
methylhydrazine to the compound bc in the presence of a solvent
such as methanol, THF, dioxane, acetonitrile, etc. or in a mixed
solvent thereof, and performing a reaction at -10.degree. C. to
80.degree. C., preferably 10.degree. C. to 60.degree. C. for 0.5
hours to 24 hours, preferably 1 to 12 hours.
Fourth Step
[0661] A compound be can be obtained by adding Boc.sub.2O to the
compound bd in the presence of a solvent such as THF, dioxane,
acetonitrile etc. or in a mixed solvent thereof, and performing a
reaction at -10.degree. C. to 80.degree. C., preferably 10.degree.
C. to 60.degree. C. for 0.5 hours to 24 hours, preferably 1 to 12
hours.
Fifth Step
[0662] A compound bf can be obtained by subjecting the compound be
to the known general deprotecting reaction of an amino protective
group.
Sixth Step
[0663] A compound bh can be obtained by adding a compound bg to the
compound bf in the presence of a solvent such as toluene, THF,
dioxane, acetonitrile etc. or in a mixed solvent thereof, and
performing a reaction at 20.degree. C. to 110.degree. C.,
preferably 40.degree. C. to under heat-refluxing for 0.5 hours to
24 hours, preferably 1 hour to 12 hours.
Seventh Step
[0664] HCl-ethyl acetate, HCl-dioxane, formic acid etc. is added to
the compound bh, and they are reacted at 0.degree. C. to 40.degree.
C., preferably 0.degree. C. to 20.degree. C. for 0.5 hours to 12
hours, preferably 1 hour to 6 hours. After the solvent is distilled
off under reduced pressure, an aqueous saturated sodium bicarbonate
solution is added, and the mixture is stirred, thereby, a compound
bi can be obtained.
Eighth Step
[0665] A compound bj can be obtained by adding a base such as
potassium carbonate, sodium carbonate, lithium carbonate, cesium
carbonate etc. and a compound R.sup.3-L (L is a leaving group such
as halogen, OMs etc.) to the compound bi in the presence of a
solvent such as DMF, THF, DMA, NMP etc. or in a mixed solvent
thereof, and performing a reaction at 0.degree. C. to 60.degree.
C., preferably 10.degree. C. to 30.degree. C. for 0.5 hours to 12
hours, preferably 1 hour to 6 hours.
Ninth Step
[0666] A compound bk can be obtained by subjecting the compound bj
to the known general deprotecting reaction of a carboxyl protective
group and a hydroxyl protective group.
Synthesis of Compound cd of Reference Example (See: Reference
Examples 28 and 43)
##STR00155##
[0668] (wherein each symbol is same as above)
First Step
[0669] A compound cb can be obtained by adding tertiary amine such
as triethylamine, DMAP, morpholine etc. or a base such as sodium
carbonate, sodium bicarbonate etc. to a compound ca in the presence
of a solvent such as THF, dioxane, acetonitrile, water etc. or in a
mixed solvent thereof, adding Boc.sub.2O, and performing a reaction
at -10.degree. C. to 80.degree. C., preferably 10.degree. C. to
60.degree. C. for 0.5 hours to 24 hours, preferably 1 to 12
hours.
Second Step
[0670] A compound cc can be obtained by adding triphenylphosphine
and phthalimide to the compound cb in the presence of a solvent
such as DMF, THF, dioxane, acetonitrile etc. or in a mixed solvent
thereof, adding a dehydration-condensation reagent such as DIAD,
DEAD etc., and performing a reaction at -10.degree. C. to
60.degree. C., preferably 0.degree. C. to 50.degree. C. for 0.1
hours to 24 hours, preferably 0.2 hours to 12 hours.
Third Step
[0671] A compound cd can be obtained by adding hydrazine hydrate to
the compound cc in the presence of a solvent such as methanol, THF,
dioxane, acetonitrile etc. or in a mixed solvent thereof, and
performing a reaction at -10.degree. C. to 80.degree. C.,
preferably 10.degree. C. to 60.degree. C. for 0.5 hours to 24
hours, preferably 1 to 12 hours.
Synthesis of Compound dg of Reference Example (See: Reference
Examples 36, 41, and 46)
##STR00156##
[0673] (wherein B.sup.1 and B.sup.2 are same as those of item 1,
and other each symbol is same as above).
[0674] First Step
[0675] A compound db can be obtained by subjecting the compound da
obtained by the same method as the synthesis method of bi to the
known general carboxyl deprotecting reaction.
Second Step
[0676] A decarbonized compound dc can be obtained by reacting the
compound db for 1 minute to 2 hours under microwave irradiation in
a solvent such as diphenyl ether etc. And, a decarbonized compound
d can be obtained by adding copper in a quinoline solvent, and
performing a reaction at 180.degree. C. for 2 to 48 hours.
Third Step
[0677] A compound bd can be obtained by adding a base such as
potassium carbonate, sodium carbonate, lithium carbonate, cesium
carbonate etc. and a compound R.sup.3-L (L is a leaving group such
as halogen, OMs etc.) to the compound da obtained by the method
described in Reference example 12 in the presence of a solvent such
as DMF, THF, DMA, NMP etc. or in a mixed solvent thereof, and
performing a reaction at 0.degree. C. to 60.degree. C., preferably
10.degree. C. to 30.degree. C. for 0.5 hours to 12 hours,
preferably 1 hour to 6 hours.
Fourth Step
[0678] A compound de can be obtained by the same method as that of
the first step.
Fifth Step
[0679] A compound df can be obtained by the same method as that of
the second step.
Sixth Step
[0680] A compound df can be obtained by the same method as that of
the third step.
Seventh Step
[0681] A compound dg can be obtained by subjecting the compound df
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound ec of Reference Example (See: Reference
Example 48)
##STR00157##
[0683] (wherein each symbol is same as above)
First Step
[0684] A base such as triethylamine, N-methylmorpholine,
diisopropylethylamine etc. and ethyl chloroformate are added to a
compound ea in the presence of a solvent such as THF, dioxane,
dichloromethane, toluene etc. or in a mixed solvent thereof. A
reducing agent having a low reducing power such as sodium
borohydride etc. is added thereto, and a reaction is performed at
-20.degree. C. to 60.degree. C., preferably -10.degree. C. to
20.degree. C. for 0.2 hours to 12 hours, preferably 0.5 hours to 6
hours, thereby, a compound eb can be obtained.
Second Step
[0685] A compound ec can be obtained by subjecting the compound eb
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound fh of Reference Example (See: Reference
Example 50)
##STR00158##
[0687] (wherein R.sup.1 is a group corresponding to R.sup.1a in
item 1, and other each symbol is same as above)
First Step
[0688] A compound fb and triphenylphosphine are added to a compound
fa in the presence of a solvent such as THF, dichloromethane,
dioxane, acetonitrile etc. or in a mixed solvent thereof. DIAD is
added thereto, and a reaction is performed at 0.degree. C. to
60.degree. C., preferably 10.degree. C. to 30.degree. C. for 0.5
hours to 12 hours, preferably 1 hour to 12 hours, thereby, a
compound fc can be obtained.
Second Step
[0689] A compound fd can be obtained by adding a base such as
potassium carbonate, sodium carbonate, lithium carbonate, cesium
carbonate etc. and thiol such as benzenethiol etc. to the compound
fc in the presence of a solvent such as THF, dioxane, acetonitrile
etc. or in a mixed solvent thereof, and performing a reaction at
0.degree. C. to 60.degree. C., preferably 10.degree. C. to
30.degree. C. for 0.5 hours to 12 hours, preferably 1 hour to 12
hours.
Third Step
[0690] A compound ff can be obtained by adding a compound fe having
a substituent corresponding to an objective compound to the
compound fd in a solvent such as DMF, THF, dichloromethane,
acetonitrile etc. in the presence of a dehydration-condensation
agent such as dicyclohexylcarbodiimide, carbonyldiimidazole,
dicyclohexylcarbodiimido-N-hydroxybenzotriazole,
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,
hexafluorophosphoric acid
2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl
etc., and performing a reaction at 0.degree. C. to 60.degree. C.,
preferably 10.degree. C. to 40.degree. C. for 1 hour to 48 hours,
preferably 2 hours to 24 hours.
Fourth Step
[0691] A compound fd can be obtained by subjecting the compound ff
to the known general deprotecting reaction concerning a P.sup.2
group on an amino group, subsequently, adding a base such as an
aqueous sodium carbonate solution, an aqueous potassium carbonate
solution etc. in a solvent such as water, ethanol, methanol,
acetonitrile etc. or in a mixed solvent thereof, and performing a
reaction at 20.degree. C. to 80.degree. C., preferably 20.degree.
C. to 70.degree. C. for 0.5 hours to 24 hours, preferably 1 hour to
6 hours.
Fifth Step
[0692] A compound fh can be obtained by subjecting the compound fg
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound ga of Reference Example (See: Reference
Example 51)
##STR00159##
[0694] (wherein each symbol is same as above)
First Step
[0695] A compound ga can be obtained by subjecting a compound dd to
the known general hydroxyl group deprotecting reaction.
Synthesis of Compound hh of Reference Example (See: Reference
Example 52)
##STR00160##
[0697] (wherein each symbol is same as above)
First Step
[0698] A compound hb can be obtained by adding
O,N-dimethylhydroxylamine hydrochloride to a compound ha in a
solvent such as DMF, THF, dichloromethane, acetonitrile etc. in the
presence of a dehydration-condensation agent such as
dicyclohexylcarbodiimide, carbonyldiimidazole,
dicyclohexylcarbodiimido-N-hydroxybenzotriazole,
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,
hexafluorophosphoric acid
2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl,
HATU etc., adding a tertiary base such as triethylamine,
diisopropylethylamine, N-methylmorpholine etc., and performing a
reaction at 0.degree. C. to 60.degree. C., preferably 10.degree. C.
to 40.degree. C. for 1 hour to 24 hours, preferably 1 hour to 12
hours.
Second Step
[0699] A compound he can be obtained by adding a Grignard reagent
(R-MgBr) to the compound hb at -80.degree. C. to -40.degree. C. in
the presence of a solvent such as THF, ether, dichloromethane,
dioxane etc. or in a mixed solvent thereof, and performing a
reaction at -80.degree. C. to 0.degree. C., preferably -60.degree.
C. to -20.degree. C. for 0.5 hours to 24 hours, preferably 0.5
hours to 6 hours.
Third Step
[0700] A compound hd can be obtained by adding mCPBA to the
compound he in the presence of a solvent such as chloroform and
dichloromethane, and performing a reaction at -20.degree. C. to
30.degree. C., preferably 10.degree. C. to 30.degree. C. for 0.1
hours to 12 hours, preferably 0.5 hours to 6 hours.
Fourth Step
[0701] A compound he can be obtained by adding an aqueous sodium
hydroxide solution to the compound hd in the presence of a solvent
such as ethanol etc., and performing a reaction at 0.degree. C. to
120.degree. C., preferably 30.degree. C. to 90.degree. C. for 1
minute to 10 hours, preferably 30 minutes to 120 minutes.
Fifth Step
[0702] A compound hf can be obtained by subjecting the compound he
to the known general hydroxyl group deprotecting reaction.
Sixth Step
[0703] A compound hg can be obtained by adding a compound R-Br etc.
corresponding to an objective compound to a compound he in the
presence of a solvent such as chloroform, dichloromethane, THF,
toluene etc. or in a mixed solvent thereof, adding a metal base
such as sodium hydride, sodium methylate, n-butyllithium etc., and
performing a reaction at -20.degree. C. to 120.degree. C.,
preferably 0.degree. C. to 30.degree. C. for 0.5 hours to 12 hours,
preferably 1 hour to 6 hours.
Seventh Step
[0704] A compound hh can be obtained by subjecting the compound hg
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound ic of Reference Example (See: Reference
Example 53)
##STR00161##
[0706] (wherein each symbol is same as above)
First Step
[0707] Tertiary amine such as triethylamine, diisopropylethylamine,
N-methylmorpholine etc., and a chlorinating reagent such as ethyl
chlorocarbonate, and ethyl chloroformate are added to a compound ia
in the presence of a solvent such as DMF, DMA, NMP, THF etc. or in
a mixed solvent thereof, and the mixture is stirred at 0.degree. C.
to 30.degree. C. for 0.1 hours to 1 hour. A compound
R--SO.sub.2--NH.sub.2 (e.g.: methanesulfonylamide) corresponding to
an objective substance and DMAP are added thereto, and a reaction
is performed at 40.degree. C. to 100.degree. C., preferably
40.degree. C. to 80.degree. C. for 0.5 hours to 12 hours,
preferably 1 hour to 6 hours, thereby, a compound ib can be
obtained.
Second Step
[0708] A compound ic can be obtained by subjecting the compound ib
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound je of Reference Example (See: Reference
Example 54)
##STR00162##
[0710] (wherein each symbol is same as above)
First Step
[0711] Tertiary amine such as triethylamine, N-methylmorpholine,
diisopropylethylamine etc. and ethyl chloroformate or ethyl
chlorocarbonate are added to a compound ja in the presence of a
solvent such as THF, dioxane, dichloromethane, toluene, DMF etc. or
in a mixed solvent thereof. A reducing agent having low reactivity
such as sodium borohydride etc. is added thereto, and a reaction is
performed at -20.degree. C. to 40.degree. C., preferably
-10.degree. C. to 20.degree. C. for 0.2 hours to 12 hours,
preferably 0.5 hours to 6 hours to obtain an alcohol intermediate.
This intermediate is dissolved in dichloromethane, chloroform,
etc., an oxidizing agent such as TEMPO, manganese dioxide, PDC etc.
is added, and a reaction is performed at -40.degree. C. to
30.degree. C., preferably 0.degree. C. to 30.degree. C. for 0.1
hours to 24 hours, preferably 0.5 hours to 12 hours, thereby, a
compound jb can be obtained.
Second Step
[0712] A compound jc can be obtained by adding 28% aqueous ammonia
and iodine to the compound jb in the presence of a solvent such as
THF, dioxane, dichloromethane etc., and performing a reaction at
0.degree. C. to 40.degree. C., preferably 10.degree. C. to
30.degree. C. for 0.5 hours to 24 hours, preferably 1 hour to 6
hours.
Third Step
[0713] A compound jd can be obtained by adding sodium azide, and
tertiary amine such as triethylamine, diisopropylethylamine,
N-methylmorpholine etc. to the compound jc in the presence of a
solvent such as toluene, xylene, THF, dioxane etc. or in a mixed
solvent thereof, and performing a reaction at 0.degree. C. to
60.degree. C., preferably 10.degree. C. to 40.degree. C. for 0.5
hours to 24 hours, preferably 1 hour to 12 hours.
Fourth Step
[0714] A compound je can be obtained by subjecting the compound jd
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compounds kd and kf of Reference Example (See:
Reference Example 56 and Derivative Thereof)
##STR00163##
[0716] (wherein R.sup.m is lower alkyl, R is a substituent
corresponding to an objective compound, W is --C(.dbd.O)-- or
--SO.sub.2--, and other each symbol is same as above)
First Step
[0717] Tertiary amine such as triethylamine, N-methylmorpholine,
diisopropylethylamine etc. and ethyl chloroformate or ethyl
chlorocarbonate are added to a compound ka in the presence of a
solvent such as THF, dioxane, dichloromethane, toluene, DMF etc. or
in a mixed solvent thereof. Sodium azide is added thereto to
perform a reaction at 0.degree. C. to 40.degree. C., preferably
10.degree. C. to 30.degree. C. for 0.5 hours to 24 hours,
preferably 1 hour to 12 hours. Thereafter, an alcohol (R.sup.m--OH)
is added, and a reaction is performed at 20.degree. C. to
60.degree. C., preferably 20.degree. C. to 50.degree. C. for 0.5
hours to 24 hours, preferably 1 hour to 12 hours, thereby, a
compound kb can be obtained.
Second Step
[0718] A compound kc can be obtained by adding a base such as an
aqueous sodium hydroxide solution, an aqueous potassium hydroxide
solution etc. to the compound kb in a solvent such as ethanol,
methanol, water etc. or in a mixed solvent thereof, and performing
a reaction at 20.degree. C. to 80.degree. C., preferably 40.degree.
C. to 60.degree. C. for 0.5 hours to 24 hours, preferably 1 hour to
12 hours.
Third Step
[0719] A compound kd can be obtained by subjecting the compound kc
to the known general hydroxyl group deprotecting reaction.
Fourth Step
[0720] A compound ke can be obtained by adding acid chloride
(R--CO--Cl) or sulfonyl chloride (R--SO.sub.2--Cl) corresponding to
an objective substance to a compound kc in a solvent such as THF,
dioxane, toluene, dichloromethane etc., adding tertiary amine such
as pyridine, triethylamine, N-methylmorpholine etc. as necessary,
and performing a reaction at -20.degree. C. to 40.degree. C.,
preferably 0.degree. C. to 30.degree. C. for 0.1 hours to 12 hours,
preferably 0.2 hours to 6 hours.
Fifth Step
[0721] A compound kf can be obtained by subjecting the compound ke
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound lc of Reference Example (See: Reference
Example 60)
##STR00164##
[0723] (wherein R is a substituent corresponding to an objective
compound, and other each symbol is same as above)
First Step
[0724] Sodium hydride is added to a compound la in a solvent such
as THF, dichloromethane, DMF etc. R-L (L is a leaving group such as
halogen, OMs etc.) corresponding to an objective substance is added
thereto, and a reaction is performed at -20.degree. C. to
40.degree. C., preferably 0.degree. C. to 30.degree. C. for 0.1
hours to 12 hours, preferably 0.2 hours to 6 hours, thereby, a
compound lb can be obtained.
[0725] Alternatively, a compound lb can be obtained by adding
formaldehyde to a compound la in a solvent of formic acid, and
performing a reaction at 70.degree. C. to 110.degree. C. for 0.5
hours to 24 hours, preferably 1 hour to 12 hours.
Second Step
[0726] A compound lc can be obtained by subjecting the compound lb
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound md of Reference Example (See: Reference
Example 61)
##STR00165##
[0728] (wherein R is a substituent corresponding to an objective
compound, and other each symbol is same as above)
First Step
[0729] An amino-protected body mb can be obtained by adding
Boc.sub.2O etc. to a compound ma in a solvent such as THF, dioxane,
acetonitrile, water etc. or in a mixed solvent thereof, and
subjecting this to an amine protecting reaction.
Second Step
[0730] Sodium hydride is added to a compound mb in a solvent such
as THF, dichloromethane, DMF etc. R-L (L is a leaving group such as
halogen, OMs etc.) corresponding to an objective substance is added
thereto, and a reaction is performed at -20.degree. C. to
40.degree. C., preferably 0.degree. C. to 30.degree. C. for 0.1
hours to 12 hours, preferably 0.2 hours to 6 hours, thereby, a
compound mc can be obtained.
Third Step
[0731] A compound md can be obtained by subjecting the compound me
to the known general amino group and hydroxyl group deprotecting
reaction.
Synthesis of Compound nc and Compound ne of Reference Example (See:
Reference Examples 63 and 64)
##STR00166##
[0732] (wherein X is halogen, M is boronic acid ester such as
B(O-phenyl).sub.3 etc., and other each symbol is same as above)
First Step
[0733] A compound nb can be obtained by adding a halogenating
reagent (e.g. NBS, NCS, bromine etc.) to a compound na in a solvent
such as dichloromethane, toluene, THF, dioxane etc., and performing
a reaction for 0.1 hours to 12 hours, preferably 0.2 hours to 6
hours under the overheating refluxing condition.
Second Step
[0734] A compound nc can be obtained by subjecting the compound nb
to the known general hydroxyl group deprotecting reaction.
Third Step
[0735] Boronic acid ester (R-M) corresponding to an objective
substance is added to a compound nb in a solvent such as toluene,
THF, DMF etc. or in a mixed solvent thereof, and a base such as
potassium carbonate, sodium carbonate, sodium hydroxide etc. is
added. A 0-valent palladium catalyst (e.g.: Pd(PPh.sub.3).sub.4) is
added thereto under nitrogen stream, and a reaction is performed at
60.degree. C. to 120.degree. C., preferably 80.degree. C. to
110.degree. C. for 1 hour to 48 hours, preferably 2 hours to 24
hours, thereby, a compound nd can be obtained.
Fourth Step
[0736] A compound ne can be obtained by subjecting the compound nd
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound oh of Reference Example (See: Reference
Example 65)
##STR00167##
[0738] (wherein R is a carboxyl protective group such as lower
alkyl etc., R.sup.7 is same as R.sup.7a in item 1, L.sup.1 is a
leaving group such as halogen, OMs, OTs etc., and other symbol is
same as above)
First Step
[0739] A compound ob can be obtained by adding sodium chlorite and
amidosulfuric acid to a compound oa in the presence of a solvent
such as THF, dioxane, dichloromethane, acetonitrile etc., and
performing a reaction at 0.degree. C. to 40.degree. C., preferably
0.degree. C. to 30.degree. C. for 0.1 hours to 24 hours, preferably
1 hour to 12 hours.
Second Step
[0740] A compound oc can be obtained by adding a condensation agent
such as HATU, WSC.HCl etc. to the compound ob in the presence of a
solvent such as DMF, DMA, NMP, THF etc., adding amine
(R.sup.3--NH.sub.2) corresponding to an objective substance, and
tertiary amine such as triethylamine, N-methylmorpholine, pyridine
etc., and performing a reaction at 10.degree. C. to 60.degree. C.,
preferably 20.degree. C. to 40.degree. C. for 0.1 hours to 24
hours, preferably 1 hour to 12 hours.
Third Step
[0741] A compound od can be obtained by adding potassium carbonate,
sodium carbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the
compound oc in the presence of a solvent such as DMF, DMA, NMP, THF
etc., and performing a reaction at 10.degree. C. to 60.degree. C.,
preferably 20.degree. C. to 40.degree. C. for 0.1 hours to 24
hours, preferably 1 hour to 12 hours.
Fourth Step
[0742] A compound oe can be obtained by adding
R.sup.5--C(.dbd.O)--R.sup.6 and acetic acid to the compound od in
the presence of a solvent such as toluene, DMF, DMA, NMP, THF etc.,
and performing a reaction at 60.degree. C. to 120.degree. C.,
preferably 80.degree. C. to 110.degree. C. for 0.1 hours to 24
hours, preferably 1 hour to 12 hours.
Fifth Step
[0743] A compound of can be obtained by adding a compound
R.sup.7-L.sup.1 corresponding to an objective substance, and a base
such as sodium carbonate, potassium carbonate, cesium carbonate
etc. to the compound oe in the presence of a solvent such as DMF,
DMA, NMP, THF etc., and performing a reaction at 0.degree. C. to
60.degree. C., preferably 10.degree. C. to 40.degree. C. for 0.1
hours to 24 hours, preferably 1 hour to 12 hours.
Sixth Step
[0744] A compound og can be obtained by subjecting the compound of
to the known general carboxyl group deprotecting reaction.
Seventh Step
[0745] A compound oh can be obtained by subjecting the compound og
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound pg of Reference Example (See: Reference
Example 95)
##STR00168##
[0747] (wherein each symbol is same as above)
First Step
[0748] A compound pb can be obtained by adding aqueous ammonia to a
compound pa, and performing a reaction at 0.degree. C. to
30.degree. C., preferably 10.degree. C. to 30.degree. C. for 0.5
hours to 48 hours, preferably 1 hour to 24 hours.
Second Step
[0749] A compound pc can be obtained by adding a condensation agent
such as HATU, WSC.HCl etc. to the compound pb in the presence of a
solvent such as DMF, DMA, NMP, THF etc. or in a mixed solvent
thereof, adding amine (R.sup.3--NH.sub.2) corresponding to an
objective substance and, if necessary, tertiary amine such as
triethylamine, N-methylmorpholine etc., and performing a reaction
at 10.degree. C. to 60.degree. C., preferably 20.degree. C. to
40.degree. C. for 0.1 hours to 24 hours, preferably 1 hour to 12
hours.
Third Step
[0750] A compound pd can be obtained by adding potassium carbonate,
sodium carbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the
compound pc in the presence of a solvent such as DMF, DMA, NMP, THF
etc., and performing a reaction at 10.degree. C. to 60.degree. C.,
preferably 20.degree. C. to 40.degree. C. for 0.1 hours to 24
hours, preferably 1 hour to 12 hours.
Fourth Step
[0751] A compound pe can be obtained by adding
R.sup.5--C(.dbd.O)--R.sup.6 and acetic acid to the compound pd in
the presence of a solvent such as toluene, DMF, DMA, NMP, THF etc.,
and performing a reaction at 60.degree. C. to 120.degree. C.,
preferably 80.degree. C. to 110.degree. C. for 0.1 hours to 12
hours, preferably 0.2 hours to 6 hours.
Fifth Step
[0752] A compound pf can be obtained by adding a compound
R.sup.7-L.sup.1 corresponding to an objective substance, and a base
such as sodium carbonate, potassium carbonate, cesium carbonate
etc. to the compound pe in the presence of a solvent such as DMF,
DMA, NMP, THF etc., and performing a reaction at 0.degree. C. to
60.degree. C., preferably 10.degree. C. to 40.degree. C. for 0.1
hours to 24 hours, preferably 1 hour to 12 hours.
Sixth Step
[0753] A compound pg can be obtained by subjecting the compound pf
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound qg, Compound qi, and Compound qk of Reference
Example (See: Reference Example 128)
##STR00169##
[0755] (wherein R represents a carboxyl protective group, n
represents an integer of 0 to 6, R.sup.Z7 and R.sup.Z8 are same as
R.sup.C7 and R.sup.C8 in item 1, and other each symbol is same as
above)
First Step
[0756] A compound qc can be obtained by adding a condensation agent
such as HATU, WSC.HCl etc. to a compound qa in the presence of a
solvent such as pyridine, DMF, DMA, NMP, THF etc. or in a mixed
solvent thereof, adding a compound qb and, if necessary, tertiary
amine such as triethylamine, N-methylmorpholine etc., and
performing a reaction at 10.degree. C. to 60.degree. C., preferably
20.degree. C. to 40.degree. C. for 0.1 hours to 24 hours,
preferably 1 hour to 12 hours.
Second Step
[0757] A compound qd can be obtained by adding potassium carbonate,
sodium carbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the
compound qc in the presence of a solvent such as DMF, DMA, NMP, THF
etc. or in a mixed solvent thereof, and performing a reaction at
10.degree. C. to 60.degree. C., preferably 20.degree. C. to
40.degree. C. for 0.1 hours to 48 hours, preferably 1 hour to 24
hours.
Third Step
[0758] A compound pe can be obtained by adding
R.sup.5--C(.dbd.O)--R.sup.6 and acetic acid to the compound qd in
the presence of a solvent such as toluene, DMF, DMA, NMP, THF etc.
or in a mixed solvent thereof, and performing a reaction at
60.degree. C. to 120.degree. C., preferably 80.degree. C. to
110.degree. C. for 0.1 hours to 12 hours, preferably 0.2 hours to 6
hours.
[0759] Alternatively, a compound qe can be obtained by performing a
reaction at 100.degree. C. to 200.degree. C. for 5 minutes to 1
hour under microwave irradiation condition in a solvent such as
ethanol, isopropyl alcohol etc.
Fourth Step
[0760] A compound qf can be obtained by adding a compound
R.sup.7-L.sup.1 corresponding to an objective substance, and a base
such as sodium carbonate, potassium carbonate, cesium carbonate
etc. to the compound qe in the presence of a solvent such as DMF,
DMA, NMP etc. or in a mixed solvent thereof, and performing a
reaction at 0.degree. C. to 60.degree. C., preferably 10.degree. C.
to 40.degree. C. for 0.1 hours to 48 hours, preferably 1 hour to 24
hours.
Fifth Step
[0761] A compound qg can be obtained by subjecting the compound qf
to the known general hydroxyl group deprotecting reaction.
Sixth Step
[0762] A compound qh can be obtained by subjecting the compound qf
to the known general carboxyl group deprotecting reaction.
Seventh Step
[0763] A compound qi can be obtained by subjecting the compound qh
to the known general hydroxyl group deprotecting reaction.
Eighth Step
[0764] A compound qj can be obtained by adding a condensation agent
such as HATU, WSC.HCl etc. to a compound qh in the presence of a
solvent such as pyridine, DMF, DMA, NMP, THF etc. or in a mixed
solvent thereof, adding a compound HNR.sup.Z7R.sup.Z8 and, if
necessary, tertiary amine such as triethylamine,
diisopropylethylamine, N-methylmorpholine etc., and performing a
reaction at 10.degree. C. to 60.degree. C., preferably 20.degree.
C. to 40.degree. C. for 0.1 hours to 24 hours, preferably 1 hour to
12 hours.
Ninth Step
[0765] A compound qk can be obtained by subjecting the compound qj
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound qq of Reference Example, Compound qs of
Reference Example, Compound qu of Reference Example, and Compound
qw of Reference Example (See: Reference Example 128)
##STR00170##
[0767] (wherein R.sup.Z2, R.sup.Z4, R.sup.Z9, R.sup.Z10, and
R.sup.Z13 are same as R.sup.C2, R.sup.C4, R.sup.C9, R.sup.C10, and
R.sup.C13 in item 1, and other each symbol is same as above)
First Step
[0768] A compound qm can be obtained by adding a condensation agent
such as HATU, WSC.HCl, etc. to a compound qa in the presence of a
solvent such as pyridine, DMF, DMA, NMP etc. or in a mixed solvent
thereof, adding a compound ql and, if necessary, tertiary amine
such as triethylamine, diisopropylethylamine, N-methylmorpholine,
etc., and performing a reaction at 10.degree. C. to 60.degree. C.,
preferably 20.degree. C. to 40.degree. C. for 0.1 hours to 24
hours, preferably 1 hour to 12 hours.
Second Step
[0769] A compound qn can be obtained by adding potassium carbonate,
sodium carbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the
compound qm in the presence of a solvent such as DMF, DMA, NMP, THF
etc., and performing a reaction at 10.degree. C. to 60.degree. C.,
preferably 20.degree. C. to 40.degree. C. for 0.1 hours to 48
hours, preferably 1 hour to 24 hours.
Third Step
[0770] A compound pe can be obtained by adding
R.sup.5--C(.dbd.O)--R.sup.6 and acetic acid to the compound qn in
the presence of a solvent such as toluene, DMF, DMA, NMP, THF etc.
or in a mixed solvent thereof, and performing a reaction at
60.degree. C. to 120.degree. C., preferably 80.degree. C. to
110.degree. C. for 0.1 hours to 12 hours, preferably 0.2 hours to 6
hours.
[0771] Alternatively, a compound qo can be obtained by performing a
reaction at 100.degree. C. to 200.degree. C. for 5 minutes to 1
hour under microwave irradiation condition in a solvent such as
ethanol etc.
Fourth Step
[0772] A compound qp can be obtained by adding a compound
R.sup.7-L.sup.1 corresponding to an objective substance, and a base
such as sodium carbonate, potassium carbonate, cesium carbonate,
etc. to the compound qo in the presence of a solvent such as DMF,
DMA, NMP, THF, etc. or in a mixed solvent thereof, and performing a
reaction at 0.degree. C. to 60.degree. C., preferably 10.degree. C.
to 40.degree. C. for 0.1 hours to 48 hours, preferably 1 hour to 24
hours.
Fifth Step
[0773] A compound qq can be obtained by subjecting the compound qp
to the known general hydroxyl group deprotecting reaction.
Sixth Step
[0774] A compound qr can be obtained by subjecting the compound qp
to the known general amino group deprotecting reaction.
Seventh Step
[0775] A compound qs can be obtained by subjecting the compound qr
to the known general hydroxyl group deprotecting reaction.
Eighth Step
[0776] A compound qt can be obtained by adding a compound
R.sup.Z10-L.sup.1 corresponding to an objective substance, and a
base such as sodium carbonate, potassium carbonate, cesium
carbonate, etc. to the compound qr in the presence of a solvent
such as DMF, DMA, NMP, THF, etc. or in a mixed solvent thereof, and
performing a reaction at 0.degree. C. to 60.degree. C., preferably
10.degree. C. to 40.degree. C. for 0.1 hours to 48 hours,
preferably 1 hour to 24 hours.
Ninth Step
[0777] A compound qu can be obtained by subjecting the compound qt
to the known general hydroxyl group deprotecing reaction.
Tenth Step
[0778] A base such as sodium carbonate, potassium carbonate, cesium
carbonate etc. is added to the compound qr in the presence of a
solvent such as THF, dioxane, dichloromethane, acetonitrile, etc. A
compound (R.sup.Z4COCl, R.sup.Z2SO.sub.2Cl, or R.sup.Z13OCOCl)
corresponding to an objective substance is slowly added thereto,
and a reaction is performed at -20.degree. C. to 60.degree. C.,
preferably 0.degree. C. to 30.degree. C. for 0.1 hours to 48 hours,
preferably 1 hour to 24 hours, thereby, a compound qv can be
obtained.
Eleventh Step
[0779] A compound qw can be obtained by subjecting the compound qv
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound rb of Reference Example (See: Reference
Example 155)
##STR00171##
[0781] (wherein each symbol is same as above)
[0782] A compound rb can be obtained by adding a compound
R.sup.3NH.sub.2 having a substituent corresponding to an objective
compound to a compound ra in the presence of a
dehydration-condensation agent such as dicyclohexylcarbodiimide,
carbonyldiimidazole,
dicyclohexylcarbodiimido-N-hydroxybenzotriazole,
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,
hexafluorophosphoric acid
2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl,
HATU, etc. in a solvent such as DMF, THF, dichloromethane,
acetonitrile, etc. or in a mixed solvent thereof, and performing a
reaction at -20.degree. C. to 60.degree. C., preferably -10.degree.
C. to 40.degree. C. for 0.1 hours to 24 hours, preferably 1 hour to
12 hours.
[0783] Alternatively, a compound rb can be obtained by adding an
acylating reagent such as diphenylchlorophosphate, thionyl
chloride, oxalyl chloride, etc. to a compound ra in the presence or
absence of a base such as pyridine, triethylamine,
diisopropylethylamine, 1-methylimidazole, etc. in the presence of a
solvent such as THF, dioxane, dichloromethane, DMF, etc. to
generate acid chloride, adding a compound R.sup.3--NH.sub.2 having
a substituent corresponding to an objective compound, and
performing a reaction at -20.degree. C. to 60.degree. C.,
preferably -10.degree. C. to 40.degree. C. for 0.1 hours to 24
hours, preferably 0.5 hours to 12 hours.
Synthesis of Compound sl of Reference Example (See: Reference
Example 49)
##STR00172##
[0785] (wherein P.sup.3 is an amino protective group, and may be a
group which can be protected and/or deprotected by the method
described in Protective Groups in Organic Synthesis, Theodora W
Green (John Wiley & Sons) etc. and, for example, P.sup.3 is
aryl lower alkyloxycarbonyl, lower alkylcarbonyl, etc. B is same as
substituent group D in item 1, and other each symbol is same as
above)
First Step
[0786] A compound sb can be obtained by adding an oxidizing reagent
such as Dess Martin Periodinane, manganese dioxide, PDC, etc, to a
compound sa in the presence of a solvent such as dichloromethane,
THF, dioxane, toluene etc., and performing a reaction at
-20.degree. C. to 60.degree. C., preferably 0.degree. C. to
40.degree. C. for 0.1 hours to 24 hours, preferably 0.5 hours to 12
hours.
Second Step
[0787] A compound sd can be obtained by adding sodium sulfate and
an aminoalcohol sc corresponding to an objective substance to the
compound sb in the presence or absence of a solvent such as
toluene, THF etc., and performing a reaction at 0.degree. C. to
80.degree. C., preferably 20.degree. C. to 60.degree. C. for 0.1
hours to 24 hours, preferably 0.5 hours to 12 hours.
Third Step
[0788] A compound se can be obtained by subjecting the compound sd
to the known general amino group deprotecting reaction.
Fourth Step
[0789] A compound sg can be obtained by adding a compound sf to the
compound se in the presence of a solvent such as toluene, THF,
dioxane etc., and performing a reaction at 40.degree. C. to
110.degree. C., preferably 60.degree. C. to 100.degree. C. for 0.5
hours to 24 hours, preferably 1 hour to 12 hours.
Fifth Step
[0790] A compound sh can be obtained by subjecting the compound sg
to the known general amino group deprotecting reaction and,
thereafter, performing a reaction at 40.degree. C. to 110.degree.
C., preferably 60.degree. C. to 100.degree. C. for 0.1 hours to 12
hours, preferably 0.2 hours to 6 hours in the presence of a solvent
such as toluene, THF, dioxane, etc.
Sixth Step
[0791] A compound si can be obtained by subjecting the compound sh
to the known general carboxyl group deprotecting reaction.
Seventh Step
[0792] A compound sj can be obtained by subjecting the compound si
to the known general hydroxyl group deprotecting reaction.
Eighth Step
[0793] A decarbonized compound sk can be obtained by reacting the
compound si for 1 minute to 2 hours under microwave irradiation in
a solvent such as diphenyl ether etc.
Ninth Step
[0794] A compound sl can be obtained by subjecting the compound sk
to the known general hydroxyl group deprotecting reaction.
Synthesis of Compound un of Reference Example (See: Reference
Example 177)
##STR00173##
[0796] (wherein L.sup.1 represents a leaving group such as halogen,
OMs, OTs etc., and other each symbol is same as above)
First Step
[0797] A compound ub can be obtained by subjecting a compound ua to
a secondary amino group protecting reaction.
Second Step
[0798] A compound uc can be obtained by subjecting the compound ub
to a general amino group protecting reaction.
Third Step
[0799] A compound ue can be obtained by adding a compound
R.sup.7-L.sup.1 corresponding to an objective compound to the
compound uc in the presence of a solvent such as DMF, DMA, NMP,
etc. and a base such as NaH etc., and performing a reaction at
0.degree. C. to 80.degree. C., preferably 20.degree. C. to
60.degree. C. for 0.5 hours to 12 hours, preferably 1 hour to 6
hours.
Fourth Step, Fifth Step
[0800] (wherein R.sup.3 and R.sup.7 may be bound adjacently and, in
this case, a fourth step and a fifth step are performed
simultaneously)
[0801] A compound ue can be obtained by reacting a compound ud
sequentially with compounds corresponding to an objective compound,
R.sup.3-L.sup.1 and R.sup.7-L.sup.1 in the presence of a solvent
such as DMF, DMA, NMP etc. and a base such as NaH etc.
Sixth Step
[0802] A compound ug can be obtained by subjecting a compound uf to
a secondary amino group protecting reaction.
Seventh Step
[0803] A compound uh can be obtained by subjecting the compound ug
to a secondary amino group protecting reaction.
Eighth Step
[0804] A compound ue can be obtained by adding a base such as NaH
etc. to the compound uh in the presence of a solvent such as DMF,
DMA, NMP, acetonitrile etc. or in a mixed solvent thereof, and
performing a reaction with a compound R.sup.3-L.sup.1 corresponding
to an objective compound.
Ninth Step
[0805] A compound uj can be obtained by subjecting the compound ue
to a general secondary amine deprotecting reaction.
Tenth Step
[0806] A compound ul can be obtained by adding a condensation agent
such as HATU, WSC.HCl etc. to a compound uk in the presence of a
solvent such as DMF, DMA, THF, etc., adding amine uj corresponding
to an objective substance, and tertiary amine such as pyridine,
triethylamine, N-methylmorpholine etc., and performing a reaction
at 10.degree. C. to 60.degree. C., preferably 20.degree. C. to
40.degree. C. for 0.1 hours to 24 hours, preferably 1 hour to 12
hours.
Eleventh Step
[0807] A compound um can be obtained by subjecting the compound ul
to a general amino group protecting reaction.
Twelfth Step
[0808] A compound un can be obtained by adding
R.sup.5--C(.dbd.O)--R.sup.6, tertiary amine such as, triethylamine,
diisopropylethylamine, N-methylmorpholine, etc. and acetic acid, to
the compound um in the presence of a solvent such as toluene, DMF,
DMA, NMP etc., and performing a reaction at 60.degree. C. to
120.degree. C., preferably 80.degree. C. to 100.degree. C. for 0.1
hours to 24 hours, preferably 1 hour to 12 hours.
Synthesis of Compound te of Reference Example
##STR00174##
[0810] (wherein R' may be a group which can be protected and/or
deprotected by the method described in Protective Groups in Organic
Synthesis, Theodora W Green (John Wiley & Sons) etc. and, for
example, R' is lower alkyl etc. X is halogen, and other each symbol
is same as above)
First Step
[0811] An alcohol (P.sup.1--OH) corresponding to an objective
substance is added to an organometallic base such as sodium
tert-pentoxide, n-butyllithium, tert-butyllithium etc. in a solvent
such as THF, ether, dichloromethane, DMI, DMF, DMA, etc. or in a
mixed solution thereof. A solution of a compound ta is added
dropwise thereto, and a reaction is performed at -20.degree. C. to
40.degree. C., preferably 0.degree. C. to 30.degree. C. for 0.1
hours to 12 hours, preferably 0.5 hours to 6 hours, thereby, a
compound tb can be obtained.
Second Step
[0812] A compound tc can be obtained by adding
N,N-dimethylformamidodimethylacetal to the compound tb in a solvent
such as THF, dioxane, toluene, ethyl acetate etc. or in a mixed
solvent thereof, or without a solvent, and performing a reaction at
0.degree. C. to 80.degree. C., preferably 20.degree. C. to
40.degree. C. for 0.5 hours to 24 hours, preferably 1 hour to 12
hours.
Third Step
[0813] A compound td corresponding to an objective substance is
added to an organometallic base such as sodium tert-pentoxide,
n-butyllithium, tert-butyllithium, sodium metoxide, sodium
ethoxide, sodium tert-butoxide, potassium tert-butoxide etc. in a
solvent such as THF, ether, DMI, methanol, ethanol, etc. or in a
mixed solvent thereof. A solution of the compound tc is added
dropwise thereto, a reaction is performed at -20.degree. C. to
60.degree. C., preferably 0.degree. C. to 30.degree. C. for 0.5
hours to 24 hours, preferably 1 hour to 12 hours and, thereafter,
an acid such as hydrochloric acid, sulfuric acid etc. is added to
perform a reaction at -20.degree. C. to 60.degree. C., preferably
0.degree. C. to 30.degree. C. for 0.5 hours to 24 hours, preferably
1 hour to 12 hours, thereby, a compound te can be obtained.
Synthesis of Compound tm of Reference Example and Compound tp of
Reference Example (See: Reference Examples 165, and 169)
##STR00175##
[0815] (wherein R.sup.P may be an acetal protective group which can
protect and/or can be deprotected by the method described in
Protective Groups in Organic Synthesis, Theodora W Green (John
Wiley & Sons) etc. and, for example, R.sup.P is lower alkyl
etc. Other each symbol is same as above)
First Step
[0816] A compound th can be obtained by adding allylamine to a
compound tf which can be synthesized by the same method as that of
a compound te in the presence of a solvent such as ethanol, THF,
dioxane, acetonitrile, etc. or in a mixed solvent thereof, and
performing a reaction at 0.degree. C. to 80.degree. C., preferably
20.degree. C. to 60.degree. C. for 0.5 hours to 48 hours,
preferably 1 hour to 24 hours.
Second Step
[0817] A compound ti can be obtained by adding a compound tg to a
compound tf in the presence of a solvent such as ethanol, THF,
dioxane, acetonitrile etc. or in a mixed solvent thereof, and
performing a reaction at 0.degree. C. to 80.degree. C., preferably
20.degree. C. to 60.degree. C. for 0.5 hours to 48 hours,
preferably 1 hour to 24 hours.
Third Step
[0818] A compound tj can be obtained by adding potassium osmate
dihydrate, sodium periodate, and water to the compound th in the
presence of a solvent such as THF, ethyl acetate, dioxane, etc. or
in a mixed solvent thereof, and performing a reaction at 0.degree.
C. to 60.degree. C., preferably 10.degree. C. to 40.degree. C. for
0.5 hours to 24 hours, preferably 1 hour to 12 hours.
[0819] Alternatively, a compound tj can be obtained by introducing
ozone into the compound th at -10.degree. C. to 20.degree. C. in
the presence of a solvent such as THF, ethyl acetate, dioxane etc.
or in a mixed solvent thereof and, subsequent to completion of the
reaction, adding zinc-acetic acid, (EtO).sub.3P, or dimethyl
sulfide.
Fourth Step
[0820] A compound tk can be obtained by adding an acid such as
formic acid, trifluoroacetic acid, paratoluenesulfonic acid, etc.
to the compound ti in a solvent such as acetone, acetonitrile,
ethanol, water, etc. or in a mixed solvent thereof, or adding
sulfuric acid in a formic acid solvent, and performing a reaction
at 0.degree. C. to 90.degree. C., preferably 20.degree. C. to
80.degree. C. for 0.5 hours to 24 hours, preferably 1 hour to 12
hours.
Fifth Step
[0821] A compound tm can be obtained by adding a compound tl and
acetic acid to the compound tj or the compound tk in the presence
of a solvent such as chloroform, dichloromethane, THF, etc., and
performing a reaction at 0.degree. C. to 40.degree. C., preferably
10.degree. C. to 30.degree. C. for 0.5 hours to 24 hours,
preferably 1 hour to 12 hours.
Sixth Step
[0822] A compound to can be obtained by adding a compound tn and
acetic acid to the compound tj or the compound tk in the presence
of a solvent such as chloroform, dichloromethane, THF, etc., and
performing a reaction at 0.degree. C. to 40.degree. C., preferably
10.degree. C. to 30.degree. C. for 0.5 hours to 24 hours,
preferably 1 hour to 12 hours.
Seventh Step
[0823] A compound tp can be obtained by adding a compound B-L.sup.1
corresponding to an objective compound to the compound to in the
presence of a solvent such as DMF, DMA, NMP, THF, etc. or in a
mixed solvent thereof, and performing a reaction at 0.degree. C. to
80.degree. C., preferably 20.degree. C. to 60.degree. C. for 0.5
hours to 12 hours, preferably 1 hour to 6 hours.
Synthesis of Compound vf of Reference Example (See: Reference
Examples 583, and 584)
##STR00176##
[0825] (wherein Y1 is a substituent corresponding to R.sup.3a, and
Y2 is a substituent corresponding to R.sup.11a. Other each symbol
is same as above)
First Step
[0826] A compound vc can be obtained by adding a compound vb having
a substituent corresponding to an objective compound to a compound
va in the presence of a dehydration-condensation agent such as
dicyclohexylcarbodiimide, carbonyldiimidazole,
dicyclohexylcarbodiimido-N-hydroxybenzotriazole,
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,
hexafluorophosphoric acid
2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC.HCl,
HATU, etc. in a solvent such as DMF, THF, dichloromethane,
acetonitrile etc. or in a mixed solvent thereof, and performing a
reaction at -20.degree. C. to 60.degree. C., preferably -10.degree.
C. to 40.degree. C. for 0.1 hours to 24 hours, preferably 1 hour to
12 hours.
[0827] Alternatively, a compound vc can be obtained by adding an
acylating reagent such as diphenylchlorophosphate, thionyl
chloride, oxalyl chloride etc. to a compound va in the presence or
absence of a base such as pyridine, triethylamine,
diisopropylethylamine, 1-methylimidazole, etc. in the presence of a
solvent such as THF, dioxane, dichloromethane, DMF etc., thereby,
generating acid chloride, and adding a compound vb having a
substituent corresponding to an objective compound, and performing
a reaction at -20.degree. C. to 60.degree. C., preferably
-10.degree. C. to 40.degree. C. for 0.1 hours to 24 hours,
preferably 0.5 hours to 12 hours.
Second Step
[0828] A compound vd can be obtained by adding potassium carbonate,
sodium carbonate, and O-(2,4-dinitrophenyl)hydroxylamine to the
compound vc in the presence of a solvent such as DMF, DMA, NMP,
THF, etc., and performing a reaction at 10.degree. C. to 60.degree.
C., preferably 20.degree. C. to 40.degree. C. for 0.1 hours to 48
hours, preferably 1 hour to 24 hours.
Third Step
[0829] A deprotecting reaction of an acetal protective group of the
compound vd can be performed by the general method described in
Protective Groups in Organic Synthesis, Theodora W Green (John
Wiley & Sons) etc. Thereafter, a generated aldehyde group is
subjected to an intramolecular reaction, thereby, a compound ve can
be obtained.
[0830] For example, a compound ve can be obtained by adding acetic
acid and/or paratoluenesulfonic acid to the compound vd in the
presence of a solvent such as DMF, toluene, THF, etc., and
performing a reaction at 10.degree. C. to 80.degree. C., preferably
30.degree. C. to 60.degree. C. for 0.5 hours to 12 hours,
preferably 1 hour to 6 hours.
Fourth Step
[0831] A compound vf can be obtained by adding a compound
R.sup.7-L.sup.1 corresponding to an objective substance, and a base
such as sodium carbonate, potassium carbonate, cesium carbonate,
etc. to the compound ve in the presence of a solvent such as DMF,
DMA, NMP, THF, etc. or in a mixed solvent thereof, and performing a
reaction at 0.degree. C. to 60.degree. C., preferably 10.degree. C.
to 40.degree. C. for 0.1 hours to 48 hours, preferably 1 hour to 24
hours.
Synthesis of Compound wd of Reference Example (See: Reference
Example 592, Etc.)
##STR00177##
[0833] (wherein each symbol is same as above, and P.sup.1 may be a
group which can be protected and/or deprotected by the method
described in Protective Groups in Organic Synthesis, Theodora W
Green (John Wiley & Sons) etc. and, for example, P.sup.1 is
arylalkyl, etc.)
First Step
[0834] A compound wb can be obtained by adding a cation-forming
reagent (e.g.: dichloroacetic acid) to the compound wa in the
presence of a solvent such as 1,2-dichloroethane, THF, dioxane,
chloroform, etc. and adding a reagent, R.sup.7--OH corresponding to
an objective substance, and performing a reaction at 10.degree. C.
to 60.degree. C., preferably 20.degree. C. to 40.degree. C. for 0.1
hours to 24 hours, preferably 0.5 hours to 12 hours.
Second Step
[0835] Abase (e.g.:
2-tert-butylimino2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphori-
ne) is added to the compound wb in the presence of a solvent such
as DMF, DMA, NMP, THF, etc., paraformaldehyde is added, and they
are reacted at 0.degree. C. to 60.degree. C., preferably 10.degree.
C. to 40.degree. C. for 0.1 hours to 24 hours, preferably 0.5 hours
to 12 hours. Next, a compound we can be obtained by adding a
detachment reagent (e.g.: p-toluenesulfonyl chloride), and
performing a reaction at 0.degree. C. to 60.degree. C., preferably
10.degree. C. to 40.degree. C. for 0.1 hours to 24 hours,
preferably 0.5 hours to 12 hours.
Synthesis of Compound of Example (Prodrug: Formula (I)) from
Compound of Reference Example (Parent Compound: Formula (II)) (See:
Examples 1, 98, 105, 106, 106, 107, 108, 111, 112, 113, 122, 151,
152, 163, 177, 178, 186, 190, 192, 194, 196, 197, 199, 200, 201,
and 203)
##STR00178##
[0837] (wherein each substituent is same as in item 1)
[0838] A compound of Example can be obtained by the general method
including converting a hydroxyl group into an ester group or ether
group, using a compound shown in Reference example as a source.
[0839] For example, the method described in Protective Groups in
Organic Synthesis, Theodora W Green (John Wiley & Sons), Prog.
Med. 5: 2157-2161 (1985), and Supplied by The British Library--"The
world's Knowledge", etc. can be utilized.
[0840] The present invention will be explained in more detail below
by way of Examples, Reference examples, Intermediate Synthesis
Examples, as well as Test Examples of the present invention, but
the present invention is not limited by them.
[0841] Hereinbelow, structural formulae of compounds of Reference
examples 1 to 775 that are parent compounds, and Synthesis Examples
are shown.
Reference Example 1
##STR00179##
[0842] First Step
[0843] A dichloromethane (90 mL) solution of compound 1A (12.8 g,
89.4 mmol) and pyridine (8.50 g, 107 mmol) was cooled to 1 to
3.degree. C., and a dichloromethane (90 mL) solution of
benzyloxyacetyl chloride (19.8 g, 107 mmol) was added dropwise over
50 minutes while the same temperature was retained. After the
reaction solution was stirred at the same temperature for 30
minutes, temperature was gradually raised to 15.degree. C. over 60
minutes, and ice water was added. The dichloromethane layer was
separated, and the aqueous layer was extracted with dichloromethane
once. The combined extracts were washed with water three times,
washed with an aqueous saturated sodium chloride solution, and
dried. The solvent was distilled off, and the resulting oil was
purified by silica gel column chromatography. The materials were
eluted firstly with n-hexane and, then, with n-hexane-ethyl acetate
(1:1, v/v). Concentration of objective fraction afforded 22.2 g of
compound 1B as an oil.
[0844] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (3H, t, J=7.2 Hz),
2.90 (3H, brs), 3.24 (3H, brs), 4.15 (2H, q, J=7.2 Hz), 4.45 (2H,
s), 4.58 (2H, s), 7.25-7.38 (5H, m), 7.72 (1H, s).
Second Step
[0845] A 1N lithiumhexamethyldisilazane THF solution (4.29 ml, 4.29
mmol) was cooled to -78.degree. C., and a THF solution (4 ml) of
compound 1B (500 mg, 1.72 mmol) and cinnamoyl chloride (343.2 mg,
2.06 mmol) were added dropwise thereto over 3 minutes while the
same temperature was retained. After the reaction solution was
stirred at the same temperature for 25 minutes, 2N hydrochloric
acid (10 ml) was added, and the mixture was further stirred at room
temperature for 10 minutes. To the reaction solution was added
ethyl acetate, the organic layer was separated, and the aqueous
layer was extracted with ethyl acetate three times. The combined
extracts were dried with sodium sulfate. The solvent was distilled
off, and the resulting oil was purified by silica gel column
chromatography. From fraction eluted with n-hexane-ethyl acetate
(1:1, v/v), 364.3 mg (yield 56%) of compound 1C was obtained as a
solid.
[0846] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.40 (3H, t, J=7.2 Hz),
4.39 (2H, q, J=7.2 Hz), 5.27 (2H, s), 6.99 (1H, d, J=16.2 Hz), 7.23
(1H, d, J=16.2), 7.26-7.48 (10H, m), 8.45 (1H, s).
Third Step
[0847] To a MeCN (5 ml) solution of compound 1C and ruthenium
chloride (2.76 mg, 0.0133 mmol) was added dropwise an aqueous
solution (8 ml) of sodium periodate (625.8 mg, 2.93 mmol) and 96%
sulfuric acid (287.4 mg, 2.93 mmol) over 10 minutes at room
temperature under nitrogen stream. After the reaction solution was
stirred at the same temperature for 5 minutes, ethyl acetate was
added, the organic layer was separated, and the aqueous layer was
extracted with ethyl acetate two times. The combined extracts were
dried with sodium sulfate. The solvent was distilled off, and the
resulting oil was purified by silica gel column chromatography.
From fraction eluted with n-hexane-ethyl acetate (1:1, v/v), 303.2
mg (yield 75%) of compound 1D was obtained as an oil.
[0848] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39 (3H, t, J=6.9 Hz),
4.40 (2H, q, J=6.9 Hz), 5.54 (2H, s), 7.37 (5H, s), 8.48 (1H, s),
9.85 (1H, s).
Fourth Step
[0849] To a MeCN (15 ml) solution of compound 1D (1.00 g, 3.31
mmol) was added an aqueous solution (10 ml) of 96% sulfuric acid
(421.7 mg, 4.30 mmol) and amidosululic acid (642.7 mg, 6.62 mmol)
at room temperature, the mixture was stirred, and an aqueous
solution (10 ml) of sodium chlorite (388.9 mg, 4.30 mmol) was added
dropwise over 5 minutes while the same temperature was retained.
After the reaction solution was stirred at the same temperature for
5 minutes, an aqueous saturated sodium chloride solution was added,
and the mixture was extracted with ethyl acetate three times. The
combined extracts were dried with sodium sulfate. The solvent was
distilled off, and the resulting oil was purified by silica gel
column chromatography. The materials were eluted firstly with
chloroform and, then, with chloroform-MeOH (7:3, v/v).
Concentration of objective fraction afforded 748.8 mg (yield 71%)
of compound 1E as an oil.
[0850] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.40 (3H, t, J=7.2 Hz),
3.93 (1H, brs), 4.40 (2H, q, J=7.2 Hz), 5.61 (2H, s), 7.38-7.44
(10H, m), 8.52 (1H, s).
Fifth Step
[0851] To a DMF (10 ml) solution of compound 1E (1.00 g, 3.14 mmol)
were added WSC HCl (1.20 g, 6.28 mmol) and HOBt (551.6 mg, 4.08
mmol) at room temperature, and the mixture was stirred at the same
temperature for 90 minutes. The reaction solution was cooled to
0.degree. C., and a DMF (2 ml) solution of 2-methoxyethanamine
(236.0 mg, 3.14 mmol) was added dropwise over 3 minutes. The
reaction solution was stirred at the same temperature for 1 hour,
water was added, and the mixture was extracted with ethyl acetate
three times. The extract was washed with water three times, and
dried with sodium sulfate. The solvent was distilled off, and the
resulting oil was purified by silica gel chromatography. The
materials were eluted firstly with n-hexane-ethyl acetate (1:1,
v/v) and, then, with n-hexane-ethyl acetate (1:9, v/v).
Concentration of objective fraction afforded 928.5 mg (yield 79%)
of compound 1F as an oil.
[0852] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39 (3H, t, J=7.2 Hz),
3.29 (3H, s), 3.41 (2H, t, J=5.4 Hz), 3.47-3.53 (2H, m), 4.39 (2H,
q, J=7.2 Hz), 5.44 (2H, s), 7.36 (3H, m), 7.44-7.47 (2H, m), 8.07
(1H, brs), 8.54 (1H, s).
Sixth Step
[0853] A xylene (2 ml) solution of compound 1F (500 mg, 1.33 mmol)
and (S)-2-amino-3-phenylpropan-1-ol (604.2 mg, 4.0 mmol) was heated
to 120.degree. C., and stirred for 30 minutes. After the reaction
solution was cooled to room temperature, and the solvent was
distilled off, the resulting oil was purified by silica gel
chromatography. The materials were eluted firstly with chloroform
and, then, with chloroform-MeOH (9:1, v/v). Concentration of
objective fraction afforded 487 mg (yield 72%) of compound 1G as an
oil.
[0854] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.41 (3H, t, J=6.9 Hz),
2.24-2.34 (1H, m), 2.24-3.00 (1H, m), 3.03-3.16 (1H, m), 3.05 (3H,
m), 3.25-3.32 (2H, m), 4.13-4.19 (1H, m), 4.17-4.30 (1H, m),
4.36-4.47 (1H, m), 4.51-4.54 (1H, m), 4.55 (1H, d, J=10.5 Hz), 5.78
(1H, t, J=6.9 Hz), 7.17-7.26 (4H, m), 7.28-7.35 (5H, m), 7.49 (1H,
t, J=5.4 Hz), 6.32 (1H, s).
Seventh Step
[0855] To a THF (6 ml) solution of compound 1G (2.86 g, 5.63 mmol)
and triphenylphosphine (2.21 g, 8.45 mmol) was added dropwise a
DEAD 40 wt % toluene solution (3.68 g, 8.45 mmol) at room
temperature over 3 minutes. The reaction solution was stirred at
the same temperature for 30 minutes, the solvent was distilled off,
and the resulting oil was purified by silica gel chromatography.
From a fraction eluted with ethyl acetate-MeOH (9:1, v/v), 1.37 g
(yield 50%) of compound 1H was obtained as an oil.
[0856] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, t, J=7.2 Hz),
3.07 (2H, d, J=6.9 Hz), 3.33 (3H, s), 3.57-3.80 (4H, m), 3.95 (1H,
dd, J=3.0 Hz, 6.6 Hz), 4.01-4.14 (1H, m), 4.16-4.34 (2H, m), 5.24
(1H, d, J=9.9 Hz), 5.51 (1H, d, J=9.9 Hz), 7.01-7.03 (2H, m),
7.21-7.37 (5H, m), 7.41-7.58 (1H, m), 7.64-7.69 (2H, m).
Eighth Step
[0857] To an EtOH (6 ml) solution of compound 1H (1.0 g, 2.04 mmol)
was added a 2N aqueous sodium hydroxide solution (6 ml), and the
mixture was stirred at room temperature for 30 minutes. The
reaction solution was neutralized with 2N hydrochloric acid, and
the precipitated solid was filtered, and dried to obtain 754 mg
(yield 80%) of compound 1I.
[0858] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.10 (2H, d, J=7.8 Hz),
3.33 (3H, s), 3.57-3.69 (4H, m), 3.82-3.90 (1H, m), 3.95 (1H, dd,
J=3.3 Hz, 13.8 Hz), 4.36 (1H, dd, J=6.3 Hz, 7.5 Hz), 5.36 (1H, d,
J=10.2 Hz), 5.45 (1H, d, J=10.2 Hz), 6.98-7.01 (2H, m), 7.28-7.39
(6H, m), 7.59 (2H, dd, J=1.8 Hz, 8.1 Hz), 7.87 (1H, s).
Ninth Step
[0859] Compound 1I (1.0 g, 2.16 mmol) was dissolved in THF (10 ml),
10% Pd--C (200 mg) was added, and the mixture was subjected to a
catalytic reduction reaction under hydrogen stream. The catalyst
was removed by filtration, and the filtrate was concentrated. The
resulting residue was washed with ether to obtain 512 mg (yield
64%) of compound 1.
[0860] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.24 (2H, d, J=6.3 Hz),
3.36 (3H, s), 3.60-3.86 (5H, m), 4.14 (1H, d, J=12.9 Hz), 4.47 (1H,
s), 7.03-7.05 (2H, m), 7.30-7.35 (3H, m), 7.88 (1H, s), 12.68 (1H,
s), 14.83 (1H, s).
Reference Example 2
##STR00180## ##STR00181##
[0861] First Step
[0862] To (S)-tert-butyl 3-hydroxy-1,1-diphenylpropan-2-ylcarbamate
(5.00 g, 15.3 mmol) was added trifluoroacetic acid (40 ml), and the
mixture was stirred for 1 hour under ice-cooling. After
trifluoroacetic acid was distilled off, toluene was added, and
distilled off again under reduced pressure to obtain crude
(S)-2-amino-3,3-diphenylpropan-1-ol. To the resulting
(S)-2-amino-3,3-diphenylpropan-1-ol were added compound 1F (5.73 g,
15.3 mmol), toluene (50 ml), and triethylamine (6.4 ml, 45.8 mmol),
the mixture was stirred at 90.degree. C. for 1 hour, and cooled to
room temperature and, thereafter, the solvent was distilled off. To
the resulting residue was added dichloromethane, and the mixture
was washed with 2N aqueous hydrochloric acid solution, an aqueous
saturated sodium bicarbonate solution, and an aqueous saturated
sodium chloride solution. After separation of the organic layer,
after magnesium sulfate was added, the mixture was filtered with
celite, and the filtrate was distilled off to obtain candy-like
compound 2A (9.12 g).
[0863] MS: m/z=585.2 [M+H].sup.+.
Second Step
[0864] The compound 2A (8.60 g, 14.7 mmol) and triphenylphosphine
(7.72 g, 29.4 mmol) were dissolved in tetrahydrofuran (90 ml), and
a 2.2M toluene solution of diethyl azodicarboxylate (10.0 ml, 22.0
mmol) was added dropwise under ice-cooling. After the mixture was
stirred for 2 hours under ice-cooling, and for 18 hours under room
temperature, the solvent was distilled off. The resulting residue
was purified by silica gel column chromatography to obtain foamy
compound 2B (3.88 g, 6.85 mmol).
[0865] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.18 (3H, m), 3.11 (3H,
s), 3.16 (1H, m), 3.28 (1H, m), 3.76 (1H, m), 3.97-4.13 (3H, m),
4.31 (1H, d, J=11.3 Hz), 5.08 (2H, s), 5.52 (1H, d, J=12.0 Hz),
7.18-7.25 (6H, m), 7.25-7.45 (6H, m), 7.55-7.66 (6H, m).
[0866] MS: m/z=567.7 [M+H].sup.+.
Third Step
[0867] To compound 2B (3.4 g, 6.0 mmol) were added ethanol (36 ml),
water (12 ml), and a 2N aqueous sodium hydroxide solution (4.5 ml,
9.0 mmol), and the mixture was stirred at room temperature for 40
minutes, thereafter, ethanol (10 ml) and water (10 ml) were added,
and the mixture was further stirred for 30 minutes. Ethanol was
distilled off, ethyl acetate and water were added, and the mixture
was stirred vigorously and, thereafter, layers were separated. The
ethyl acetate layer was washed with 2N sodium hydroxide three
times, and the aqueous layers were combined into one aqueous layer.
To the aqueous layer was added ethyl acetate, the mixture was
neutralized using 2N hydrochloric acid, then the mixture was
stirred vigorously and, thereafter, the ethyl acetate layer was
separated. To the ethyl acetate layer was added magnesium sulfate,
the mixture was filtered with celite, and the filtrate was
distilled off. The resulting residue was dissolved in MeOH, and the
solvent was distilled off to obtain a solid of compound 2C (3.0 g,
5.64 mmol).
[0868] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.11 (3H, s), 3.16 (1H,
m), 3.25 (1H, m), 3.75 (1H, m), 4.11 (1H, m), 4.36 (1H, d, J=11.6
Hz), 5.18 (2H, dd, J=15.7 Hz, 10.4 Hz), 5.71 (1H, d, J=11.6 Hz),
7.08-7.20 (5H, m), 7.29-7.45 (6H, m), 7.55 (2H, d, J=6.7 Hz), 7.61
(2H, d, J=7.5 Hz), 7.98 (1H, s).
[0869] MS: m/z=539.4 [M+H].sup.+.
Fourth Step
[0870] To compound 2C (1.50 g, 2.79 mmol) were added methanol (22
ml), and 10% palladium carbon-50% wet (150 mg), and the mixture was
stirred for 1 hour under hydrogen atmosphere. Ethyl acetate (44 ml)
was added, the mixture was filtered with celite, and the filtrate
was distilled off. The resulting residue was dissolved in methanol
(20 ml), water (10 ml) was added, and methanol was distilled off.
The precipitate was filtered, and dried to obtain compound 2 (1.15
g, 2.56 mmol).
[0871] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.15 (3H, s), 3.50-3.70
(5H, m), 4.19 (1H, dd, J=13.8 Hz, 3.1 Hz), 4.49 (1H, d, J=11.6 Hz),
5.78 (1H, d, J=9.6 Hz), 7.10-7.27 (6H, m), 7.34 (1H, m), 7.46 (2H,
t, J=7.5 Hz), 7.63 (2H, t, J=7.7 Hz), 7.94 (1H, s), 12.94 (1H, s),
15.08 (1H, s).
[0872] MS: m/z=449.4 [M+H].sup.+.
Reference Example 3
##STR00182##
[0874] According to Reference example 2, compound 3 was synthesized
by the same procedure.
[0875] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.15 (1H, m), 3.26 (3H,
s), 3.52-3.70 (4H, m), 3.70-3.80 (2H, m), 4.10 (1H, d, J=12.9 Hz),
4.92 (1H, brs), 6.98 (1H, t, J=7.4 Hz), 7.03 (1H, brs), 7.08 (1H,
t, 7.6 Hz), 7.34 (1H, d, J=7.8 Hz), 7.47 (1H, d, J=7.3 Hz), 7.80
(1H, s), 10.94 (1H, brs), 15.38 (1H, brs).
[0876] MS: m/z=412.4 [M+H].sup.+.
Reference Example 4
##STR00183##
[0878] According to Reference example 2, compound 4 was synthesized
by the same procedure.
[0879] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.13 (3H, s), 3.46-3.72
(5H, m), 4.16 (1H, d, J=12.6 Hz), 4.48 (1H, d, J=10.9 Hz), 5.77
(1H, d, J=11.6 Hz), 7.10-7.27 (6H, m), 7.32 (1H, m), 7.44 (2H, m),
7.61 (2H, m), 7.93 (1H, s), 15.04 (1H, s).
[0880] MS: m/z=449.3 [M+H].sup.+.
Reference Example 5
##STR00184##
[0882] According to Reference example 2, compound 5 was synthesized
by the same procedure.
[0883] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.28 (3H, s), 3.52-3.68
(4H, m), 4.06 (1H, m), 4.25 (2H, m), 4.41 (1H, brs), 4.56 (1H, d,
J=13.6 Hz), 4.82 (1H, d, J=13.9 Hz), 6.74 (2H, d, J=7.6 Hz), 6.92
(1H, t, J=7.20 Hz), 7.25 (2H, t, J=7.8 Hz), 8.58 (1H, s), 12.48
(1H, brs), 15.55 (1H, brs).
[0884] MS: m/z=389.4 [M+H].sup.+.
Reference Example 6
##STR00185##
[0886] According to Reference example 2, compound 6 was synthesized
by the same procedure.
[0887] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.16 (1H, m), 3.26 (3H,
s), 3.50-3.70 (4H, m), 3.70-3.80 (2H, m), 4.10 (1H, d, J=13.4 Hz),
4.92 (1H, brs), 6.98 (1H, t, J=7.1 Hz), 7.03 (1H, brs), 7.08 (1H,
t, J=7.3 Hz), 7.34 (1H, d, J=7.8 Hz), 7.48 (1H, d, J=7.3 Hz), 7.81
(1H, s), 12.91 (1H, s), 15.36 (1H, s).
[0888] MS: m/z=412.4 [M+H].sup.+.
Reference Example 7
##STR00186##
[0890] According to Reference example 2, compound 7 was synthesized
by the same procedure.
[0891] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.85-0.95 (2H, m),
1.05-1.25 (5H, m), 1.45-1.80 (8H, m), 3.28 (3H, s), 3.46 (1H, m),
3.58 (1H, m), 3.72 (1H, d, J=13.9 Hz), 3.93 (1H, m), 4.04 (1H, d,
J=13.1 Hz), 4.88 (1H, s), 8.56 (1H, s), 12.80 (1H, s), 15.51 (1H,
s).
[0892] MS: m/z=379.3 [M+H].sup.+.
Reference Example 8
##STR00187##
[0894] According to Reference example 2, compound 8 was synthesized
by the same procedure.
[0895] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.07 (2H, m), 2.55 (1H,
m), 2.74 (1H, m), 3.17 (1H, s), 3.23 (3H, s), 3.48-3.65 (4H, m),
3.79 (1H, d, J=13.6 Hz), 3.87 (1H, m), 4.09 (1H, d, J=13.6 Hz),
4.80 (1H, s), 7.10-7.29 (5H, m), 8.59 (1H, s), 12.77 (1H, s), 15.49
(1H, s).
[0896] MS: m/z=387.3 [M+H].sup.+.
Reference Example 9
##STR00188##
[0898] According to Reference example 2, compound 9 was synthesized
by the same procedure.
[0899] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.80 (1H, dd, J=14.5 Hz,
J2=8.5 Hz), 2.93 (1H, dd, J=14.4 Hz, 5.6 Hz), 3.21 (3H, s),
3.40-3.55 (4H, m), 3.77 (2H, s), 3.82 (1H, d, J=13.1 Hz), 3.88 (1H,
m), 4.13 (1H, d, J=13.6 Hz), 4.85 (1H, s), 7.20-7.35 (5H, m), 8.61
(1H, s), 12.79 (1H, s), 15.43 (1H, s).
[0900] MS: m/z=419.3 [M+H].sup.+.
Reference Example 10
##STR00189##
[0902] According to Reference example 2, compound 10 was
synthesized by the same procedure.
[0903] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.22 (3H, d, J=6.2 Hz),
3.29 (3H, s), 3.43 (1H, m), 3.58 (2H, m), 3.94 (1H, m), 4.12 (1H,
brs), 4.41 (1H, d, J=13.6 Hz), 4.49 (1H, d, J=13.1 Hz), 8.59 (1H,
s), 12.65 (1H, s), 15.53 (1H, s).
[0904] MS: m/z=297.2 [M+H].sup.+.
Reference Example 11
##STR00190##
[0906] According to Reference example 2, compound 11 was
synthesized by the same procedure.
[0907] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.46 (4H, brs),
1.76-1.90 (2H, m), 2.22 (1H, brs), 3.27 (3H, s), 3.57 (1H, d, J=5.3
Hz), 4.07 (1H, m), 4.69 (1H, m), 8.47 (1H, s), 13.04 (1H, s), 15.52
(1H, s).
[0908] MS: m/z=337.2 [M+H].sup.+.
Reference Example 12
##STR00191## ##STR00192##
[0909] First Step
[0910] Compound 12A (1.53 g, 5.80 mmol) were dissolved in THF (6
ml) and water (6 ml), potassium carbonate (2.41 g, 17.4 mmol) was
added, the mixture was stirred, and benzyl chloroformate (1.09 g,
6.38 mmol) was added dropwise at 0.degree. C. After stirring at
0.degree. C. for 10 minutes, the mixture was stirred at room
temperature for 2 hours. The reaction solution was poured into
sodium bicarbonate water, and the mixture was extracted with ethyl
acetate. The extract was washed with 1N hydrochloric acid and an
aqueous saturated sodium chloride solution, and dried with sodium
sulfate. The solvent was distilled off to obtain 2.32 g of compound
12B as a colorless gummy substance.
[0911] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.98 (1H, brs), 3.55 (1H,
m), 3.75 (1H, m), 4.20 (1H, d, J=10.5 Hz), 4.58 (1H, m), 4.83 (1H,
brs), 5.07 (2H, s), 7.16-7.39 (15H, m).
Second Step
[0912] The compound 12B (1.94 g, 5.37 mmol), triphenylphosphine
(2.11 g, 8.05 mmol) and phthalimide (948 mg, 6.44 mmol) were added
to THF (20 ml), and diisopropyl azodicarboxylate (2.2M in toluene,
3.66 ml, 8.05 mmol) was added dropwise at room temperature. After
stirring at room temperature for 4 hours, the solvent was distilled
off under reduced pressure. The resulting crude product was
purified by silica gel column chromatography (n-hexane-ethyl
acetate, 1:1, v/v) to obtain 2.39 g of compound 12C as a colorless
solid.
[0913] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.73 (2H, m), 4.05 (1H, d,
J=10.1 Hz), 4.70 (1H, d, J=9.6 Hz), 4.77 (2H, d, J=7.2 Hz) 5.02
(1H, m), 7.03-7.42 (15H, m), 7.68 (2H, dd, J=5.7, 2.1 Hz), 7.78
(2H, dd, J=5.7, 2.1 Hz).
Third Step
[0914] The compound 12C (2.39 g, 4.87 mmol) was added to THF (20
ml) and methanol (20 ml), hydrazine hydrate (4.88 g, 97.4 mmol) was
added, and the mixture was stirred at 50.degree. C. for 4 hours.
The white precipitate was removed by filtration, and washed with
methanol. After the filtrate was distilled off under reduced
pressure, the resulting crude product was purified by amino column
chromatography (chloroform-methanol, 99:1, v/v) to obtain 1.41 g of
compound 12D as a colorless solid.
[0915] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.63 (1H, dd, J=13.2, 5.8
Hz), 2.86 (1H, d, J=9.9 Hz), 4.07 (1H, d, J=10.4 Hz), 4.53 (1H, m),
4.81 (1H, m), 5.00 (2H, d, 8.4 Hz), 7.20-7.36 (10H, m).
Fourth Step
[0916] Compound 12D (1.41 g, 3.91 mmol) was dissolved in THF (15
ml), and Boc2O (896 mg, 4.11 mmol) was added at room temperature.
After stirring for 1.5 hours, the solvent was concentrated under
reduced pressure. The resulting crude product was purified by
silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v)
to obtain 1.77 g of compound 12E as a colorless solid.
[0917] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.41 (9H, s), 3.23 (2H,
brm), 3.97 (1H, d, J=9.8 Hz), 4.58-4.80 (3H, m), 5.00 (2H, d, J=9.8
Hz), 7.15-7.29 (10H, m).
Fifth Step
[0918] Compound 12E (1.73 g, 3.76 mmol) and palladium-active carbon
(10%, wet, 200 mg) were added to methanol (20 ml), and the mixture
was stirred at room temperature for 1 hour under hydrogen
atmosphere. After filtration with celite, the solvent was
concentrated under reduced pressure to obtain 1.01 g of a colorless
oily substance 12F.
[0919] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (9H, s), 2.82 (1H,
m), 3.31 (1H, m), 3.73 (2H, d, J=6.9 Hz), 4.98 (1H, s), 7.18-7.39
(10H, m).
Sixth Step
[0920] Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (974
mg, 3.06 mmol) obtained by the method shown in Intermediate
Synthesis Example 1, and 12F (999 mg, 3.06 mmol) were added to
toluene (10 ml), and the mixture was stirred at 110.degree. C. for
5 hours. After the solvent was distilled off under reduced
pressure, the resulting crude product was purified by silica gel
column chromatography (chloroform-methanol, 98:2, v/v) to obtain
1.51 g of compound 12G as a pale yellow solid.
[0921] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.36 (9H, s), 3.40 (1H,
m), 3.53 (1H, m), 3.82 (3H, s), 3.91 (3H, s), 4.29 (1H, d, J=11.3
Hz), 4.78 (1H, m), 4.82 (1H, m), 5.11 (1.9H, d, J=7.5 Hz),
7.10-7.38 (10H, m), 8.27 (1H, s).
Seventh Step
[0922] To compound 12G (1.45 g, 2.31 mmol) was added 4N HCl (ethyl
acetate solution, 20 ml), and the mixture was stirred at room
temperature for 1.5 hours. After the solvent was distilled off
under reduced pressure, sodium bicarbonate water was added, and the
mixture was stirred at room temperature for 1.5 hours. This was
extracted with chloroform, and dried with sodium sulfate. After the
solvent was distilled off under reduced pressure, the resulting
crude product was purified by silica gel column chromatography
(chloroform-methanol, 95:5, v/v) to obtain 1.01 g of compound 12H
as a colorless solid.
[0923] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.40 (1H, dd, J=13.6, 6.6
Hz), 3.78 (3H, s), 3.80 (1H, m), 4.37 (1H, d, J=11.6 Hz), 4.59 (1H,
d, J=11.0 Hz), 5.43 (2H, d, J=10.2 Hz), 5.93 (1H, d, J=5.8 Hz),
7.03-7.21 (5H, m), 7.37 (9H, m), 7.63 (2H, m).
Eighth Step
[0924] Compound 12H (50 mg, 0.10 mmol) was dissolved in DMF (1 ml),
and cesium carbonate (165 mg, 0.50 mmol) was added. After stirring
at room temperature for 30 minutes, iodomethane (0.032 ml, 0.50
mmol) was added, and the mixture was stirred at room temperature
for 3.5 hours. The reaction solution was poured into water, and the
mixture was extracted with ethyl acetate, and dried with sodium
sulfate. After the solvent was distilled off under reduced
pressure, the resulting crude product was purified by silica gel
column chromatography (chloroform-methanol, 95:5, v/v) to obtain 49
mg of compound 12I as a colorless solid.
Ninth Step
[0925] Compound 12I (49 mg, 0.096 mmol) was dissolved in THF (0.5
ml) and methanol (0.5 ml), a 2N aqueous sodium hydroxide solution
(0.24 ml, 0.48 mmol) was added at room temperature, and the mixture
was stirred for 1.5 hours. After 1N hydrochloric acid was added,
and the mixture was extracted with ethyl acetate, the extract was
dried with sodium sulfate. After the solvent was distilled off
under reduced pressure, 54 mg of compound 12J was obtained as a
colorless solid.
[0926] MS: m/z=481 [M+H].sup.+.
Tenth Step
[0927] To compound 12J obtained in the ninth step was added
trifluoroacetic acid (1 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 3 with sodium bicarbonate water and 2N
hydrochloric acid, and the mixture was extracted with chloroform,
and dried with sodium sulfate. After the solvent was distilled off
under reduced pressure, chloroform-methanol-ethyl ether were added,
and the precipitated solid was filtered to obtain 26 mg of compound
12 as a colorless solid.
[0928] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.01 (3H, s), 3.26 (1H,
t, J=14.4 Hz), 4.23 (1H, dd, J=13.5, 3.8 Hz), 4.57 (1H, d, J=11.6
Hz), 5.78 (1H, d, J=11.3 Hz), 7.16-7.70 (10H, m), 8.00 (1H, s),
13.00 (1H, s), 15.10 (1H, s).
[0929] MS: m/z=405 [M+H].sup.+.
Reference Example 13
##STR00193##
[0931] According to Reference example 12, compound 13 was
synthesized by the same procedure.
[0932] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.05 (3H, t, J=6.9 Hz),
3.43-3.65 (3H, m), 4.22 (1H, d, J=10.6 Hz), 4.55 (1H, d, J=11.6
Hz), 5.81 (1H, d, J=10.1 Hz), 7.15-7.68 (10H, m), 7.97 (1H, s),
12.96 (1H, s), 15.07 (1H, s).
[0933] MS: m/z=463 [M+H].sup.+.
Reference Example 14
##STR00194##
[0935] According to Reference example 12, compound 14 was
synthesized by the same procedure.
[0936] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.98 (3H, t, J=7.17 Hz),
3.44-3.64 (3H, m), 4.15 (1H, dd, J=13.7, 3.5 Hz), 4.45 (1H, d,
J=11.6 Hz), 5.79 (1H, d, J=12.2 Hz), 7.08-7.63 (10H, m), 7.89 (1H,
s), 13.01 (1H, s), 15.06 (1H, s).
[0937] MS: m/z=419 [M+H].sup.+.
Reference Example 15
##STR00195##
[0939] According to Reference example 12, compound 15 was
synthesized by the same procedure.
[0940] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.22 (1H, s), 3.47 (1H,
d, J=13.3 Hz), 4.17 (2H, m), 4.44 (2H, dd, J=16.7, 3.0 Hz), 5.79
(1H, d, J=12.2 Hz), 7.10-7.64 (10H, m), 7.98 (1H, s), 12.56 (1H,
s), 15.05 (1H, brs).
Reference Example 16
##STR00196##
[0942] According to Reference example 12, compound 16 was
synthesized by the same procedure.
[0943] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.24 (1H, d, J=13.2 Hz),
4.23 (1H, m), 4.25 (1H, d, J=14.7 Hz), 4.40 (1H, d, J=14.8 Hz),
4.92 (1H, d, J=15.4 Hz), 5.79 (1H, m), 7.03-7.48 (10H, m), 7.93
(1H, s), 12.82 (1H, s), 15.06 (1H, s).
Reference Example 17
##STR00197##
[0945] According to Reference example 12, compound 17 was
synthesized by the same procedure.
[0946] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.23 (1H, d, J=13.4 Hz),
4.22 (1H, m), 4.25 (1H, d, J=12.0 Hz), 4.45 (1H, d, J=14.9 Hz),
4.93 (1H, d, J=15.3 Hz), 5.77 (1H, d, J=11.6 Hz), 7.09-7.56 (10H,
m), 7.92 (1H, s), 12.74 (1H, s), 15.06 (1H, s).
Reference Example 18
##STR00198##
[0948] According to Reference example 12, compound 18 was
synthesized by the same procedure.
[0949] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.63 (2H, m), 3.20 (3H,
s), 3.44 (5H, m), 4.19 (1H, d, J=10.2 Hz), 4.51 (1H, d, J=11.8 Hz),
5.80 (1H, d, J=11.0 Hz), 7.13-7.65 (10H, m), 7.93 (1H, s), 13.02
(1H, s).
[0950] MS: m/z=463 [M+H].sup.+.
Reference Example 19
##STR00199##
[0952] According to Reference example 12, compound 19 was
synthesized by the same procedure.
[0953] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.15 (1H, d, J=9.5 Hz),
3.95 (1H, dd, J=13.5, 3.4 Hz), 4.51 (1H, d, J=11.6 Hz), 5.74 (1H,
d, J=11.1 Hz), 7.11-7.62 (10H, m), 7.93 (1H, s), 9.34 (1H, s),
12.97 (1H, s), 15.07 (1H, brs).
[0954] MS: m/z=391 [M+H].sup.+.
Reference Example 20
##STR00200##
[0956] According to Reference example 12, compound 20 was
synthesized by the same procedure.
[0957] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.26 (1H, m), 4.24 (1H,
m), 4.27 (1H, d, J=12.0 Hz), 4.41 (1H, d, J=14.8 Hz), 4.87 (1H, d,
J=14.9 Hz), 5.75 (1H, d, J=7.6 Hz), 7.09-7.77 (12H, m), 7.93 (1H,
s), 8.52 (2H, m), 12.79 (1H, s), 15.07 (1H, brs).
[0958] MS: m/z=482 [M+H].sup.+.
Reference Example 21
##STR00201##
[0960] According to Reference example 12, compound 21 was
synthesized by the same procedure.
[0961] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.62 (3H, d, J=6.9 Hz),
0.82 (3H, d, J=6.6 Hz), 3.18 (1H, m), 3.75 (1H, d, J=10.2 Hz), 4.25
(1H, d, J=11.8 Hz), 4.58 (1H, m), 5.65 (1H, d, J=11.3 Hz),
6.89-7.43 (10H, m), 7.67 (1H, s), 12.94 (1H, s).
[0962] MS: m/z=433 [M+H].sup.+.
Reference Example 22
##STR00202##
[0964] According to Reference example 12, compound 22 was
synthesized by the same procedure.
[0965] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.07-1.70 (5H, m),
3.04-3.34 (5H, m), 3.82 (2H, dm), 4.18 (1H, d, J=10.2 Hz), 4.42
(1H, d, J=12.0 Hz), 5.81 (1H, d, J=11.7 Hz), 7.11-7.59 (10H, m),
7.86 (1H, s), 12.96 (1H, s), 15.07 (1H, brs).
[0966] MS: m/z=489 [M+H].sup.+.
Reference Example 23
##STR00203##
[0968] According to Reference example 12, compound 23 was
synthesized by the same procedure.
[0969] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.01-0.79 (5H, m), 3.05
(1H, dd, J=14.1, 7.5 Hz), 3.49-3.59 (2H, m), 4.16 (1H, dd, J=14.0,
3.3 Hz), 4.50 (1H, d, J=11.9 Hz), 5.82 (1H, d, J=11.1 Hz),
7.11-7.62 (10H, m), 7.89 (1H, s), 12.99 (1H, s), 15.07 (1H,
brs).
[0970] MS: m/z=445 [M+H].sup.+.
Reference Example 24
##STR00204##
[0972] According to Reference example 12, compound 24 was
synthesized by the same procedure.
[0973] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.23 (1H, d, J=13.7 Hz),
4.16 (1H, dd, J=13.2, 3.3 Hz), 4.19 (2H, d, J=12.0 Hz), 4.38 (1H,
d, J=14.6 Hz), 4.84 (1H, d, J=14.6 Hz), 5.72 (1H, d, J=11.4 Hz),
7.08-7.33 (15H, m), 7.98 (1H, s), 12.88 (1H, s), 15.07 (1H, s).
[0974] MS: m/z=481 [M+H].sup.+.
Reference Example 25
##STR00205##
[0976] According to Reference example 12, compound 25 was
synthesized by the same procedure.
[0977] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.39 (3H, s), 3.37 (1H,
m), 4.21 (1H, dd, J=14.4, 3.9 Hz), 4.40 (1H, dd, J=11.7 Hz), 4.45
(1H, d, J=15.3 Hz), 4.81 (1H, d, J=15.4 Hz), 5.78 (1H, d, J=12.0
Hz), 6.30 (1H, s), 7.09-7.42 (10H, m), 7.95 (1H, s), 12.65 (1H, s),
15.07 (1H, s).
[0978] MS: m/z=486 [M+H].sup.+.
Reference Example 26
##STR00206##
[0980] According to Reference example 12, compound 26 was
synthesized by the same procedure.
[0981] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20-1.77 (6H, m),
3.11-3.61 (6H, m), 4.21 (1H, d, J=9.9 Hz), 4.53 (1H, d, J=11.7 Hz),
5.80 (1H, d, J=11.8 Hz), 7.14-7.65 (10H, m), 7.95 (1H, s), 12.95
(1H, brs), 15.06 (1H, brs).
[0982] MS: m/z=489 [M+H].sup.+.
Reference Example 27
##STR00207##
[0984] According to Reference example 12, compound 27 was
synthesized by the same procedure.
[0985] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.36 (1H, m), 4.28 (1H,
d, J=12.0 Hz), 4.54 (1H, d, J=11.4 Hz), 4.62 (1H, d, J=15.3 Hz),
4.79 (1H, d, J=15.4 Hz), 5.77 (1H, d, J=9.9 Hz), 7.09-7.79 (13H,
m), 7.98 (1H, s), 8.46 (1H, d, J=4.6 Hz), 12.82 (1H, brs), 15.06
(1H, brs).
[0986] MS: m/z=482 [M+H].sup.+.
Reference Example 28
##STR00208## ##STR00209##
[0987] First Step
[0988] Compound 28A (3.20 g, 17.1 mmol) was added to THF (20 ml),
triethylamine (2.60 ml, 18.8 mmol) was added, and the mixture was
stirred at room temperature for 10 minutes. After Boc2O (4.09 g,
18.8 mmol) was added at room temperature, the mixture was stirred
for 2 hours. The solvent was distilled off under reduced pressure,
water was added, and the mixture was extracted with ethyl acetate.
The organic layer was washed with an aqueous saturated sodium
chloride solution, and dried with sodium sulfate. The solvent was
distilled off under reduced pressure to obtain 5.17 g of compound
28B as a colorless solid.
[0989] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.52 (9H, s), 2.77 (2H,
m), 3.03-3.12 (1H, m), 3.38 (1H, m), 3.90-3.98 (1H, m), 4.93 (1H,
brs), 7.20-7.35 (5H, m).
Second Step
[0990] Compound 28B (4.29 g, 17.1 mmol), triphenylphosphine (5.37
g, 20.5 mmol) and phthalimide (2.76 g, 18.8 mmol) were added to THF
(60 ml), and diethyl azodicarboxylate (2.2M in toluene, 11.6 ml,
25.6 mmol) was added dropwise at room temperature. After the
mixture was stirred at room temperature for 1 hour, the solvent was
distilled off under reduced pressure. The resulting crude product
was purified by silica gel column chromatography (n-hexane-ethyl
acetate, 2:1, v/v) to obtain 6.13 g of compound 28C as a colorless
solid.
[0991] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (9H, s), 3.14 (1H,
dd, J=13.8, 6.2 Hz), 3.39 (2H, m), 3.87 (1H, m), 4.67 (1H, m), 4.81
(1H, brs), 7.16-7.19 (5H, m), 7.66 (2H, dd, J=5.3, 3.1 Hz), 7.75
(2H, dd, J=5.7, 3.0 Hz).
Third Step
[0992] Compound 28C (1.00 g, 2.63 mmol) was added to THF (7 ml) and
methanol (7 ml), hydrazine hydrate (2.63 g, 52.6 mmol) was added,
and the mixture was stirred at 50.degree. C. for 2 hours. The white
precipitate was removed by filtration, and washed with methanol.
After the filtrate was distilled off under reduced pressure, the
resulting crude product was purified by amino column chromatography
(chloroform-methanol, 99:1, v/v) to obtain 249 mg of compound 28D
as a colorless solid.
[0993] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (9H, s), 1.95 (2H,
brs), 2.55-3.31 (5H, m), 5.06 (1H, brs), 7.18-7.33 (5H, m).
Fourth Step
[0994] Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (313
mg, 0.983 mmol) and 28D (246 mg, 0.983 mmol) were added to toluene
(3 ml), and the mixture was stirred at 100.degree. C. for 2.5
hours. After the solvent was distilled off under reduced pressure,
the resulting crude product was purified by silica gel column
chromatography (chloroform-methanol, 98:2, v/v) to obtain 320 mg of
compound 28E as a pale yellow gummy substance.
[0995] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.42 (9H, s), 3.07 (2H,
m), 3.56 (2H, m), 3.68 (3H, s), 3.95 (3H, s), 4.26 (1H, s), 4.86
(1H, s), 5.18 (1H, d, J=10.8 Hz), 5.22 (1H, d, J=10.8 Hz), 7.01
(2H, m), 7.24-7.38 (8H, m), 8.22 (1H, s).
[0996] MS: m/z=551 [M+H].sup.+.
Fifth Step
[0997] To compound 28E (315 mg, 0.572 mmol) was added 4N HCl (ethyl
acetate solution, 5 ml), and the mixture was stirred at room
temperature for 30 minutes. After the solvent was distilled off
under reduced pressure, aqueous sodium bicarbonate water was added,
and the mixture was extracted with chloroform, and dried with
sodium sulfate. After the solvent was distilled off under reduced
pressure, the resulting crude product was purified by silica gel
column chromatography (chloroform-methanol, 95:5, v/v) to obtain
210 mg of compound 28F as a colorless solid.
[0998] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.07-3.15 (2H, m), 3.34
(1H, dd, J=13.2, 6.0 Hz), 3.74 (2H, m), 3.86 (3H, s), 4.12 (1H, m),
5.27 (1H, d, J=10.1 Hz), 5.47 (1H, d, J=10.1 Hz), 6.76 (1H, d,
J=6.4 Hz), 7.04 (2H, m), 7.32 (6H, m), 7.62 (2H, dd, J=7.7, 1.4
Hz), 7.70 (1H, s).
[0999] MS: m/z=419 [M+H].sup.+.
Sixth Step
[1000] Compound 28F (50 mg, 0.12 mmol) was dissolved in DMF (1 ml),
and cesium carbonate (195 mg, 0.597 mmol) was added. After the
mixture was stirred at room temperature for 30 minutes, iodoethane
(0.048 ml, 0.60 mmol) was added, and the mixture was stirred at
room temperature for 3.5 hours. The reaction solution was poured
into water, and the mixture was extracted with ethyl acetate, and
dried with sodium sulfate. After the solvent was distilled off
under reduced pressure, the resulting crude product was purified by
silica gel column chromatography (chloroform-methanol, 95:5, v/v)
to obtain 47 mg of compound 28G as a colorless solid.
[1001] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (3H, t, J=7.2 Hz),
3.00-3.15 (2H, m), 3.28 (1H, dd, J=13.6, 1.6 Hz), 3.48 (1H, m),
3.75 (1H, m), 3.85 (3H, s), 3.88 (1H, dd, J=13.3, 3.2 Hz), 4.15
(1H, m), 5.25 (1H, d, J=9.9 Hz), 5.50 (1H, d, J=9.9 Hz), 7.04 (2H,
m), 7.29-7.38 (6H, m), 7.60 (1H, s), 7.68 (2H, m).
[1002] MS: m/z=447 [M+H].sup.+.
Seventh Step
[1003] Compound 28G (47 mg, 0.11 mmol) was dissolved in THF (0.5
ml) and methanol (0.5 ml), a 2N aqueous sodium hydroxide solution
(0.26 ml, 0.53 mmol) was added at room temperature, and the mixture
was stirred for 1 hour. After 1N hydrochloric acid was added, and
the mixture was extracted with ethyl acetate, the extract was dried
with sodium sulfate. After the solvent was distilled off under
reduced pressure, 40 mg of compound 28H was obtained as a colorless
solid.
[1004] MS: m/z=433 [M+H].sup.+.
Eighth Step
[1005] To compound 28H obtained in the seventh step was added
trifluoroacetic acid (1 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 3 with sodium bicarbonate water and 2N
hydrochloric acid, and the mixture was extracted with chloroform,
and dried with sodium sulfate. After the solvent was distilled off
under reduced pressure, chloroform-methanol-ethyl ether were added,
and the precipitated solid was filtered to obtain 17 mg of compound
28 as a colorless solid.
[1006] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.17 (3H, t, J=7.2 Hz),
3.08 (2H, m), 3.51-3.63 (3H, m), 4.08 (1H, dd, J=13.6, 3.9 Hz),
5.03 (1H, brs), 7.21 (5H, m), 8.07 (1H, s), 12.98 (1H, s), 15.07
(1H, brs).
[1007] MS: m/z=343 [M+H].sup.+.
Reference Example 29
##STR00210##
[1009] According to Reference example 28, compound 29 was
synthesized by the same procedure.
[1010] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.96 (2H, d, J=7.6 Hz),
3.46 (1H, d, J=13.3 Hz), 4.06 (1H, dd, J=13.6, 3.8 Hz), 4.64 (1H,
d, J=14.9 Hz), 4.89 (1H, d, J=14.6 Hz), 4.98 (1H, m), 6.97 (2H, m),
7.10-7.37 (5H, m), 7.57 (1H, m), 8.12 (1H, s), 12.75 (1H, s), 15.07
(1H, brs).
Reference Example 30
##STR00211##
[1012] According to Reference example 28, compound 30 was
synthesized by the same procedure.
[1013] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.99 (2H, dd, J=7.5, 3.6
Hz), 3.48 (1H, d, J=13.4 Hz), 4.09 (1H, dd, J=13.4, 4.0 Hz), 4.73
(1H, d, J=15.1 Hz), 4.92 (1H, d, J=15.1 Hz), 4.99 (1H, m), 6.97
(2H, m), 7.18-7.29 (4H, m), 7.49 (1H, m), 7.61 (1H, m), 8.15 (1H,
s), 12.69 (1H, s), 15.06 (1H, brs).
Reference Example 31
##STR00212##
[1015] According to Reference example 28, compound 31 was
synthesized by the same procedure.
[1016] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.91 (2H, m), 3.45 (1H,
d, J=13.1 Hz), 4.02 (1H, dd, J=13.6, 4.0 Hz), 4.57 (1H, d, J=14.6
Hz), 4.91 (1H, d, J=14.6 Hz), 4.93 (1H, m), 6.89 (2H, m), 7.18 (3H,
m), 7.40 (5H, m), 8.16 (1H, s), 12.86 (1H, brs), 15.06 (1H,
brs).
[1017] MS: m/z=405 [M+H].sup.+.
Reference Example 32
##STR00213##
[1019] According to Reference example 28, compound 32 was
synthesized by the same procedure.
[1020] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.10 (2H, m), 3.39 (1H,
d, J=13.6 Hz), 3.84 (1H, dd, J=13.6, 4.0 Hz), 4.94 (1H, m), 7.23
(5H, m), 8.19 (1H, s), 9.44 (1H, brs), 12.97 (1H, s), 15.06 (1H,
brs).
[1021] MS: m/z=315 [M+H].sup.+.
Reference Example 33
##STR00214##
[1023] According to Reference example 28, compound 33 was
synthesized by the same procedure.
[1024] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.09 (3H, t, J=6.9 Hz),
3.10 (2H, m), 3.42-3.50 (2H, m), 3.71 (5H, m), 4.11 (1H, dd,
J=13.6, 3.8 Hz), 4.99 (1H, brs), 7.11-7.29 (5H, m), 7.99 (1H, s),
12.88 (1H, s), 15.06 (1H, brs).
[1025] MS: m/z=387 [M+H].sup.+.
Reference Example 34
##STR00215##
[1027] According to Reference example 28, compound 34 was
synthesized by the same procedure.
[1028] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.16 (3H, d, J=6.9 Hz),
1.21 (3H, d, J=6.9 Hz), 2.98 (1H, dd, J=13.6, 9.8 Hz), 3.13 (1H,
dd, J=13.7, 5.8 Hz), 3.68 (1H, d, J=12.8 Hz), 3.87 (1H, dd, J=13.6,
3.7 Hz), 4.83 (1H, quin, J=6.8 Hz), 5.07 (1H, brs), 7.19 (5H, m),
7.90 (1H, s), 13.09 (1H, s), 15.08 (1H, brs).
[1029] MS: m/z=357 [M+H].sup.+.
Reference Example 35
##STR00216##
[1031] According to Reference example 28, compound 35 was
synthesized by the same procedure.
[1032] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.07 (3H, s), 3.14 (2H,
m), 3.49 (1H, d, J=13.3 Hz), 4.08 (1H, dd, J=13.7, 4.0 Hz), 4.99
(1H, m), 7.13-7.31 (5H, m), 8.18 (1H, s), 12.95 (1H, s), 15.06 (1H,
brs).
[1033] MS: m/z=329 [M+H].sup.+.
Reference Example 36
##STR00217##
[1034] First Step
[1035] Compound 12H (460 mg, 0.930 mmol) was dissolved in THF (2.5
ml) and methanol (2.5 ml), a 2N aqueous sodium hydroxide solution
(2.33 ml, 4.65 mmol) was added at room temperature, and the mixture
was stirred for 1.5 hours. After 1N hydrochloric acid was added,
and the mixture was extracted with ethyl acetate, the extract was
dried with sodium sulfate. After the solvent was distilled off
under reduced pressure, 405 mg of compound 36A was obtained as a
colorless solid.
[1036] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.45 (1H, ddd, J=13.8,
6.9, 1.3 Hz), 3.80 (1H, dd, J=13.5, 2.1 Hz), 4.35 (1H, d, J=11.6
Hz), 4.77 (1H, d, J=11.3 Hz), 5.46 (1H, d, J=10.5 Hz), 5.52 (1H, d,
J=10.5 Hz), 6.11 (1H, d, J=5.8 Hz), 6.94-6.98 (2H, m), 7.17 (3H,
m), 7.31-7.46 (8H, m), 7.58 (3H, m).
Second Step
[1037] Compound 36A (402 mg, 0.837 mmol) was added to diphenyl
ether (5 ml), and the mixture was stirred at 245.degree. C. for 1
hour under microwave irradiation. The reaction solution was poured
into n-hexane, and the precipitated solid was filtered. The
resulting crude product was purified by amino column chromatography
(chloroform-methanol, 99:1, v/v) to obtain 164 mg of compound 36B
as a colorless solid.
[1038] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.36 (1H, dd, J=13.0, 7.0
Hz), 3.72 (1H, d, J=11.1 Hz), 4.35 (1H, d, J=11.4 Hz), 4.49 (1H, d,
J=10.2 Hz), 5.38 (1H, d, J=10.5 Hz), 5.43 (1H, d, J=10.4 Hz), 5.94
(1H, d, J=7.2 Hz), 6.29 (1H, d, J=6.6 Hz), 6.38 (1H, d, J=7.5 Hz),
6.99 (2H, m), 7.17 (3H, m), 7.36 (8H, m), 7.60 (2H, m).
Third Step
[1039] Compound 36B (40 mg, 0.092 mmol) was dissolved in DMF (1
ml), and cesium carbonate (179 mg, 0.55 mmol) was added. After
stirring at room temperature for 30 minutes, iodomethane (0.029 ml,
0.46 mmol) was added, and the mixture was stirred at room
temperature for 3.5 hours. The reaction solution was poured into
water, and the mixture was extracted with ethyl acetate, and dried
with sodium sulfate. After the solvent was distilled off under
reduced pressure, the resulting crude product was purified by
silica gel column chromatography (chloroform-methanol, 95:5, v/v)
to obtain 44 mg of compound 36C as a colorless gummy substance.
Fourth Step
[1040] To compound 36C obtained in the third step was added
trifluoroacetic acid (1 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 6 with sodium bicarbonate water and 2N
hydrochloric acid, the mixture was extracted with chloroform, and
the extract was dried with sodium sulfate. After the solvent was
distilled off under reduced pressure, chloroform-ethyl ether were
added, and the precipitated solid was filtered to obtain 24 mg of
compound 36 as a colorless solid.
[1041] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.93 (3H, s), 3.17 (1H,
d, J=13.0 Hz), 4.13 (1H, dd, J=13.6, 3.4 Hz), 4.47 (1H, d, J=11.4
Hz), 5.52 (1H, dd, J=9.3, 3.4 Hz), 5.99 (1H, d, J=7.3 Hz), 7.18
(4H, m), 7.30 (3H, m), 7.41 (2H, t, J=7.5 Hz), 7.60 (2H, d, J=7.2
Hz).
[1042] MS: m/z=361 [M+H].sup.+.
Reference Example 37
##STR00218##
[1044] According to Reference example 36, compound 37 was
synthesized by the same procedure.
[1045] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.16 (2H, d, J=13.3 Hz),
4.05 (1H, d, J=10.5 Hz), 4.15 (1H, d, J=11.7 Hz), 4.38 (1H, d,
J=14.9 Hz), 4.74 (1H, d, J=14.5 Hz), 5.35 (1H, d, J=11.4 Hz), 5.65
(1H, d, J=7.3 Hz), 6.99 (1H, d, J=7.5 Hz), 7.21 (15H, m).
[1046] MS: m/z=437 [M+H].sup.+.
Reference Example 38
##STR00219##
[1048] According to Reference example 36, compound 38 was
synthesized by the same procedure.
[1049] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.57 (2H, m), 3.17 (3H,
s), 3.21-3.31 (5H, m), 4.07 (1H, dd, J=13.5, 3.7 Hz), 4.36 (1H, d,
J=11.6 Hz), 5.42 (1H, d, J=9.2 Hz), 5.61 (1H, d, J=7.3 Hz), 6.89
(1H, d, J=7.5 Hz), 7.13-7.31 (6H, m), 7.40 (2H, t, J=6.3 Hz), 7.57
(2H, d, J=7.3 Hz), 12.31 (1H, brs).
[1050] MS: m/z=419 [M+H].sup.+.
Reference Example 39
##STR00220##
[1052] According to Reference example 36, compound 39 was
synthesized by the same procedure.
[1053] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.12 (1H, dd, J=13.6,
5.5 Hz), 3.87 (1H, d, J=9.5 Hz), 4.44 (1H, d, J=11.7 Hz), 5.45 (1H,
d, J=10.4 Hz), 5.83 (1H, d, J=7.5 Hz), 7.04 (1H, d, J=7.2 Hz),
7.14-7.31 (6H, m), 7.40 (2H, t, J=7.5 Hz), 7.58 (2H, d, J=7.5 Hz),
9.09 (1H, d, J=5.2 Hz).
[1054] MS: m/z=347 [M+H].sup.+.
Reference Example 40
##STR00221##
[1056] According to Reference example 36, compound 40 was
synthesized by the same procedure.
[1057] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.88-3.15 (2H, m), 3.27
(3H, s), 3.53-3.73 (5H, m), 3.99 (1H, dd, J=13.27, 3.97 Hz),
4.56-4.60 (1H, m), 5.89 (1H, d, J=7.32 Hz), 7.08-7.30 (6H, m).
Reference Example 41
##STR00222##
[1058] First Step
[1059] Compound 41A (290 mg, 0.555 mmol) synthesized according to
Reference example 12 was added to diphenyl ether (5 ml), and the
mixture was stirred at 245.degree. C. for 1 hour under microwave
irradiation. The reaction solution was poured into n-hexane, and
the precipitated solid was filtered. The resulting crude product
was purified by amino column chromatography (chloroform-methanol,
99:1.fwdarw.97:3, v/v) to obtain 86 mg of compound 41B as a
colorless solid.
[1060] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.76 (3H, d, J=6.7 Hz),
0.98 (3H, d, J=6.9 Hz), 3.43-3.52 (2H, m), 3.62 (1H, dd, J=13.6,
3.5 Hz), 4.22 (1H, d, J=11.6 Hz), 4.52 (1H, d, J=11.6 Hz),
4.86-4.95 (1H, m), 5.37 (1H, d, J=10.2 Hz), 5.45 (1H, d, J=10.2
Hz), 5.90 (1H, d, J=7.5 Hz), 6.22 (1H, d, J=7.5 Hz), 6.89 (2H, m),
7.15 (3H, m), 7.36 (8H, m), 7.67 (2H, m).
Second Step
[1061] To compound 41B obtained in the first step was added
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 6 with sodium bicarbonate water and 2N
hydrochloric acid, the mixture was extracted with chloroform, and
the extract was dried with sodium sulfate. After the solvent was
distilled off under reduced pressure, methylene chloride-ethyl
ether were added, and the precipitated solid was filtered to obtain
45 mg of compound 41 as a colorless solid.
[1062] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.82 (3H, d, J=6.7 Hz),
1.05 (3H, d, J=6.7 Hz), 3.90 (1H, dd, J=13.6, 3.4 Hz), 4.39 (1H, d,
J=11.9 Hz), 4.77-4.86 (1H, m), 5.50 (1H, d, J=8.6 Hz), 5.69 (1H, d,
J=7.4 Hz), 6.92 (1H, d, J=7.4 Hz), 7.15-7.48 (8H, m), 7.63 (2H, d,
J=7.7 Hz) 12.51 (1H, Brs).
[1063] MS: m/z=389 [M+H].sup.+.
Reference Example 42
##STR00223##
[1065] According to Reference example 41, compound 42 was
synthesized by the same procedure.
[1066] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.12 (3H, s), 3.51 (5H,
m), 4.05 (1H, dd, J=13.9, 3.5 Hz), 4.37 (1H, d, J=11.4 Hz), 5.38
(1H, d, J=11.6 Hz), 5.60 (1H, d, J=7.3 Hz), 6.90 (1H, d, J=7.5 Hz),
7.22 (6H, m), 7.40 (2H, t, J=7.5 Hz), 7.56 (2H, d, J=7.2 Hz).
[1067] MS: m/z=405 [M+H].sup.+.
Reference Example 43
##STR00224## ##STR00225##
[1068] First Step
[1069] Compound 43A (2.00 g, 6.11 mmol), triphenylphosphine (2.40
g, 9.16 mmol) and phthalimide (1.08 g, 7.33 mmol) were added to THF
(20 ml), and diethyl azodicarboxylate (2.2M in toluene, 4.16 ml,
9.16 mmol) was added dropwise at room temperature. After stirring
at room temperature for 3 hours, the solvent was distilled off
under reduced pressure. The resulting crude product was purified by
silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v)
to obtain 2.39 g of compound 43B as a colorless solid.
[1070] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.00 (9H, s), 3.30 (1H,
m), 3.61 (1H, dd, J=13.4, 10.2 Hz), 4.15 (1H, d, J=12.2 Hz), 4.75
(1H, m), 6.79 (1H, d, J=9.5 Hz), 7.25 (15H, m), 7.76-7.89 (4H,
m).
Second Step
[1071] Compound 43B (2.06 g, 4.51 mmol) was added to THF (20 ml)
and methanol (20 ml), hydrazine hydrate (4.52 g, 90.2 mmol) was
added, and the mixture was stirred at 60.degree. C. for 5 hours.
The white precipitate was removed by filtration, and washed with
methanol. After the filtrate was distilled off under reduced
pressure, the resulting crude product was purified by amino column
chromatography (chloroform-methanol, 99:1, v/v), n-hexane was
added, and the precipitated solid was filtered to obtain 1.25 g of
compound 43C as a colorless solid.
[1072] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.32 (9H, s), 2.55 (1H,
dd, J=13.3, 6.0 Hz), 2.80 (1H, dd, J=13.3, 3.5 Hz), 3.99 (1H, d,
J=10.1 Hz), 4.47 (2H, m), 7.13-7.33 (10H, m).
Third Step
[1073] Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (488
mg, 1.53 mmol) and 43C (500 mg, 1.53 mmol) were added to toluene (8
ml), and the mixture was stirred at 110.degree. C. for 1 hour.
After the solvent was distilled off under reduced pressure, the
resulting crude product was purified by silica gel column
chromatography (chloroform-methanol, 97:3.fwdarw.96:4.fwdarw.94:6,
v/v) to obtain 667 mg of compound 43D as a pale yellow gummy
substance.
[1074] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28 (9H, s), 3.63 (3H,
s), 3.80 (1H, m), 3.87 (3H, s), 4.02 (1H, dd, J=14.5, 10.1 Hz),
4.21 (1H, d, J=10.4 Hz), 4.47 (2H, m), 5.20 (1H, d, J=10.8 Hz),
5.26 (1H, d, J=10.7 Hz), 7.30 (15H, m), 8.05 (1H, s).
[1075] MS: m/z=627 [M+H].sup.+.
Fourth Step
[1076] To compound 43D (664 mg, 1.06 mmol) was added 4N HCl (ethyl
acetate solution, 10 ml), and the mixture was stirred at room
temperature for 1 hour. After the solvent was distilled off under
reduced pressure, THF and saturated sodium bicarbonate water were
added, and the mixture was stirred for 2.5 hours. This was
extracted with chloroform, and dried with sodium sulfate. After the
solvent was distilled off under reduced pressure, methylene
chloride-ethyl ether were added, and the precipitated solid was
filtered to obtain 458 mg of compound 43E as a colorless solid.
[1077] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.86 (3H, m), 3.92 (3H,
s), 4.41-4.48 (1H, m), 5.32 (1H, d, J=10.8 Hz), 5.42 (1H, d, J=10.1
Hz), 5.92 (1H, s), 7.21-7.39 (13H, m), 7.59 (2H, m), 7.89 (1H,
s).
[1078] MS: m/z=495 [M+H].sup.+.
Fifth Step
[1079] Compound 43E (50 mg, 0.10 mmol) was dissolved in DMF (1 ml),
and cesium carbonate (165 mg, 0.51 mmol) was added. After the
mixture was stirred at room temperature for 30 minutes, iodomethane
(0.025 ml, 0.40 mmol) was added, and the mixture was stirred at
room temperature for 1 hour. The reaction solution was poured into
water, and the mixture was extracted with ethyl acetate, and dried
with sodium sulfate. After the solvent was distilled off under
reduced pressure, the resulting crude product was purified by
silica gel column chromatography (chloroform-methanol,
97:3.fwdarw.95:5, v/v) to obtain 60 mg of compound 43F as a
colorless solid.
[1080] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.57 (3H, s), 3.75 (2H, d,
J=11.3 Hz), 3.93 (3H, s), 4.20-4.29 (2H, m), 5.25 (1H, d, J=9.9
Hz), 5.57 (1H, d, J=9.9 Hz), 7.15-7.41 (13H, m), 7.63 (1H, s),
7.72-7.76 (2H, m).
Sixth Step
[1081] Compound 43F obtained in the fifth step was dissolved in THF
(0.5 ml) and methanol (0.5 ml), a 2N aqueous sodium hydroxide
solution (0.25 ml, 0.50 mmol) was added at room temperature, and
the mixture was stirred for 1 hour. After 1N hydrochloric acid was
added, and the mixture was extracted with ethyl acetate, the
extract was dried with sodium sulfate. After the solvent was
distilled off under reduced pressure, a colorless gummy compound
43G was obtained.
Seventh Step
[1082] To compound 43G obtained in the sixth step was added
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 3 with sodium bicarbonate water and 2N
hydrochloric acid, and the mixture was extracted with chloroform,
and dried with sodium sulfate. After the solvent was distilled off
under reduced pressure, chloroform-ethyl ether were added, and the
precipitated solid was filtered to obtain 27 mg of compound 43 as a
colorless solid.
[1083] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.53 (3H, s), 4.26 (1H,
d, J=10.9 Hz), 4.35 (1H, d, J=13.3 Hz), 4.58 (1H, dd, J=13.8, 3.5
Hz), 5.06 (1H, d, J=10.9 Hz), 7.36 (10H, m), 8.36 (1H, s), 12.58
(1H, s), 15.62 (1H, s).
[1084] MS: m/z=405 [M+H].sup.+.
Reference Example 44
##STR00226##
[1086] According to Reference example 43, compound 44 was
synthesized by the same procedure.
[1087] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.19 (2H, m), 4.42 (1H,
dd, J=13.3, 3.8 Hz), 4.90 (1H, d, J=9.2 Hz), 7.17-7.41 (10H, m),
8.40 (1H, s), 9.66 (1H, s), 12.70 (1H, s), 15.60 (1H, s).
[1088] MS: m/z=391 [M+H].sup.+.
Reference Example 45
##STR00227##
[1090] According to Reference example 43, compound 45 was
synthesized by the same procedure.
[1091] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.17-2.26 (1H, m), 3.22
(3H, s), 3.39 (2H, m), 3.58-3.67 (1H, m), 4.19 (1H, d, J=10.7 Hz),
4.38 (2H, m), 4.95 (1H, d, J=10.8 Hz), 7.20-7.44 (10H, m), 8.28
(1H, s), 12.40 (1H, s), 15.60 (1H, s).
[1092] MS: m/z=449 [M+H].sup.+.
Reference Example 46
##STR00228##
[1093] First Step
[1094] Compound 43E (289 mg, 0.584 mmol) obtained in Reference
example 35 was dissolved in THF (3 ml) and methanol (3 ml), a 2N
aqueous sodium hydroxide solution (1.46 ml, 2.92 mmol) was added at
room temperature, and the mixture was stirred for 1.5 hours. After
1N hydrochloric acid was added, and the mixture was extracted with
ethyl acetate, the extract was dried with sodium sulfate. After the
solvent was distilled off under reduced pressure, 342 mg of
compound 46A was obtained as a colorless solid.
[1095] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.72-4.04 (3H, m), 4.46
(1H, m), 5.39 (1H, d, J=10.4 Hz), 5.44 (1H, d, J=10.4 Hz), 6.04
(1H, brs), 7.19-7.60 (15H, m), 8.10 (1H, s).
Second Step
[1096] Compound 46A (402 mg, 0.837 mmol) was added to diphenyl
ether (5 ml), and the mixture was stirred at 245.degree. C. for 1
hour under microwave irradiation. The reaction solution was poured
into n-hexane, and the precipitated solid was filtered. The
resulting crude product was purified by silica gel column
chromatography (chloroform-methanol, 97:3.fwdarw.95:5.fwdarw.92:8,
v/v) to obtain 85 mg of compound 46B as a colorless solid.
[1097] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.86 (3H, m), 4.45 (1H,
m), 5.35 (1H, d, J=10.5 Hz), 5.41 (1H, d, J=10.4 Hz), 5.94 (1H,
brs), 6.48 (1H, d, J=7.4 Hz), 7.00 (1H, d, J=7.4 Hz), 7.25-7.44
(13H, m), 7.62 (2H, m).
Third Step
[1098] Compound 46B (39 mg, 0.089 mmol) was dissolved in DMF (1
ml), and cesium carbonate (145 mg, 0.445 mmol) was added. After
stirring at room temperature for 30 minutes,
1-bromo-2-methoxyethane (0.033 ml, 0.36 mmol) was added, and the
mixture was stirred at room temperature for 3.5 hours. The reaction
solution was poured into water, and the mixture was extracted with
ethyl acetate, and dried with sodium sulfate. After the solvent was
distilled off under reduced pressure, the resulting crude product
was purified by silica gel column chromatography
(chloroform-methanol, 97:3.fwdarw.95:5.fwdarw.92:8, v/v) to obtain
66 mg of compound 46C as a colorless gummy substance.
Fourth Step
[1099] To compound 46C obtained in the third step was added
trifluoroacetic acid (1 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 6 with sodium bicarbonate water and 2N
hydrochloric acid, the mixture was extracted with chloroform, and
the extract was dried with sodium sulfate. After the solvent was
distilled off under reduced pressure, methylene chloride-ethyl
ether were added, and the precipitated solid was filtered to obtain
21 mg of compound 46 as a colorless solid.
[1100] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.12-2.21 (1H, m), 3.20
(3H, s), 3.55-3.64 (3H, m), 3.81 (1H, d, J=13.0 Hz), 3.99 (1H, d,
J=11.0 Hz), 4.22 (1H, dd, J=13.3, 3.1 Hz), 4.86 (1H, d, J=11.0 Hz),
6.11 (1H, d, J=7.2 Hz), 7.18-7.45 (11H, m).
[1101] MS: m/z=405 [M+H].sup.+.
Reference Example 47
##STR00229##
[1103] According to Reference example 46, compound 47 was
synthesized by the same procedure.
[1104] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.70 (1H, d, J=12.2 Hz),
4.02 (1H, d, J=10.7 Hz), 4.17 (1H, dd, J=13.2, 3.6 Hz), 4.79 (1H,
t, J=3.4 Hz), 6.11 (1H, d, J=7.3 Hz), 7.18-7.44 (11H, m), 9.23 (1H,
d, J=4.3 Hz).
[1105] MS: m/z=347 [M+H].sup.+.
Reference Example 48
##STR00230##
[1106] First Step
[1107] Compound 41A (400 mg, 0.743 mmol) was dissolved in DMF (5
ml), triethylamine (0.21 ml, 1.5 mmol) and ethyl chloroformate
(0.143 ml, 1.49 mmol) were added at 0.degree. C., and the mixture
was stirred for 20 minutes. Sodium borohydride (70.2 mg, 1.86 mmol)
was added at 0.degree. C., and the mixture was stirred at room
temperature for 30 minutes. Sodium borohydride (70.2 mg, 1.86 mmol)
was further added at 0.degree. C., and the mixture was stirred at
room temperature for 2 hours. The reaction solution was poured into
water, the mixture was extracted with ethyl acetate, and the
extract was dried with sodium sulfate. After the solvent was
distilled off under reduced pressure, the resulting crude product
was purified by silica gel column chromatography
(chloroform-methanol, 97:3, v/v) to obtain 160 mg of compound 48A
as a colorless solid.
[1108] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.19 (3H, s), 3.37-3.54
(3H, m), 3.65-3.73 (1H, m), 3.87 (1H, m), 4.06 (2H, d, J=13.9 Hz),
4.31 (1H, d, J=11.2 Hz), 4.39 (1H, d, J=13.8 Hz), 4.77 (1H, d,
J=11.2 Hz), 5.36 (1H, d, J=10.1 Hz), 5.41 (1H, d, J=10.1 Hz), 6.65
(1H, brs), 7.00 (2H, m), 7.19 (3H, m), 7.33-7.49 (8H, m), 7.70 (2H,
m).
Second Step
[1109] To compound 48A (50 mg, 0.095 mmol) was added
trifluoroacetic acid (1 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 6 with sodium bicarbonate water and 2N
hydrochloric acid, the mixture was extracted with chloroform, and
the extract was dried with sodium sulfate. The solvent was
distilled off under reduced pressure, chroloform-ethyl ether were
added, and the precipitated solid was filtered to obtain 3.5 mg of
compound 48 as a colorless solid.
[1110] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.12 (3H, s), 3.51 (5H,
m), 3.71 (1H, d, J=13.7 Hz), 4.02 (1H, d, J=9.9 Hz), 4.09 (1H, d,
J=12.0 Hz), 4.36 (1H, d, J=11.6 Hz), 4.73 (1H, brs), 5.45 (1H, d,
J=12.5 Hz), 7.00 (1H, s), 7.15 (5H, m), 7.28 (1H, t, J=7.2 Hz),
7.40 (2H, t, J=7.5 Hz), 7.59 (2H, d, J=7.6 Hz).
[1111] MS: m/z=435 [M+H].sup.+.
Reference Example 49
##STR00231## ##STR00232##
[1112] First Step
[1113] To Dess-Martin Periodinane (0.3M, methylene chloride
solution, 52.0 ml, 15.6 mmol) was added dropwise a methylene
chloride solution (20 ml) of compound 49A (2.97 g, 10.4 mmol) at
0.degree. C. After stirring at room temperature for 3 hours, the
reaction mixture was poured into a 1N aqueous sodium hydroxide
solution, and the mixture was extracted with ethyl ether. The
organic layer was washed with a 1N aqueous sodium hydroxide
solution and an aqueous saturated sodium chloride solution, and
dried with magnesium sulfate. After the solvent was distilled off
under reduced pressure, 2.08 g of compound 49B was obtained as a
white solid.
[1114] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.13 (2H, d, J=6.6 Hz),
4.53 (1H, q, J=6.7 Hz), 5.12 (2H, s), 5.28 (1H, brs), 7.26 (10H,
m), 9.64 (1H, s).
Second Step
[1115] Compound 49B (700 mg, 2.47 mmol), 2-aminoethanol (166 mg,
2.72 mmol) and sodium sulfate (1.76 g, 12.4 mmol) were added to
toluene (20 ml), and the mixture was stirred at room temperature
for 1 hour. Boc2O (0.631 ml, 2.72 mmol) was added at room
temperature, and the mixture was stirred for 18 hours. The reaction
solution was filtered, and the filtrate was concentrated under
reduced pressure. The resulting crude product was purified by
silica gel column chromatography (n-hexane-ethyl acetate, 1:1, v/v)
to obtain 893 mg of 49C as a colorless gummy substance.
Third Step
[1116] Compound 49C (890 mg, 2.09 mmol) and palladium-active carbon
(10%, wet, 200 mg) were added to ethanol (20 ml), and the mixture
was stirred at room temperature for 2 hours under hydrogen
atmosphere. After filtration with celite, the solvent was
concentrated under reduced pressure to obtain 656 mg of a colorless
oily substance 49D.
[1117] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.40 (9H, s), 2.65-2.86
(2H, m), 3.32 (2H, m), 3.80 (2H, m), 4.03-4.12 (1H, m), 4.86 (1H,
brs), 7.22 (5H, m).
Fourth Step
[1118] Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (610
mg, 2.09 mmol) and 49D (664 mg, 2.09 mmol) were added to toluene (6
ml), and the mixture was stirred at 100.degree. C. for 4 hours.
After the solvent was distilled off under reduced pressure, the
resulting crude product was purified by silica gel column
chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 884 mg
of compound 49E as a pale yellow gummy substance.
[1119] MS: m/z=593 [M+H].sup.+.
Fifth Step
[1120] To compound 49E (860 mg, 1.45 mmol) was added 4N HCl (ethyl
acetate solution, 10 ml). After stirring at room temperature for 30
minutes, the solvent was distilled off under reduced pressure.
Subsequently, toluene (10 ml) and 2-aminoethanol (0.175 ml, 2.90
mmol) were added, and the mixture was stirred at 80.degree. C. for
30 minutes. After the solvent was distilled off under reduced
pressure, the resulting crude product was purified by silica gel
column chromatography (chloroform-methanol,
99:1.fwdarw.95:5.fwdarw.90:10, v/v) to obtain 157 mg of compound
49F as a colorless gummy substance and 217 mg of compound 49G as a
yellow solid.
[1121] 49F: .sup.1H-NMR (CDCl.sub.3) .delta.: 2.48 (1H, dd, J=14.0,
11.4 Hz), 3.22 (1H, dd, J=14.1, 3.3 Hz), 3.69 (1H, m), 3.77 (3H,
s), 3.83-3.95 (1H, m), 4.08 (1H, m), 4.29 (1H, m), 4.41 (1H, m),
5.34 (2H, m), 5.48 (1H, d, J=10.1 Hz), 6.86 (2H, m), 7.20-7.39 (7H,
m), 7.64 (2H, m)
[1122] 49G: .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.70 (2H, t, J=5.3
Hz), 3.73 (3H, s), 3.86 (2H, t, J=5.3 Hz), 4.14 (2H, s), 4.98 (1H,
t, J=5.0 Hz), 5.06 (2H, s), 6.98 (1H, s), 7.35 (8H, m), 7.62 (2H,
d, J=7.1 Hz), 8.34 (1H, d, J=0.8 Hz).
Sixth Step
[1123] The compound 49G (214 mg, 0.465 mmol) was dissolved in THF
(4 ml), ethanol (2 ml) and methylene chloride (2 ml), a 2N aqueous
sodium hydroxide solution (1.16 ml, 2.32 mmol) was added at room
temperature, and the mixture was stirred for 2.5 hours. After 1N
hydrochloric acid was added, and the mixture was extracted with
chloroform, the extract was dried with sodium sulfate. After the
solvent was distilled off under reduced pressure, 158 mg of
compound 49H was obtained as a yellow solid.
[1124] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.70 (2H, q, J=5.2 Hz),
3.89 (2H, t, J=5.3 Hz), 4.22 (2H, s), 4.97 (1H, t, J=5.6 Hz), 5.12
(2H, s), 7.23-7.41 (9H, m), 7.60 (2H, m), 8.54 (1H, s).
Seventh Step
[1125] Compound 49H (50.0 mg, 0.112 mmol) and palladium-active
carbon (10%, wet, 12 mg) were added to methanol (1 ml) and DMF (3
ml), and the mixture was stirred at room temperature for 5 hours
under hydrogen atmosphere. After filtration with celite, the
solvent was concentrated under reduced pressure,
chloroform-methanol-ethyl ether were added, and the precipitated
solid was filtered to obtain 9.0 mg of compound 49 as a colorless
solid.
[1126] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.10 (2H, m), 3.51-3.69
(4H, m), 4.10 (1H, d, J=10.7 Hz), 4.94 (2H, m), 7.11-7.26 (5H, m),
8.03 (1H, s), 12.94 (1H, brs), 15.30 (1H, brs).
[1127] MS: m/z=359 [M+H].sup.+.
Reference Example 50
##STR00233##
[1128] First Step
[1129] Compound 50A (1.00 g, 3.98 mmol), triphenylphosphine (1.15
g, 4.48 mmol) and N-methyl-2-nitrobenzenesulfonamide (860 mg, 3.98
mmol) were added to THF (10 ml), and diethyl azodicarboxylate (2.2M
in toluene, 1.99 ml, 4.38 mmol) was added dropwise at room
temperature. After stirring at room temperature for 3 hours, the
solvent was distilled off under reduced pressure. The resulting
crude product was purified by silica gel column chromatography
(n-hexane-ethyl acetate, 1:1, v/v) to obtain 710 mg of compound 50B
as a colorless gummy substance.
Second Step
[1130] Compound 50B (458 mg, 1.02 mmol) was dissolved in
acetonitrile, potassium carbonate (422 mg, 3.06 mmol) and
benzenethiol (0.126 ml, 1.22 mmol) were added, and the mixture was
stirred at room temperature for 5 hours. The reaction solution was
poured into a 1N aqueous sodium hydroxide solution, the mixture was
extracted with methylene chloride, and the extract was dried with
sodium sulfate. The resulting crude product was purified by amino
column chromatography (chloroform-methanol, 95:5, v/v) to obtain
147 mg of compound 50C as a colorless oily substance.
[1131] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.36 (9H, s), 2.40 (3H,
s), 2.51-2.89 (4H, m), 3.90 (1H, s), 4.69 (1H, s), 7.17-7.31 (5H,
m).
Third Step
[1132] Compound 50C (140 mg, 0.530 mmol) and
3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (WO 2006/116764, 119
mg, 0.482 mmol) were added to THF (3 ml),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111
mg, 0.578 mmol) and 1-hydroxybenzotriazole (65.1 mg, 0.482 mmol)
were added, and the mixture was stirred at room temperature for 18
hours. The reaction solution was poured into sodium bicarbonate
water, the mixture was extracted with ethyl acetate, and the
extract was dried with sodium sulfate. The resulting crude product
was purified by silica gel column chromatography
(chloroform-methanol, 97:3, v/v) to obtain 219 mg of compound 50D
as a colorless solid.
[1133] MS: m/z=493 [M+H].sup.+.
Fourth Step
[1134] To compound 50D (216 mg, 0.439 mmol) was added 4N HCl (ethyl
acetate solution, 3 ml). After the mixture was stirred at room
temperature for 1 hour, the solvent was distilled off under reduced
pressure. Subsequently, ethanol (4 ml) and an aqueous saturated
sodium carbonate solution (3 ml) were added, and the mixture was
stirred at 60.degree. C. for 2 hours. After water was added, and
the mixture was extracted with ethyl acetate, the extract was dried
with sodium sulfate. The resulting crude product was purified by
amino column chromatography (chloroform-methanol, 95:5, v/v) to
obtain 108 mg of compound 50E as a pale yellow gummy substance.
[1135] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.00 (2H, m), 3.13 (3H,
s), 3.18 (1H, m), 3.88 (1H, dd, J=13.5, 3.4 Hz), 4.00-4.07 (1H, m),
5.26 (1H, d, J=10.2 Hz), 5.46 (1H, d, J=10.1 Hz), 6.25 (1H, d,
J=7.5 Hz), 6.73 (1H, d, J=7.5 Hz), 6.99-7.02 (2H, m), 7.28-7.37
(6H, m), 7.63-7.67 (2H, m).
Fifth Step
[1136] To compound 50E (105 mg, 0.280 mmol) was added
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 30 minutes. After concentration under reduced
pressure, pH was adjusted to 6 with sodium bicarbonate water and 2N
hydrochloric acid, the mixture was extracted with chloroform, and
the extract was dried with sodium sulfate. After the solvent was
distilled off under reduced pressure, methylene
chloride-methanol-ethyl ether were added, and the precipitated
solid was filtered to obtain 29 mg of compound 50 as a colorless
solid.
[1137] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.99 (3H, s), 3.26-3.47
(3H, m), 4.07 (1H, d, J=11.1 Hz), 4.80 (1H, m), 6.43 (1H, d, J=6.9
Hz), 7.11-7.29 (5H, m), 7.50 (1H, d, J=6.9 Hz).
[1138] MS: m/z=285 [M+H].sup.+.
Reference Example 51
##STR00234##
[1139] First Step
[1140] Compound 1D (60 mg, 0.11 mmol) was dissolved in
trifluoroacetic acid (1 ml), and the mixture was stirred at room
temperature for 1 hour. The reaction solution was distilled off,
and the resulting residue was purified by LC/MS to obtain compound
51 (43 mg, 0.09 mmol).
[1141] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.17 (3H, t, J=6.9 Hz),
3.11 (3H, s), 3.48-3.58 (2H, m), 3.95-4.12 (3H, m), 4.40 (1H, d,
J=11.4 Hz), 5.59 (1H, d, J=11.4 Hz), 7.11 (1H, d, J=7.3 Hz), 7.17
(2H, t, J=7.2 Hz), 7.26 (2H, d, J=7.1 Hz), 7.30 (1H, t, J=7.3 Hz),
7.42 (2H, t, J=7.2 Hz), 7.60 (3H, m), 12.55 (1H, brs).
[1142] MS: m/z=477.2 [M+H].sup.+.
Reference Example 52
##STR00235##
[1143] First Step
[1144] To a DMF (10 ml) solution of compound 1I (2.0 g, 4.32 mmol)
were added WSC HCl (1.24 g, 6.49 mmol) and HOBt (876.9 mg, 6.49
mmol) at room temperature, and the mixture was stirred at the same
temperature for 1 hour. To the reaction solution were added
O,N-dimethylhydroxylamine hydrochloride (842.7 mg, 8.64 mmol) and
triethylamine (2.19 g, 21.6 mmol), the mixture was stirred at the
same temperature for 3 hours, thereafter, water was added, and the
mixture was extracted with ethyl acetate three times. After the
extract was washed with water three times, and dried with sodium
sulfate, the solvent was distilled off, and the resulting oil was
purified by silica gel chromatography. The materials were eluted
firstly with n-hexane-ethyl acetate (7:3, v/v) and, then, with only
ethyl acetate. Concentration of an objective fraction afforded 543
mg (yield 25%) of compound 52A as an oil.
[1145] MS: m/z=506 [M+H].sup.+.
Second Step
[1146] A THF (5 ml) solution of compound 52A (543 mg, 1.07 mmol)
was cooled to -78.degree. C., a methylmagnesium bromide 0.97M THF
solution (1.66 ml, 1.61 mmol) was added, and temperature was raised
up to -20.degree. C. over 2 hours. To the reaction solution was
added 1N hydrochloric acid, and the mixture was extracted with
ethyl acetate three times. After the extract was dried with sodium
sulfate, the solvent was distilled off, and the resulting oil was
purified by silica gel chromatography. The materials were eluted
firstly with n-hexane-ethyl acetate (7:3, v/v) and, then, with only
ethyl acetate. Concentration of an objective fraction afforded
256.8 mg (yield 52%) of compound 52B as an oil.
[1147] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.65 (3H, s), 3.08 (2H, d,
J=7.5 Hz), 3.12 (3H, s), 3.53-3.68 (4H, m), 3.79-3.95 (1H, m), 3.92
(1H, dd, J=3.3 Hz, 13.5 Hz), 4.10-4.16 (1H, m), 5.30 (1H, d, J=10.2
hz), 5.45 (1H, d, J=10.2 Hz), 6.99-7.02 (2H, m), 7.25-7.38 (6H, m),
7.49 (1H, s), 7.63-7.66 (2H, m).
Third Step
[1148] To a dichloromethane (4 ml) solution of compound 52B (256
mg, 0.558 mmol) was added mCPBA (144.3 mg, 0.836 mmol) under
ice-cooling, and the mixture was stirred at room temperature for 2
hours. To the reaction solution was added an aqueous sodium
thiosulfate solution, and the mixture was extracted with ethyl
acetate three times. After the extract was washed with saturated
sodium bicarbonate water two times, and dried with sodium sulfate,
the solvent was distilled off, the resulting oil was dissolved in
ethanol (4 ml), and a 2N-aqueous sodium hydroxide solution (1 ml)
was added, followed by refluxing for 1 hour. After the solvent was
distilled off, the precipitated solid was washed with diisopropyl
ether to obtain 242 mg (yield 100%) of compound 52C.
[1149] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.09 (2H, d, J=6.9 Hz),
3.32 (3H, s), 3.54 (1H, d, J=14.1 Hz), 3.59-3.71 (2H, m), 3.76-3.85
(1H, m), 3.92 (1H, dd, J=3.6 Hz, 13.5 Hz), 4.03 (1H, brt), 5.28
(1H, d, J=10.2 Hz), 5.47 (1H, d, J=10.2 Hz), 6.68 (1H, s),
7.00-7.04 (2H, m), 7.23-7.37 (6H, m), 7.64 (2H, d, J=6.3 Hz).
Fourth Step
[1150] To a THF (3 ml) solution of compound 52C (242 mg, 0.558
mmol) was added 10% Pd--C (50 mg), and the mixture was subjected to
a catalytic reduction reaction under hydrogen stream. The catalyst
was removed by filtration, and the filtrate was concentrated. To
the resulting residue was added diisopropyl ether, and the
precipitated solid was filtered to obtain 60 mg (yield 31%) of
compound 52.
[1151] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.05 (2H, brs), 3.36 (3H,
s), 3.58 (1H, d, J=12 Hz), 3.66-3.68 (2H, m), 3.74-3.75 (2H, m),
4.11-4.19 (2H, m), 6.80 (1H, brs), 6.90-7.04 (2H, m), 7.30 (3H,
brs).
Reference Example 53
##STR00236##
[1152] First Step
[1153] To a DMF (10 ml) solution of compound 1I (1.0 mg, 2.23 mmol)
were added triethylamine (677 mg, 6.69 mmol) and ethyl
chlorocarbonate (729 mg, 6.69 mmol) under ice-cooling, and the
mixture was stirred at room temperature for 10 minutes. To the
reaction solution were added methanesulfonamide (1.06 g, 11.15
mmol) and DMAP (272.4 mg, 2.23 mmol), and the mixture was heated to
stir at 80.degree. C. for 2 hours. To the reaction solution was
added water, and the mixture was extracted with ethyl acetate three
times. After the extract was washed with water three times, and
dried with sodium sulfate, the solvent was distilled off, and the
resulting oil was purified by silica gel chromatography. The
materials were eluted firstly with only chloroform and, then, with
chloroform-MeOH (9:1, v/v). Concentration of an objective fraction
afforded 535 mg (yield 46%) of compound 53A as an oil.
[1154] MS: m/z=463 [M+H].sup.+.
Second Step
[1155] To a THF (5 ml) solution of compound 53A (535 mg, 0.991
mmol) was added 10% Pd--C (218 mg), and the mixture was subjected
to a catalytic reduction reaction under hydrogen stream. The
catalyst was removed by filtration, and the filtrate was
concentrated. To the resulting residue was added diisopropyl ether,
and the precipitated solid was filtered to obtain 235 mg (yield
53%) of compound 53.
[1156] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.99-3.17 (2H, m), 3.27
(3H, s), 3.33 (3H, s), 3.53-3.76 (5H, m), 4.06 (1H, dd, J=3.6 Hz,
13.8 Hz), 4.98 (1H, brs), 7.14 (2H, d, J=6.6 Hz), 7.19-7.30 (3H,
m), 8.07 (1H, s), 12.84 (1H, s), 13.24 (1H, s).
Reference Example 54
##STR00237##
[1157] First Step
[1158] To a DMF (10 ml) solution of compound 1I (1.0 mg, 2.23 mmol)
were added triethylamine (677 mg, 6.69 mmol) and ethyl
chlorocarbonate (729 mg, 6.69 mmol) under ice-cooling, and the
mixture was stirred at the same temperature for 10 minutes. The
reaction solution was added dropwise to an ice-cooled solution of
sodium borohydride (441 mg, 11.7 mmol) in water (5 ml), and the
mixture was stirred at the same temperature for 2 hours. To the
reaction solution was added 2N hydrochloric acid to stop the
reaction, and the mixture was neutralized with a 2N aqueous sodium
hydroxide solution, and extracted with ethyl acetate three times.
After the extract was washed with water three times, and dried with
sodium sulfate, the solvent was distilled off, and the resulting
crude product was dissolved in dichloromethane (5 ml).
[1159] To the dichloromethane solution was added manganese dioxide
(2.1 g, 24.15 mmol), and the mixture was stirred at room
temperature for 6 hours. After the reaction solution was filtered,
and the solvent was distilled off, the resulting oil was purified
by silica gel chromatography. Elution with ethyl acetate-MeOH (9:1,
v/v) and concentration of an objective fraction afforded 188 mg
(yield 19%) of compound 54A.
[1160] MS: m/z=447 [M+H].sup.+.
Second Step
[1161] Compound 54A (188 mg, 0.422 mmol) was dissolved in THF (6
ml), 28% aqueous ammonia and iodine (117.7 mg, 0.464 mmol) were
added at room temperature, and the mixture was stirred at the same
temperature for 2 hours. To the reaction solution was added an
aqueous sodium thiosulfate solution, and the mixture was extracted
with ethyl acetate three times. After the extract was dried with
sodium sulfate, the solvent was distilled off, and the resulting
oil was purified by silica gel chromatography. Elution with ethyl
acetate-MeOH (9:1, v/v) and concentration of an objective fraction
afforded 54.7 mg (yield 29%) of compound 54B.
[1162] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.05 (2H, d, J=7.5 Hz),
3.33 (3H, s), 3.56-3.79 (5H, m), 3.99 (1H, dd, J=3.6 Hz, 13.8 Hz),
4.08 (1H, brt), 5.33 (1H, d, J=10.2 Hz), 5.46 (1H, d, J=10.2 Hz),
6.83 (1H, s), 6.93-6.97 (2H, m), 7.25-7.37 (5H, m), 7.58-7.62 (2H,
m).
Third Step
[1163] To a toluene (2 ml) solution of compound 54B (216 mg, 0.487
mmol) were added sodium azide (95 mg, 1.46 mmol) and triethylamine
(201 mg, 1.46 mmol), and the mixture was stirred at room
temperature for 6 hours. The reaction solution was extracted with a
2N aqueous sodium hydroxide solution two times, and the extract was
neutralized with 2N hydrochloric acid, and extracted with ethyl
acetate three times. After drying of the organic layer with sodium
sulfate, the solvent was distilled off to obtain 65 mg (yield 27%)
of compound 54C.
[1164] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.08-3.21 (2H, m), 3.33
(3H, s), 3.55-3.70 (4H, m), 3.81-3.90 (1H, m), 3.96-4.01 (1H, m),
4.51 (1H, brt), 5.31 (1H, d, J=10.2 Hz), 5.42 (1H, d, J=10.2 Hz),
7.03-7.05 (2H, m), 7.18-7.37 (6H, m), 7.58-7.61 (2H, m), 8.33 (1H,
s).
Fourth Step
[1165] To a THF (2 ml)-MeOH (2 ml) solution of compound 54C (500
mg, 1.03 mmol) was added 10% Pd--C (100 mg), and the mixture was
subjected to a catalytic reduction reaction under hydrogen stream.
The catalyst was removed by filtration, and the filtrate was
concentrated. The resulting residue was dissolved in
dichloromethane (10 ml), and the solution was extracted with a 2N
aqueous sodium hydroxide solution two times. After the extract was
neutralized with 2N hydrochloric acid, the mixture was extracted
with ethyl acetate three times. The organic layer was dried with
sodium sulfate, the solvent was distilled off, and the resulting
solid was washed with diisopropyl ether, and filtered to obtain 55
mg (yield 14%) of compound 54.
[1166] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.01-3.19 (2H, m), 3.28
(3H, s), 3.51-3.79 (5H, m), 4.09 (1H, dd, J=3.9 Hz, 13.5 Hz), 4.95
(1H, brs), 7.13-7.26 (5H, m), 8.20 (1H, s), 12.23 (1H, s).
Reference Example 55
##STR00238##
[1167] First Step
[1168] To a THF (5 ml) solution of compound 1I (500 mg, 1.08 mmol)
was added a trimethylsilyldiazomethane 2M hexane solution (1 ml,
2.0 mmol) at room temperature, and the mixture was heated to
50.degree. C., and stirred. After the solvent was distilled off,
the resulting oil was purified by silica gel chromatography.
Elution with n-hexane-ethyl acetate (1:1, v/v) and concentration of
objective fraction afforded 115 mg (yield 22%) of compound 55A.
[1169] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.06 (2H, d, J=7.5 Hz),
3.31 (3H, s), 3.51-3.72 (5H, m), 3.81 (3H, s), 3.98 (1H, dd, J=3.6
Hz), 13.5 Hz), 4.11 (1H, brt), 5.22 (1H, d, J=9.6 Hz), 5.46 (1H, d,
J=9.6 Hz), 6.99-7.02 (2H, m), 7.26-7.37 (6H, m), 7.46 (1H, s),
7.65-7.69 (2H, m).
Second Step
[1170] Compound 55A (210 mg, 0.441 mmol) was dissolved in THF (2
ml), 10% Pd--C (85.7 mg) was added, and the mixture was subjected
to a catalytic reduction reaction under hydrogen stream. The
catalyst was removed by filtration, and the filtrate was
concentrated. The resulting residue was washed with diisopropyl
ether ether to obtain 50 mg (yield 23%) of compound 55.
[1171] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.55 (2H, d, J=7.5 Hz),
3.37 (3H, s), 3.59-3.84 (5H, m), 4.23-4.32 (2H, m), 7.00 (2H, dd,
J=1.5 Hz, 6.9 Hz), 7.23-7.32 (3H, m), 7.39 (1H, s), 12.31 (1H,
brs).
Reference Example 56
##STR00239##
[1172] First Step
[1173] A DMF (5 ml) solution of compound 2D (424 mg, 0.787 mmol)
was ice-cooled, and triethylamine (327 ul, 2.36 mmol) and,
subsequently, ethyl chloroformate (150 ul, 1.57 mmol) were added.
After the reaction solution was stirred at room temperature for 10
minutes, it was ice-cooled again, sodium azide (154 mg, 2.36 mmol)
was added, and the mixture was stirred for 1 hour. To the reaction
solution were added dichloromethane, water and a small amount of
methanol, the dichloromethane layer was separated, and the aqueous
layer was extracted with dichloromethane once. The combined
extracts were concentrated, methanol (8 ml) was added to the
resulting residue, the mixture was stirred at 50.degree. C. for 3
hours, and the solvent was distilled off. The resulting oil was
purified by silica gel column chromatography. The materials were
eluted firstly with n-hexane-ethyl acetate (1:1, v/v) and, then,
with only ethyl acetate. Concentration of objective fraction
afforded 160 mg of compound 56A as a white solid.
[1174] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.08-3.18 (4H, m),
3.35-3.49 (3H, m), 3.68 (3H, s), 3.98 (2H, dt, J=23.1, 5.6 Hz),
4.32 (1H, d, J=11.3 Hz), 4.59 (1H, d, J=11.3 Hz), 5.37 (2H, dd,
J=12.0, 10.4 Hz), 6.98-7.70 (15H, m).
[1175] MS: m/z=568.25 [M+H].sup.+.
Second Step
[1176] Compound 56A (160 mg, 0.102 mmol) was dissolved in EtOH (10
mL), a 2N aqueous sodium hydroxide solution (14 ml) was added, and
the mixture was stirred at 60.degree. C. for 2 hours. After the
reaction solution was concentrated under reduced pressure, the
residue was distributed between dichloromethane and water. The
dichloromethane layer was separated, and the aqueous layer was
extracted with dichloromethane three times. The solvent was
distilled off to obtain compound 56B.
[1177] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.97-3.06 (1H, m), 3.15
(3H, s), 3.38-3.44 (3H, m), 3.71 (2H, s), 3.93-3.99 (2H, m), 4.35
(2H, dd, J=19.3, 11.1 Hz), 5.37 (2H, dd, J=31.6, 10.1 Hz), 6.04
(1H, s), 6.98 (2H, dd, J=6.4, 2.9 Hz), 7.17 (4H, t, J=3.3 Hz),
7.28-7.69 (12H, m).
[1178] MS: m/z=509.23 [M+H].sup.+.
Third Step
[1179] Compound 56B (56 mg, 0.11 mmol) was dissolved in TFA (3 mL),
and the mixture was stirred at room temperature for 1 hour. The
reaction mixture was subjected to toluene azeotropy, and the
resulting residue was purified using an LCMS fractionating device.
The eluted solvent was distilled off, isopropyl ether was added to
the residue, and the precipitated solid was filtered. Washing with
isopropyl ether and drying afforded 7 mg of compound 56.
[1180] MS: m/z=420.07 [M+H].sup.+.
Reference Example 57
##STR00240##
[1181] First Step
[1182] To a THF (1 mL) solution of compound 56B (25 mg, 0.049 mmol)
were added triethylamine (20 uL, 0.15 mmol) and, subsequently,
acetic acid anhydride (7.0 ul, 0.074 mmol) under ice-cooling, and
the mixture was stirred at room temperature for 15 minutes. Then,
4-fluorobenzyl amine (330 mg, 1.75 mmol) was added, and the mixture
was stirred for 7 hours. Further, triethylamine (20 uL, 0.15 mmol)
and, subsequently, acetic acid anhydride (7.0 ul, 0.074 mmol) were
added, and the mixture was stirred overnight. To the reaction
solution were added water, ethyl acetate, and brine, the ethyl
acetate layer was separated, and the aqueous layer was extracted
with ethyl acetate. To the combined extracts was added sodium
sulfate, and filtration and concentration afforded 18 mg of
compound 57A as a white solid.
[1183] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.05 (3H, s), 3.09-3.14
(4H, m), 3.41-3.45 (3H, m), 3.95-4.02 (2H, m), 4.31 (1H, d, J=11.4
Hz), 4.59 (1H, d, J=12.4 Hz), 5.36 (2H, s), 7.00 (2H, d, J=4.0 Hz),
7.11-7.16 (3H, m), 7.36 (7H, tt, J=14.5, 5.1 Hz), 7.62 (2H, t,
J=7.3 Hz), 8.02 (1H, s), 8.18 (1H, s).
[1184] MS: m/z=552.20 [M+H].sup.+.
Second Step
[1185] Compound 57A (21 mg, 0.038 mmol) was dissolved in TFA (3
mL), and the mixture was stirred at room temperature for 3.5 hours.
The reaction mixture was subjected to toluene azeotropy, isopropyl
ether was added to the resulting residue, and the precipitated
solid was filtered. Washing with isopropyl ether, and drying
afforded 10 mg of compound 57.
[1186] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.12 (3H, s), 3.20 (3H,
s), 3.39-3.60 (4H, m), 3.76-3.86 (1H, m), 4.08 (1H, dd, J=13.7, 3.7
Hz), 4.31 (1H, d, J=11.5 Hz), 4.68 (1H, dd, J=8.5, 4.3 Hz),
6.96-7.19 (4H, m), 7.30-7.44 (6H, m), 8.11 (1H, s).
[1187] MS: m/z=462.20 [M+H].sup.+.
Reference Example 58
##STR00241##
[1189] According to Reference example 57, compound 58 was
synthesized by the same procedure.
[1190] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.20 (3H, s), 3.41-3.54
(3H, m), 3.60-3.68 (2H, m), 3.73-3.85 (1H, m), 4.12 (1H, dt,
J=14.0, 3.5 Hz), 4.31 (1H, d, J=11.4 Hz), 4.68 (1H, dd, J=11.4, 2.6
Hz), 6.95-7.21 (5H, m), 7.39 (5H, dt, J=26.9, 7.6 Hz), 7.94 (1H,
s), 8.88 (1H, s).
[1191] MS: m/z=516.10 [M+H].sup.+.
Reference Example 59
##STR00242##
[1193] According to Reference example 57, compound 59 was
synthesized by the same procedure.
[1194] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.21 (3H, s), 3.43-3.63
(4H, m), 3.82 (1H, d, J=14.0 Hz), 4.12 (1H, dd, J=8.3, 4.2 Hz),
4.35 (1H, d, J=11.2 Hz), 4.74 (1H, d, J=8.3 Hz), 6.90-7.18 (5H, m),
7.34-7.60 (8H, m), 7.82 (2H, d, J=6.8 Hz), 8.34 (1H, s), 8.89 (1H,
s).
[1195] MS: m/z=523.21 [M+H].sup.+.
Reference Example 60
##STR00243##
[1197] To compound 56B (30 mg, 0.059 mmol) were added formic acid
(1.0 mL, 26 mmol) and, subsequently, a 37% formaldehyde solution
(0.5 mL, 6.7 mmol), and the mixture was stirred at 100.degree. C.
for 7 hours. The reaction solution was subjected to toluene
azeotropy, DMSO was added, insolubles were filtered and,
thereafter, purification was performed using an LCMS fractionating
device. The eluted solvent was distilled off, isopropyl ether was
added to the residue, and the precipitated solid was filtered.
Washing with isopropyl ether, and drying afforded 3 mg of compound
60.
[1198] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.37 (6H, s), 3.18 (3H,
s), 3.29-3.66 (4H, m), 3.82 (1H, d, J=12.5 Hz), 4.06-4.15 (1H, m),
4.31 (1H, d, J=11.7 Hz), 4.54 (1H, d, J=8.1 Hz), 5.97 (1H, s), 7.01
(2H, dd, J=6.4, 2.8 Hz), 7.17 (3H, t, J=2.9 Hz), 7.32-7.45 (6H,
m).
[1199] MS: m/z=448.15 [M+H].sup.+.
Reference Example 61
##STR00244##
[1200] First Step
[1201] Compound 56B (50 mg, 0.098 mmol) was dissolved in THF (1
mL), Boc2O (0.068 mL, 0.29 mmol) and, subsequently, DMAP (6.0 mg,
0.049 mmol) were added, and the mixture was stirred at room
temperature for 5 hours. To the reaction solution were added water
and ethyl acetate, the ethyl acetate layer was separated, and the
aqueous layer was extracted with ethyl acetate. To the combined
extracts was added sodium sulfate, the mixture was filtered, and
the solvent was distilled off. The resulting residue was purified
by silica gel column chromatography. Concentration of an objective
fraction afforded 20 mg of compound 61A as a colorless transparent
oil.
[1202] MS: m/z=610.50 [M+H].sup.+.
Second Step
[1203] Compound 61A (20 mg, 0.033 mmol) was dissolved in DMF (1
mL), sodium hydride (2.6 mg, 0.066 mmol) was added under
ice-cooling, the mixture was stirred for 10 minutes, methyl iodide
(4.1 uL, 0.066 mmol) was added, and the mixture was stirred at room
temperature for 1.5 hours. Ice water, ethyl acetate and brine were
added, the ethyl acetate layer was separated, and the aqueous layer
was extracted with ethyl acetate. To the combined extracts was
added sodium sulfate, the mixture was filtered, and the solvent was
distilled off. The resulting residue was purified by silica gel
column chromatography. Concentration of an objective fraction
afforded 13 mg of compound 61B as a white solid.
[1204] MS: m/z=624.25 [M+H].sup.+.
Third Step
[1205] Compound 61B (13 mg, 0.021 mmol) was dissolved in TFA (3
mL), and the mixture was stirred at room temperature for 3 hours.
The reaction mixture was subjected to toluene azeotropy, and the
resulting residue was purified using an LCMS fractionating device.
The eluted solvent was distilled off, isopropyl ether-hexane were
added to the residue, and the precipitated solid was filtered.
Washing with isopropyl ether, and drying afforded 7.5 mg of
compound 61.
[1206] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.19 (3H, s), 3.26 (3H,
s), 3.46-3.70 (4H, m), 4.23 (1H, d, J=11.0 Hz), 4.58-4.60 (1H,
brm), 5.41-5.44 (1H, brm), 6.28 (1H, brs), 6.99 (2H, brs), 7.13
(3H, brs), 7.31-7.46 (6H, m).
[1207] MS: m/z=434.10 [M+H].sup.+.
Reference Example 62
##STR00245##
[1208] First Step
[1209] Compound 2D (112 mg, 0.208 mmol) was dissolved in DMF (2
mL), triethylamine (0.144 ml, 1.04 mmol) and, subsequently, ethyl
chloroformate (0.040 mL, 0.42 mmol) were added under ice-cooling,
the mixture was stirred at room temperature for 10 minutes,
thereafter, N,O-dimethylhydroxyamine hydrochloride (41 mg, 0.42
mmol) and, subsequently, DMAP (3 mg, 0.02 mmol) were added, and the
mixture was stirred at room temperature for 1 hour. To the reaction
solution were added water and ethyl acetate, the ethyl acetate
layer was separated, and the aqueous layer was extracted with ethyl
acetate. To the combined extracts was added sodium sulfate, the
mixture was filtered, and the solvent was distilled off. The
resulting residue was purified by silica gel column chromatography.
Concentration of an objective fraction afforded 127 mg of crude
purified product 62A as a yellow oil.
[1210] MS: m/z=582.20 [M+H].sup.+.
Second Step
[1211] Compound 62A (137 mg, 0.236 mmol) was dissolved in THF (8
mL), a 2M THF solution of methylmagnesium bromide (0.444 ml, 0.471
mmol) was added at -78.degree. C. under nitrogen stream, and the
mixture was stirred for 30 minutes while temperature was raised to
-50.degree. C. To the reaction solution was added 1M hydrochloric
acid (4 ml), the mixture was stirred at 0.degree. C. for 20
minutes, ethyl acetate was added, the ethyl acetate layer was
separated, and the aqueous layer was extracted with ethyl acetate.
The combined extracts were neutralized with an aqueous saturated
sodium bicarbonate solution, sodium sulfate was added to the
organic layer, the mixture was filtered, and the solvent was
distilled off. The resulting residue was purified by silica gel
column chromatography. Concentration of an objective fraction
afforded 67 mg of compound 62B as a yellow oil.
[1212] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.55 (3H, s), 3.01-3.14
(1H, m), 3.16 (3H, s), 3.37-3.54 (3H, m), 3.91-4.07 (2H, m), 4.28
(1H, d, J=11.3 Hz), 4.50-4.60 (1H, m), 5.42 (2H, d, J=1.2 Hz),
6.97-6.99 (2H, m), 7.14-7.17 (4H, m), 7.31-7.45 (8H, m), 7.65 (2H,
d, J=6.5 Hz).
[1213] MS: m/z=537.20 [M+H].sup.+.
Third Step
[1214] Compound 62B (67 mg, 0.13 mmol) was dissolved in
dichloromethane (4 mL), mCPBA (32 mg, 0.19 mmol) was added at
0.degree. C. under nitrogen stream, and the mixture was stirred at
room temperature for 3 hours. The reaction solution was ice-cooled,
an aqueous sodium thiosulfate solution, and ethyl acetate were
added, the ethyl acetate layer was separated, and the aqueous layer
was extracted with ethyl acetate. The combined extracts were
neutralized with an aqueous saturated sodium bicarbonate solution,
sodium sulfate was added to the organic layer, the mixture was
filtered, and the solvent was distilled off to obtain 64 mg of
compound 62C.
[1215] MS: m/z=553.23 [M+H].sup.+.
Fourth Step
[1216] Compound 62C (64 mg, 0.12 mmol) was dissolved in ethanol (8
mL), and the solution was heated to reflux for 4 hours. The
reaction solution was concentrated, and the resulting residue was
purified by silica gel column chromatography. Concentration of an
objective fraction afforded 42 mg of compound 62D.
[1217] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.93-3.09 (1H, m), 3.16
(3H, s), 3.33-3.53 (4H, m), 3.90-4.07 (2H, m), 4.29-4.47 (2H, m),
5.41 (2H, q, J=10.4 Hz), 6.34 (1H, s), 6.95-6.99 (2H, m), 7.12-7.21
(4H, m), 7.33-7.42 (8H, m), 7.64 (2H, d, J=6.9 Hz).
[1218] MS: m/z=511.21 [M+H].sup.+.
Fifth Step
[1219] Compound 62D (41 mg, 0.080 mmol) was dissolved in DMF (1
mL), sodium hydride (6.4 mg, 0.16 mmol) was added under
ice-cooling, the mixture was stirred for 10 minutes, methyl iodide
(0.010 ml, 0.16 mmol) was added, and the mixture was stirred at
room temperature for 1.5 hours. To the reaction solution were added
ice water and ethyl acetate, the ethyl acetate layer was separated,
and the aqueous layer was extracted with ethyl acetate. To the
combined extracts was added sodium sulfate, the mixture was
filtered, and the solvent was distilled off. The resulting residue
was purified by silica gel column chromatography. Concentration of
an objective fraction afforded 41 mg of compound 62E as a white
solid.
[1220] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.99-3.09 (1H, m), 3.16
(3H, s), 3.25 (3H, s), 3.32-3.38 (1H, m), 3.42-3.50 (2H, m),
3.94-4.03 (2H, m), 4.28 (1H, d, J=11.3 Hz), 4.43 (1H, brs), 5.40
(2H, dd, J=28.3, 10.2 Hz), 6.01 (1H, s), 6.90-7.19 (5H, m),
7.28-7.44 (8H, m), 7.66 (2H, d, J=6.4 Hz).
[1221] MS: m/z=525.21 [M+H].sup.+.
Sixth Step
[1222] Compound 62E (40 mg, 0.076 mmol) was dissolved in TFA (3
mL), and the mixture was stirred at room temperature for 30
minutes. The reaction mixture was subjected to toluene azeotropy,
and the resulting residue was purified using an LCMS fractionating
device. The eluted solvent was distilled off, ethyl
acetate-isopropyl ether-hexane were added to the residue, and the
precipitated solid was filtered. Washing with isopropyl ether, and
drying afforded 7.1 mg of compound 62 as a pink solid.
[1223] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.17 (3H, s), 3.22 (3H,
s), 3.40-3.53 (4H, m), 3.63-3.71 (1H, m), 4.24 (1H, d, J=11.5 Hz),
4.45 (1H, d, J=13.3 Hz), 4.60 (1H, d, J=11.2 Hz), 6.08 (1H, d,
J=11.7 Hz), 6.96-6.99 (2H, brm), 7.13-7.17 (3H, m), 7.30-7.43 (5H,
m).
[1224] MS: m/z=435.15 [M+H].sup.+.
Reference Example 63
##STR00246##
[1225] First Step
[1226] Compound 2D (164 mg, 0.304 mmol) was dissolved in diphenyl
ether (1 mL), the mixture was stirred at 245.degree. C. for 1 hour
using a microwave apparatus and, thereafter, the reaction solution
was purified by silica gel column chromatography. Concentration of
an objective fraction afforded 72 mg of compound 63A as a brown
solid.
[1227] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.92-3.01 (1H, m), 3.16
(3H, s), 3.32-3.50 (3H, m), 3.90-4.46 (4H, m), 5.42 (2H, dd,
J=26.1, 10.3 Hz), 5.94 (1H, d, J=7.4 Hz), 6.28 (1H, d, J=7.5 Hz),
6.96-6.99 (2H, m), 7.15-7.19 (3H, m), 7.28-7.44 (8H, m), 7.62-7.65
(2H, m).
[1228] MS: m/z=495.21 [M+H].sup.+.
Second Step
[1229] To a dichloromethane (4 mL) solution of compound 63A (21 mg,
0.042 mmol) was added NBS (11 mg, 0.062 mmol), and the mixture was
heated to reflux for 1 hour. The reaction solution was allowed to
cool, and purified by silica gel column chromatography.
Concentration of an objective fraction afforded 26 mg of compound
63B as a white solid.
[1230] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.01-3.09 (1H, m), 3.16
(3H, s), 3.35-3.53 (3H, m), 3.92-4.47 (4H, m), 5.41 (2H, dd,
J=32.6, 10.0 Hz), 6.72 (1H, s), 6.97-7.00 (2H, brm), 7.20-7.22 (3H,
m), 7.30-7.46 (8H, m), 7.66-7.70 (2H, m).
[1231] MS: m/z=573.20 [M+H].sup.+.
Third Step
[1232] Compound 63B (10 mg, 0.017 mmol) was dissolved in TFA (3
mL), and the mixture was stirred at room temperature for 50
minutes. The reaction mixture was subjected to toluene azeotropy,
isopropyl ether was added to the resulting residue, and the
precipitated solid was filtered. Washing with isopropyl ether, and
drying afforded 1.4 mg of compound 63 as an orange solid.
[1233] MS: m/z=483.15 [M+H].sup.+.
Reference Example 64
##STR00247##
[1234] First Step
[1235] To a DMF solution (2 mL) of compound 63B (20 mg, 0.035 mmol)
were added pyrazole-4-boronic acid pinacol ester (36 mg, 0.19 mmol)
and, subsequently, potassium carbonate (29 mg, 0.21 mmol) and,
thereafter, tetrakistriphenylphosphinepalladium (24 mg, 0.021 mmol)
was added under nitrogen atmosphere, and the mixture was stirred at
110.degree. C. for 8.5 hours. After the reaction solution was
concentrated, ethyl acetate and methanol were added, and insolubles
were removed. The filtrate was concentrated, and the resulting
residue was purified by silica gel column chromatography.
Concentration of an objective fraction afforded 18 mg of compound
64A as a white solid.
[1236] MS: m/z=561.30 [M+H].sup.+.
Second Step
[1237] Compound 64A (14 mg, 0.025 mmol) was dissolved in TFA (2
mL), and the mixture was stirred at room temperature for 30
minutes. The reaction mixture was subjected to toluene azeotropy,
and the resulting residue was purified using an LCMS fractionating
device. The eluted solvent was distilled off, isopropyl ether was
added to the residue, and the precipitated solid was filtered.
Washing with isopropyl ether, and drying afforded 1.1 mg of
compound 64 as an orange solid.
[1238] MS: m/z=471.20 [M+H].sup.+.
Reference Example 65
##STR00248##
[1239] First Step
[1240] A THF (1.1 L) solution of compound 65A (WO 2006/088173, 20.0
g, 69.6 mmol) was retained at 25.degree. C. on a water bath, an
aqueous (378 mL) solution of sodium chlorite (25.2 g, 278 mmol) and
amidosulfuric acid (27.0 g, 278 mmol) was added dropwise over 30
minutes. The reaction solution was stirred at the same temperature
for 1 hour, and concentrated under reduced pressure. To the residue
were added ice water (100 mL) and diethyl ether (100 mL), and the
precipitated solid was filtered. The resulting crude purified
product was washed with water and diethyl ether to obtain 20.3 g of
compound 65B as a white solid.
[1241] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.74 (3H, s), 5.11 (2H,
s), 7.31-7.38 (3H, m), 7.48 (2H, d, J=7.2 Hz), 8.11 (1H, s), 12.07
(1H, brs).
Second Step
[1242] Compound 65B (2.0 g, 6.59 mmol) was dissolved in DMF (340
mL), HATU (2.76 g, 7.25 mmol), methylamine (2 mol/L THF solution,
3.63 mL, 7.25 mmol) and triethylamine (9.89 mmol) were added, and
the mixture was stirred at room temperature for 5 hours. The
reaction solution was distributed between ethyl acetate and water.
The ethyl acetate layer was separated, and the aqueous layer was
extracted with ethyl acetate once. The combined extracts were
washed with water and an aqueous saturated sodium chloride
solution, and dried. The solvent was distilled off to obtain 1.66 g
of a crude purified product of compound 65C as a white solid.
[1243] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.38 (3H, brs), 3.75
(3H, s), 5.37 (2H, s), 7.34-7.44 (5H, m), 8.10 (1H, s), 8.38 (1H,
s), 11.84 (1H, brs).
Third Step
[1244] To a DMF (20 mL) solution of compound 65C (1.2 g, 3.79 mmol)
were added potassium carbonate (1.04 g, 7.59 mmol) and
O-(2,4-dinitrophenyl)hydroxylamine (831 mg, 4.17 mmol), and the
mixture was stirred at room temperature for 3 hours. To the
reaction solution was added water, and the precipitated solid was
filtered, and washed with water to obtain 1.0 g of a crude purified
product of compound 65D.
[1245] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.74 (3H, s), 3.83 (3H,
brs), 5.05 (2H, s), 6.46 (2H, brs), 7.31-7.38 (5H, m), 8.20 (1H,
s), 8.52 (1H, brs).
Fourth Step
[1246] To a DMF (10 mL) solution of compound 65D (1.0 g, 3.02 mmol)
were added paraformaldehyde (109 mg, 3.62 mmol) and acetic acid
(0.017 ml, 0.302 mmol) at room temperature, and the mixture was
stirred at 105.degree. C. for 2 hours. The reaction solution was
cooled to 0.degree. C., cesium carbonate (3.44 g, 10.6 mmol) was
added, and the mixture was stirred at room temperature for 1 hour.
To the reaction solution was added water, and the mixture was
distributed between ethyl acetate and water. The organic layer was
washed with an aqueous saturated sodium chloride solution, and
dried. The solvent was distilled off to obtain 120 mg of compound
65E.
[1247] MS: m/z=344 [M+H].sup.+.
Fifth Step
[1248] To a DMF (1 mL) solution of compound 65E (17.0 mg, 0.05
mmol) were added cesium carbonate (81.4 mg, 0.25 mmol) and
methylamine (2 mol/L THF solution, 0.125 ml, 0.25 mmol), and the
mixture was stirred at room temperature for 5 hours. The reaction
solution was filtered, and the filtrate was fractionated and
purified by LCMS to obtain compound 65F.
[1249] MS: m/z=358 [M+H].sup.+.
Sixth Step
[1250] To a DMF (0.5 mL) solution of compound 65F was added a 2N
aqueous sodium hydroxide solution (0.2 mL), and the mixture was
stirred at room temperature for 2 hours. To the reaction solution
was added ion-exchange resin DOWEX (50W-X8), and the mixture was
filtered, and washed with DMF. After concentration of the filtrate,
trifluoroacetic acid (0.5 mL) was added, and the mixture was
stirred at 80.degree. C. for 4 hours. After concentration of the
reaction solution, water and chloroform were added, and the organic
layer was separated. The organic layer was concentrated, and
fractionation-purified by LCMS to obtain 6.47 mg of compound
65.
[1251] MS: m/z=254 [M+H].sup.+.
[1252] According to Reference example 65, compounds of Reference
examples 66 to 92 shown in Tables 10 to 14 below were synthesized
by the same procedure.
TABLE-US-00010 TABLE 10 Reference example Structure MS Reference
example 66 ##STR00249## 348 Reference example 67 ##STR00250## 296
Reference example 68 ##STR00251## 340 Reference example 69
##STR00252## 348 Reference example 70 ##STR00253## 442 Reference
example 71 ##STR00254## 318
TABLE-US-00011 TABLE 11 Reference example Structure MS Reference
example 72 ##STR00255## 362 Reference example 73 ##STR00256## 388
Reference example 74 ##STR00257## 438 Reference example 75
##STR00258## 298 Reference example 76 ##STR00259## 430 Reference
example 77 ##STR00260## 442
TABLE-US-00012 TABLE 12 Reference example Structure MS Reference
example 78 ##STR00261## 442 Reference example 79 ##STR00262## 454
Reference example 80 ##STR00263## 438 Reference example 81
##STR00264## 492 Reference example 82 ##STR00265## 443
TABLE-US-00013 TABLE 13 Reference example Structure MS Reference
example 83 ##STR00266## 513 Reference example 84 ##STR00267## 500
Reference example 85 ##STR00268## 454 Reference example 86
##STR00269## 452 Reference example 87 ##STR00270## 480
TABLE-US-00014 TABLE 14 Reference example Structure MS Reference
example 88 ##STR00271## 406 Reference example 89 ##STR00272## 445
Reference example 90 ##STR00273## 500 Reference example 91
##STR00274## 416 Reference example 92 ##STR00275## 450
Reference Example 93
##STR00276##
[1254] According to Reference example 65, compound 93 was
synthesized by the same procedure.
[1255] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.34 (3H, s), 3.57-3.68
(2H, m), 3.73 (2H, brs), 4.18 (2H, s), 4.75 (2H, brs), 7.06-7.12
(2H, m), 7.21-7.24 (2H, m), 8.10 (1H, s), 11.96 (1H, brs), 14.52
(1H, brs).
Reference Example 94
##STR00277##
[1256] First Step
[1257] Using compound 94A (WO 2007/049675), and according to the
same procedure as that of the fifth step of Reference example 65,
compound 94B was synthesized.
[1258] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.00-3.09 (1H, m), 3.18
(3H, s), 3.44 (2H, dd, J=7.55, 2.82 Hz), 4.02-4.08 (1H, m),
4.44-4.59 (3H, m), 4.86 (1H, d, J=13.57 Hz), 5.25 (1H, s), 5.36
(2H, dd, J=14.87, 9.99 Hz), 6.74-6.84 (2H, m), 7.09-7.60 (16H, m),
7.90 (1H, s), 10.07 (1H, t, J=5.87 Hz).
Second Step
[1259] To a MeCN (20 ml) solution of compound 94B (1.1 g, 1.655
mmol) were added DMAP (202 mg, 1.655 mmol) and Boc2O (20 ml, 86
mmol) at room temperature under nitrogen stream, and the mixture
was heated to reflux for 5 hours. Further, Boc2O (20 ml, 86 mmol)
was added, and the mixture was heated to reflux for 5 hours. After
concentration under reduced pressure, to the residue were added
ethanol (20.00 ml) and an aqueous sodium hydroxide solution (40%,
25 ml), and the mixture was stirred at room temperature for 5
hours. To the reaction mixture were added ethyl acetate-water to
make the aqueous layer acidic. After extraction with ethyl acetate
(2.times.200 mL), the organic layer was washed with an aqueous
saturated sodium chloride solution. After drying with magnesium
sulfate, the solvent was distilled off under reduced pressure. The
crude product was purified by silica gel column chromatography
(CHCl.sub.3/MeOH 20:1) to obtain compound 94C. (750 mg, 63%)
[1260] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.13 (3H, s), 3.25-3.34
(3H, m), 3.79 (1H, d, J=13.73 Hz), 4.42 (1H, d, J=14.03 Hz),
5.11-5.27 (3H, m), 5.48 (1H, s), 7.18-7.21 (5H, m), 7.33-7.49 (6H,
m), 7.56-7.58 (2H, m), 7.74 (2H, d, J=7.32 Hz), 8.01 (1H, s).
Third Step
[1261] Using compound 94C, and according to the same procedure as
that of the tenth step of Reference example 12, compound 94 was
synthesized.
[1262] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.13 (3H, s), 3.41-3.56
(4H, m), 4.50 (1H, d, J=13.57 Hz), 5.21 (1H, d, J=13.42 Hz), 5.58
(1H, s), 7.16-7.50 (8H, m), 7.72 (2H, d, J=7.32 Hz), 7.93 (1H, s),
12.12 (1H, s).
Reference Example 95
##STR00278##
[1263] First Step
[1264] Compound 95A (WO 2006/116764, 1 g, 4.06 mmol) was dissolved
in 28% aqueous ammonia, and the solution was stirred at room
temperature for 12 hours. After concentration of the reaction
solution, the resulting residue was neutralized with 2N
hydrochloric acid, and the precipitated solid was suspended in
ethyl acetate, filtered, and dried to obtain 1.14 g (yield 100%) of
compound 95B.
[1265] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 5.14 (2H, s), 7.31 (1H,
d, J=6.6 Hz), 7.34-7.41 (3H, m), 7.45-7.51 (2H, m), 8.17 (1H, d,
J=6.6 Hz).
Second Step
[1266] To a DMF (10 ml) solution of the compound 95B (3.00 g, 10.65
mmol) were added WSC HCl (3.06 g, 15.98 mmol) and HOBt (1.58 g,
11.7 mmol) at room temperature, the mixture was stirred for 10
minutes, and a methylamine 33 wt % ethanol solution (1.50 g, 15.98
mmol) was added dropwise. After the reaction solution was stirred
at the same temperature for 2 hours, water was added, and the
mixture was extracted with chloroform five times. The extract was
dried with sodium sulfate, the solvent was distilled off, and the
resulting oil was purified by silica gel chromatography. From a
fraction eluted with ethyl acetate-MeOH (6:4, v/v), 2.62 g (yield
95%) of compound 95C was obtained as a solid.
[1267] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.77 (3H, d, J=4.8 Hz),
5.49 (2H, s), 6.57 (1H, d, J=6.9 Hz), 7.25-7.43 (5H, m), 7.48 (1H,
t, J=6.0 Hz), 8.23 (1H, brs), 9.77 (1H, brs).
Third Step
[1268] To a DMF (10 ml) solution of the compound 95C (2.62 g, 10.14
mmol) was suspended potassium carbonate (4.20 g, 30.42 mmol) at
room temperature, the suspension was stirred for 5 minutes,
O-(2,4-dinitrophenyl)hydroxylamine (3.03 g, 15.21 mmol) was added,
and the mixture was stirred at the same temperature for 3 hours. To
the reaction solution was added water, the mixture was extracted
with chloroform five times, and the extract was dried with sodium
sulfate. After the solvent was distilled off, the resulting oil was
purified by silica gel chromatography. From a fraction eluted with
ethyl acetate-MeOH (6:4, v/v), 1.41 g (yield 51%) of compound 95D
was obtained as a solid.
[1269] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.62 (3H, d, J=5.1 Hz),
5.06 (2H, s), 5.22 (2H, s), 6.18 (1H, d, J=7.8 Hz), 7.25-7.36 (5H,
m), 5.89 (1H, d, J=7.8 Hz), 7.57 (1H, q, J=5.1 Hz).
Fourth Step
[1270] A toluene (10 ml) solution of the compound 95D (1.0 g, 3.66
mmol) were added paraformaldehyde (109.9 mg, 3.66 mmol) and acetic
acid (22 mg, 0.37 mmol), and the mixture was heated to stir at
100.degree. C. for 40 minutes. After cooling, the solvent was
distilled off, the residue was dissolved in DMF (10 ml) without
purification, cesium carbonate (3.58 g, 10.98 mmol) was added under
ice-cooling, and the mixture was stirred for 10 minutes. To the
reaction solution was added benzohydryl bromide (1.36 g, 5.49
mmol), the mixture was stirred at room temperature for 3 hours,
water was added, and the mixture was extracted with ethyl acetate
three times. The extract was washed with water three times, and
dried with sodium sulfate. The solvent was distilled off, and the
resulting oil was purified by silica gel chromatography. From a
fraction eluted with ethyl acetate-MeOH (9:1, v/v), 1.26 g (yield
71%) of compound 95E was obtained as a solid.
[1271] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.91 (3H, s), 4.26 (1H, d,
J=13.2 Hz), 4.77 (1H, d, J=13.2 Hz), 5.12 (1H, s), 5.42 (1H, J=13.2
Hz), 5.45 (1H, d, J=13.2 Hz), 5.82 (1H, J=7.5 Hz), 6.71 (1H, d,
J=7.5 Hz), 7.10-7.23 (5H, m), 7.27-7.46 (6H, m), 7.52 (2H, d, J=6.9
Hz), 7.60-7.64 (2H, m).
Fifth Step
[1272] Compound 95E (100 mg, 0.221 mmol) was dissolved in
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 1 hour. The solvent was distilled off, the residue
was dissolved in dichloromethane (2 ml), and the solution was
neutralized with saturated sodium bicarbonate water. The resulting
solution was made acidic with an aqueous citric acid solution, and
the organic layer was separated. The aqueous layer was extracted
with dichloromethane once, and the combined organic layers were
washed with water, and dried with sodium sulfate. After the solvent
was distilled off, the resulting solid was washed with diisopropyl
ether to obtain 50 mg (yield 63%) of compound 95.
[1273] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.95 (3H, s), 4.36 (1H, d,
J=13.2 Hz), 4.95 (1H, d, J=13.2 Hz), 5.22 (1H, s), 5.71 (1H, d,
J=7.8 Hz), 6.75 (1H, d, J=7.8 Hz), 7.21 (5H, brs), 7.33-7.47 (4H,
m), 7.55 (2H, d, J=6.6 Hz).
[1274] According to Reference example 95, the following compounds
were synthesized by the same procedure.
Reference Example 96
##STR00279##
[1276] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.12-3.18 (1H, m), 3.21
(3H, s), 3.38-3.52 (2H, m), 3.81 (1H, ddd, J=3.3 Hz, 4.2 Hz, 14.1
Hz), 4.52 (1H, d, J=13.2 Hz), 5.00 (1H, d, J=13.2 Hz), 5.28 (1H,
s), 5.71 (1H, d, J=7.8 Hz), 6.74 (1H, d, J=7.8 Hz), 7.14-7.21 (5H,
m), 7.32-7.46 (3H, m), 7.53 (2H, d, J=7.5 Hz).
Reference Example 97
##STR00280##
[1278] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.99-3.06 (0.54H, m),
3.18-3.23 (3.9H, m), 3.42-3.54 (2.5H, m), 3.86-3.91 (0.42H, m),
4.03-4.08 (0.58H, m), 4.37 (0.58H, d, J=13.5 Hz), 4.54 (0.42H, d,
J=13.8 Hz), 4.98 (0.58H, d, J=13.5 Hz), 5.08 (0.42H, d, J=13.8 Hz),
5.36 (0.58H, s), 5.43 (0.42H, s), 5.70-5.77 (1H, m), 6.77 (0.42H,
d, J=7.5 Hz), 6.94 (0.58H, d, J=7.8 Hz), 7.08-7.53 (6H, m),
7.60-7.78 (2H, m), 8.55 (0.58H, d, J=4.2 Hz), 8.72 (0.42H, d, J=3.9
Hz).
Reference Example 98
##STR00281##
[1280] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.930 (3H, d, J=6.9 Hz),
1.09 (3H, d, J=6.9 Hz), 4.58 (1H, d, J=12.6 Hz), 4.79 (1H, d,
J=12.6 Hz), 4.83-4.90 (1H, m), 5.20 (1H, s), 5.67 (1H, d, J=7.5
Hz), 6.66 (1H, d, J=7.5 Hz), 7.07-7.09 (2H, m), 7.13-7.19 (3H, m),
7.34-7.46 (3H, m), 7.52 (1H, d, J=7.5 Hz).
Reference Example 99
##STR00282##
[1282] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.30 (3H, s), 3.49 (1H,
brs), 3.54-3.56 (2H, m), 3.73 (1H, brs), 4.11 (2H, brs), 4.25 (1H,
brs), 4.78 (1H, brs), 6.00 (1H, d, J=7.5 Hz), 8.33 (1H, d, J=7.5
Hz), 7.19-7.24 (3H, m), 7.34-7.37 (2H, m), 7.38-7.48 (4H, m).
Reference Example 100
##STR00283##
[1284] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.32 (1H, d, J=14.7 Hz),
4.41 (1H, d, J=12.9 Hz), 4.69 (1H, d, J=14.7 Hz), 4.88 (1H, d,
J=12.9 Hz), 4.97 (1H, s), 5.68 (1H, d, J=7.5 Hz), 6.70 (1H, d,
J=7.5 Hz), 6.91-6.98 (2H, m), 7.05-7.08 (2H, m), 7.12-7.20 (7H, m),
7.30-7.32 (4H, m).
Reference Example 101
##STR00284##
[1286] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.35 (3H, s), 3.66-3.69
(3H, m), 3.89 (1H, brs), 4.51 (1H, brs), 4.64 (2H, brs), 5.05 (1H,
brs), 5.89 (1H, d, J=7.5 Hz), 6.58 (1H, d, J=7.5H), 7.11 (1H, d,
J=7.2 Hz), 7.26-7.40 (1H, m), 7.54-7.62 (2H, m), 7.86-7.93 (2H, m),
8.13 (1H, d, J=8.4 Hz).
Reference Example 102
##STR00285##
[1288] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.54 (1H, d, J=12.9 Hz),
4.56 (2H, s), 4.94 (1H, d, J=12.9 Hz), 5.14 (1H, s), 5.68 (1H, d,
J=7.8 Hz), 6.20 (1H, d, J=3.0 Hz), 6.25-6.27 (1H, m), 6.72 (1H, d,
J=7.8 Hz), 7.10-7.37 (11H, m).
Reference Example 103
##STR00286##
[1290] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.33 (3H, s), 3.63-3.66
(2H, m), 3.75 (2H, brs), 4.27 (2H, brs), 4.67 (1H, brs), 5.00 (1H,
brs), 6.09 (1H, d, J=7.8 Hz), 6.99 (1H, d, J=7.8 Hz), 7.18 (1H, d,
J=7.8 Hz), 7.27-7.32 (1H, m), 7.66-7.71 (1H, m), 8.63-8.65 (1H,
m).
Reference Example 104
##STR00287##
[1292] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.12-3.22 (1H, m), 3.21
(3H, m), 3.38-3.55 (3H, m), 3.74-3.80 (0.55H, m), 3.87-3.94 (0.44H,
m), 4.46-4.54 (1H, m), 5.00-5.07 (1H, m), 5.30-5.39 (1H, m), 5.70
(0.55H, d, J=7.5 Hz), 5.77 (0.45H, d, J=7.5 Hz), 6.74 (0.55H, d,
J=7.8 Hz), 6.81 (0.45H, d, J=7.8 Hz), 7.11-7.54 (7.45H, m), 7.90
(0.55H, d, J=7.8 Hz), 8.459-8.783 (2H, m).
Reference Example 105
##STR00288##
[1294] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.34 (3H, s), 3.65-3.70
(4H, m), 4.18 (1H, brs), 4.21 (1H, brs), 4.48 (1H, brs), 4.98 (1H,
brs), 6.12 (1H, d, J=7.8 Hz), 6.97 (1H, d, J=7.8 Hz), 7.36 (1H, d,
J=7.5 Hz), 7.49 (1H, t, J=7.8 Hz), 7.61-7.66 (2H, m).
Reference Example 106
##STR00289##
[1296] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.54 (2H, t, J=7.5 Hz),
3.01 (2H, t, J=7.5 Hz), 4.38 (2H, brs), 4.77 (2H, brs), 6.27 (1H,
d, J=7.5 Hz), 6.96-7.00 (2H, m), 7.04-7.09 (3H, m), 7.19-7.33 (5H,
m).
Reference Example 107
##STR00290##
[1297] First Step
[1298] To a DMF (30 ml) solution of compound 107A (3.0 g, 9.96
mmol) synthesized according to the method of synthesizing compound
95D were added paraformaldehyde (299 mg, 9.96 mmol) and acetic acid
(1 ml), and the mixture was heated to stir at 120.degree. C. for 4
hours. After the solvent was distilled off, to the residue were
added ethyl acetate-diisopropyl ether, and the precipitated solid
was filtered to obtain 2.85 g (yield 91%) of compound 107B.
[1299] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (6H, J=6.6 Hz), 4.34
(2H, J=7.5 Hz), 4.72-4.86 (1H, m), 5.30 (2H, s), 5.49 (1H, t, J=7.5
Hz), 6.36 (1H, d, J=7.8 Hz), 7.26-7.35 (4H, m), 7.37 (1H, d, J=7.8
Hz), 7.55-7.58 (2H, m).
Second Step
[1300] To an acetic acid (2 ml) solution of compound 107B (100 mg,
0.319 mmol) were added 96% sulfuric acid (0.5 ml) and
bis(3-chlorophenyl)methanol (242.3 mg, 0.957 mmol) at room
temperature, and the mixture was stirred at 80.degree. C. for 2
hours. After the reaction solution was cooled to room temperature,
water was added, and the mixture was extracted with ethyl acetate
three times. The organic layer was washed with water once, and
dried with sodium sulfate. After the solvent was distilled off, to
the residue was added diisopropyl ether, and the precipitated solid
was filtered to obtain 42 mg (yield 29%) of compound 107.
[1301] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.953 (3H, d, J=3.9 Hz),
1.12 (3H, d, J=4.2 Hz), 4.51 (1H, 13.5 Hz), 4.83 (1H, d, J=13.5
Hz), 4.83-4.92 (1H, m), 5.18 (1H, s), 5.74 (1H, d, J=7.8 Hz), 6.73
(1H, d, J=7.8 Hz), 6.90 (1H, d, J=7.5 Hz), 7.12 (2H, dd, J=7.2 Hz,
8.1 Hz), 7.19-7.22 (1H, m), 7.37-7.41 (3H, m), 7.55 (1H, s).
[1302] According to Reference example 107, the following compounds
were synthesized by the same procedure.
Reference Example 108
##STR00291##
[1304] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.465-0.549 (1H, m),
0.642-0.738 (1H, m), 0.754-0.907 (2H, m), 2.71-2.79 (1H, m), 2.86
(1H, ddd, J=4.8 Hz, 5.7 Hz, 14.7 Hz), 3.01 (2H, ddd, J=4.2 Hz, 16.0
Hz, 16.8 Hz), 3.88 (1H, ddd, J=4.8 Hz, 5.1 Hz, 16.8 Hz), 4.08-4.14
(1H, m), 4.16 (1H, d, J=12.9 Hz), 4.70 (1H, d, J=12.9 Hz), 4.96
(1H, s), 5.75 (1H, d, J=7.8 Hz), 6.58 (1H, d, J=7.8 Hz), 6.61 (1H,
d, J=7.5 Hz), 6.92 (1H, dd, J=6.0 Hz, 7.5 Hz), 7.11-7.80 (6H,
m).
Reference Example 109
##STR00292##
[1306] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (3H, d, J=6.9 Hz),
1.18 (3H, d, J=6.9 Hz), 2.82 (1H, ddd, J=4.5 Hz, 4.8 Hz, 14.1 Hz),
3.08 (1H, ddd, J=4.2 Hz, 13.2 Hz, 17.7 Hz), 3.53 (1H, ddd, J=4.2
Hz, 4.5 Hz, 17.7 Hz), 4.27 (1H, d, J=12.9 Hz), 4.26-4.37 (1H, m),
4.62-4.71 (1H, m), 4.68 (1H, d, J=12.9 Hz), 5.05 (1H, s), 5.71 (1H,
d, J=7.5 Hz), 6.63 (2H, d, J=7.2 Hz), 6.90 (1H, t, J=7.5 Hz),
7.08-7.63 (6H, m).
Reference Example 110
##STR00293##
[1308] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.16-3.28 (1H, m), 3.22
(3H, s), 3.46-3.50 (2H, m), 3.86 (1H, ddd, J=3.6 Hz, 3.6 Hz, 14.4
Hz), 4.47 (1H, d, J=13.2 Hz), 5.01 (1H, d, J=13.2 Hz), 5.30 (1H,
s), 5.76 (1H, d, J=7.5 Hz), 6.72 (1H, d, J=7.5 Hz), 6.90 (2H, t,
J=8.4 Hz), 7.06-7.18 (4H, m), 7.51 (2H, dd, J=5.4 Hz, 8.7 Hz).
Reference Example 111
##STR00294##
[1310] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.903 (1.3H, d, J=6.9 Hz),
0.982 (1.5H, d, J=6.6 Hz), 1.08-1.14 (3.2H, m), 4.55 (1H, dd,
J=13.2 Hz, 16.5 Hz), 4.78-4.93 (2H, m), 5.20 (1H, s), 5.66 (0.58H,
d, J=7.5 Hz), 5.75 (0.42H, d, J=7.5 Hz), 6.67 (0.55H, d, J=7.5 Hz),
6.73 (0.45H, d, J=7.5 Hz), 6.92 (0.45H, d, J=7.2 Hz), 7.04-7.59
(8.6H, m).
Reference Example 112
##STR00295##
[1312] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.22 (3H, s), 3.24-3.32
(1H, m), 3.47-3.50 (2H, m), 3.84 (1H, ddd, J=3.3 Hz, 3.9 Hz, 14.4
Hz), 4.51 (1H, d, J=13.5 Hz), 5.03 (1H, d, J=13.5 Hz), 5.32 (1H,
s), 5.77 (1H, d, J=7.8 Hz), 6.80 (1H, d, J=7.8 Hz), 6.84 (1H, d,
J=7.8 Hz), 6.93 (2H, t, J=8.4 Hz), 7.06-7.20 (2H, m), 7.25-7.29
(2H, m), 7.39-7.47 (1H, m).
Reference Example 113
##STR00296##
[1314] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.88 (3H, d, J=6.9 Hz),
1.10 (3H, d, J=6.6 Hz), 2.10 (3H, s), 4.62-4.69 (1H, m), 4.79-4.92
(2H, m), 5.32 (1H, s), 5.64 (0.74H, 7.5 Hz), 5.72 (0.26H, d, J=7.5
Hz), 6.61 (0.74H, d, J=7.8 Hz), 6.82 (0.26H, d, J=7.8 Hz),
6.96-7.52 (8.26H, m), 7.48 (0.74H, d, J=7.5 Hz).
Reference Example 114
##STR00297##
[1316] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.976 (2H, d, J=6.9 Hz),
1.09-1.14 (3H, m), 5.63 (0.74H, d, J=7.8 Hz), 5.65 (0.74H, s), 5.73
(0.26H, d, J=7.8 Hz), 6.20 (0.26H, s), 6.65 (0.74H, d, J=7.8 Hz),
6.79 (0.26H, d, J=7.8 Hz), 7.05-7.24 (4.26H, m), 7.31-7.56 (4H, m),
8.02 (0.74H, d, J=6.3 Hz).
Reference Example 115
##STR00298##
[1318] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.893 (1.2H, d, J=6.6 Hz),
0.958 (1.8H, d, J=6.9 Hz), 1.09-1.13 (3H, m), 4.44 (0.56H, d,
J=13.2 Hz), 4.63 (0.44H, d, J=13.5 Hz), 4.81-4.93 (2H, m), 5.35
(1H, m), 5.67 (0.56H, d, J=7.8 Hz), 5.72 (0.44H, d, J=7.8 Hz),
6.67-6.73 (1H, m), 7.03 (1H, d, J=6.6 Hz), 7.20-7.51 (5H, m), 7.75
(1H, d, 0.8.4 Hz), 8.06 (0.88H, d, J=8.7 Hz), 8.33 (1.1H, d, J=8.7
Hz).
Reference Example 116
##STR00299##
[1320] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.91-0.0.948 (3H, m),
1.10-1.14 (3H, m), 3.61-3.68 (1H, m), 4.44 (0.56H, d, J=12.9 Hz),
4.59 (0.44H, d, J=12.9 Hz), 4.79-4.91 (2H, m), 5.29 (1H, s),
5.67-5.69 (1H, m), 6.63-6.70 (2H, m), 6.90-7.81 (8H, m).
Reference Example 117
##STR00300##
[1322] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.19-3.28 (1H, m), 3.22
(3H, s), 3.46-3.50 (2H, m), 3.85 (1H, ddd, J=3 Hz, 4.2 Hz, 14.4
Hz), 4.47 (1H, d, J=13.2 Hz), 5.01 (1H, d, J=13.2 Hz), 5.28 (1H,
s), 5.78 (1H, d, J=7.8 Hz), 6.73 (1H, d, J-=7.8 Hz), 7.04 (2H, d,
J=8.4 Hz), 7.19 (2H, d, 8.4 Hz), 7.36-7.50 (4H, m).
Reference Example 118
##STR00301##
[1324] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.914-0.957 (3H, m),
1.08-1.14 (3H, m), 2.20 (1.4H, s). 2.39 (1.6H, s), 4.56 (0.48H, d,
J=4.5 Hz), 4.60 (0.52H, d, J=4.2 Hz), 4.77-4.89 (2H, m), 5.16 (1H,
s), 5.66-5.70 (1H, m), 6.65-6.69 (1H, m), 6.85-6.91 (1H, m),
6.98-7.10 (2H, m), 7.14-7.19 (2H, m), 7.30-7.39 (2H, m), 7.44 (1H,
t, J=6.9 Hz), 7.51 (1H, d, J=6.9 Hz).
Reference Example 119
##STR00302##
[1326] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.893-0.982 (3H, m),
1.08-1.14 (3H, m), 4.49-4.60 (1H, m), 4.78-4.90 (2H, m), 5.20 (1H,
s), 5.65 (0.57H, J=7.5 Hz), 5.76 (0.43H, d, J=7.8 Hz), 6.64-6.70
(1H, m), 7.03 (2H, d, J=8.1 Hz), 7.10-7.20 (3H, m), 7.28-7.51 (4H,
m).
Reference Example 120
##STR00303##
[1328] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.526 (3H, d, J=6.9 Hz),
1.01 (3H, d, J=6.6 Hz), 4.69 (1H, d, J=13.8 Hz), 4.75-4.83 (1H, m),
4.86 (1H, d, J=13.8 Hz), 5.69 (1H, d, J=7.8 Hz), 6.03 (1H, s), 6.70
(1H, d, J=7.8 Hz), 7.16 (5H, s), 7.40-7.48 (2H, m), 7.67 (1H, t,
J=7.8 Hz), 7.81-7.91 (3H, m), 8.16 (1H, d, J=7.2 Hz).
Reference Example 121
##STR00304##
[1330] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.947 (3H, d, J=6.9 Hz),
1.09 (3H, d, J=7.2 Hz), 2.22 (3H, s), 2.37 (3H, s), 4.58 (1H, d,
J=12.9 Ha), 4.76 (1H, d, J=12.9 Hz), 4.78-4.88 (1H, m), 5.13 (1H,
s), 5.72 (1H, d, J=7.8 Hz), 6.67 (1H, d, J=7.8 Hz), 6.72 (1H, s),
6.90-6.98 (4H, m), 7.22 (2H, d, J=7.8 Hz), 7.38 (2H, d, J=7.8
Hz).
Reference Example 122
##STR00305##
[1332] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.932 (3H, d, J=6.6 Hz),
1.12 (3H, d, J=6.9 Hz), 4.44 (1H, d, J=13.2 Hz), 4.86 (1H, d,
J=13.2 Hz), 4.87-4.93 (1H, m), 5.38 (1H, s), 5.67 (1H, d, J=7.8
Hz), 6.67 (1H, d, J=7.8 Hz), 7.21-7.24 (1H, m), 7.32-7.40 (2H, m),
7.52 (1H, d, J=7.5 Hz), 7.60-7.72 (2H, m), 7.77-7.79 (2H, m).
Reference Example 123
##STR00306##
[1334] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.08-3.17 (1H, m), 3.23
(3H, s), 3.40-3.54 (2H, m), 3.71 (3H, s), 3.82 (3H, s), 3.95 (1H,
ddd, J=3.3 Hz, 3.9 Hz, 14.4 Hz), 4.48 (1H, d, J=13.5 Hz), 4.96 (1H,
d, J=13.5 Hz), 5.16 (1H, s), 5.76 (1H, d, J=7.5 Hz), 6.70 (2H, d,
J=9.0 Hz), 6.73 (1H, d, J=7.5 Hz), 6.94 (2H, d, J=8.7 Hz), 7.03
(2H, d, J=8.7 Hz), 7.42 (2H, d, J=8.7 Hz).
Reference Example 124
##STR00307##
[1336] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.966 (3H, d, J=6.9 Hz),
1.10 (3H, d, J=6.9 Hz), 3.67 (3H, s), 3.83 (3H, s), 4.60 (1H, d,
J=12.9 Hz), 4.78 (1H, d, J=12.9 Hz), 4.80-4.90 (1H, m), 5.13 (1H,
m), 5.23 (1H, d, J=7.8 Hz), 6.66 (2H, d, J=7.2 Hz), 6.72-6.87 (2H,
m), 6.87-6.90 (1H, m), 7.06-7.11 (3H, m), 7.34 (1H, t, J=8.1
Hz).
Reference Example 125
##STR00308##
[1338] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.05 (2H, d, J=7.0 Hz),
1.15 (1H, d, J=7.5 Hz), 2.73-3.63 (8H, m), 4.20-4.93 (4H, m), 5.25
(0.4H, s), 5.30 (0.6H, s), 5.46 (1H, d, J=7.8 Hz), 6.68-7.46 (11H,
m).
[1339] MS: m/z=446 [M+H].sup.+.
Reference Example 126
##STR00309##
[1340] First Step
[1341] Compound 95B (1.00 g, 3.55 mmol) and cyclopropanamine (0.492
ml, 7.10 mmol) were added to pyridine (20 ml),
1-hydroxybenzotriazole (544 mg, 3.55 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.36
g, 7.10 mmol) were sequentially added, and the mixture was stirred
at room temperature for 18 hours. After the solvent was distilled
off under reduced pressure, the resulting crude product was
purified by silica gel column chromatography (chloroform-methanol,
95:5, v/v) and, subsequently, amino column chromatography
(chloroform-methanol, 99:1, v/v) to obtain 1.19 g of compound 126A
as a colorless solid.
[1342] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.22 (1H, m), 0.70 (2H,
m), 2.76-2.83 (1H, m), 5.50 (2H, s), 6.59 (1H, dd, J=7.0, 1.9 Hz),
7.44 (5H, d, J=0.7 Hz), 7.53 (1H, dd, J=6.9, 6.2 Hz), 8.30 (1H,
brs), 9.71 (1H, brs).
Second Step
[1343] Compound 126A (1.19 g, 4.19 mmol) was dissolved in DMF (15
ml), potassium carbonate (2.90 g, 20.1 mmol) was added, and the
mixture was stirred at room temperature for 30 minutes.
O-(2,4-dinitrophenyl)hydroxylamine (1.67 g, 8.38 mmol) was added,
and the mixture was stirred at room temperature for 18 hours. To
the reaction solution was added chloroform, the precipitated yellow
precipitate was removed by filtration, and the filtrate was
concentrated under reduced pressure. The resulting crude product
was purified by amino column chromatography (chloroform-methanol,
97:3.fwdarw.95:5, v/v) to obtain 851 mg of compound 126B as a
yellow solid.
[1344] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.41-0.46 (2H, m), 0.76
(2H, m), 2.73-2.81 (1H, m), 5.19 (2H, s), 5.61 (2H, s), 6.26 (1H,
d, J=7.2 Hz), 7.38 (5H, s), 7.44 (1H, d, J=7.8 Hz), 7.70 (1H,
s).
Third Step
[1345] Compound 126B (847 mg, 2.83 mmol) and paraformaldehyde (255
mg, 8.49 mmol) were added to ethanol (12 ml), and the mixture was
stirred at 140.degree. C. for 30 minutes under microwave
irradiation. The reaction solution was concentrated under reduced
pressure, the resulting crude product was purified by silica gel
column chromatography (chloroform-methanol,
97:3.fwdarw.95:5.fwdarw.90:10, v/v) and, subsequently, amino column
chromatography (chloroform-methanol, 97:3, v/v), methylene
chloride-ethyl ether were added, and the precipitated solid was
filtered to obtain 665 mg of compound 126C as a colorless
solid.
[1346] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.61-0.66 (2H, m), 0.87
(2H, m), 2.68-2.76 (1H, m), 4.32 (2H, d, J=7.9 Hz), 5.28 (2H, s),
6.33 (1H, d, J=7.7 Hz), 6.45 (1H, t, J=7.7 Hz), 7.33 (3H, m), 7.38
(1H, d, J=7.7 Hz), 7.52 (2H, m).
Fourth Step
[1347] Compound 126C (100 mg, 0.321 mmol) was dissolved in DMF (0.5
ml), cesium carbonate (314 mg, 0.964 mmol) and
(bromomethylene)dibenzene (119 mg, 0.482 mmol) were added at
0.degree. C., and the mixture was stirred at room temperature for 2
hours. The reaction solution was poured into water, the mixture was
extracted with ethyl acetate, and the organic layer was washed with
water, and dried with sodium sulfate. The solvent was distilled off
under reduced pressure, and the resulting crude product was
purified by silica gel column chromatography (chloroform-methanol,
97:3.fwdarw.95:5, v/v) to obtain 124 mg of compound 126D as a
colorless gummy substance.
[1348] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.37-0.47 (2H, m), 0.74
(2H, m), 2.63-2.68 (1H, m), 4.35 (1H, d, J=13.4 Hz), 4.65 (1H, d,
J=13.4 Hz), 5.07 (1H, s), 5.40 (1H, d, J=10.7 Hz), 5.47 (1H, d,
J=10.5 Hz), 5.79 (1H, d, J=7.6 Hz), 6.67 (1H, d, J=7.8 Hz),
7.04-7.62 (15H, m).
Fifth Step
[1349] To compound 126D obtained in the fourth step was added
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 1.5 hours. After concentration under reduced
pressure, pH was adjusted to 6 with sodium bicarbonate water and 2N
hydrochloric acid, the mixture was extracted with chloroform, and
the extract was dried with sodium sulfate. After the solvent was
distilled off under reduced pressure, methylene chloride-ethyl
ether were added, and the precipitated solid was filtered to obtain
52 mg of compound 126 as a colorless solid.
[1350] .sup.1H-NMR (DMSO-d.sub.6) .delta.: -0.19--0.06 (1H, m),
0.44-0.54 (1H, m), 0.82 (2H, m), 2.62-2.69 (1H, m), 4.21 (1H, d,
J=13.3 Hz), 5.11 (1H, d, J=13.1 Hz), 5.32 (1H, s), 5.47 (1H, t,
J=11.1 Hz), 7.13 (1H, d, J=7.6 Hz), 7.23 (3H, m), 7.28-7.47 (8H,
m), 7.69 (2H, t, J=8.5 Hz).
[1351] MS: m/z=388 [M+H].sup.+.
Reference Example 127
##STR00310##
[1353] According to Reference example 126, compound 127 was
synthesized by the same procedure.
[1354] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.86 (1.5H, d, J=7.0
Hz), 1.04 (1.5H, d, J=7.2 Hz), 3.08 (1.5H, s), 3.16 (1.5H, s),
4.52-5.05 (3H, m), 5.48 (2H, m), 7.31-7.47 (9H, m), 7.66 (2H, t,
J=8.4 Hz).
[1355] MS: m/z=420 [M+H].sup.+.
Reference Example 128
##STR00311##
[1356] First Step
[1357] Compound 95B (2.40 g, 8.52 mmol) and ethyl 3-aminopropanoate
hydrochloride (2.62 g, 17.0 mmol) were added to pyridine (30 ml),
1-hydroxybenzotriazole (1.31 g, 8.52 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.27
g, 17.0 mmol) were sequentially added, and the mixture was stirred
at room temperature for 2 hours. The solvent was distilled off
under reduced pressure, and the resulting crude product was
purified by amino column chromatography (chloroform-methanol, 95:5,
v/v) to obtain 1.90 g of compound 128A as a colorless solid.
[1358] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, t, J=7.1 Hz),
2.48 (2H, t, J=6.4 Hz), 3.58 (2H, q, J=6.3 Hz), 4.17 (2H, q, J=7.1
Hz), 5.59 (2H, s), 6.57 (1H, dd, J=7.1, 1.6 Hz), 7.37-7.52 (6H, m),
8.73 (1H, brs), 9.72 (1H, brs).
Second Step
[1359] Compound 128A (2.58 g, 7.49 mmol) was dissolved in DMF (30
ml), potassium carbonate (5.18 g, 37.5 mmol) was added, and the
mixture was stirred at room temperature for 30 minutes.
O-(2,4-dinitrophenyl)hydroxylamine (2.98 g, 15.0 mmol) was added,
and the mixture was stirred at room temperature for 20 hours. To
the reaction solution was added chloroform, the precipitated yellow
precipitate was removed by filtration, and the filtrate was
concentrated under reduced pressure. The resulting crude product
was purified by amino column chromatography (chloroform-methanol,
97:3.fwdarw.95:5, v/v) and, subsequently, silica gel column
chromatography (chloroform-methanol, 95:5.fwdarw.92:8, v/v) to
obtain 1.67 g of compound 128B as a yellow solid.
[1360] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26 (3H, t, J=7.2 Hz),
2.42 (2H, t, J=6.6 Hz), 3.43 (2H, q, J=6.4 Hz), 4.12 (2H, q, J=7.1
Hz), 5.13 (2H, s), 5.53 (2H, s), 6.21 (1H, d, J=7.6 Hz), 7.33 (5H,
s), 7.39 (1H, d, J=7.6 Hz), 7.85 (1H, t, J=5.6 Hz).
Third Step
[1361] Compound 128B (1.66 g, 4.62 mmol) and paraformaldehyde (416
mg, 13.9 mmol) were added to ethanol (20 ml), and the mixture was
stirred at 140.degree. C. for 30 minutes under microwave
irradiation. The reaction solution was concentrated under reduced
pressure, the resulting crude product was purified by amino column
chromatography (chloroform-methanol, 99:1.fwdarw.95:5, v/v) to
obtain 1.57 g of compound 128C as a colorless solid.
[1362] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27 (3H, t, J=7.2 Hz),
2.70 (2H, t, J=5.7 Hz), 3.57 (2H, t, J=5.8 Hz), 4.13 (2H, q, J=7.1
Hz), 4.50 (2H, d, J=7.9 Hz), 5.27 (2H, s), 5.87 (1H, t, J=7.8 Hz),
6.32 (1H, d, J=7.6 Hz), 7.31 (4H, m), 7.54 (2H, m).
Fourth Step
[1363] Compound 128C (1.00 g, 2.69 mmol) was dissolved in DMF (10
ml), cesium carbonate (2.63 g, 8.08 mmol) and
(bromomethylene)dibenzene (998 mg, 4.04 mmol) were added at
0.degree. C., and the mixture was stirred at room temperature for
18 hours. The reaction solution was poured into water, the mixture
was extracted with ethyl acetate, and the organic layer was washed
with water, and dried with sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting crude
product was purified by silica gel column chromatography
(chloroform/methanol, 98:2, v/v) to obtain 500 mg of compound 128D
as a colorless gummy substance.
[1364] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (3H, t, J=7.3 Hz),
2.46 (1H, m), 2.70-2.80 (1H, m), 2.87-2.96 (1H, m), 4.11 (2H, q,
J=7.3 Hz), 4.12 (1H, m), 4.48 (1H, d, J=13.7 Hz), 4.85 (1H, d,
J=13.7 Hz), 5.10 (1H, s), 5.47 (2H, s), 5.83 (1H, d, J=8.0 Hz),
6.73 (1H, d, J=8.0 Hz), 7.37 (15H, m).
Fifth Step
[1365] To compound 128D (40 mg, 0.074 mmol) was added
trifluoroacetic acid (1 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 6 with sodium bicarbonate water and 2N
hydrochloric acid, the mixture was extracted with chloroform, and
the extract was dried with sodium sulfate. After the solvent was
distilled off under reduced pressure, methylene chloride-ethyl
ether were added, and the precipitated solid was filtered to obtain
20 mg of compound 128 as a colorless solid.
[1366] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.16 (3H, t, J=7.1 Hz),
2.45-2.58 (3H, m), 3.70 (1H, m), 4.02 (2H, q, J=7.1 Hz), 4.39 (1H,
d, J=13.4 Hz), 5.09 (1H, d, J=13.3 Hz), 5.48 (1H, d, J=3.2 Hz),
5.51 (1H, s), 7.19-7.38 (7H, m), 7.45 (2H, t, J=7.3 Hz), 7.69 (2H,
d, J=7.2 Hz).
[1367] MS: m/z=448 [M+H].sup.+.
Reference Example 129
##STR00312##
[1368] First Step
[1369] Compound 128D (426 mg, 0.792 mmol) was dissolved in ethanol
(3 ml) and THF (3 ml), a 2N aqueous sodium hydroxide solution (1.19
ml, 2.38 mmol) was added, and the mixture was stirred at room
temperature for 1.5 hours. To the reaction solution was added 2N
hydrochloric acid, and the mixture was extracted with chloroform,
and dried with sodium sulfate. To the resulting crude product were
added methylene chloride-ethyl ether, and the precipitated solid
was filtered to obtain 359 mg of compound 129A as a colorless
solid.
Second Step
[1370] To compound 129A (40 mg, 0.079 mmol) was added
trifluoroacetic acid (1 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 3 with sodium bicarbonate water and 2N
hydrochloric acid, and the mixture was extracted with chloroform,
and dried with sodium sulfate. After the solvent was distilled off
under reduced pressure, chloroform-methanol-ethyl ether were added,
and the precipitated solid was filtered to obtain 25 mg of compound
129 as a colorless solid.
[1371] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.31-2.41 (1H, m), 2.57
(1H, m), 3.63-3.72 (1H, m), 4.37 (1H, d, J=13.3 Hz), 5.09 (1H, d,
J=13.3 Hz), 5.47 (1H, s), 5.50 (1H, d, J=7.8 Hz), 7.28 (7H, m),
7.44 (2H, t, J=7.5 Hz), 7.69 (2H, d, J=7.2 Hz), 12.40 (1H,
brs).
[1372] MS: m/z=420 [M+H].sup.+.
Reference Example 130
##STR00313##
[1373] First Step
[1374] Compound 129A (50 mg, 0.098 mmol) was added to DMF (1 ml),
1-hydroxybenzotriazole (14 mg, 0.098 mmol), dimethylamine
hydrochloride (24 mg, 0.29 mmol), triethylamine (0.048 ml, 0.34
mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (28 mg, 0.15 mmol) were added, and the mixture was
stirred at room temperature for 1.5 hours. The reaction solution
was poured into water, and the mixture was extracted with ethyl
acetate, washed with sodium bicarbonate water, and dried with
sodium sulfate. The solvent was distilled off under reduced
pressure to obtain compound 130A as a colorless gummy
substance.
Second Step
[1375] To compound 130A obtained in the first step was added
trifluoroacetic acid (1 ml), and the mixture was stirred at room
temperature for 2 hours. After concentration under reduced
pressure, pH was adjusted to 6 with sodium bicarbonate water and an
aqueous ammonium chloride solution, and the mixture was extracted
with chloroform, and dried with sodium sulfate. The solvent was
distilled off under reduced pressure, chloroform-ethyl ether were
added, and the precipitated solid was filtered to obtain 25 mg of
compound 130 as a colorless solid.
[1376] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.33-2.43 (1H, m), 2.66
(1H, m), 2.78 (3H, s), 2.89 (3H, s), 3.56 (2H, m), 4.45 (1H, d,
J=13.6 Hz), 5.05 (1H, d, J=13.6 Hz), 5.47 (s, 1H), 5.49 (1H, d,
J=7.5 Hz), 7.27 (7H, m), 7.44 (2H, t, J=7.3 Hz), 7.69 (2H, d, J=7.3
Hz).
Reference Example 131
##STR00314##
[1378] According to Reference example 130, compound 131 was
synthesized by the same procedure.
[1379] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.60-2.77 (3H, m), 3.94
(1H, m), 4.42 (1H, d, J=13.4 Hz), 5.15 (1H, d, J=13.4 Hz), 5.49
(1H, s), 5.55 (1H, d, J=7.2 Hz), 7.07 (1H, t, J=7.3 Hz), 7.12-7.49
(13H, m), 7.73 (2H, d, J=7.2 Hz), 10.01 (1H, s).
[1380] MS: m/z=495 [M+H].sup.+.
Reference Example 132
##STR00315##
[1382] According to Reference example 130, compound 132 was
synthesized by the same procedure.
[1383] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.14 (3H, s), 3.65 (4H,
m), 4.34 (1H, d, J=13.6 Hz), 5.06 (1H, d, J=13.6 Hz), 5.42 (1H, s),
5.53 (1H, d, J=7.5 Hz), 7.42-7.58 (16H, m).
[1384] MS: m/z=509 [M+H].sup.+.
Reference Example 133
##STR00316##
[1386] According to Reference example 130, compound 133 was
synthesized by the same procedure.
[1387] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.08-1.55 (8H, m), 2.33
(1H, m), 2.68 (1H, m), 4.45 (1H, d, J=13.6 Hz), 5.05 (1H, d, J=13.6
Hz), 5.50 (2H, brs), 7.46-7.68 (11H, m).
[1388] MS: m/z=487 [M+H].sup.+.
Reference Example 134
##STR00317##
[1390] According to Reference example 130, compound 134 was
synthesized by the same procedure.
[1391] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.34-2.40 (1H, m),
2.61-2.77 (1H, m), 3.51-3.69 (10H, m), 4.44 (1H, d, J=13.4 Hz),
5.03-5.11 (1H, d, J=13.4 Hz), 5.51 (2H, s), 7.18-7.52 (9H, m),
7.69-7.75 (2H, m).
Reference Example 135
##STR00318##
[1392] First Step
[1393] Compound 95B (1.50 g, 5.32 mmol) and tert-butyl
2-aminoethyl(methyl)carbamate (1.86 g, 10.7 mmol) were added to
pyridine (20 ml), 1-hydroxybenzotriazole (815 mg, 5.32 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.04
g, 10.7 mmol) were sequentially added, and the mixture was stirred
at room temperature for 2 hours. The reaction solution was poured
into 1N hydrochloric acid, and the mixture was extracted with ethyl
acetate, and dried with sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting crude product was
purified by amino column chromatography (chloroform-methanol, 95:5,
v/v) and, subsequently, silica gel column chromatography
(chloroform-methanol, 95:5, v/v) to obtain 1.63 g of compound 135A
as a colorless gummy substance.
[1394] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (9H, s), 2.82 (3H,
s), 3.28 (4H, m), 5.59 (2H, s), 6.57 (1H, d, J=6.0 Hz), 7.46 (6H,
m), 8.46 (1H, m), 9.68 (1H, brs).
Second Step
[1395] Compound 135A (1.05 g, 2.62 mmol) was dissolved in DMF (15
ml), potassium carbonate (1.81 g, 13.1 mmol) was added, and the
mixture was stirred at room temperature for 30 minutes.
O-(2,4-dinitrophenyl)hydroxylamine (1.04 g, 5.23 mmol) was added,
and the mixture was stirred at room temperature for 18 hours. To
the reaction solution was added chloroform, the precipitated yellow
precipitate was removed by filtration, and the filtrate was
concentrated under reduced pressure. The resulting crude product
was purified by amino column chromatography (chloroform-methanol,
97:3.fwdarw.95:5, v/v) to obtain 887 mg of compound 135B as a pale
yellow solid.
[1396] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (9H, s), 2.84 (3H,
s), 3.38 (4H, m), 5.33 (2H, s), 5.68 (1H, brs), 5.80 (1H, brs),
6.35 (1H, d, J=7.6 Hz), 6.74 (1H, brs), 7.39 (5H, brm), 7.52 (1H,
t, J=9.5 Hz).
Third Step
[1397] Compound 135B (880 mg, 2.11 mmol) and paraformaldehyde (190
mg, 6.34 mmol) were added to ethanol (18 ml), and the mixture was
stirred at 140.degree. C. for 30 minutes under microwave
irradiation. The reaction solution was concentrated under reduced
pressure, and the resulting crude product was purified by silica
gel column chromatography (chloroform-methanol,
97:3.fwdarw.95:5.fwdarw.90:10 v/v) and, subsequently, amino column
chromatography (chloroform-methanol, 97:3, v/v) to obtain 721 mg of
compound 135C as a colorless solid.
[1398] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (9H, s), 2.95 (3H,
s), 4.38 (2H, brs), 5.33 (2H, brs), 6.36 (1H, d, J=7.6 Hz), 6.85
(1H, t, J=7.4 Hz), 7.33 (4H, m), 7.55 (2H, m).
[1399] MS: m/z=429 [M+H].sup.+.
Fourth Step
[1400] Compound 135C (720 mg, 1.68 mmol) was dissolved in DMF (3.5
ml), cesium carbonate (1.64 g, 5.04 mmol) and
(bromomethylene)dibenzene (623 mg, 2.52 mmol) were added at
0.degree. C., and the mixture was stirred at room temperature for
18 hours. The reaction solution was poured into water, the mixture
was extracted with ethyl acetate, and the organic layer was washed
with water, and dried with sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting crude
product was purified by silica gel column chromatography
(chloroform-methanol, 97:3.fwdarw.95:5 v/v) to obtain 732 mg of
compound 135D.
Fifth Step
[1401] To compound 135D (727 mg, 1.22 mmol) was added 4N HCl (ethyl
acetate solution, 10 ml). After the mixture was stirred at room
temperature for 1 hour, the solvent was distilled off under reduced
pressure. Saturated sodium bicarbonate water was added, the mixture
was extracted with chloroform, and the extract was dried with
sodium sulfate. The solvent was distilled off under reduced
pressure, to the resulting crude product were added methylene
chloride-ethyl ether, and the precipitated solid was filtered to
obtain 575 mg of compound 135E as a colorless solid.
Sixth Step
[1402] To compound 135E (50 mg, 0.10 mmol) was added
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 1.5 hours. After concentration under reduced
pressure, pH was adjusted to 6 with sodium bicarbonate water and an
aqueous ammonium chloride solution, and the mixture was extracted
with chloroform, and dried with sodium sulfate. After the solvent
was distilled off under reduced pressure, methylene chloride-ethyl
ether were added, and the precipitated solid was filtered to obtain
15 mg of compound 135 as a colorless solid.
[1403] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.40 (3H, s), 2.80 (1H,
s), 3.12 (3H, m), 3.87 (1H, m), 4.37 (1H, d, J=13.6 Hz), 5.10 (1H,
d, J=13.4 Hz), 5.52 (1H, s), 5.53 (1H, d, J=5.5 Hz), 7.15-7.70
(11H, m).
[1404] MS: m/z=405 [M+H].sup.+.
Reference Example 136
##STR00319##
[1405] First Step
[1406] Compound 135E (50 mg, 0.10 mmol) was dissolved in methylene
chloride (1 ml), triethylamine (0.042 ml, 0.30 mmol) and acetyl
chloride (0.011 ml, 0.15 mmol) were added, and the mixture was
stirred at room temperature for 1 hour. The solvent was distilled
off under reduced pressure, and the resulting crude product was
purified by silica gel column chromatography (chloroform-methanol,
97:3.fwdarw.95:5, v/v) and, subsequently, amino column
chromatography (chloroform-methanol, 97:3, v/v) to obtain 72 mg of
compound 136A as a colorless solid.
Second Step
[1407] To compound 136A obtained in the first step was added
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 1.5 hours. After concentration under reduced
pressure, pH was adjusted to 6 with sodium bicarbonate water and an
aqueous ammonium chloride solution, and the mixture was extracted
with chloroform, and dried with sodium sulfate. After the solvent
was distilled off under reduced pressure, methylene chloride-ethyl
ether were added, and the precipitated solid was filtered to obtain
23 mg of compound 136 as a colorless solid.
[1408] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.89 (2H, s), 1.92 (1H,
s), 2.73 (1H, s), 2.95 (2H, s), 3.00-3.06 (1H, m), 3.43 (2H, m),
3.80 (1H, m), 4.34 (0.7H, d, J=13.3 Hz), 4.45 (0.3H, d, J=13.1 Hz),
5.11 (1H, m), 5.49 (2H, m), 7.20-7.73 (11H, m).
Reference Example 137
##STR00320##
[1410] According to Reference example 136, compound 137 was
synthesized by the same procedure.
[1411] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.95 (3H, s), 3.13-4.07
(4H, m), 4.46 (1H, d, J=13.2 Hz), 5.16 (1H, d, J=13.0 Hz), 5.51
(1H, d, J=7.3 Hz), 5.62 (1H, s), 7.17-7.78 (16H, m).
[1412] MS: m/z=509 [M+H].sup.+.
Reference Example 138
##STR00321##
[1414] According to Reference example 136, compound 138 was
synthesized by the same procedure.
[1415] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.62 (3H, s), 3.03-3.22
(4H, m), 3.72 (2H, d, J=13.3 Hz), 4.39 (1H, d, J=13.3 Hz), 5.08
(1H, d, J=13.3 Hz), 5.53 (1H, d, J=7.8 Hz), 5.55 (1H, s), 7.19-7.79
(16H, m).
[1416] MS: m/z=545 [M+H].sup.+.
Reference Example 139
##STR00322##
[1418] According to Reference example 136, compound 139 was
synthesized by the same procedure.
[1419] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.72 (3H, s), 2.88 (3H,
s), 3.12-3.24 (3H, m), 3.75-3.80 (1H, m), 4.37 (1H, d, J=13.0 Hz),
5.10 (1H, d, J=13.4 Hz), 5.51 (1H, d, J=7.6 Hz), 5.54 (1H, s),
7.19-7.46 (19H, m), 7.72 (2H, d, J=7.0 Hz).
[1420] MS: m/z=483 [M+H].sup.+.
Reference Example 140
##STR00323##
[1422] According to Reference example 136, compound 140 was
synthesized by the same procedure.
[1423] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.88 (3H, s), 2.98-3.12
(3H, m), 3.77 (1H, m), 4.31 (1H, d, J=13.3 Hz), 5.13 (1H, d, J=13.3
Hz), 5.51 (1H, s), 5.52 (1H, d, J=7.6 Hz), 7.13-7.46 (9H, m), 7.71
(2H, d, J=7.2 Hz).
[1424] MS: m/z=469 [M+H].sup.+.
Reference Example 141
##STR00324##
[1426] According to Reference example 136, compound 141 was
synthesized by the same procedure.
[1427] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.07 (9H, s), 2.84 (1H,
m), 3.19 (2H, d, J=3.9 Hz), 3.96 (1H, d, m), 4.28 (1H, d, J=13.1
Hz), 5.21 (1H, d, J=13.1 Hz), 5.52 (1H, s), 5.56 (1H, t, J=4.2 Hz),
7.25-7.59 (10H, m), 7.75 (2H, d, J=7.7 Hz).
[1428] MS: m/z=475 [M+H].sup.+.
Reference Example 142
##STR00325##
[1430] According to Reference example 136, compound 142 was
synthesized by the same procedure.
[1431] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.10 (6H, m), 2.98 (3H,
m), 3.78 (1H, m), 4.27 (1H, d, J=13.6 Hz), 4.68 (1H, m), 5.11 (1H,
d, J=12.8 Hz), 5.51 (2H, m), 7.07-7.46 (10OH, m), 7.70 (2H, d,
J=7.2 Hz).
[1432] MS: m/z=477 [M+H].sup.+.
Reference Example 143
##STR00326##
[1434] According to Reference example 136, compound 143 was
synthesized by the same procedure.
[1435] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.89 (3H, m), 3.62 (1H,
m), 4.17 (1H, d, J=13.1 Hz), 4.99 (1H, d, J=13.1 Hz), 5.45 (1H, s),
5.51 (1H, d, J=7.8 Hz), 7.18-7.77 (17H, m).
[1436] MS: m/z=531 [M+H].sup.+.
Reference Example 144
##STR00327##
[1437] First Step
[1438] To compound 144A synthesized according to the first to fifth
steps of Reference example 135 were added formic acid and formalin,
and the mixture was stirred at 80.degree. C. for 1.5 hours. The
solvent was distilled off under reduced pressure, saturated sodium
bicarbonate water was added, then the mixture was extracted with
chloroform, and the extract was dried with sodium sulfate. The
solvent was concentrated under reduced pressure, and the resulting
crude product was purified by silica gel column chromatography
(chloroform-methanol, 95:5.fwdarw.92:8, v/v) to obtain 26 mg of
compound 144B.
[1439] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.06 (6H, s), 2.18-2.26
(1H, m), 2.36-2.45 (1H, m), 2.89-2.98 (1H, m), 3.91 (1H, dt,
J=14.1, 5.9 Hz), 4.43 (1H, d, J=13.6 Hz), 4.82 (1H, d, J=13.4 Hz),
5.20 (1H, s), 5.41 (1H, d, J=10.8 Hz), 5.46 (1H, d, J=10.7 Hz),
5.80 (1H, d, J=7.8 Hz), 6.69 (1H, d, J=7.8 Hz), 7.05-7.64 (15H,
m).
Second Step
[1440] To compound 144B obtained in the first step was added
trifluoroacetic acid (1 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 6 with sodium bicarbonate water and an aqueous
ammonium chloride solution, and the mixture was extracted with
chloroform, and dried with sodium sulfate. After the solvent was
distilled off under reduced pressure, methylene chloride-ethyl
ether were added, and the precipitated solid was filtered to obtain
13 mg of compound 144 as a colorless solid.
[1441] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.17 (6H, s), 2.38-2.46
(3H, m), 3.59 (1H, m), 4.41 (1H, d, J=13.1 Hz), 5.09 (1H, d, J=13.3
Hz), 5.50 (1H, d, J=6.4 Hz), 5.51 (1H, s), 7.19-7.47 (9H, m), 7.66
(2H, d, J=7.3 Hz).
[1442] MS: m/z=419 [M+H].sup.+.
Reference Example 145
##STR00328##
[1443] First Step
[1444] To a dichloromethane (5 ml) solution of compound 95E (300
mg, 0.664 mmol) was added NBS (130 mg, 0.731 mmol) under
ice-cooling, temperature was raised to room temperature and,
thereafter, the mixture was refluxed for 1 hour. After the solvent
was distilled off, the resulting residue was purified by silica gel
chromatography. The materials were eluted firstly with
n-hexane-ethyl acetate (1:1, v/v) and, then, with ethyl acetate.
Concentration of an objective fraction afforded 326.7 mg (yield
93%) of compound 145A as a solid.
[1445] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.93 (3H, s), 4.27 (1H, d,
J=13.5 Hz), 4.82 (1H, d, J=13.5 Hz), 5.13 (1H, s), 5.41 (2H, s),
5.41-7.12 (2H, m), 7.15 (1H, s), 7.17-7.28 (3H, m), 7.31-7.47 (6H,
m), 7.52 (2H, d, J=6.6 Hz), 7.63-7.67 (2H, m).
Second Step
[1446] To a DMF (3 ml) solution of compound 145A (100 mg, 0.189
mmol) were added a solution of potassium carbonate (78.4 mg, 0.567
mmol) in water (0.5 ml),
4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (47.6
mg, 0.284 mmol) and tetakistriphenylphosphinepalladium (21.8 mg,
0.0189 mmol), and the mixture was heated to stir at 80.degree. C.
for 4 hours. After the reaction solution was cooled to room
temperature, water was added, and the mixture was extracted with
ethyl acetate three times. The extract was washed with water three
times, and dried with sodium sulfate and, thereafter, the resulting
oil was purified by silica gel chromatography. Elution with only
ethyl acetate, and concentration of an objective fraction afforded
42.0 mg (yield 45%) of compound 145B as an oil.
[1447] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.73 (3H, s), 2.92 (3H,
s), 4.29 (1H, d, J=13.5 Hz), 4.83 (1H, d, J=13.5 Hz), 4.96-4.97
(1H, m), 5.15 (1H, s), 5.21-5.21 (1H, m), 5.37 (1H, d, J=10.8 Hz),
5.40 (1H, d, J=10.8 Hz), 6.82 (1H, s), 7.15-7.21 (5H, m), 7.27-7.47
(6H, m), 7.54 (2H, d, J=6.9 Hz), 7.64-7.69 (2H, m).
Third Step
[1448] To a THF (2 ml) solution of compound 145B (40 mg, 0.081
mmol) was added 10% Pd--C (8 mg), and the mixture was subjected to
a catalytic reduction reaction under hydrogen stream. The catalyst
was removed by filtration, and the filtrate was concentrated. The
resulting residue was washed with ether to obtain 6.8 mg (yield
21%) of compound 145.
[1449] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.629 (3H, d, J=6.9 Hz),
0.900 (3H, d, J=6.9 Hz), 2.87-3.00 (1H, m), 2.94 (3H, s), 4.37 (1H,
d, J=13.2 Hz), 4.93 (1H, d, J=13.2 Hz), 5.21 (1H, s), 6.69 (1H, s),
7.21 (5H, s), 7.35-7.47 (3H, m), 7.57 (2H, d, J=7.5 Hz).
Reference Example 146
##STR00329##
[1451] According to Reference example 145, compound 146 was
synthesized by the same procedure.
[1452] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.738 (3H, t, J=7.2 Hz),
1.05-1.18 (2H, m), 2.01-2.18 (2H, m), 2.94 (3H, s), 4.35 (1H. d,
J=13.2 Hz), 4.95 (1H, d, J=13.2 Hz), 5.22 (1H, s), 6.71 (1H, s),
7.20 (5H, s), 7.35-7.47 (3H, m), 7.55 (2H, d, J=6.9 Hz).
Reference Example 147
##STR00330##
[1453] First Step
[1454] Compound 145A (60 mg, 0.113 mg) was dissolved in
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 1 hour. The solvent was distilled off, the residue
was dissolved in dichloromethane (2 ml), and the solution was
neutralized with saturated sodium bicarbonate water. The resulting
solution was made acidic with an aqueous citric acid solution, and
the organic layer was separated. The aqueous layer was extracted
with dichloromethane once, and the combined organic layers were
washed with water, and dried with sodium sulfate. After the solvent
was distilled off, the resulting solid was washed with diisopropyl
ether to obtain 30 mg (yield 60%) of compound 147.
[1455] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.97 (3H, s), 4.36 (1H, d,
J=13.2 Hz), 5.01 (1H, d, J=13.2 Hz), 5.21 (1H, s), 7.14 (1H, s),
7.17-7.25 (5H, m), 7.36-7.48 (3H, m), 7.54 (2H, d, J=7.2 Hz).
Reference Example 148
##STR00331##
[1457] Compound 145B (41 mg, 0.083 mg) was dissolved in
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 1 hour. The solvent was distilled off, the residue
was dissolved in dichloromethane (2 ml), and the solution was
neutralized with saturated sodium bicarbonate water. The resulting
solution was made acidic with an aqueous citric acid solution, and
the organic layer was separated. The aqueous layer was extracted
with dichloromethane once, and the combined organic layers were
washed with water, and dried with sodium sulfate. After the solvent
was distilled off, the resulting solid was washed with diisopropyl
ether to obtain 12 mg (yield 36%) of compound 148.
[1458] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.70 (3H, s), 2.95 (3H,
s), 4.36 (1H, d, J=12.9 Hz), 4.95 (1H, d, J=12.9 Hz), 4.96-4.98
(1H, m), 5.23 (1H, s), 5.32-5.33 (1H, m), 6.86 (1H, s), 7.21 (5H,
s), 7.35-7.48 (3H, m), 7.56 (2H, d, J=7.2 Hz).
Reference Example 149
##STR00332##
[1460] To a THF (2 ml) solution of compound 145A (100 mg, 0.189 mg)
were added a 2N methylzinc chloride THF solution (0.377 ml, 0.754
mmol) and tetrakistriphenylphosphinepalladium (10.9 mg, 0.0945
mmol) at room temperature, and the mixture was heated to stir at
60.degree. C. for 4 hours. After the reaction solution was cooled
to room temperature, water was added, and the mixture was extracted
with chloroform three times. After the extract was dried with
sodium sulfate, the solvent was distilled off, and the resulting
oil was purified by a MS trigger reverse layer column to obtain 9.6
mg (yield 14%) of compound 149.
[1461] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.63 (3H, s), 2.95 (3H,
s), 4.34 (1H, d, J=12.9 Hz), 4.68 (1H, d, J=12.9 Hz), 5.21 (1H, s),
6.70 (1H, s), 7.18 (5H, s), 7.37-7.47 (3H, m), 7.54 (2H, d, J=6.9
Hz).
Reference Example 150
##STR00333##
[1462] First Step
[1463] Reference compound 150A (465 mg, 0.801 mmol) synthesized
according to the first to fourth step of Reference example 135 was
dissolved in a 4N hydrochloric acid dioxane solution (5 ml), and
the mixture was stirred at room temperature for 2 hours. The
reaction solution was neutralized with saturated sodium bicarbonate
water, and was extracted with dichloromethane three times. After
the extract was dried with sodium sulfate, the solvent was
distilled off, and 100 mg of the resulting oil was dissolved in
dichloromethane (2 ml). To the dichloromethane solution were added
triethylamine (63.2 mg, 0.624 mmol) and benzoyl chloride (31.9 mg,
0.312 mmol) under ice-cooling, and the mixture was stirred at room
temperature for 1 hour. To the reaction solution was added water,
and the mixture was extracted with dichloromethane three times.
After the extract was dried with sodium sulfate, the solvent was
distilled off, and the resulting residue was washed with diethyl
ether to obtain 68 mg (yield 56%) of compound 150B.
[1464] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.05-3.12 (1H, m),
3.38-3.45 (1H, m), 3.64-3.70 (1H, m), 3.93-3.99 (1H, m), 4.22 (1H,
d, J=13.2 Hz), 5.04 (1H, s), 5.07 (1H, d, J=13.2 Hz), 5.22 (1H, d,
J=10.2 Hz), 5.31 (1H, d, J=10.2 Hz), 5.70 (1H, d, J=7.8 Hz), 6.55
(1H, d, J=7.8 Hz), 6.98 (2H, d, J=6.6 Hz), 7.08-7.19 (4H, m),
7.29-7.46 (5H, m), 7.49-7.53 (2H, m), 7.87 (2H, d, J=7.2 Hz), 8.06
(1H, brs).
Second Step
[1465] Compound 150B (30 mg, 0.051 mg) was dissolved in
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 1 hour. The solvent was distilled off, the residue
was dissolved in dichloromethane (2 ml), and the solution was
neutralized with saturated sodium bicarbonate water. The resulting
solution was made acidic with an aqueous citric acid solution, and
the organic layer was separated. The aqueous layer was extracted
with dichloromethane once, and the combined organic layers were
washed with water, and dried with sodium sulfate. After the solvent
was distilled off, the resulting solid was washed with diisopropyl
ether to obtain 15 mg (yield 59%) of compound 150.
[1466] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.91-2.98 (1H, m),
3.54-3.66 (1H, m), 3.76-3.84 (1H, m), 4.13-4.18 (1H, m), 4.28 (1H,
d, J=12.9 Hz), 5.11 (1H, s), 5.43 (1H, d, J=12.9 Hz), 5.45 (1H, d,
J=7.5 Hz), 6.68 (1H, d, J=7.5 Hz), 7.10-7.18 (4H, m), 7.35-7.47
(8H, m), 7.89 (2H, d, J=7.2 Hz), 8.41 (1H, s).
Reference Example 151
##STR00334##
[1468] According to Reference example 150, compound 151 was
synthesized by the same procedure.
[1469] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.02 (3H, s), 2.69 (1H,
brt, J=10.8 Hz), 3.40-3.49 (1H, m), 3.06-3.74 (1H, m), 4.12-4.22
(1H, m), 4.20 (1H, d, J=12.9 Hz), 5.08 (1H, s), 5.47 (1H, d, J=7.8
Hz), 5.50 (1H, d, J=12.9 Hz), 6.67 (1H, d, J=7.8 Hz), 7.12-7.21
(5H, m), 7.28-7.46 (5H, m), 8.31 (1H, brs).
Reference Example 152
##STR00335##
[1470] First Step
[1471] Compound 150A (50 mg, 0.801 mmol) was dissolved in a 4N
hydrochloric acid dioxane solution (5 ml), and the mixture was
stirred at room temperature for 2 hours. The reaction solution was
neutralized with saturated sodium bicarbonate water, and was
extracted with dichloromethane three times. After the extract was
dried with sodium sulfate, the solvent was distilled off, and 50 mg
of the resulting oil was dissolved in methanol (2 ml). To the
methanol solution was added 10% Pd--C (10 mg), and the mixture was
subjected to a catalytic reduction reaction under hydrogen stream.
The catalyst was removed by filtration, and the filtrate was
concentrated. To the resulting residue was added diisopropyl ether,
and the precipitated solid was filtered to obtain 10 mg (yield 25%)
of compound 152.
[1472] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.74-2.78 (2H, m),
3.00-3.07 (1H, m), 3.78-3.85 (1H, m), 4.34 (1H, d, J=13.5 Hz), 5.13
(1H, d, J=13.5 Hz), 5.48-5.54 (1H, m), 5.10 (1H, s), 7.20-7.47 (9H,
m), 7.63-7.71 (2H, m).
Reference Example 153
##STR00336##
[1473] First Step
[1474] To a THF (3 ml) solution of compound 150A (30 mg, 0.052
mmol) was added 10% Pd--C (10 mg), and the mixture was subjected to
a catalytic reduction reaction under hydrogen stream. The catalyst
was removed by filtration, and the filtrate was concentrated. To
the resulting residue was added diisopropyl ether, and the
precipitated solid was filtered to obtain 20 mg (yield 79%) of
compound 153.
[1475] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.34 (9H, s), 2.84-2.91
(1H, m), 3.18-3.25 (2H, m), 4.03-4.11 (1H, m), 4.35 (1H, d, J-=13.2
Hz), 5.20 (1H, s), 5.24 (1H, d, J=13.2 Hz), 5.49 (1H, brs), 5.70
(1H, d, J=7.8 Hz), 6.73 (1H, d, J=7.8 Hz), 7.16-7.20 (5H, m),
7.32-7.46 (3H, m), 7.53 (2H, d, J=7.2 Hz).
Reference Example 154
##STR00337##
[1476] First Step
[1477] To a DMF (10 ml) solution of compound 154A (539 mg, 1.01
mmol) synthesized according to the synthesis method of Reference
example 65 were added triethylamine (615.7 mg, 6.08 mmol) and ethyl
chlorocarbonate (328.8 mg, 3.03 mmol) under ice-cooling, and the
mixture was stirred at room temperature for 10 minutes. To the
reaction solution were added O,N-dimethylhydroxylamine
hydrochloride (295.0 mg, 3.03 mmol) and DMAP (12.3 mg, 0.101 mmol),
the mixture was stirred at the same temperature for 2 hours, water
was added, and was extracted with ethyl acetate three times. After
the extract was washed with water three times, and dried with
sodium sulfate, the solvent was distilled off, and the resulting
oil was purified by silica gel chromatography. The materials were
eluted firstly with n-hexane-ethyl acetate (7:3, v/v) and, then,
with only ethyl acetate. Concentration of an objective fraction
afforded 445.4 mg (yield 76%) of compound 154B as an oil.
[1478] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.09 (3H, s), 3.52 (3H,
s), 3.94 (2H, s), 4.40 (1H, brs), 4.64 (2H, s), 4.96 (1H, brs),
5.15 (2H, s), 7.06-7.15 (4H, m), 7.21 (2H, t, J=8.7 Hz), 7.28-7.38
(3H, m), 7.43 (2H, dd, J=5.7 Hz, 8.4 Hz), 7.52-7.54 (2H, m), 7.66
(1H, s).
Second Step
[1479] A THF (5 ml) solution of compound 154B (250 mg, 0.435 mmol)
was cooled to -78.degree. C., a methylmagnesium bromide 0.97M THF
solution (0.673 ml, 0.653 mmol) was added, and temperature was
raised to -20.degree. C. over 2 hours. To the reaction solution was
added 1N hydrochloric acid, and the mixture was extracted with
ethyl acetate three times. After the extract was dried with sodium
sulfate, the solvent was distilled off, and the resulting oil was
purified by silica gel chromatography. The materials were eluted
firstly with only chloroform and, then, with chloroform-methanol
(7:3, v/v). Concentration of an objective fraction afforded 117.0
mg (yield 51%) of compound 154C as an oil.
[1480] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.68 (3H, s), 3.80 (2H,
brs), 4.29 (2H, brs), 4.71 (2H, brs), 5.45 (2H, brs), 6.83 (2H, m),
6.92-6.98 (2H, m), 7.03-7.10 (2H, m), 7.28-7.39 (5H, m), 7.90 (1H,
s).
Third Step
[1481] To a dichloromethane (2 ml) solution of compound 154C (117
mg, 0.221 mmol) was added mCPBA (52.7 mg, 0.332 mmol) under
ice-cooling, and the mixture was stirred at room temperature for 2
hours. To the reaction solution was added an aqueous sodium
thiosulfate solution, and the mixture was extracted with ethyl
acetate three times. After the extract was washed with saturated
sodium bicarbonate water two times, and dried with sodium sulfate,
the solvent was distilled off, the resulting oil was dissolved in
ethanol (2 ml), and the solution was refluxed for 1 hour. After the
solvent was distilled off, the precipitated solid was washed with
diisopropyl ether to obtain 54 mg (yield 49%) of compound 154D.
[1482] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.74 (1H, brs), 3.85 (1H,
brs), 4.20 (2H, brs), 4.61 (1H, brs), 4.93 (1H, brs), 5.41 (2H,
brs), 6.79-6.86 (2H, m), 6.91-6.96 (2H, m), 7.02-7.09 (2H, m),
7.15-7.16 (1H, m), 7.26-7.34 (5H, m), 7.56-7.65 (2H, m).
Fourth Step
[1483] To a THF (3 ml) solution of compound 154D (54 mg, 0.107
mmol) was added 10% Pd--C (20 mg), and the mixture was subjected to
a catalytic reduction reaction under hydrogen stream. The catalyst
was removed by filtration, and the filtrate was concentrated. To
the resulting residue was added diisopropyl ether, and the
precipitated solid was filtered to obtain 21 mg (yield 47%) of
compound 154.
[1484] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.90 (2H, brs), 3.95
(2H, s), 4.66 (2H, brs), 7.07-7.12 (4H, m), 7.22 (2H, t, J=8.7 Hz),
7.29 (1H, s), 7.43-7.47 (2H, m).
Reference Example 155
##STR00338## ##STR00339##
[1485] First Step
[1486] To a toluene (150 mL) solution of compound 155A (WO
2006/066414, 15.0 g, 38.4 mmol) were sequentially added
N,N-diisopropylethylamine (16.1 mL, 92.0 mmol), 1-methylimidazole
(3.70 mL, 46.4 mmol) and 2-methoxyethylamine (4.05 mL, 46.4 mmol)
under ice-cooling and, thereafter, diphenyl chlorophosphate (9.60
mL, 46.1 mmol) was further added dropwise over 10 minutes. After
the reaction solution was stirred for 20 minutes under ice-cooling,
acetonitrile (50 mL) was added, and the mixture was further stirred
for 2 hours. To the reaction solution was added an aqueous acetic
acid solution (10%, 100 mL) under ice-cooling and, thereafter, the
mixture was extracted with ethyl acetate. The extract was
sequentially washed with water (100 mL), saturated sodium
bicarbonate water (150 mL) and an aqueous saturated sodium chloride
solution (100 mL) and, thereafter, dried with sodium sulfate. The
solvent was distilled off under reduced pressure, and the resulting
residue was purified by silica gel column chromatography (ethyl
acetate/n-hexane=25%-50%) to obtain compound 155B (7.86 g, 46%) as
a colorless oil.
[1487] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.10 (6H, s), 0.93 (9H,
s), 3.29 (3H, s), 3.39 (2H, m), 3.47 (2H, m), 4.56 (2H, d, J=1.2
Hz), 5.41 (2H, s), 6.60 (1H, s), 7.35-7.42 (5H, m), 8.11 (1H,
brt).
Second Step
[1488] To an ethanol (80 mL) solution of compound 155B (7.70 g,
17.2 mmol) was added aqueous ammonia (40 mL) at room temperature,
and the mixture was stirred for 18 hours. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel column chromatography (ethyl
acetate/n-hexane=75%-100%) to obtain compound 155C (7.15 g, 93%) as
a colorless oil.
[1489] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.14 (6H, s), 0.97 (9H,
s), 3.28 (3H, s), 3.38 (2H, m), 3.49 (2H, m), 4.64 (2H, s), 5.53
(2H, s), 6.31 (1H, s), 7.34-7.49 (5H, m), 8.61 (1H, brs), 9.94 (1H,
brs).
Third Step
[1490] To a DMF (125 mL) solution of compound 155C (7.15 g, 16.0
mmol) and potassium carbonate (6.64 g, 48.0 mmol) was added
O-(2,4-dinitrophenyl)hydroxylamine (7.97 g, 40.0 mmol) at room
temperature, and the mixture was stirred for 2 days. To the
reaction solution was added water (250 mL) under ice-cooling and,
thereafter, the mixture was extracted with ethyl acetate (300
mL.times.2). After the extract was sequentially washed with water
(300 mL), saturated sodium bicarbonate water (300 mL.times.2) and
an aqueous saturated sodium chloride solution (150 mL), the mixture
was dried with sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (methanol/chloroform=0%-10%) to obtain
compound 155D (6.47 g, 88%) as a pale yellow solid.
[1491] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.11 (6H, s), 0.94 (9H,
s), 3.26 (3H, s), 3.35 (4H, m), 4.66 (2H, s), 5.16 (2H, s), 5.24
(2H, s), 6.43 (1H, s), 7.31-7.40 (5H, m), 7.59 (1H, brs).
Fourth Step
[1492] To a toluene (100 mL) solution of compound 155D (6.47 g,
14.0 mmol) and acetic acid (0.080 mL, 1.4 mmol) was added
paraformaldehyde (0.422 g, 14.1 mmol) at room temperature, and the
mixture was stirred at 80.degree. C. for 2 hours. The solvent was
distilled off under reduced pressure, and the resulting crude
product of compound 155E was utilized in a next step without
purification.
Fifth Step
[1493] To a DMF (100 mL) solution of the crude product of compound
155E obtained in the fourth step was added cesium carbonate (22.7
g, 69.8 mmol) under ice-cooling, and the mixture was stirred for 1
hour. Under ice-cooling, bromodiphenylmethane (5.20 g, 21.0 mmol)
was added, and the mixture was stirred at room temperature for 19
hours. To the reaction solution was added water (200 mL) under
ice-cooling and, thereafter, the mixture was extracted with ethyl
acetate (200 mL.times.3). The extract was sequentially washed with
water (200 mL.times.2) and an aqueous saturated sodium chloride
solution (100 mL), and dried with sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting crude
product of compound 155F was utilized in a next step without
purification.
[1494] MS: m/z=640 [M+H].sup.+.
Sixth Step
[1495] To a methanol (100 mL) solution of the crude product of
compound 155F obtained in the fifth step was added hydrogen
chloride (4N ethyl acetate solution, 40 mL) at room temperature,
and the mixture was stirred for 2.5 hours. To the reaction solution
was added an aqueous sodium hydroxide solution (2N, 75 mL) to
perform neutralization (pH=6) under ice-cooling, and the mixture
was extracted with chloroform (200 mL.times.3). The extract was
dried with sodium sulfate, the solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (methanol/chloroform=5%-40%) to obtain
compound 155G (5.18 g, 3 step 70%) as an orange oil.
[1496] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.16 (3H, s), 3.18-3.43
(3H, m), 3.60-3.74 (2H, m), 4.06 (1H, d, J=13.5 Hz), 4.19 (1H,
brs), 4.58 (1H, d, J=14.7 Hz), 5.00 (1H, d, J=13.5 Hz), 5.24 (1H,
s), 5.27 (2H, s), 5.96 (1H, s), 6.78 (2H, m), 6.98-7.10 (3H, m),
7.30-7.42 (8H, m), 7.72 (2H, m).
Seventh Step
[1497] To a THF (2 mL) solution of compound 155G (100 mg, 0.190
mmol), (bromomethyl)cyclopropane (0.110 mL, 1.12 mmol) and sodium
iodide (5.0 mg, 0.033 mmol) was added potassium tert-butoxide (78.0
mg, 0.695 mmol) at room temperature, the mixture was stirred at
room temperature for 22 hours and, thereafter, the mixture was
stirred at 100.degree. C. for 10 minutes under microwave
irradiation. To the reaction solution were added water and
hydrochloric acid (2N) (pH=1), the mixture was extracted with
chloroform, and the extract was dried with sodium sulfate. The
solvent was distilled off under reduced pressure, and the resulting
crude product of compound 155H was utilized in a next step without
purification.
[1498] MS: m/z=580 [M+H].sup.+.
Eighth Step
[1499] To a DMF (2 mL) solution of the crude product of compound
155H obtained in the seventh step was added lithium chloride (35.0
mg, 0.826 mmol) at room temperature, and the mixture was stirred at
150.degree. C. for 15 minutes under microwave irradiation. The
reaction solution was purified by preparative LCMS to obtain
compound 155 (4.3 mg, 2 step 5%) as a white solid.
[1500] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.16 (2H, m), 0.52 (2H,
m), 0.98 (1H, m), 3.08 (3H, m), 3.20 (3H, s), 3.46 (2H, m), 3.68
(1H, dd, J=0.6, 14.1 Hz), 3.90 (1H, m), 4.52 (1H, d, J=13.2 Hz),
4.58 (1H, d, J=14.1 Hz), 4.93 (1H, d, J=13.2 Hz), 5.38 (1H, s),
6.01 (1H, s), 6.98 (2H, m), 7.11-7.48 (8H, m).
[1501] MS: m/z=490 [M+H].sup.+.
Reference Example 156
##STR00340##
[1503] According to Reference example 155, compound 156 was
synthesized by the same procedure.
[1504] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.88 (3H, t, J=7.4 Hz),
1.51 (2H, m), 3.15-3.23 (6H, m), 3.46 (2H, m), 3.69 (1H, dd, J=0.6,
14.1 Hz), 3.88 (1H, m), 4.54 (2H, d, J=14.1 Hz), 4.58 (1H, d,
J=14.1 Hz), 4.93 (1H, d, J=13.5 Hz), 5.39 (1H, s), 6.12 (1H, s),
6.97 (2H, m), 7.12-7.47 (8H, m).
[1505] MS: m/z=478 [M+H].sup.+.
Reference Example 157
##STR00341##
[1507] According to Reference example 155, compound 157 was
synthesized by the same procedure.
[1508] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.13-3.22 (1H, m), 3.18
(3H, s), 3.20 (3H, s), 3.41-3.51 (2H, m), 3.60 (1H, d, J=13.8 Hz),
3.89 (1H, ddd, J=3.3 Hz, 4.2 Hz, 14.4 Hz), 4.52 (1H, d, J=13.2 Hz),
4.53 (1H, d, J=13.8 Hz), 4.92 (1H, d, J=13.2 Hz), 5.38 (1H, s),
5.98 (1H, s), 6.98 (2H, d, J=8.4 Hz), 7.11-7.22 (3H, m), 7.36-7.48
(5H, m).
Reference Example 158
##STR00342##
[1509] First Step
[1510] To a THF (100 mL) solution of compound 155G (960 mg, 1.83
mmol) was added manganese dioxide (2.06 g, 92.0 mmol) at room
temperature, and the mixture was stirred for 2 days. After the
reaction solution was filtered, the filtrate was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel column chromatography (ethyl acetate/n-hexane=60%-100%)
to obtain compound 158A (554 mg, 58%) as a pale yellow foam.
[1511] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.96 (1H, m), 3.18 (3H,
s), 3.44 (2H, m), 4.18 (1H, m), 4.56 (1H, d, J=13.8 Hz), 4.98 (1H,
d, J=13.8 Hz), 5.28 (1H, s), 5.54 (1H, d, J=10.5 Hz), 5.64 (1H, d,
J=10.5 Hz), 6.35 (1H, s), 6.85 (2H, m), 7.03 (2H, m), 7.18 (1H, m),
7.26-7.48 (8H, m), 7.64 (2H, m), 10.10 (1H, s).
Second Step
[1512] To a methylene chloride (4 mL) solution of compound 158A
(83.0 mg, 0.159 mmol), pyrrolidine (0.0400 mL, 0.484 mmol) and
acetic acid (0.100 mL) was added sodium triacetoxyborohydride (136
mg, 0.642 mmol) at room temperature, and the mixture was stirred
for 28 hours. To the reaction solution was added water, the mixture
was extracted with chloroform, and the extract was dried with
sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting crude product of compound 158B was
utilized in a next step without purification.
[1513] MS: m/z=579 [M+H].sup.+.
Third Step
[1514] To a DMF (2 mL) solution of the crude product of compound
158B obtained in the second step was added lithium chloride (39.2
mg, 0.925 mmol) at room temperature, and the mixture was stirred at
150.degree. C. for 15 minutes under microwave irradiation. The
reaction solution was distilled off under reduced pressure, and the
resulting residue was purified by preparative LCMS to obtain
compound 158 (8.8 mg, 2 step 11%) as a yellow oil.
[1515] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.84 (4H, m), 2.70-2.85
(5H, m), 3.19 (3H, s), 3.20-3.47 (3H, m), 3.80 (1H, m), 4.25 (1H,
d, J=14.7 Hz), 4.57 (1H, d, J=13.5 Hz), 5.07 (1H, d, J=13.5 Hz),
5.39 (1H, s), 6.06 (1H, s), 6.97 (2H, m), 7.12-7.54 (8H, m), 8.29
(1H, s).
[1516] MS: m/z=489 [M+H].sup.+.
Reference Example 159
##STR00343##
[1517] First Step
[1518] To a methylene chloride (20 mL) solution of compound 155G
(950 mg, 1.81 mmol) and N,N-diisopropylethylamine (0.380 mL, 2.18
mmol) was added dropwise methanesulfonyl chloride (0.148 mL, 1.90
mmol) under ice-cooling, and the mixture was stirred for 90
minutes. To the reaction solution was added water (20 mL), the
mixture was extracted with chloroform (50 mL), and the extract was
dried with sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting crude product (1.06 g) of
compound 159A was utilized in a next step without purification.
[1519] MS: m/z=604 [M+H].sup.+.
Second Step
[1520] To the crude product (161 mg) of compound 159A obtained in
the first step was added dimethylamine (2M THF solution, 2.00 mL,
4.00 mmol) at room temperature, and the mixture was stirred for 3
days. To the reaction solution was added an aqueous saturated
sodium chloride solution (2 mL), the mixture was extracted with
ethyl acetate, and the extract was dried with sodium sulfate. The
solvent was distilled off under reduced pressure, and the resulting
crude product of compound 159B was utilized in a next step without
purification.
[1521] MS: m/z=553 [M+H].sup.+.
Third Step
[1522] To a DMF (2 mL) solution of the crude product of compound
159B obtained in the second step was added lithium chloride (56.0
mg, 1.32 mmol) at room temperature, and the mixture was stirred at
150.degree. C. for 30 minutes under microwave irradiation. The
reaction solution was distilled off under reduced pressure, and the
resulting residue was purified by preparative LCMS to obtain
compound 159 (33.6 mg, 3 step 27%) as a white solid.
[1523] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.37 (6H, s), 2.69 (1H, d,
J=14.4 Hz), 3.19 (3H, s), 3.30-3.46 (3H, m), 3.76 (1H, m), 4.00
(1H, d, J=14.4 Hz), 4.60 (1H, d, J=13.5 Hz), 5.20 (1H, d, J=13.5
Hz), 5.40 (1H, s), 6.01 (1H, s), 6.97 (2H, m), 7.11-7.42 (8H,
m).
[1524] MS: m/z=463 [M+H].sup.+.
Reference Example 160
##STR00344##
[1525] First Step
[1526] To a crude product (95.8 mg) of compound 159A was added
methylamine (2M THF solution, 2.00 mL, 4.00 mmol) at room
temperature, and the mixture was stirred for 3 days. The reaction
solution was filtered, the solvent was distilled off under reduced
pressure, and the resulting crude product of compound 160A was
utilized in a next step without purification.
[1527] MS: m/z=539 [M+H].sup.+.
Second Step
[1528] To an acetonitrile (3 mL) suspension of the crude product of
compound 160A and sodium iodide (100 mg, 0.667 mmol) was added
chlorotrimethylsilane (0.0850 mL, 0.665 mmol) at room temperature,
and the mixture was stirred for 5 hours. To the reaction solution
was added water (1 mL), the solvent was distilled off under reduced
pressure, and the resulting residue was purified by preparative
LCMS to obtain compound 160 (59.8 mg, 3 step 84%) as a white
solid.
[1529] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.75 (3H, s), 3.08 (1H, d,
J=13.5 Hz), 3.24 (3H, s), 3.30-3.40 (3H, m), 3.75 (1H, m), 4.32
(1H, d, J=13.8 Hz), 4.66 (1H, d, J=13.8 Hz), 5.33 (1H, s), 5.58
(1H, d, J=13.5 Hz), 6.40 (1H, s), 6.98 (2H, m), 7.12-7.25 (3H, m),
7.40-7.51 (2H, m), 7.60 (2H, m).
[1530] MS: m/z=449 [M+H].sup.+.
Reference Example 161
##STR00345##
[1531] First Step
[1532] After a DMF (2 mL) suspension of a crude product (156 mg) of
compound 159A, imidazole (19.5 mg, 0.286 mmol) and potassium
carbonate (37.7 mg, 0.273 mmol) was stirred at room temperature for
4 hours, sodium hydride (60%, 11.7 mg, 0.293 mmol) was added, and
the mixture was stirred for 3 days. To the reaction solution was
added an aqueous acetic acid solution (10%), the mixture was
extracted with chloroform, and the extract was dried with sodium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting crude product of compound 161A was utilized in a next
step without purification.
[1533] MS: m/z=576 [M+H].sup.+.
Second Step
[1534] To the crude product of compound 161A was added
trifluoroacetic acid (1 mL) at room temperature, and the mixture
was stirred for 18 hours and, thereafter, the mixture was stirred
at 60.degree. C. for 3 hours. The reaction solution was distilled
off under reduced pressure, and the resulting residue was purified
by preparative LCMS to obtain compound 161 (19.8 mg, 3 step 16%) as
a pale orange amorphous substance.
[1535] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.17-3.25 (1H, m), 3.21
(3H, s), 3.38-3.47 (2H, m), 3.82 (1H, m), 4.40 (1H, d, J=16.5 Hz),
4.54 (1H, d, J=13.5 Hz), 5.02 (1H, d, J=13.5 Hz), 5.09 (1H, s),
5.32 (1H, d, J=16.5 Hz), 5.40 (1H, s), 6.65 (1H, brs), 7.03 (2H,
m), 7.15-7.49 (8H, m), 8.08 (1H, brs).
[1536] MS: m/z=486 [M+H].sup.+.
Reference Example 162
##STR00346##
[1537] First Step
[1538] To a DMF (2 mL) solution of a crude product (192 mg) of
compound 159A was added sodium azide (24.2 mg, 0.372 mmol) at room
temperature, and the mixture was stirred at 60.degree. C. for 2
hours. The reaction solution was distilled off under reduced
pressure, and the resulting crude product of compound 162A was
utilized in a next step without purification.
[1539] MS: m/z=551 [M+H].sup.+.
Second Step
[1540] To a THF (4 mL) solution of the crude product of compound
162A were sequentially added water (0.200 mL) and
triphenylphosphine (83.0 mg, 0.316 mmol) at room temperature, and
the mixture was stirred at 60.degree. C. for 1 hour. The reaction
solution was distilled off under reduced pressure, and the
resulting residue was purified by preparative LCMS to obtain
compound 162B (110 mg, 3 step 66%) as a colorless oil.
[1541] MS: m/z=525 [M+H].sup.+.
Third Step
[1542] To an acetonitrile (1 mL) suspension of compound 162B (50.0
mg, 0.0950 mmol) and sodium iodide (56.2 mg, 0.375 mmol) was added
chlorotrimethylsilane (0.0490 mL, 0.381 mmol) at room temperature,
and the mixture was stirred for 6 hours. To the reaction solution
was added water (0.5 mL), the solvent was distilled off under
reduced pressure, and the resulting residue was purified by
preparative LCMS to obtain compound 162 (25.9 mg, 63%) as a pale
orange solid.
[1543] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.12 (1H, d, J=14.7 Hz),
3.27 (3H, s), 3.35-3.48 (3H, m), 3.81 (1H, m), 4.65 (1H, d, J=13.5
Hz), 5.31 (1H, s), 5.59 (1H, d, J=13.5 Hz), 6.40 (1H, s), 6.98 (2H,
m), 7.19 (3H, m), 7.40 (1H, m), 7.50 (2H, m), 7.62 (2H, m), 8.11
(1H, s).
[1544] MS: m/z=435 [M+H].sup.+.
Reference Example 163
##STR00347##
[1545] First Step
[1546] To an acetonitrile (3 mL) solution of compound 162B (50.0
mg, 0.0950 mmol) and N,N-diisopropylethylamine (0.0366 mL, 0.210
mmol) was added acetic anhydride (0.0100 mL, 0.106 mmol) at room
temperature, and the mixture was stirred for 6 hours. The reaction
solution was distilled off under reduced pressure, and the
resulting crude product of compound 163A was utilized in a next
step without purification.
[1547] MS: m/z=567 [M+H].sup.+.
Second Step
[1548] To an acetonitrile (5 mL) suspension of the crude product of
compound 163A and sodium iodide (59.2 mg, 0.395 mmol) was added
chlorotrimethylsilane (0.0487 mL, 0.381 mmol) at room temperature,
and the mixture was stirred for 16 hours. To the reaction solution
was added water (0.5 mL), the solvent was distilled off under
reduced pressure, and the resulting residue was purified by
preparative LCMS to obtain compound 163 (28.1 mg, 2 step 62%) as a
pale orange foam.
[1549] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.07 (3H, s), 3.24 (3H,
s), 3.27-3.52 (4H, m), 3.67 (1H, m), 4.54 (1H, d, J=13.5 Hz), 4.78
(1H, dd, J=6.5, 14.9 Hz), 5.17 (1H, d, J=13.5 Hz), 5.28 (1H, s),
5.61 (1H, s), 7.01 (2H, m), 7.01-7.58 (9H, m).
[1550] MS: m/z=477 [M+H].sup.+.
Reference Example 164
##STR00348##
[1551] First Step
[1552] Compound 155G (43.3 mg, 0.221 mmol) was dissolved in
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 1 hour. The solvent was distilled off, the residue
was dissolved in dichloromethane (2 ml), and the solution was
neutralized with saturated sodium bicarbonate water. The resulting
solution was made acidic with an aqueous citric acid solution, and
the organic layer was separated. The aqueous layer was extracted
with dichloromethane once, and the combined organic layers were
washed with water, and dried with sodium sulfate. After the solvent
was distilled off, the resulting solid was washed with diisopropyl
ether to obtain 22 mg (yield 61%) of compound 164.
[1553] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (6H, d, J=6.0 Hz),
3.18-3.77 (7H, m), 3.26 (3H, s), 4.49 (1H, d, J=12.3 Hz), 4.76 (1H,
d, J=12.3 Hz), 5.27 (2H, brs), 5.89 (1H, s), 6.90 (2H, d, J=7.2
Hz), 6.98-7.14 (3H, m), 7.315-7.50 (5H, m).
Reference Example 165
##STR00349##
[1554] First Step
[1555] To a DMF (370 mL) solution of compound 165A (WO 2006/088173,
37.0 g, 108 mmol) were sequentially added potassium carbonate (17.9
g, 129 mmol) and methyl iodide (8.03 mL, 129 mmol) at room
temperature, and the mixture was stirred for 1.5 hours. The
reaction solution was added to a solution of ammonium chloride
(20.8 g, 390 mmol) in water (1110 mL) under ice-cooling, and the
precipitated solid was filtered, and washed with water to obtain a
crude product (33 g). In addition, the aqueous layer was salted out
with sodium chloride, and the mixture was extracted with ethyl
acetate, and dried with sodium sulfate. The solvent was distilled
off under reduced pressure, and a crude product (9 g) was obtained
from the resulting residue. The crude products were combined and
purified by silica gel column chromatography (ethyl
acetate/n-hexane=50%-100%) to obtain compound 165B (36.5 g, 95%) as
a white solid.
Second Step
[1556] To a 1,4-dioxane (548 mL) solution of compound 165B (36.5 g,
102 mmol) were sequentially added potassium osmate dihydrate (1.13
g, 3.06 mmol), sodium periodate (87.3 g, 408 mmol) and water (365
mmol) at room temperature, and the mixture was stirred for 6 hours.
The reaction solution was extracted with methylene chloride, and
the extract was dried with sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (ethyl
acetate/n-hexane=50% 100%) to obtain compound 165C (33.0 g, 90%) as
a bronzed foam.
Third Step
[1557] To a toluene (25 mL) suspension of compound 165C (1.38 g,
3.66 mmol) were sequentially added ethylenediamine (0.247 mL, 3.66
mmol) and acetic acid (0.0210 mL, 0.366 mmol) at room temperature
and, thereafter, the mixture was stirred for 1 hour, and further
stirred at 50.degree. C. for 17 hours. The precipitated solid was
filtered, and washed with ether to obtain compound 165D (1.11 g,
100%) as a pale yellow solid.
[1558] .sup.1HNMR (DMSO-d.sub.6) .delta.: 3.05 (2H, m), 3.26 (1H,
m), 3.63 (2H, m), 3.75 (3H, s), 3.87 (1H, m), 4.52 (1H, dd, J=3.3,
12.6 Hz), 4.69 (1H, m), 4.99 (1H, d, J=10.4 Hz), 5.15 (1H, d,
J=10.4 Hz), 7.35 (3H, m), 7.54 (2H, m), 8.41 (1H, s).
Fourth Step
[1559] To an acetonitrile (30 mL) suspension of compound 165D (2.77
g, 7.50 mmol), potassium carbonate (2.23 g, 16.1 mmol) and sodium
iodide (102 mg, 0.680 mmol) was added bromodiphenylmethane (2.26 g,
9.14 mmol) at room temperature, and the mixture was stirred at
90.degree. C. for 7 hours. The reaction solution was poured into
hydrochloric acid (2N, 10 mL) and an ice (20 g), the mixture was
extracted with chloroform (100 mL.times.2), and the extract was
dried with sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (chloroform/methanol=0%-5%) to obtain
compound 165E (2.72 g, 68%) as a pale yellow solid.
Fifth Step
[1560] To an ethanol (30 mL) solution of compound 165E (2.72 g,
5.08 mmol) was added an aqueous sodium hydroxide solution (2N, 10
mL) at room temperature, and the mixture was stirred for 3 days. To
the reaction solution was added hydrochloric acid (1N, 20 mL)
(pH=1) at room temperature, the mixture was extracted with
chloroform (100 mL.times.2), and the extract was dried with sodium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (chloroform/methanol=0%-10%) to obtain compound 165F
(1.77 g, 67%) as a pale yellow solid.
[1561] .sup.1HNMR (DMSO-d.sub.6) .delta.: 2.63 (1H, m), 3.16 (1H,
m), 3.49 (1H, m), 3.73 (1H, m), 4.12 (2H, m), 4.56 (1H, m), 5.04
(1H, s), 5.09 (1H, d, J=10.7 Hz), 5.19 (1H, d, J=10.7 Hz),
7.28-7.53 (15H, m), 8.32 (1H, s), 8.39 (1H, s).
Sixth Step
[1562] A N,N'-dimethylimidazolidinone (20 mL) solution of compound
165F (1.77 g, 3.39 mmol) and lithium chloride (0.515 g, 12.2 mmol)
was stirred at 90.degree. C. for 1 hour. To the reaction solution
were sequentially added water (10 mL), hydrochloric acid (2N, 10
mL) and water (10 mL) at room temperature. The precipitated solid
was filtered, and washed with ether, DMF-water were added, and the
precipitated solid was filtered to obtain compound 165 (599 mg,
41%) as a white solid.
[1563] .sup.1HNMR (DMSO-d.sub.6) .delta.: 2.60 (1H, m), 3.20 (1H,
m), 3.64 (2H, m), 4.00 (2H, m), 4.55 (1H, m), 5.01 (1H, s),
7.28-7.47 (10H, m), 8.16 (1H, s), 11.97 (1H, brs).
[1564] MS: m/z=432 [M+H].sup.+.
Reference Example 166
##STR00350##
[1566] According to Reference example 165, following compound 166
was synthesized by the same procedure.
[1567] .sup.1HNMR (DMSO-d.sub.6) .delta.: 1.54 (1H, d, J=12.6H),
1.66-1.78 (1H, m), 2.60 (1H, t, J=9.9 Hz), 2.83 (1H, d, J=11.7 Hz),
3.01 (1H, t, J=11.7 Hz), 3.34-3.38 (1H, m), 3.94 (1H, d, J=13.8
Hz), 4.44-4.59 (3H, m), 4.82 (1H, d, J=14.7 Hz), 7.06 (2H, t, J=8.7
Hz), 7.18-7.23 (2H, m), 8.27 (1H, s), 12.84 (1H, brs).
Reference Example 167
##STR00351##
[1568] First Step
[1569] To a xylene (30 ml) solution of compound 167A (WO
2006/11674, 3.58 g, 7.61 mmol) were added
(S)--N1-benzyl-3-phenylpropane-1,2-diamine (Journal of the American
Chemical Society; English; 127; 30; 2005; 10504, 1.83 g, 7.61 mmol)
and acetic acid (0.5 ml), and the mixture was refluxed for 2 hours.
After cooling to room temperature, the solvent was distilled off,
and the resulting oil was purified by silica gel chromatography.
The materials were eluted firstly with n-hexane-ethyl acetate (9:1,
v/v) and, then, with n-hexane-ethyl acetate (1:1, v/v).
Concentration of an objective fraction afforded 349 mg (yield 7%)
of compound 167B as an oil.
[1570] .sup.1HNMR (CDCl.sub.3) .delta.: 2.54 (1H, t, J=9.6 Hz),
2.77 (1H, dd, J=9.0 Hz, 13.2 Hz), 3.31 (1H, dd, J=6.9 Hz, 9.6 Hz),
3.43-3.78 (5H, m), 4.04-4.15 (1H, m), 4.42-4.48 (1H, m), 4.62 (2H,
d, J=6.0 Hz), 5.29 (1H, d, J=10.5 Hz), 5.43 (1H, d, J=10.5 Hz),
6.77-6.85 (2H, m), 7.19-7.39 (14H, m), 7.60 (2H, d, J=6.3 Hz), 8.05
(1H, s).
Second Step
[1571] To a MeCN (10 ml) solution of compound 167B (968 mg, 1.47
mmol) were added Boc2O (3 ml) and DMAP (180 mg, 1.47 mmol), and the
mixture was heated to reflux for 5 hours. To the reaction solution
was added a 2N aqueous sodium hydroxide solution to stop the
reaction, the reaction solution was neutralized using 2N
hydrochloric acid and, thereafter, the mixture was extracted with
ethyl acetate three times. After the extract was washed with an
aqueous saturated sodium chloride solution, the solvent was
distilled off, and the resulting oil was purified by silica gel
chromatography. The materials were eluted firstly with
n-hexane-ethyl acetate (6:4, v/v) and, then, only with ethyl
acetate. Concentration of an objective fraction afforded 349 mg
(yield 45%) of compound 167C.
[1572] .sup.1HNMR (CDCl.sub.3) .delta.: 2.54 (1H, t=9.0 Hz), 2.76
(1H, dd, J=9.3 Hz, 16.5 Hz), 3.31 (1H, dd, J=6.9 Hz, 9.6 Hz), 3.45
(1H, dd, J=3.3 Hz, 12.6 Hz), 3.51-3.78 (4H, m), 4.04-4.13 (1H, m),
4.42-4.52 (1H, m), 4.61 (2H, d, J=6.0 Hz), 2.79 (1H, d, J=10.2 Hz),
5.29 (1H, d, J=10.2 Hz), 5.43 (1H, d, J=10.2 Hz), 6.76-7.39 (11H,
m), 7.60 (2H, d, J=6.6 Hz), 8.05 (1H, s), 10.42 (1H, t, J=5.7
Hz).
Third Step
[1573] The compound 167C (150 mg, 0.280 mmol) was dissolved in
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 1 hour. The solvent was distilled off, the residue
was dissolved in dichloromethane (2 ml), and the solution was
neutralized with saturated sodium bicarbonate water. The resulting
solution was made acidic with an aqueous citric acid solution, and
the organic layer was separated. The aqueous layer was extracted
with dichloromethane once, and the combined organic layers were
washed with water, and dried with sodium sulfate. After the solvent
was distilled off, the resulting solid was washed with diisopropyl
ether to obtain 71 mg (yield 57%) of compound 167.
[1574] .sup.1HNMR (CDCl.sub.3) .delta.: 2.65 (1H, dd, J=8.4 Hz, 9.6
Hz), 2.97 (1H, dd, J=9 Hz, 13.5 Hz), 3.43 (1J, dd, J=7.2 Hz, 9.6
Hz), 3.55 (1H, dd, J=3.0 Hz, 13.2 Hz), 3.61-3.80 (4H, m), 4.15 (1H,
dd, J=4.2 Hz, 9.9 Hz), 4.51-4.60 (1H, m), 7.15-7.18 (2H, m),
7.28-7.38 (8H, m), 8.02 (1H, s), 12.04 (1H, s).
Reference Example 168
##STR00352##
[1575] First Step
[1576] To a DMF (3 mL) solution of compound 168A (WO 2006/116764,
400 mg, 0.840 mmol) were added cesium carbonate (821 mg, 2.52 mmol)
and, subsequently, bromomethylenedibenzene (311 mg, 1.26 mmol), and
the mixture was stirred at 100.degree. C. for 5 hours. To the
reaction solution were added 2N aqueous hydrochloric acid solution,
water and ethyl acetate, the ethyl acetate layer was separated, and
the aqueous layer was extracted with ethyl acetate once. The
combined extracts were washed with an aqueous saturated sodium
bicarbonate solution and brine, dried with magnesium sulfate,
filtered and concentrated. The resulting residue was purified by
silica gel column chromatography. Concentration of an objective
fraction afforded 100 mg of compound 168B as a yellow oil.
[1577] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.79-1.84 (2H, m),
2.67-2.77 (1H, m), 2.84-3.05 (2H, m), 4.03 (1H, dd, J=13.0, 4.2
Hz), 4.28 (1H, dd, J=13.6, 6.5 Hz), 4.49 (1H, dd, J=6.4, 3.8 Hz),
4.57 (2H, d, J=5.7 Hz), 4.78 (1H, dd, J=13.4, 5.7 Hz), 4.93 (1H,
s), 5.27 (2H, s), 7.00 (2H, t, J=8.8 Hz), 7.15-7.37 (14H, m),
7.57-7.63 (2H, m), 7.76 (1H, s), 10.44 (1H, t, J=5.9 Hz).
[1578] MS: m/z=643.20 [M+H].sup.+.
Second Step
[1579] Compound 168B (100 mg, 0.156 mmol) was dissolved in
acetonitrile (3 mL), Boc2O (4.0 mL, 17.3 mmol) and, subsequently,
DMAP (84 mg, 0.69 mmol) were added, and the mixture was stirred at
80.degree. C. for 6 hours. The reaction solution was allowed to
cool, a 2N aqueous sodium hydroxide solution (8 mL) and,
subsequently, ethanol (3 mL) were added, and the mixture was
stirred at 60.degree. C. for 2 hours. To the reaction solution were
added 2N aqueous hydrochloric acid solution and ethyl acetate, the
ethyl acetate layer was separated, and the aqueous layer was
extracted with ethyl acetate. The solvent was distilled off, and
the resulting residue was purified by silica gel chromatography.
Elution with ethyl acetate-methanol, and concentration of an
objective fraction afforded 84 mg of compound 168C.
[1580] MS: m/z=536.25 [M+H].sup.+.
Third Step
[1581] To a DMI (2 mL) solution of compound 168C (80 mg, 0.15 mmol)
was added lithium chloride (19 mg, 0.45 mmol), and the mixture was
stirred at 90.degree. C. for 2 hours. To the reaction mixture were
added water and 2N aqueous hydrochloric acid solution, the
precipitated solid was filtered, and the resulting solid was
purified using an LCMS fractionating device. The eluted solvent was
distilled off, isopropyl ether was added to the residue, and the
precipitated solid was filtered. Washing with isopropyl ether and
drying afforded 12 mg of compound 168.
[1582] MS: m/z=446.05 [M+H].sup.+.
Reference Example 169
##STR00353##
[1583] First Step
[1584] To an ethanol (5 mL) solution of compound 95A (WO
2006/116764, 500 mg, 2.03 mmol) was added 2,2-dimethoxyethanamine
(0.49 ml, 4.47 mmol), and the mixture was stirred at 80.degree. C.
for 3 hours. After the reaction solution was allowed to cool,
acetic acid (0.27 ml, 4.69 mmol) was added at room temperature, and
the mixture was concentrated under reduced pressure. The resulting
residue was dissolved in DMF (5 mL), DBU (0.66 mL, 4.4 mmol) and,
subsequently, methyl iodide (1.02 mL, 16.2 mmol) were added under
nitrogen atmosphere, and the mixture was stirred at room
temperature for 3 hours. To the reaction solution were added an
aqueous saturated sodium bicarbonate solution and ethyl acetate,
the ethyl acetate layer was separated, and the aqueous layer was
extracted with ethyl acetate. To the combined extracts was added
sodium sulfate, the mixture was filtered and concentrated, and the
resulting residue was purified by silica gel chromatography.
Elution with chloroform-methanol (9:1) and concentration of an
objective fraction afforded 258 mg of compound 169A as a brown
oil.
[1585] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.37 (6H, s), 3.80 (3H,
s), 3.87 (2H, d, J=4.8 Hz), 4.46 (1H, t, J=4.8 Hz), 5.30 (2H, s),
6.75 (1H, d, J=6.0 Hz), 7.30-7.41 (6H, m).
Second Step
[1586] To compound 169A (1.00 g, 2.88 mmol) were added formic acid
(31 mL) and, subsequently, water (5 mL), and the mixture was
stirred at 70.degree. C. for 6.5 hours. To the reaction mixture
were added water and ethyl acetate, the ethyl acetate layer was
separated, and the aqueous layer was extracted with ethyl acetate.
After the combined extracts were washed with an aqueous saturated
sodium bicarbonate solution, and sodium sulfate was added, then the
mixture was filtered and concentrated, and the resulting residue
was purified by silica gel chromatography. Elution with ethyl
acetate-methanol, and concentration of an objective fraction
afforded a mixture of aldehyde hydride and methylacetal as a
colorless transparent oil. The resulting oil was dissolved in
dichloromethane (5 mL), 1,3-diaminopropane dihydrochloride (354 mg,
2.41 mmol) and, subsequently, acetic acid (0.069 ml, 1.2 mmol) were
added, and the mixture was stirred at room temperature for 6 hours.
The reaction solution was diluted with dichloromethane, insolubles
were filtered and, thereafter, the mixture was concentrated under
reduced pressure to obtain a crude purified product of compound
169B.
[1587] MS: m/z=326.20 [M+H].sup.+.
Third Step
[1588] To an acetonitrile (4 mL) solution of compound 169B (391 mg,
1.20 mmol) were added potassium carbonate (498 mg, 3.61 mmol) and,
subsequently, bromomethylenedibenzene (890 mg, 3.61 mmol). After
the reaction solution was stirred at 90.degree. C. for 2 hours, to
the reaction solution were added water, ethyl acetate and brine,
the ethyl acetate layer was separated, and the aqueous layer was
extracted with ethyl acetate once. After the combined extracts were
dried with magnesium sulfate, then the mixture was filtered and
concentrated. The resulting residue was purified by silica gel
column chromatography. Elution with ethyl acetate-methanol, and
concentration of an objective fraction afforded 106 mg of compound
169C as an orange solid.
[1589] MS: m/z=492.15 [M+H].sup.+.
Fourth Step
[1590] To a DMI (2 mL) solution of compound 169C (105 mg, 0.214
mmol) was added lithium chloride (27.2 mg, 0.641 mmol), and the
mixture was stirred at 90.degree. C. for 3 hours. Further, lithium
chloride (27.2 mg, 0.641 mmol) was added, and the mixture was
stirred at 90.degree. C. for 1 hour. The reaction solution was
concentrated under reduced pressure, and the resulting residue was
purified using an LCMS fractionating device. The eluted solvent was
distilled off, to the residue was added diethyl ether, and the
precipitated solid was filtered. Washing with diethyl ether, and
drying afforded 27 mg of compound 169.
[1591] .sup.1H-NMR (CD.sub.3OD) .delta.: 1.63 (1H, dd, J=13.4, 2.8
Hz), 1.84 (1H, brs), 2.55-2.64 (1H, m), 2.90-3.10 (2H, m), 4.30
(1H, dd, J=14.5, 4.0 Hz), 4.52 (4H, dd, J=14.5, 3.8 Hz), 4.63-4.75
(4H, m), 5.16 (1H, s), 6.16 (1H, d, J=7.2 Hz), 6.78 (1H, d, J=7.2
Hz), 7.16-7.32 (10H, m).
[1592] MS: m/z=402.10 [M+H].sup.+.
Reference Example 170
##STR00354##
[1593] First Step
[1594] Compound 49F (87 mg, 0.19 mmol) was dissolved in ethanol (1
ml) and THF (1 ml), a 2N aqueous sodium hydroxide solution (0.47
ml, 0.95 mmol) was added, and the mixture was stirred at room
temperature for 1.5 hours. To the reaction solution was added 2N
hydrochloric acid, the mixture was extracted with ethyl acetate,
and the extract was dried with sodium sulfate. The resulting crude
product was purified by silica gel column chromatography
(chloroform-methanol 95:5.fwdarw.90:10, v/v) to obtain 60 mg of
compound 170A.
[1595] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.48 (1H, dd, J=13.8, 11.8
Hz), 3.27 (1H, dd, J=14.2, 3.4 Hz), 3.73-3.80 (1H, m), 3.92 (1H,
m), 4.16 (1H, m), 4.45 (2H, m), 5.34 (1H, d, J=3.5 Hz), 5.47 (1H,
d, J=10.4 Hz), 5.52 (1H, d, J=10.7 Hz), 6.73 (2H, d, J=6.9 Hz),
7.18-7.42 (7H, m), 7.60 (2H, d, J=6.9 Hz), 14.63 (1H, s).
Second Step
[1596] To compound 170A (57 mg, 0.13 mmol) was added
trifluoroacetic acid (1 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 3 with sodium bicarbonate water and 2N
hydrochloric acid, and the mixture was extracted with chloroform,
and dried with sodium sulfate. After the solvent was distilled off
under reduced pressure, chloroform-ethyl ether were added, and the
precipitated solid was filtered to obtain 19 mg of compound 170 as
a colorless solid.
[1597] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.74 (1H, t, J=12.1 Hz),
3.10-3.22 (1H, m), 3.76 (2H, m), 4.12 (1H, q, J=8.0 Hz), 4.44 (1H,
m), 5.35 (1H, m), 5.49 (1H, d, J=3.4 Hz), 7.05 (5H, m), 7.77 (1H,
s), 12.05 (1H, brs).
Reference Example 171
##STR00355## ##STR00356##
[1598] First Step
[1599] Compound 49B (950 mg, 3.35 mmol), 3-aminopropan-1-ol (277
mg, 3.69 mmol) and sodium sulfate (1.91 g, 13.4 mmol) were added to
toluene (25 ml), and the mixture was stirred at room temperature
for 1 hour. Boc2O (0.856 ml, 3.69 mmol) was added at room
temperature, and the mixture was stirred for 18 hours. Further,
Boc2O (0.400 ml, 1.72 mmol) was added at room temperature, and the
mixture was stirred for 60 hours. The reaction solution was
filtered, and the filtrate was concentrated under reduced pressure.
The resulting crude product was purified by silica gel column
chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 1.02 g
of compound 171A as a colorless gummy substance.
Second Step
[1600] Compound 171A (1.01 g, 2.29 mmol) and palladium-active
carbon (10%, wet, 200 mg) were added to ethanol (20 ml), and the
mixture was stirred at room temperature for 1.5 hours under
hydrogen atmosphere. After filtration with celite, the solvent was
concentrated under reduced pressure to obtain 755 mg of a colorless
oily substance 171B.
[1601] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.42 (5H, s), 1.49 (4H,
s), 1.56-1.92 (2H, m), 2.49 (0.4H, dd, J=13.6, 9.8 Hz), 2.62 (0.6H,
dd, J=13.6, 8.5 Hz), 2.81 (0.4H, dd, J=13.5, 3.6 Hz), 3.16 (1.6H,
m), 3.60-4.14 (4H, m), 5.13 (0.6H, d, J=8.8 Hz), 5.19 (0.4H, d,
J=8.5 Hz), 7.22-7.37 (5H, m).
Third Step
[1602] Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (660
mg, 1.99 mmol) and compound 171B (609 mg, 1.99 mmol) were added to
toluene (8 ml), and the mixture was stirred at 100.degree. C. for
1.5 hours. After the solvent was distilled off under reduced
pressure, the resulting crude product was purified by silica gel
column chromatography (chloroform-methanol, 99:1, v/v) to obtain
1.02 g of compound 171C as a pale yellow gummy substance.
Fourth Step
[1603] To compound 171C (991 mg, 1.60 mmol) was added 4N HCl (ethyl
acetate solution, 12 ml). After the mixture was stirred at room
temperature for 1 hour, the solvent was distilled off under reduced
pressure. Subsequently, toluene (12 ml) and 3-aminopropan-1-ol
(0.244 ml, 3.19 mmol) were added, the mixture was stirred at
80.degree. C. for 10 minutes. After the solvent was distilled off
under reduced pressure, the resulting crude product was purified by
silica gel column chromatography (chloroform-methanol,
99:1.fwdarw.95:5.fwdarw.90:10, v/v) to obtain 341 mg of compound
171D as a yellow gummy substance and 338 mg of compound 171E as a
colorless solid.
[1604] 171D: .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, t, J=7.1
Hz), 1.51 (1H, d, J=13.7 Hz), 1.97 (1H, m), 2.91 (1H, dd, J=13.8,
9.8 Hz), 2.99-3.10 (2H, m), 3.90 (1H, td, J=12.1, 2.5 Hz), 4.12
(2H, m), 4.25 (2H, m), 4.83 (2H, m), 5.33 (1H, d, J=10.1 Hz), 5.51
(1H, d, J=10.1 Hz), 6.88 (2H, m), 7.23-7.40 (7H, m), 7.68 (2H,
m)
[1605] 171E: .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, t, J=7.2
Hz), 1.82-1.99 (2H, m), 2.73 (1H, dd, J=14.0, 11.3 Hz), 3.13 (1H,
m), 3.35 (1H, dd, J=14.0, 3.4 Hz), 3.63 (1H, m), 3.90-4.26 (4H, m),
4.43 (1H, d, J=13.6 Hz), 5.27 (1H, t, J=3.5 Hz), 5.31 (2H, s), 6.78
(2H, dd, J=6.3, 3.2 Hz), 7.01 (1H, d, J=7.0 Hz), 7.18 (3H, t, J=3.1
Hz), 7.28-7.39 (3H, m), 7.67 (2H, m).
Fifth Step
[1606] Compound 171D (329 mg, 0.673 mmol) was dissolved in ethanol
(2 ml) and THF (4 ml), a 2N aqueous sodium hydroxide solution (1.69
ml, 3.38 mmol) was added, and the mixture was stirred at room
temperature for 1 hour. To the reaction solution was added 2N
hydrochloric acid, the mixture was extracted with ethyl acetate,
and the extract was dried with sodium sulfate. The solvent was
concentrated under reduced pressure to obtain 215 mg of compound
171F as a colorless solid.
[1607] MS: m/z=461 [M+H].sup.+.
Sixth Step
[1608] To compound 171F (50 mg, 0.11 mmol) was added
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 6 with sodium bicarbonate water and 2N
hydrochloric acid, the mixture was extracted with chloroform, and
the extract was dried with sodium sulfate. After the solvent was
distilled off under reduced pressure, chloroform-methanol-ethyl
ether were added, and the precipitated solid was filtered to obtain
24 mg of compound 171 as a colorless solid.
[1609] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.63 (1H, d, J=12.6 Hz),
1.83 (1H, m), 2.96-3.29 (3H, m), 4.05 (2H, m), 4.55 (1H, dd,
J=13.2, 4.4 Hz), 5.08 (1H, dd, J=9.2, 5.4 Hz), 5.30 (1H, s), 7.19
(5H, m), 8.09 (1H, s), 12.84 (1H, brs).
[1610] MS: m/z=371 [M+H].sup.+.
Reference Example 172
##STR00357##
[1612] According to Reference example 171, using compound 171E,
compound 172 was synthesized by the same procedure.
[1613] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.91 (2H, m), 2.94 (1H,
dd, J=14.0, 10.8 Hz), 3.11-3.21 (3H, m), 3.71 (1H, m), 4.19 (1H,
m), 4.29-4.35 (1H, m), 5.08-5.14 (1H, m), 5.47 (1H, d, J=4.0 Hz),
6.92-7.22 (5H, m), 7.71 (1H, s), 12.80 (1H, brs), 15.06 (1H,
brs).
[1614] MS: m/z=371 [M+H].sup.+.
Reference Example 173
##STR00358##
[1615] First Step
[1616] Compound 171F (159 mg, 0.345 mmol) was added to diphenyl
ether (2.5 ml), and the mixture was stirred at 245.degree. C. for 1
hour under microwave irradiation. The reaction solution was poured
into n-hexane, and the precipitated solid was filtered. The
resulting crude product was purified by silica gel column
chromatography (chloroform-methanol, 95:5.fwdarw.90:10, v/v) to
obtain compound 173A.
Second Step
[1617] To compound 173A obtained in the first step was added
trifluoroacetic acid (1 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 6 with sodium bicarbonate water and 2N
hydrochloric acid, the mixture was extracted with chloroform, and
the extract was dried with sodium sulfate. After the solvent was
distilled off under reduced pressure, methylene chloride-ethyl
ether were added, and the precipitated solid was filtered to obtain
10 mg of compound 173 as a colorless solid.
[1618] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.55-1.86 (2H, m),
2.84-3.26 (3H, m), 3.92-4.09 (2H, m), 4.55 (2H, m), 5.15 (1H, s),
5.89 (1H, d, J=7.5 Hz), 7.17 (6H, m), 12.11 (1H, brs)
[1619] MS: m/z=327 [M+H].sup.+.
Reference Example 174
##STR00359##
[1621] According to Reference example 173, compound 174 was
synthesized by the same procedure.
[1622] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.86 (2H, m), 2.87 (1H,
t, J=12.3 Hz), 3.18 (2H, m), 3.68 (1H, t, J=10.4 Hz), 4.16 (1H, d,
J=10.1 Hz), 4.29 (1H, d, J=12.4 Hz), 4.71 (1H, d, J=9.2 Hz), 5.37
(1H, d, J=3.5 Hz), 5.75 (1H, d, J=7.5 Hz), 7.00 (6H, m), 12.51 (1H,
brs).
[1623] MS: m/z=327 [M+H].sup.+.
Reference Example 175
##STR00360## ##STR00361##
[1624] First Step
[1625] To Dess-Martin Periodinane (0.3M, methylene chloride
solution, 25.0 ml, 7.50 mmol) was added dropwise a methylene
chloride solution (10 ml) of compound 2B (1.98 g, 5.48 mmol) at
0.degree. C. After stirring at room temperature for 3 hours, the
reaction mixture was poured into a 1N aqueous sodium hydroxide
solution, and the mixture was extracted with ethyl ether. The
organic layer was washed with a 1N aqueous sodium hydroxide
solution and an aqueous saturated sodium chloride solution, and
dried with magnesium sulfate. After the solvent was distilled off
under reduced pressure, purification was performed by silica gel
column chromatography (n-hexane-ethyl acetate, 2:1, v/v) to obtain
1.73 g of compound 175A as a white solid.
[1626] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.55 (1H, d, J=7.3 Hz),
5.09 (2H, s), 5.14 (2H, m), 7.22-7.35 (15H, m), 9.62 (1H, s).
Second Step
[1627] Compound 175A (1.30 g, 4.59 mmol), 3-aminopropan-1-ol (379
mg, 5.05 mmol) and sodium sulfate (3.26 g, 22.4 mmol) were added to
toluene (40 ml), and the mixture was stirred at room temperature
for 1 hour. Boc2O (1.17 ml, 5.05 mmol) was added at room
temperature, and the mixture was stirred for 18 hours. Boc2O (1.17
ml, 5.05 mmol) and sodium sulfate (3.26 g, 22.4 mmol) were added,
and the mixture was stirred for 60 hours. The reaction solution was
filtered, and the filtrate was concentrated under reduced pressure.
The resulting crude product was purified by silica gel column
chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 635 mg
of compound 175B as a colorless solid.
Third Step
[1628] Compound 175B (632 mg, 1.22 mmol) and palladium-active
carbon (10%, wet, 100 mg) were added to ethanol (10 ml) and THF (5
ml), and the mixture was stirred at room temperature for 3 hours
under hydrogen atmosphere. After filtration with celite, the
solvent was concentrated under reduced pressure to obtain 502 mg of
a colorless oily substance 175C.
[1629] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (9H, s), 1.77 (2H,
m), 3.18-3.27 (1H, m), 3.43-3.51 (1H, m), 4.04 (4H, m), 4.92 (1H,
d, J=4.7 Hz), 7.28 (10H, m).
Fourth Step
[1630] Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (390
mg, 1.22 mmol) and compound 175C (468 mg, 1.22 mmol) were added to
toluene (5 ml), and the mixture was stirred at 100.degree. C. for 2
hours. After the solvent was distilled off under reduced pressure,
the resulting crude product was purified by silica gel column
chromatography (n-hexane-ethyl acetate, 1:1, v/v) to obtain 391 mg
of compound 175D as a pale yellow gummy substance.
Fifth Step
[1631] To compound 175D (388 mg, 0.568 mmol) was added 4N HCl
(ethyl acetate solution, 4 ml). After the mixture was stirred at
room temperature for 1 hour, the solvent was distilled off under
reduced pressure. Subsequently, toluene (4 ml) and
3-aminopropan-1-ol (0.0870 ml, 1.14 mmol) were added, and the
mixture was stirred at 80.degree. C. for 5 hours. After the solvent
was distilled off under reduced pressure, the resulting crude
product was purified by silica gel column chromatography
(chloroform-methanol, 98:2, v/v) to obtain 57 mg of compound 175E
as a yellow gummy substance and 44 mg of compound 175F as a brown
gummy substance.
[1632] 175E: .sup.1H-NMR (CDCl.sub.3) .delta.: 1.91-2.00 (2H, m),
2.87 (1H, m), 3.78 (3H, s), 3.87-4.15 (3H, m), 4.61 (1H, d, J=12.1
Hz), 4.78 (2H, m), 5.33 (1H, d, J=10.2 Hz), 5.63 (1H, d, J=10.2
Hz), 6.95 (2H, m), 7.13-7.53 (12H, m), 7.76 (2H, m)
[1633] 175F: .sup.1H-NMR (CDCl.sub.3) .delta.: 1.83-1.97 (2H, m),
3.12-3.22 (1H, m), 3.50 (1H, m), 3.85 (3H, s), 3.90 (1H, m),
4.34-4.40 (1H, m), 4.74 (1H, d, J=8.6 Hz), 4.84-4.89 (1H, m), 5.09
(1H, d, J=3.3 Hz), 5.15 (1H, d, J=9.9 Hz), 5.26 (1H, d, J=9.6 Hz),
7.08-7.50 (13H, m), 7.65-7.77 (3H, m).
Sixth Step
[1634] Compound 175E (57 mg, 0.10 mmol) was dissolved in THF (0.5
ml) and ethanol (0.5 ml), a 2N aqueous sodium hydroxide solution
(0.25 ml, 0.50 mmol) was added at room temperature, and the mixture
was stirred for 1 hour. After 1N hydrochloric acid was added, and
the mixture was extracted with chloroform, the extract was dried
with sodium sulfate. The solvent was distilled off under reduced
pressure, the resulting crude product was purified by silica gel
column chromatography (chloroform-methanol, 98:2, v/v) to obtain
compound 175G.
Seventh Step
[1635] To compound 175G obtained in the sixth step was added
trifluoroacetic acid (1 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 3 with sodium bicarbonate water and 2N
hydrochloric acid, and the mixture was extracted with chloroform,
and dried with sodium sulfate. After the solvent was distilled off
under reduced pressure, chloroform-methanol-ethyl ether were added,
and the precipitated solid was filtered to obtain 11 mg of compound
175 as a colorless solid.
[1636] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50 (1H, d, J=13.1 Hz),
1.79 (1H, m), 3.17 (1H, m), 3.86 (1H, t, J=11.0 Hz), 4.03 (1H, dd,
J=10.8, 4.1 Hz), 4.46 (1H, d, J=12.0 Hz), 4.53 (1H, dd, J=12.7, 4.2
Hz), 4.84 (1H, s), 5.85 (1H, d, J=11.7 Hz), 7.22 (7H, m), 7.44 (2H,
t, J=7.6 Hz), 7.65 (2H, d, J=7.3 Hz), 8.14 (1H, s), 12.75 (1H, s),
15.33 (1H, brs).
[1637] MS: m/z=447 [M+H].sup.+.
Reference Example 176
##STR00362##
[1639] According to Reference example 175, using compound 175F,
compound 176 was synthesized by the same procedure.
[1640] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.75 (2H, m), 3.17 (2H,
m), 3.43 (1H, m), 3.60 (1H, d, J=10.7 Hz), 4.31 (1H, d, J=12.7 Hz),
4.73 (1H, d, J=9.8 Hz), 5.52 (1H, d, J=3.4 Hz), 5.87 (1H, dd,
J=9.9, 3.4 Hz), 7.10 (7H, m), 7.29 (2H, t, J=7.5 Hz), 7.58 (2H, d,
J=7.3 Hz), 8.37 (1H, s), 12.65 (1H, brs).
[1641] MS: m/z=447 [M+H].sup.+.
Reference Example 177
##STR00363##
[1642] First Step
[1643] Tert-butyl pyrazolidine-1-carboxylate (275 mg, 1.60 mmol)
synthesized according to the method of the reference (Journal of
the Chemical Society, Perkin Transactions 1: Organic and
Bio-Organic Chemistry (1972-1999), 1975, p. 1712), and compound 95B
(409 mg, 1.45 mmol) were dissolved in pyridine (5 ml), HATU (607
mg, 1.60 mmol) was added at room temperature, and the mixture was
stirred for 18 hours. The reaction solution was poured into 1N
hydrochloric acid, and the mixture was extracted with ethyl
acetate, and dried with sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting crude product was
purified by silica gel column chromatography (chloroform-methanol,
97:3.fwdarw.95:5, v/v) to obtain 529 mg of compound 177A as a
yellow solid.
[1644] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.35 (9H, s), 1.88-2.10
(2H, m), 3.04 (1H, s), 3.31 (1H, s), 3.86 (2H, m), 4.96 (1H, d,
J=9.3 Hz), 5.45 (1H, d, J=11.0 Hz), 6.56 (1H, d, J=6.7 Hz),
7.29-7.43 (6H, m).
Second Step
[1645] To compound 177A (525 mg, 1.31 mmol) was added 4N HCl
(dioxane solution, 6 ml). After the mixture was stirred at room
temperature for 1.5 hours, the solvent was distilled off under
reduced pressure to obtain 413 mg of compound 177B as a colorless
solid.
[1646] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.95-2.05 (2H, m), 2.78
(2H, t, J=6.6 Hz), 3.41-3.54 (2H, m), 5.11 (2H, s), 7.38 (5H, m),
7.46 (1H, d, J=6.6 Hz), 8.36 (1H, d, J=6.7 Hz).
Third Step
[1647] Compound 177B (100 mg, 0.298 mmol) was added to ethanol (2
ml), 2,2-diphenylacetaldehyde (58 mg, 0.30 mmol), triethylamine
(0.083 ml, 0.596 mmol) and acetic acid (0.051 ml, 0.89 mmol) were
added, and the mixture was stirred at 80.degree. C. for 3 hours.
The reaction solution was poured into water, the mixture was
extracted with chloroform, and the extract was dried with sodium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting crude product was purified by silica gel column
chromatography (chloroform-methanol,
97:3.fwdarw.95:5.fwdarw.93:7.fwdarw.90:10, v/v) to obtain 106 mg of
compound 177C as a yellow gummy substance.
[1648] MS: m/z=478 [M+H].sup.+.
Fourth Step
[1649] To compound 177C obtained in the third step was added
trifluoroacetic acid (2 ml), and the mixture was stirred at room
temperature for 1 hour. After concentration under reduced pressure,
pH was adjusted to 6 with sodium bicarbonate water and 2N
hydrochloric acid, the mixture was extracted with chloroform, and
the extract was dried with sodium sulfate. After the solvent was
distilled off under reduced pressure, methylene chloride-ethyl
ether were added, and the precipitated solid was filtered to obtain
7 mg of compound 177 as a colorless solid.
[1650] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.95 (2H, m), 2.76 (1H,
m), 2.96-3.17 (2H, m), 4.04 (1H, m), 4.68 (1H, d, J=10.4 Hz), 5.66
(1H, d, J=7.3 Hz), 6.56 (1H, d, J=10.5 Hz), 7.03 (1H, d, J=7.2 Hz),
7.17 (6H, m), 7.34 (2H, t, J=7.3 Hz), 7.55 (2H, d, J=7.5 Hz).
[1651] MS: m/z=388 [M+H].sup.+.
Reference Example 178
##STR00364##
[1653] According to Reference example 177, compound 178 was
synthesized by the same procedure.
[1654] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.55 (4H, m), 2.35-7.49
(1H, m), 2.39 (1H, t, J=12.6 Hz), 2.77 (1H, t, J=10.0 Hz), 3.09
(1H, d, J=11.4 Hz), 4.34 (1H, d, J=12.8 Hz), 4.55 (1H, d, J=10.8
Hz), 5.71 (1H, d, J=7.0 Hz), 6.17 (1H, d, J=10.8 Hz), 6.82 (1H, d,
J=7.3 Hz), 7.13-7.40 (8H, m), 7.48 (2H, d, J=7.3 Hz).
[1655] MS: m/z=402 [M+H].sup.+.
Reference Example 179
##STR00365##
[1657] According to Reference example 177, compound 179 was
synthesized by the same procedure.
[1658] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.31 (6H, m), 2.68 (2H,
m), 3.21 (1H, m), 4.04 (1H, m), 4.40 (1H, d, J=10.8 Hz), 5.77 (1H,
t, J=5.2 Hz), 6.26 (1H, d, J=10.8 Hz), 6.78 (1H, d, J=7.3 Hz), 7.27
(8H, m), 7.53 (2H, d, J=7.2 Hz).
[1659] MS: m/z=416 [M+H].sup.+.
Reference Example 180
##STR00366##
[1661] According to Reference example 177, compound 180 was
synthesized by the same procedure.
[1662] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.78-3.74 (7H, m), 4.17
(1H, m), 4.49 (1H, d, J=10.8 Hz), 5.79 (1H, d, J=7.2 Hz), 6.32 (1H,
d, J=10.8 Hz), 6.79 (1H, d, J=7.2 Hz), 7.28 (8H, m), 7.55 (2H, d,
J=7.6 Hz).
[1663] MS: m/z=418 [M+H].sup.+.
[1664] Using amines which are commercially available or known in
the references and halides which are commercially available or
known in the references, and according to the method of Reference
example 12, Reference examples 181 to 187 were synthesized.
Reference Example 181
##STR00367##
[1666] MS: m/z=433 [M+H].sup.+.
Reference Example 182
##STR00368##
[1668] MS: m/z=459 [M+H].sup.+.
Reference Example 183
##STR00369##
[1670] MS: m/z=529 [M+H].sup.+.
Reference Example 184
##STR00370##
[1672] MS: m/z=477 [M+H].sup.+.
Reference Example 185
##STR00371##
[1674] MS: m/z=473 [M+H].sup.+.
Reference Example 186
##STR00372##
[1676] MS: m/z=447 [M+H].sup.+.
Reference Example 187
##STR00373##
[1678] MS: m/z=461 [M+H].sup.+
Reference Example 188
##STR00374##
[1680] According to Reference example 12 and Reference example 129,
Compound 188 was synthesized by the same procedure.
[1681] MS: m/z=449 [M+H].sup.+.
[1682] Using amines which are commercially available or known in
the references and halides which are commercially available or
known in the references, and according to Reference example 95,
Compounds 189-229 were synthesized by the same procedure.
Reference Example 189
##STR00375##
[1684] MS: m/z=399 [M+H].sup.+
Reference Example 190
##STR00376##
[1686] MS: m/z=488 [M+H].sup.+
Reference Example 191
##STR00377##
[1688] MS: m/z=470 [M+H].sup.+
Reference Example 192
##STR00378##
[1690] MS: m/z=422 [M+H].sup.+.
Reference Example 193
##STR00379##
[1692] MS: m/z=422 [M+H].sup.+
Reference Example 194
##STR00380##
[1694] MS: m/z=486 [M+H].sup.+
Reference Example 195
##STR00381##
[1696] MS: m/z=365 [M+H].sup.+
Reference Example 196
##STR00382##
[1698] MS: m/z=418 [M+H].sup.+
Reference Example 197
##STR00383##
[1700] MS: m/z=339 [M+H].sup.+
Reference Example 198
##STR00384##
[1702] MS: m/z=344 [M+H].sup.+
Reference Example 199
##STR00385##
[1704] MS: m/z=383 [M+H].sup.+
Reference Example 200
##STR00386##
[1706] MS: m/z=339 [M+H].sup.+
Reference Example 201
##STR00387##
[1708] MS: m/z=440 [M+H].sup.+
Reference Example 202
##STR00388##
[1710] MS: m/z=365 [M+H].sup.+
Reference Example 203
##STR00389##
[1712] MS: m/z=396 [M+H].sup.+
Reference Example 204
##STR00390##
[1714] MS: m/z=370 [M+H].sup.+
Reference Example 205
##STR00391##
[1716] MS: m/z=390 [M+H].sup.+
Reference Example 206
##STR00392##
[1718] MS: m/z=420 [M+H].sup.+
Reference Example 207
##STR00393##
[1720] MS: m/z=350 [M+H].sup.+
Reference Example 208
##STR00394##
[1722] MS: m/z=428 [M+H].sup.+
Reference Example 209
##STR00395##
[1724] MS: m/z=386 [M+H].sup.+
Reference Example 210
##STR00396##
[1726] MS: m/z=378 [M+H].sup.+
Reference Example 211
##STR00397##
[1728] MS: m/z=366 [M+H].sup.+
Reference Example 212
##STR00398##
[1730] MS: m/z=362 [M+H].sup.+
Reference Example 213
##STR00399##
[1732] MS: m/z=358 [M+H].sup.+
Reference Example 214
##STR00400##
[1734] MS: m/z=350 [M+H].sup.+
Reference Example 215
##STR00401##
[1736] MS: m/z=350 [M+H].sup.+
Reference Example 216
##STR00402##
[1738] MS: m/z=411 [M+H].sup.+
Reference Example 217
##STR00403##
[1740] MS: m/z=445 [M+H].sup.+
Reference Example 218
##STR00404##
[1742] MS: m/z=366 [M+H].sup.+
Reference Example 219
##STR00405##
[1744] MS: m/z=354 [M+H].sup.+
Reference Example 220
##STR00406##
[1746] MS: m/z=368 [M+H].sup.+
Reference Example 221
##STR00407##
[1748] MS: m/z=314 [M+H].sup.+
Reference Example 222
##STR00408##
[1750] MS: m/z=330 [M+H].sup.+
Reference Example 223
##STR00409##
[1752] MS: m/z=346 [M+H].sup.+
Reference Example 224
##STR00410##
[1754] MS: m/z=418 [M+H].sup.+.
Reference Example 225
##STR00411##
[1756] MS: m/z=445 [M+H].sup.+.
Reference Example 226
##STR00412##
[1758] MS: m/z=473 [M+H].sup.+.
Reference Example 227
##STR00413##
[1760] MS: m/z=444 [M+H].sup.+.
Reference Example 228
##STR00414##
[1762] MS: m/z=434 [M+H].sup.+.
Reference Example 229
##STR00415##
[1764] MS: m/z=443 [M+H].sup.+.
Reference Example 230
##STR00416##
[1766] According to Reference example 128, compound 230 was
synthesized by the same procedure.
[1767] MS: m/z=461 [M+H].sup.+.
Reference Example 231
##STR00417##
[1769] According to Reference example 129, compound 231 was
synthesized by the same procedure.
[1770] MS: m/z=420 [M+H].sup.+.
Reference Example 232
##STR00418##
[1772] According to Reference example 129, compound 232 was
synthesized by the same procedure.
[1773] MS: m/z=434 [M+H].sup.+.
Reference Example 233
##STR00419##
[1775] According to Reference example 130, compound 233 was
synthesized by the same procedure.
[1776] MS: m/z=433 [M+H].sup.+.
Reference Example 234
##STR00420##
[1778] According to Reference example 130, compound 234 was
synthesized by the same procedure.
[1779] MS: m/z=447 [M+H].sup.+.
Reference Example 235
##STR00421##
[1781] According to Reference example 130, compound 235 was
synthesized by the same procedure.
[1782] MS: m/z=473 [M+H].sup.+.
Reference Example 236
##STR00422##
[1784] According to Reference example 130, compound 236 was
synthesized by the same procedure.
[1785] MS: m/z=447 [M+H].sup.+.
Reference Example 237
##STR00423##
[1787] According to Reference example 130, compound 237 was
synthesized by the same procedure.
[1788] MS: m/z=487 [M+H].sup.+.
Reference Example 238
##STR00424##
[1790] According to Reference example 130, compound 238 was
synthesized by the same procedure.
[1791] MS: m/z=509 [M+H].sup.+.
Reference Example 239
##STR00425##
[1793] MS: m/z=376 [M+H].sup.+.
[1794] According to Reference example 157, compound 239 was
synthesized by the same procedure.
[1795] Using amines which are commercially available or known in
the references and alcohols which are commercially available or
known in the references, and according to the method of Reference
example 107, Examples 240 to 245 were synthesized.
Reference Example 240
##STR00426##
[1797] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.05 (3H, d, J=6.9 Hz),
1.04-1.14 (4H, m), 4.49 (1H, d, J=13.2 Hz), 4.83 (1H, d, J=13.2
Hz), 4.91-4.99 (1H. m), 5.73 (1H, d, J=7.8 Hz), 6.50 (1H, s), 6.70
(1H, d, J=7.8 Hz), 7.12-7.30 (4H, m), 7.33-7.43 (2H, m), 7.46-7.54
(1H, m), 8.06 (1H, d, J=7.5 Hz).
Reference Example 241
##STR00427##
[1799] MS: m/z=478 [M+H].sup.+
Reference Example 242
##STR00428##
[1801] MS: m/z=478 [M+H].sup.+
Reference Example 243
##STR00429##
[1803] MS: m/z=478 [M+H].sup.+
Reference Example 244
##STR00430##
[1805] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (6H, d, J=6.9 Hz),
4.59 (1H, d, J=12.6 Hz), 4.77 (1H, d, J=12.6 Hz), 4.81-4.91 (1H,
m), 5.82 (1H, d, J=7.5 Hz), 5.82 (1H, s), 6.71 (1H, brs), 6.78 (1H,
brs), 6.87 (1H, d, J=7.5 Hz), 7.05 (1H, brs), 7.16 (1H, brs), 7.25
(1H, brs), 7.41 (1H, brs).
Reference Example 245
##STR00431##
[1807] MS: m/z=490 [M+H].sup.+.
Reference Example 246
##STR00432##
[1808] First Step
[1809] To a dimethylformamide (20 ml) solution of compound 246A
(5.30 g, 18.76 mmol) and potassium carbonate (5.19 g, 27.53 mmol)
was added benzyl bromide (3.21 g, 18.76 mmol), and the mixture was
stirred at room temperature for 1 hour. To the reaction solution
was added ethyl acetate (80 ml), insolubles were filtered off, and
1N hydrochloric acid was added. The organic layer was separated,
and the aqueous layer was extracted with ethyl acetate two times.
The combined organic layers were washed with water once and,
further, washed with sodium bicarbonate water once, and with an
aqueous saturated sodium chloride solution once. The resulting
solution was dried with sodium sulfate, and the solvent was
distilled off to obtain 6.98 g of compound 246B as an oil.
[1810] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.36 (2H, s), 7.35-7.47
(6H, m), 7.78 (1H, d, J=8.4 Hz), 8.01 (1H, d, J=2.1 Hz).
Second Step
[1811] To a dimethylformamide (15 ml) solution of compound 246B (3
g, 8.05 mmol) and 1-chloro-3-ethynylbenzene (1.32 g, 9.66 mmol) and
triethylamine (4.07 g, 40.25 mmol) were added copper chloride (76.6
mg, 0.403 mmol) and dichlorobis(triphenylphosphine)palladium (282.5
mg, 0.403 mmol) under nitrogen atmosphere, and the mixture was
stirred at room temperature for 5 hours. The reaction solution was
diluted with water, and the mixture was extracted with ethyl
acetate three times. The combined extracts were washed with water
three times, and dried with sodium sulfate, then the solvent was
distilled off. The resulting oil was purified by silica gel column
chromatography. The materials were eluted firstly with hexane and,
then, with hexane-ethyl acetate (7:3, v/v). Concentration of an
objective fraction afforded 3.10 g of compound 246C as an oil.
[1812] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.39 (2H, s), 7.21-7.46
(9H, m), 7.62 (1H, d, J=2.1 Hz), 7.98 (1H, d, J=8.4 Hz).
Third Step
[1813] To a methanol (30 ml) solution of compound 246C (3.10 g,
8.05 mmol) was added 10% palladium carbon (620 mg, 20 wt %), and
the mixture was stirred at room temperature under 1 atm hydrogen
atmosphere. The reaction solution was filtered with celite, the
solvent was distilled off, to the resulting crude product were
added ethyl acetate-diisopropyl ether, and the precipitated residue
was filtered to obtain 618 mg of compound 246D as a solid.
[1814] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.90 (2H, dd, J=7.8 Hz,
10.8 Hz), 3.29 (2H, dd, J=7.5 Hz, 10.5 Hz), 7.06-7.09 (1H, m),
7.18-7.25 (4H, m), 7.31 (1H, dd, J=2.1 Hz, 8.7 Hz), 8.05 (1H, d,
J=8.4 Hz).
Fourth Step
[1815] To compound 246D (2.20 g, 7.45 mmol) was added
polyphosphoric acid (20 g), and the mixture was stirred at
200.degree. C. for 1 hour. After cooled to room temperature, water
was added, and the mixture was extracted with ethyl acetate three
times. The combined extracts were washed with saturated sodium
bicarbonate water once, and dried with sodium sulfate and,
thereafter, the solvent was distilled off. The resulting oil was
purified by silica gel column chromatography. The materials were
eluted firstly with hexane and, then, with hexane-ethyl acetate
(7:3, v/v). Concentration of an objective fraction afforded 1.05 g
of compound 246E as an oil.
[1816] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.17 (4H, s), 7.24 (2H, d,
J=2.1 Hz), 7.32 (2H, dd, J=2.1 Hz, 8.4 Hz, 8.00 (2H, d, J=8.4
Hz).
Fifth Step
[1817] A methanol (10 ml) suspension of sodium borohydride (409 mg,
10.82 mmol) was cooled to 1 to 3.degree. C., and compound 246E (1.0
g, 3.61 mmol) was added while the same temperature was retained.
After the reaction solution was stirred at the same temperature for
30 minutes, water was added. The precipitated solid was filtered to
obtain 968 mg of compound 246F.
[1818] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.25 (1H, d, J=3.0 Hz),
3.05-3.16 (2H, m), 3.27-3.38 (2H, m), 5.95 (1H, d, J=3.0 Hz),
7.14-7.17 (4H, m), 7.39 (2H, d, J=8.1 Hz).
Sixth Step
[1819] According to Reference example 107, compound 246 was
synthesized by the same procedure.
[1820] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (3H, d, J=6.9 Hz),
1.20 (3H, d, J=6.9 Hz), 2.79 (1H, ddd, J=4.5 Hz, 4.5 Hz, 14.4 Hz),
2.99-3.11 (1H, m), 3.50 (1H, ddd, J=4.8 Hz, 4.8 Hz), 17.7 Hz),
4.21-4.33 (1H, m), 4.23 (1H, d, J=12.9 Hz), 4.62-4.74 (2H, m), 5.04
(1H, s), 5.84 (1H, d, J=7.8 Hz), 6.57 (1H, d, J=8.1 Hz), 6.65-6.72
(2H, m), 6.89-6.92 (1H, m), 7.11-7.30 (4H, m).
[1821] Using amines which are commercially available or known in
the references and intermediates corresponding to compound 246A to
compound 246F which are commercially available or known in the
references, and according to the method of Reference example 246,
compounds 247 to 284 were synthesized.
Reference Example 247
##STR00433##
[1823] MS: m/z=457 [M+H].sup.+.
Reference Example 248
##STR00434##
[1825] MS: m/z=485 [M+H].sup.+.
Reference Example 249
##STR00435##
[1827] MS: m/z=471 [M+H].sup.+.
Reference Example 250
##STR00436##
[1829] MS: m/z=457 [M+H].sup.+.
Reference Example 251
##STR00437##
[1831] MS: m/z=521 [M+H].sup.+.
Reference Example 252
##STR00438##
[1833] MS: m/z=485 [M+H].sup.+.
Reference Example 253
##STR00439##
[1835] MS: m/z=471 [M+H].sup.+.
Reference Example 254
##STR00440##
[1837] MS: m/z=487 [M+H].sup.+.
Reference Example 255
##STR00441##
[1839] MS: m/z=469 [M+H].sup.+.
Reference Example 256
##STR00442##
[1841] MS: m/z=470 [M+H].sup.+.
Reference Example 257
##STR00443##
[1843] MS: m/z=434 [M+H].sup.+.
Reference Example 258
##STR00444##
[1845] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.88 (3H, m), 3.43 (2H,
m), 3.69 (1H, dt, J=16.9, 5.1 Hz), 4.01 (1H, d, J=13.4 Hz),
4.07-4.17 (2H, m), 4.97 (1H, d, J=13.4 Hz), 5.24 (1H, s), 5.50 (1H,
d, J=7.6 Hz), 6.73 (1H, d, J=7.2 Hz), 6.85-6.94 (2H, m), 7.14-7.41
(6H, m), 11.73 (1H, s).
[1846] MS: m/z=432 [M+H].sup.+.
Reference Example 259
##STR00445##
[1848] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.80 (1H, td, J=9.6, 4.5
Hz), 2.86-2.99 (1H, m), 3.00-3.18 (1H, m), 3.67 (1H, dt, J=17.1,
5.0 Hz), 4.03-4.19 (2H, m), 4.32-4.52 (1H, m), 5.05 (1H, d, J=13.3
Hz), 5.26 (1H, s), 5.53 (1H, d, J=7.6 Hz), 6.17 (1H, tt, J=55.0,
3.5 Hz), 6.72 (1H, d, J=7.5 Hz), 6.87-6.94 (2H, m), 7.12-7.27 (3H,
m), 7.30-7.43 (3H, m).
[1849] MS: m/z=438 [M+H].sup.+.
Reference Example 260
##STR00446##
[1851] MS: m/z=460 [M+H].sup.+.
Reference Example 261
##STR00447##
[1853] MS: m/z=474 [M+H].sup.+.
Reference Example 262
##STR00448##
[1855] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.80 (1H, dt, J=14.2,
5.1 Hz), 2.86-2.99 (1H, m), 3.00-3.18 (1H, m), 3.68 (1H, dt,
J=16.9, 5.3 Hz), 4.05 (1H, d, J=13.3 Hz), 4.07-4.32 (2H, m),
4.37-4.52 (1H, m), 4.53-4.67 (1H, m), 5.02 (1H, d, J=13.0 Hz), 5.26
(1H, s), 5.50 (1H, d, J=7.8 Hz), 6.73 (1H, d, J=7.6 Hz), 6.85-6.94
(2H, m), 7.12-7.27 (3H, m), 7.30-7.43 (3H, m).
[1856] MS: m/z=420 [M+H].sup.+.
Reference Example 263
##STR00449##
[1858] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.76-3.00 (2H, m),
3.46-3.73 (2H, m), 4.06-4.22 (2H, m), 4.77-4.91 (1H, m), 5.15 (1H,
d, J=12.9 Hz), 5.24 (1H, s), 5.56 (1H, d, J=7.7 Hz), 6.72 (1H, d,
J=7.1 Hz), 6.88-6.95 (1H, m), 6.96 (1H, d, J=7.7 Hz), 7.09-7.41
(7H, m).
[1859] MS: m/z=456 [M+H].sup.+
Reference Example 264
##STR00450##
[1861] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.74-2.99 (2H, m),
3.62-3.73 (1H, m), 4.01-4.20 (3H, m), 5.12 (1H, d, J=13.2 Hz), 5.15
(1H, d, J=15.7 Hz), 5.34 (1H, s), 5.52 (1H, d, J=7.7 Hz), 6.78 (1H,
d, J=8.0 Hz), 6.89-6.96 (2H, m), 7.10-7.23 (5H, m), 7.27-7.35 (3H,
m), 7.43 (1H, d, J=7.7 Hz), 7.79 (1H, td, J=7.6, 1.8 Hz), 8.45-8.50
(1H, m).
[1862] MS: m/z=465 [M+H].sup.+.
Reference Example 265
##STR00451##
[1864] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.32 (9H, s), 2.76-2.86
(1H, m), 2.87-3.01 (1H, m), 3.59-3.70 (1H, m), 4.12-4.25 (1H, m),
4.29 (1H, d, J=13.5 Hz), 4.90 (1H, d, J=13.2 Hz), 5.20 (1H, s),
5.49 (1H, d, J=7.4 Hz), 6.75 (1H, d, J=8.0 Hz), 6.81 (1H, d, J=7.4
Hz), 6.91 (1H, t, J=6.6 Hz), 7.12-7.21 (2H, m), 7.22-7.30 (1H, m),
7.33-7.38 (2H, m), 7.46 (1H, d, J=7.4 Hz).
[1865] MS: m/z=430 [M+H].sup.+.
Reference Example 266
##STR00452##
[1867] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.05 (3H, t, J=7.2 Hz),
2.80 (1H, dt, J=14.4, 5.1 Hz), 2.85-2.99 (2H, m), 3.68 (1H, dt,
J=16.8, 5.0 Hz), 3.74-3.87 (1H, m), 4.02 (1H, d, J=13.3 Hz),
4.06-4.19 (1H, m), 4.98 (1H, d, J=13.1 Hz), 5.22 (1H, s), 5.48 (1H,
d, J=7.6 Hz), 6.73 (1H, d, J=7.5 Hz), 6.83-6.94 (2H, m), 7.12-7.40
(6H, m).
[1868] MS: m/z=402 [M+H].sup.+.
Reference Example 267
##STR00453##
[1870] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.74-1.86 (2H, m),
2.71-2.82 (1H, m), 2.83-2.93 (1H, m), 2.98-3.11 (1H, m), 3.25 (3H,
s), 3.39 (2H, t, J=5.4 Hz), 3.62-3.74 (1H, m), 4.02-4.14 (2H, m),
4.16-4.28 (1H, m), 4.82 (1H, d, J=13.2 Hz), 5.03 (1H, s), 5.76 (1H,
d, J=7.7 Hz), 6.58 (1H, d, J=7.7 Hz), 6.64 (1H, d, J=7.4 Hz),
6.89-6.97 (1H, m), 7.12-7.39 (6H, m).
[1871] MS: m/z=446 [M+H].sup.+.
Reference Example 268
##STR00454##
[1873] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09 (3H, t, J=7.0 Hz),
2.65-2.77 (1H, m), 2.83-2.94 (1H, m), 2.97-3.10 (1H, m), 3.40 (2H,
q, J=7.0 Hz), 3.45-3.52 (1H, m), 3.55-3.64 (1H, m), 3.65-3.76 (1H,
m), 4.00-4.15 (2H, m), 4.36-4.45 (1H, m), 4.90 (1H, d, J=13.5 Hz),
5.02 (1H, s), 5.79 (1H, d, J=7.7 Hz), 6.59 (1H, d, J=7.7 Hz), 6.63
(1H, d, J=7.4 Hz), 6.90-6.97 (1H, m), 7.13-7.39 (6H, m).
[1874] MS: m/z=446 [M+H].sup.+.
Reference Example 269
##STR00455##
[1876] MS: m/z=480 [M+H].sup.+.
Reference Example 270
##STR00456##
[1878] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.33 (3H, s), 2.85 (2H,
m), 3.68 (1H, m), 4.16 (1H, m), 4.29 (1H, d, J=13.3 Hz), 4.45 (1H,
d, J=17.1 Hz), 5.12 (1H, d, J=13.1 Hz), 5.26 (1H, d, J=17.4 Hz),
5.36 (1H, s), 5.55 (1H, d, J=7.6 Hz), 6.74 (1H, d, J=7.6 Hz),
6.89-7.38 (8H, m).
[1879] MS: m/z=470 [M+H].sup.+.
Reference Example 271
##STR00457##
[1881] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.87 (2H, m), 3.61-3.69
(1H, m), 4.15 (1H, m), 4.18 (1H, d, J=13.2 Hz), 4.51 (1H, d, J=15.9
Hz), 5.08 (1H, d, J=13.1 Hz), 5.21 (1H, s), 5.22 (1H, d, J=15.6
Hz), 5.52 (1H, d, J=7.6 Hz), 6.72 (1H, d, J=7.5 Hz), 6.89-7.32 (8H,
m), 7.76 (2H, s).
[1882] MS: m/z=471 [M+H].sup.+.
Reference Example 272
##STR00458##
[1884] MS: m/z=476 [M+H].sup.+
Reference Example 273
##STR00459##
[1886] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.84-2.93 (1H, m), 2.98
(3H, s), 2.98-3.09 (1H, m), 3.66-3.75 (1H. m), 3.99-4.15 (1H, m),
4.06 (1H, d, J=12.9 Hz), 4.80 (1H, d, J=13.2 Hz), 5.03 (1H, s),
5.74 (1H, d, J=7.5 Hz), 6.56 (1H, d, J=7.5 Hz), 6.63 (1H, d, J=6.6
Hz), 6.90-6.96 (1H, m), 7.14-7.37 (6H, m).
Reference Example 274
##STR00460##
[1888] MS: m/z=470 [M+H].sup.+.
Reference Example 275
##STR00461##
[1890] MS: m/z=470 [M+H].sup.+
Reference Example 276
##STR00462##
[1892] MS: m/z=460 [M+H].sup.+
Reference Example 277
##STR00463##
[1894] MS: m/z=486 [M+H].sup.+.
Reference Example 278
##STR00464##
[1896] MS: m/z=446 [M+H].sup.+
Reference Example 279
##STR00465##
[1898] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08-1.21 (6H, m), 2.84
(1H, ddd, J=4.8 Hz, 4.8 Hz, 14.4 Hz), 2.97-3.08 (1H, m), 3.54 (1H,
ddd, J=4.8 Hz, 6.6 Hz, 17.1 Hz), 4.09-4.26 (1H, m), 4.24 (1H, d,
J=13.2 Hz), 4.64-4.74 (m, 1H), 4.70 (1H, d, J=13.2 Hz), 4.94 (1H,
s), 5.81 (1H, d, J=7.8 Hz), 6.42 (1H, dd, J=2.7 Hz, 9.0 Hz), 6.67
(1H, d, J=7.8 Hz), 6.89-7.12 (4H, m), 7.19-7.36 (1H, m).
Reference Example 280
##STR00466##
[1900] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, d, J=6.9 Hz),
1.20 (3H, d, J=6.9 Hz), 2.84 (1H, ddd, J=4.8 Hz, 5.1 Hz, 14.4 Hz),
2.96-3.07 (1H, m), 3.55 (1H, ddd, J=4.8 Hz, 5.1 Hz, 17.4 Hz),
4.11-4.23 (1H, m), 4.21 (1H, d, J=12.9 Hz), 4.65-4.74 (1H, m), 4.70
(1H, d, J=12.9 Hz), 4.95 (1H, s), 5.78 (1H, d, J=7.8 Hz), 6.63 (1H,
d, J=7.8 Hz), 6.69 (1H, d, J=2.1 Hz), 7.06 (1H, d, J=8.4 Hz), 7.18
(1H, dd, J=2.1 Hz, 8.4 Hz), 7.23-7.26 (2H, m), 7.24 (1H, dd, J=2.1
Hz, 8.1 Hz).
Reference Example 281
##STR00467##
[1902] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (3H, d, J=6.6 Hz),
1.20 (3H, d, J=6.9 Hz), 2.90-3.32 (1H, m), 3.36 (1H, ddd, J=4.5 Hz,
4.5 Hz, 9.6 Hz), 3.42-3.51 (1H, m), 3.95-4.02 (1H, m), 4.28 (1H, d,
J=12.9 Hz), 4.64-4.75 (1H, m), 1.89 (1H, d, J=12.9 Hz), 5.15 (1H,
s), 5.80 (1H, d, J=7.5 Hz), 6.46-6.49 (1H, m), 6.70 (1H, d, J=7.8
Hz), 6.88-7.00 (2H, m), 7.03-7.06 (1H, m), 7.11-7.22 (2H, m).
Reference Example 282
##STR00468##
[1904] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09-1.19 (6H, m),
2.80-3.10 (2H, m), 3.40-3.60 (1H, m), 4.16-4.41 (2H, m), 4.61-4.47
(2H, m), 5.06-5.10 (1H, m), 5.71 (0.45H, d, J=7.5 Hz), 5.74 (0.55H,
d, J=7.8 Hz), 6.60-6.72 (2H, m), 6.86-6.94 (1H, m), 7.10-7.46 (6H,
m).
Reference Example 283
##STR00469##
[1906] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10-1.21 (6H, m),
2.75-2.86 (1H, m), 2.99-3.14 (1H, m), 4.23-4.37 (2H, m), 4.59-4.74
(2H, m), 5.04 (1H, s), 5.67-5.80 (1H, m), 6.58-6.67 (2H, m),
6.88-7.08 (1H, m), 7.11-7.38 (5H, m).
Reference Example 284
##STR00470##
[1908] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, d, J=6.9 Hz),
1.20 (3H, d, J=6.9 Hz), 2.80 (1H, ddd, J=4.5 Hz, 4.5 Hz, 9.9 Hz),
3.07 (1H, t, J=3.9 Hz, 13.2 Hz, 13.2 Hz), 3.50 (1H, ddd, J=4.2 Hz,
4.2 Hz, 18.0 Hz), 4.24 (1H, 6.9 Hz), 4.34 (1H, ddd, J=4.2 Hz, 13.5
Hz, 13.5 Hz), 4.63-4.74 (2H, m), 5.06 (1H, s), 5.81 (1H, d, J=7.8
Hz), 6.57-6.64 (2H, m), 6.65 (1H, d, J=7.5 Hz), 6.82 (1H, d, J=9.3
Hz), 6.90 (1H, ddd, J=2.7 Hz, 8.4 Hz, 8.4 Hz), 7.02 (1H, dd, J=2.7
Hz, 9.0 Hz), 7.19-7.26 (2H, m).
Reference Example 285
##STR00471## ##STR00472##
[1909] First Step
[1910] Compound 285A (5.00 g, 29.3 mmol) was dissolved in
dimethylformamide (150 ml), potassium carbonate (14.2 mmol) and
iodoethane (7.11 ml, 88.0 mmol) were added, and the mixture was
stirred at room temperature for 2 hours. To the reaction solution
was added hexane, and the mixture was washed with water and an
aqueous saturated sodium chloride solution. The organic layer was
dried with sodium sulfate, and the solvent was distilled off under
reduced pressure to obtain a colorless oily substance 285B.
[1911] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.40 (3H, t, J=7.2 Hz),
2.60 (3H, s), 4.37 (2H, q, J=7.1 Hz), 7.17 (1H, td, J=7.9, 0.6 Hz),
7.49 (1H, ddd, J=8.0, 1.4, 0.4 Hz), 7.68 (1H, ddd, J=7.8, 1.4, 0.3
Hz).
Second Step
[1912] Compound 285B (5.63 g, 28.3 mmol) obtained in the first step
was dissolved in carbon tetrachloride (150 ml), N-bromosuccinimide
(5.55 g, 31.2 mmol) was added, and the mixture was stirred at
100.degree. C. for 18 hours. The reaction solution was cooled to
room temperature, and washed with water and an aqueous saturated
sodium chloride solution. The organic layer was dried with sodium
sulfate, and the solvent was distilled off under reduced pressure
to obtain 8.08 g of an orange oily substance 285C.
[1913] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.43 (3H, t, J=7.6 Hz),
4.42 (2H, q, J=7.1 Hz), 5.10 (2H, s), 7.31 (1H, t, J=8.6 Hz), 7.57
(1H, d, J=8.1 Hz), 7.84 (1H, d, J=8.1 Hz).
Third Step
[1914] Compound 285C (2.17 g, 7.8 mmol) obtained in the second step
was dissolved in acetone (25 ml), 4-fluorobenzenethiol (1.00 g,
7.80 mmol) and potassium carbonate (1.62 g, 11.7 mmol) were added,
and the mixture was stirred at 80.degree. C. for 18 hours. After
cooled to room temperature, the reaction solution was poured into
water, the mixture was extracted with ethyl acetate, the extract
was washed with an aqueous saturated sodium chloride solution, and
the organic layer was dried with sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting crude
product was purified by silica gel column chromatography and eluted
with n-hexane-ethyl acetate (4:1, v/v) to obtain 2.20 g of a
colorless oily substance 285D.
[1915] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.35 (3H, t, J=7.2 Hz),
4.25 (2H, d, J=7.5 Hz), 4.65 (2H, s), 6.91 (2H, t, J=8.8 Hz),
7.19-7.31 (3H, m), 7.48 (1H, dd, J=8.2, 1.4 Hz), 7.70 (1H, dd,
J=7.6, 1.5 Hz).
Fourth Step
[1916] Compound 285D (2.20 g, 6.77 mmol) obtained in the third step
was dissolved in ethanol (20 ml), a 2N aqueous sodium hydroxide
solution (16.9 ml, 33.8 mmol) was added, and the mixture was
stirred at room temperature for 3 hours. To the reaction solution
was added water, the mixture was made acidic with dilute
hydrochloric acid, and extracted with ethyl acetate. The organic
layer was washed with an aqueous saturated sodium chloride
solution, and dried with sodium sulfate, and the solvent was
distilled off under reduced pressure. To the resulting compound was
added n-hexane, and the precipitated residue was filtered to obtain
1.81 g of a white solid 285E.
[1917] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.74 (2H, s), 6.95 (2H, t,
J=8.8 Hz), 7.34 (3H, m), 7.59 (1H, dd, J=7.9, 1.5 Hz), 7.92 (1H,
dd, J=7.9, 1.3 Hz).
Fifth Step
[1918] To compound 285E (1.81 g, 6.10 mmol) obtained in the fourth
step was added polyphosphoric acid (10.0 g), and the mixture was
stirred at 120.degree. C. for 5 hours. After cooled to room
temperature, water was added, and the mixture was extracted with
ethyl acetate. The organic layer was dried with sodium sulfate, the
solvent was concentrated under reduced pressure, to the resulting
compound were added n-hexane-ethyl acetate, and the precipitated
residue was filtered to obtain 1.18 g of a white solid 285F.
[1919] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.28 (2H, s), 7.18 (1H,
ddd, J=9.3, 6.6, 2.3 Hz), 7.33 (2H, m), 7.46 (1H, dd, J=7.7, 1.5
Hz), 7.59 (1H, dd, J=7.9, 1.3 Hz), 7.91 (1H, dd, J=10.1, 2.9
Hz).
Sixth Step
[1920] To compound 285F (1.17 g, 4.20 mmol) was added methanol (15
ml), sodium borohydride (191 mg, 5.04 mmol) was added at 0.degree.
C., and the mixture was stirred at room temperature for 2 hours.
The reaction solution was poured into water, the mixture was
extracted with dichloromethane, the organic layer was dried with
sodium sulfate, and the solvent was distilled off. To the resulting
compound were added n-hexane-dichloromethane, and the precipitated
residue was filtered to obtain 945 mg of a white solid 285G.
[1921] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.58 (1H, d, J=3.2 Hz),
4.46 (1H, d, J=14.3 Hz), 4.58 (1H, d, J=14.6 Hz), 6.33 (1H, d,
J=3.7 Hz), 6.82 (1H, td, J=8.3, 2.9 Hz), 7.07 (1H, dd, J=8.5, 5.4
Hz), 7.20 (1H, t, J=7.9 Hz), 7.33 (2H, m), 7.44 (1H, d, J=6.9
Hz).
Seventh Step
[1922] According to the same procedure as that of Reference example
107, compound 285 was synthesized.
[1923] MS: m/z=486 [M+H].sup.+
[1924] Using amines which are commercially available or known in
the references and intermediates corresponding to compound 285A to
compound 285G which are commercially available or known in the
references, and according to the method of Reference example 285,
compounds 286 to compound 359 were synthesized.
Reference Example 286
##STR00473##
[1926] MS: m/z=595 [M+H].sup.+.
Reference Example 287
##STR00474##
[1928] MS: m/z=475 [M+H].sup.+.
Reference Example 288
##STR00475##
[1930] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.57 (1H, brs),
1.84-1.99 (2H, m), 2.68 (3H, d, J=4.6 Hz), 3.08-3.17 (2H, m), 3.39
(3H, brs), 3.89 (1H, d, J=13.4 Hz), 4.16 (1H, d, J=13.3 Hz), 4.54
(1H, brs), 5.10 (1H, d, J=12.7 Hz), 5.50 (1H, s), 5.63 (1H, d,
J=13.4 Hz), 5.73 (1H, d, J=7.8 Hz), 6.82-7.94 (9H, m).
[1931] MS: m/z=489 [M+H].sup.+.
Reference Example 289
##STR00476##
[1933] MS: m/z=503 [M+H].sup.+.
Reference Example 290
##STR00477##
[1935] MS: m/z=505 [M+H].sup.+.
Reference Example 291
##STR00478##
[1937] MS: m/z=517 [M+H].sup.+.
Reference Example 292
##STR00479##
[1939] MS: m/z=503 [M+H].sup.+.
Reference Example 293
##STR00480##
[1941] MS: m/z=489 [M+H].sup.+.
Reference Example 294
##STR00481##
[1943] MS: m/z=456 [M+H].sup.+.
Reference Example 295
##STR00482##
[1945] MS: m/z=488 [M+H].sup.+.
Reference Example 296
##STR00483##
[1947] MS: m/z=498 [M+H].sup.+
Reference Example 297
##STR00484##
[1949] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.21 (1H, m), 3.85 (1H,
d, J=13.4 Hz), 4.08-4.18 (3H, m), 4.28 (1H, d, J=13.4 Hz), 5.10
(1H, d, J=13.7 Hz), 5.45 (1H, s), 5.57-5.64 (2H, m), 6.82-7.50
(10H, m).
[1950] MS: m/z=504 [M+H].sup.+.
Reference Example 298
##STR00485##
[1952] According to Reference example 107, compound 298 was
synthesized by the same procedure.
[1953] MS: m/z=452 [M+H].sup.+.
Reference Example 299
##STR00486##
[1955] MS: m/z=450 [M+H].sup.+.
Reference Example 300
##STR00487##
[1957] MS: m/z=464 [M+H].sup.+.
Reference Example 301
##STR00488##
[1959] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.00 (3H, d, J=6.9 Hz),
1.06 (3H, d, J=6.9 Hz), 3.88 (1H, d, J=13.4 Hz), 4.32 (1H, d,
J=13.3 Hz), 4.67 (1H, m), 4.97 (1H, d, J=13.4 Hz), 5.43 (1H, s),
5.59 (2H, m), 6.84-7.45 (9H, m), 11.90 (1H, brs).
[1960] MS: m/z=434 [M+H].sup.+.
Reference Example 302
##STR00489##
[1962] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.11 (1H, m), 0.54-0.92
(3H, m), 2.71 (1H, m), 3.85 (1H, d, J=13.7 Hz), 4.06 (1H, d, J=13.1
Hz), 5.06 (1H, d, J=13.1 Hz), 5.35 (1H, s), 5.57 (2H, m), 7.15 (9H,
m), 11.66 (1H, brs).
[1963] MS: m/z=432 [M+H].sup.+.
Reference Example 303
##STR00490##
[1965] .sup.1HNMR (CDCl.sub.3) .delta.: 1.14 (1H, m), 1.54 (2H, m),
1.67 (1H, m), 3.60 (1H, d, J=13.5 Hz), 4.39 (1H, d, J=12.6 Hz),
5.02 (1H, s), 5.07 (1H, d, J=12.6 Hz), 5.60 (1H, d. J=13.5 Hz),
5.77 (1H, d, J=7.7 Hz), 6.69 (1H, d, J=7.7 Hz), 7.07-7.13 (3H, m),
7.25-7.44 (4H, m).
[1966] MS: m/z=457.10 [M+H].sup.+.
Reference Example 304
##STR00491##
[1968] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.33-3.42 (1H, m), 3.84
(1H, d, J=13.1 Hz), 3.90-4.10 (1H, m), 4.24 (1H, d, J=13.4 Hz),
4.35-4.66 (2H, m), 5.13 (1H, d, J=13.4 Hz), 5.43 (1H, s), 5.54-5.64
(2H, m), 6.80-6.95 (2H, m), 7.04-7.50 (8H, m).
[1969] MS: m/z=438 [M+H].sup.+.
Reference Example 305
##STR00492##
[1971] MS: m/z=487 [M+H].sup.+.
Reference Example 306
##STR00493##
[1973] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.69-3.82 (1H, m), 3.89
(1H, d, J=13.6 Hz), 4.40 (1H, d, J=12.9 Hz), 4.60-4.77 (1H, m),
5.27 (1H, d, J=13.3 Hz), 5.43 (1H, s), 5.60 (1H, d, J=13.6 Hz),
5.70 (1H, d, J=7.7 Hz), 6.84-6.95 (1H, m), 7.08-7.55 (9H, m).
[1974] MS: m/z=474 [M+H].sup.+.
Reference Example 307
##STR00494##
[1976] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.81 (1H, d, J=13.5 Hz),
4.29 (1H, d, J=13.5 Hz), 4.33 (1H, d, J=16.2 Hz), 4.96 (1H, d,
J=16.2 Hz), 5.23 (1H, d, J=13.5 Hz), 5.49 (1H, s), 5.59 (1H, d,
J=13.2 Hz), 5.64 (1H, d, J=7.7 Hz), 6.82-6.97 (2H, m), 7.05-7.41
(10H, m), 7.80 (1H, td, J=7.6, 1.7 Hz), 8.47 (1H, d, J=4.9 Hz).
[1977] MS: m/z=483 [M+H].sup.+.
Reference Example 308
##STR00495##
[1979] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.28 (9H, s), 3.86 (1H,
d, J=13.6 Hz), 4.42 (1H, d, J=13.3 Hz), 4.99 (1H, d, J=13.4 Hz),
5.32 (1H, s), 5.53 (1H, d, J=13.3 Hz), 5.60 (1H, d, J=7.6 Hz),
6.81-7.63 (10H, m).
[1980] MS: m/z=448 [M+H].sup.+.
Reference Example 309
##STR00496##
[1982] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.03 (3H, t, J=7.4 Hz),
3.12-3.26 (1H, m), 3.43-3.58 (1H, m), 3.85 (1H, d, J=13.6 Hz), 4.21
(1H, d, J=13.4 Hz), 5.07 (1H, d, J=13.4 Hz), 5.40 (1H, s), 5.57
(1H, d, J=13.1 Hz), 5.59 (1H, d, J=7.3 Hz), 6.80-6.88 (1H, m), 6.91
(1H, d, J=7.9 Hz), 7.03-7.55 (8H, m).
[1983] MS: m/z=420 [M+H].sup.+.
Reference Example 310
##STR00497##
[1985] MS: m/z=498 [M+H].sup.+.
Reference Example 311
##STR00498##
[1987] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.73-1.85 (2H, m),
2.96-3.07 (1H, m), 3.27 (3H, s), 3.42 (2H, t, J=5.6 Hz), 3.56 (1H,
d, J=13.5 Hz), 3.93-4.04 (1H, m), 4.25 (1H, d, J=13.2 Hz), 4.95
(1H, d, J=12.9 Hz), 5.13 (1H, s), 5.65 (1H, d, J=13.2 Hz), 5.82
(1H, d, J=7.7 Hz), 6.69 (1H, d, J=7.7 Hz), 6.78-6.86 (1H, m),
7.03-7.15 (3H, m), 7.17-7.47 (5H, m).
[1988] MS: m/z=464 [M+H].sup.+.
Reference Example 312
##STR00499##
[1990] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (3H, t, J=6.9 Hz),
2.79-2.91 (1H, m), 3.41 (2H, q, J=7.1 Hz), 3.46-3.69 (3H, m), 4.30
(1H, d, J=13.5 Hz), 5.01 (1H, d, J=13.5 Hz), 5.12 (1H, s), 5.65
(1H, d, J=13.5 Hz), 5.83 (1H, d, J=7.7 Hz), 6.68 (1H, d, J=7.7 Hz),
6.77-6.86 (1H, m), 7.03-7.12 (3H, m), 7.16-7.46 (5H, m).
[1991] MS: m/z=464 [M+H].sup.+.
Reference Example 313
##STR00500##
[1993] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30-1.47 (1H, m),
1.49-1.67 (1H, m), 1.73-2.02 (4H, m), 2.09-2.23 (2H, m), 3.60 (1H,
d, J=13.5 Hz), 4.39 (1H, d, J=12.9 Hz), 4.45-4.64 (1H, m), 4.93
(1H, d, J=12.6 Hz), 5.10 (1H, s), 5.65 (1H, d, J=13.5 Hz), 5.87
(1H, d, J=7.4 Hz), 6.67 (1H, d, J=8.0 Hz), 6.76-6.85 (1H, m), 7.08
(2H, d, J=3.8 Hz), 7.16 (2H, d, J=7.7 Hz), 7.23-7.31 (1H, m),
7.34-7.48 (2H, m).
[1994] MS: m/z=510 [M+H].sup.+.
Reference Example 314
##STR00501##
[1996] MS: m/z=476 [M+H].sup.+.
Reference Example 315
##STR00502##
[1998] MS: m/z=488 [M+H].sup.+.
Reference Example 316
##STR00503##
[2000] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.83 (1H, d, J=13.4 Hz),
4.34 (1H, d, J=13.1 Hz), 4.67 (1H, d, J=15.9 Hz), 5.05 (1H, d,
J=15.9 Hz), 5.20 (1H, d, J=13.4 Hz), 5.33 (1H, s), 5.60 (1H, d,
J=13.8 Hz), 5.64 (1H, d, J=7.8 Hz), 6.87 (3H, m), 7.05-7.19 (4H,
m), 7.35-7.44 (2H, m), 7.74 (1H, d, 3.3 Hz), 7.77 (1H, d, 3.3
Hz).
Reference Example 317
##STR00504##
[2002] MS: m/z=464 [M+H].sup.+
Reference Example 318
##STR00505##
[2004] MS: m/z=494 [M+H].sup.+
Reference Example 319
##STR00506##
[2006] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.18-3.35 (1H, m), 3.60
(1H, d, J=13.7 Hz), 4.37 (1H, d, J=13.2 Hz), 4.75-4.95 (1H, m),
5.07-5.15 (2H, m), 5.60 (1H, d, J=13.7 Hz), 5.85 (1H, d, J=7.7 Hz),
6.68 (1H, d, J=7.7 Hz), 6.79-6.88 (1H, m), 7.09-7.14 (3H, m), 7.16
(1H, d, J=7.7 Hz), 7.29-7.36 (1H, m), 7.36-7.41 (1H, m), 7.42-7.50
(1H, m).
[2007] MS: m/z=524 [M+H].sup.+.
Reference Example 320
##STR00507##
[2009] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.89 (9H, s), 0.97 (3H, d,
J=7.1 Hz), 3.61 (1H, d, J=13.2 Hz), 4.43 (1H, d, J=13.2 Hz),
4.84-4.92 (2H, m), 5.11 (1H, s), 5.70 (1H, d, J=13.2 Hz), 5.83 (1H,
d, J=7.7 Hz), 6.72 (1H, d, J=7.4 Hz), 6.79-6.85 (1H, m), 7.03-7.09
(2H, m), 7.16-7.24 (3H, m), 7.29-7.44 (2H, m).
[2010] MS: m/z=476 [M+H].sup.+.
Reference Example 321
##STR00508##
[2012] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.87 (0.75H, s), 3.01
(2.25H, s), 3.55 (1.5H, d, J=10.2 Hz), 3.62 (0.5H, 13.5 Hz), 4.17
(0.5H, d, J=13.2 Hz), 4.22 (1.5 Hz, J=12.9 Hz), 4.97 (1H, d, J=12.9
Hz), 5.02 (0.25H, s), 5.11 (0.75H, s), 5.63 (0.75H, d, J=13.5 Hz),
5.77-5.83 (1.25H, m), 6.64-6.68 (1H, m), 6.76-6.85 (1H, m), 7.01
(1H, d, J=7.5 Hz), 7.05-7.13 (2H, m), 7.17-7.45 (3H, m).
Reference Example 322
##STR00509##
[2014] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.63 (1H, d, J=13.4 Hz),
4.51-4.59 (2H, m), 4.68-4.98 (4H, m), 5.13 (1H, d, J=12.9 Hz), 5.28
(1H, s), 5.71 (1H, d, J=13.3 Hz), 5.85 (1H, d, J=7.7 Hz), 6.77 (1H,
d, J=7.4 Hz), 6.82-6.89 (1H, m), 7.12 (2H, d, J=3.5 Hz), 7.24 (1H,
d, J=7.6 Hz), 7.33 (2H, d, J=4.4 Hz), 7.39 (1H, d, J=7.1 Hz),
7.42-7.50 (1H, m).
[2015] MS: m/z=470 [M+H].sup.+.
Reference Example 323
##STR00510##
[2017] MS: m/z=450 [M+H].sup.+
Reference Example 324
##STR00511##
[2019] MS: m/z=482 [M+H].sup.+
Reference Example 325
##STR00512##
[2021] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.93 (3H, s), 3.13 (1H,
m), 3.86 (1H, d, J=13.6 Hz), 4.06 (3H, m), 4.26 (1H, d, J=13.3 Hz),
5.14 (1H, d, J=13.6 Hz), 5.44 (1H, s), 5.60 (2H, m), 6.82-7.49
(10H, m).
[2022] MS: m/z=478 [M+H].sup.+.
Reference Example 326
##STR00513##
[2024] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.07 (3H, d, J=6.6 Hz),
1.10 (3H, d, J=6.9 Hz), 3.70 (1H, d, J=13.5 Hz), 4.37 (1H, d,
J=12.9 Hz), 4.75-4.85 (2H, m), 5.18 (1H, s), 5.76 (1H, d, J=13.2
Hz), 5.82 (1H, d, J=7.8 Hz), 6.67 (1H, dd, J=1.2 Hz, 7.8 Hz), 6.77
(1H, t, J=7.8 Hz), 7.07 (1H, d, J=7.5 Hz), 7.18-7.30 (3H, m),
7.35-7.46 (2H, m).
Reference Example 327
##STR00514##
[2026] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.06 (3H, d, J=6.9 Hz),
1.15 (3H, d, J=7.2 Hz), 3.60 (H, d, J=13.5 Hz), 4.36 (1H, d, J=12.9
Hz), 4.75-4.83 (2H, m), 5.10 (1H, s), 5.67 (1H, d, J=13.2 Hz), 5.86
(1H, d, J=7.5 Hz), 6.65 (1H, d, J=8.1 Hz), 6.78 (1H, dd, J=1.8 Hz,
8.1 Hz), 7.08-7.18 (2H, m), 7.13 (1H, d, J=8.1 Hz), 7.24-7.30 (1H,
m), 7.33-7.36 (1H, m), 7.39-7.45 (1H, m).
Reference Example 328
##STR00515##
[2028] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.98 (0.4H, d, J=7.2 Hz),
1.07 (2.6H, d, J=6.6 Hz), 1.15 (2.6H, d, J=6.9 Hz), 1.27 (0.4H, d,
J=0.6 Hz), 3.62 (0.9H, d, J=13.2 Hz), 3.73 (0.1H, d, J=13.8 Hz),
4.36 (1H, d, J=12.9 Hz), 4.77-4.88 (1H, m), 4.83 (1H, d, J=12.9
Hz), 5.07 (1H, s), 5.62 (1H, d, J=13.2 Hz), 5.77 (0.1H, d, J=7.5
Hz), 5.85 (0.9H, d, J=7.8 Hz), 6.69-6.83 (1H, m), 6.98-7.07 (2H,
m), 7.18 (2H, d, J=7.8 Hz), 7.25-7.35 (2H, m), 7.40-7.45 (1H,
m).
Reference Example 329
##STR00516##
[2030] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.07 (3H, d, J=6.6 Hz),
1.15 (3H, d, J=6.9 Hz), 3.63 (1H, d, J=13.2 Hz), 4.37 (1H, d,
J=12.9 Hz), 4.77-4.8 (1H, m), 4.82 (1H, d, J=12.6 Hz), 5.06 (1H,
s), 5.60 (1H, d, J=12.9 Hz), 5.85 (1H, d, J=7.8 Hz), 6.53 (1H, dd,
J=3.0 Hz, 9.0 Hz), 6.80-6.86 (1H, m), 7.03 (1H, dd, J=4.2 Hz, 9.0
Hz), 7.16-7.30 (3H, m), 7.35 (1H, d, J=6.3 Hz), 7.40-7.45 (1H,
m).
Reference Example 330
##STR00517##
[2032] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.02 (3H, t, J=7.2 Hz),
3.07-3.22 (1H, m), 3.44-3.59 (1H, m), 4.00 (1H, d, J=13.4 Hz), 4.21
(1H, d, J=13.4 Hz), 5.06 (1H, d, J=13.3 Hz), 5.47-5.76 (3H, m),
6.84-6.92 (1H, m), 6.92-6.99 (1H, m), 7.04 (1H, d, J=7.6 Hz),
7.10-7.52 (6H, m).
[2033] MS: m/z=454 [M+H].sup.+.
Reference Example 331
##STR00518##
[2035] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.96 (0.79H, s), 3.00
(2.2H, s), 3.59 (0.75H, d, J=13.2 Hz), 3.62 (0.25H, d, J=13.8 Hz),
4.15 (0.25H, d, J=13.2 Hz), 4.21 (0.75H, d, J=12.9 Hz), 4.95-5.01
(2H, m), 5.07 (1H, s), 5.56 (1H, d, J=13.5 Hz), 5.75-5.79 (1H, m),
5.88 (1H, d, J=7.8 Hz), 6.63 (0.36H, d, J=7.8 Hz), 6.73 (1H, d,
J=1.8 Hz), 6.83 (0.39H, d, J=7.2 Hz), 7.01-7.46 (7.25H, m).
Reference Example 332
##STR00519##
[2037] MS: m/z=484 [M+H].sup.+
Reference Example 333
##STR00520##
[2039] MS: m/z=484 [M+H].sup.+.
Reference Example 334
##STR00521##
[2041] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.01-3.10 (1H, m), 3.16
(3H, s), 3.40 (2H, m), 3.89 (2H, d, J=13.4 Hz), 4.19 (1H, d, J=13.4
Hz), 5.06 (1H, d, J=13.6 Hz), 5.49 (1H, s), 5.58 (1H, d, J=13.4
Hz), 5.70 (1H, d, J=7.8 Hz), 6.89-7.48 (8H, m), 11.36 (1H, s).
Reference Example 335
##STR00522##
[2043] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.00-3.09 (1H, m), 3.15
(3H, s), 3.39 (2H, m), 3.94 (1H, m), 4.00 (1H, d, J=13.2 Hz), 4.20
(1H, d, J=13.4 Hz), 5.06 (1H, d, J=13.4 Hz), 5.54 (1H, s), 5.65
(2H, m), 6.86-7.50 (8H, m), 11.54 (1H, brs).
Reference Example 336
##STR00523##
[2045] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.01-3.09 (1H, m), 3.15
(3H, s), 3.40 (2H, m), 3.87-3.94 (1H, m), 3.98 (1H, d, J=13.6 Hz),
4.20 (1H, d, J=13.6 Hz), 5.06 (1H, d, J=13.4 Hz), 5.54 (1H, s),
5.62 (1H, d, J=13.6 Hz), 5.67 (1H, d, J=7.6 Hz), 6.78-7.50 (8H,
m).
[2046] MS: m/z=468 [M+H].sup.+
Reference Example 337
##STR00524##
[2048] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.07 (1H, m), 3.16 (3H,
s), 3.41 (2H, s), 3.89 (1H, d, J=13.7 Hz), 3.91 (1H, m), 4.19 (1H,
d, J=13.6 Hz), 5.06 (1H, d, J=13.6 Hz), 5.48 (1H, s), 5.61 (1H, d,
J=13.3 Hz), 5.69 (1H, d, J=7.6 Hz), 6.70-7.48 (9H, m).
[2049] MS: m/z=468 [M+H].sup.+
Reference Example 338
##STR00525##
[2051] MS: m/z=468 [M+H].sup.+
Reference Example 339
##STR00526##
[2053] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.14 (3H, s), 3.18 (s,
3H), 3.50 (4H, m), 4.00 (1H, d, J=13.1 Hz), 4.49 (1H, d, J=13.3
Hz), 4.77 (1H, m), 4.95 (1H, d, J=13.3 Hz), 5.56 (1H, s), 5.68 (2H,
m), 7.14 (8H, m).
[2054] MS: m/z=512 [M+H].sup.+
Reference Example 340
##STR00527##
[2056] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.12 (3H, s), 3.20 (3H,
s), 3.51 (4H, m), 3.96 (1H, d, J=13.3 Hz), 4.53 (1H, d, J=13.4 Hz),
4.75 (1H, m), 4.97 (1H, d, J=13.1 Hz), 5.50 (1H, d, J=13.3 Hz),
5.54 (1H, s), 5.67 (1H, d, J=7.8 Hz), 6.87-7.54 (8H, m).
[2057] MS: m/z=530 [M+H].sup.+
Reference Example 341
##STR00528##
[2059] MS: m/z=466 [M+H].sup.+
Reference Example 342
##STR00529##
[2061] MS: m/z=506 [M+H].sup.+
Reference Example 343
##STR00530##
[2063] MS: m/z=522 [M+H].sup.+
Reference Example 344
##STR00531##
[2065] MS: m/z=506 [M+H].sup.+
Reference Example 345
##STR00532##
[2067] MS: m/z=506 [M+H].sup.+
Reference Example 346
##STR00533##
[2069] MS: m/z=470 [M+H].sup.+
Reference Example 347
##STR00534##
[2071] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.88 (0.60H, s), 2.99
(2.40H, s), 3.67 (0.80H, d, J=13.8 Hz), 3.73 (0.20H, d, J=14.1 Hz),
4.16 (0.20H, d, J=11.1 Hz), 4.20 (0.80H, d, J=12.9 Hz), 4.97
(0.80H, d, J=12.9 Hz), 4.99 (0.20H, d, J=15 Hz), 5.10 (0.20H, s),
5.18 (0.80H, s), 5.69 (0.80H, d, J=13.5 Hz), 5.79 (0.20H, d, J=7.8
Hz), 5.85 (0.80H, d, J=7.5 Hz), 5.88 (0.20H, J=13.5 Hz), 6.62-6.66
(1H, m), 6.75-6.85 (1H, m), 6.98 (1H, d, J=7.5 Hz), 7.03-7.16
(0.5H, m), 7.19 (1H, d, J=6.9 Hz), 7.24-7.39 (2.5H, m), 7.43-7.48
(1H, m).
Reference Example 348
##STR00535##
[2073] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.91 (0.75H, s), 2.99
(2.25H, s), 3.57 (0.75H, d, J=13.8 Hz), 3.63 (0.25H, d, 13.8 Hz),
4.17 (0.25H, d, J=12.9 Hz), 4.10 (0.75H, d, J=12.9 Hz), 4.99
(0.75H, d, J=12.9 Hz), 5.00 (0.25H, s), 5.01 (0.25H, d, J=12.3 Hz),
5.10 (0.75H, s), 5.61 (0.75H, d, J=13.5 Hz), 5.78 (0.25H, J=7.5
Hz), 5.80 (0.25H, J=15 Hz), 5.89 (0.75H, d, J=7.5 Hz), 6.60 (0.75H,
d, J=8.4 Hz), 6.64 (0.25H, d, J=7.8 Hz), 6.78 (1H, dd, J=2.1 Hz,
8.1 Hz), 7.03 (1H, d, J=7.8 Hz), 7.04-7.21 (2H, m), 7.26-7.36 (2H,
m), 7.41-7.47 (1H, m).
Reference Example 349
##STR00536##
[2075] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.94 (0.66H, s), 3.00
(2.34H, s), 3.60 (0.78H, d, J=13.5 Hz), 3.65 (0.22H, d, J=3.8 Hz),
4.22 (1H, d, J=12.9 Hz), 4.94-5.00 (1H, m), 5.06 (1H, s), 5.54
(0.78H, d, J=13.2 Hz), 5.71 (0.22H, d, J=13.8 Hz), 5.78 (0.22H, d,
J=7.5 Hz), 5.88 (0.78H, d, J=7.8 Hz), 6.49 (1H, dd, J=3.0 Hz, 9.0
Hz), 6.66 (0.22H, d, J=7.8 Hz), 6.82-6.88 (1H, m), 6.97-7.13 (2H,
m), 7.16-7.21 (1H, m), 7.29-7.36 (2H, m), 7.41-7.46 (1H, m).
Reference Example 350
##STR00537##
[2077] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08 (3H, d, J=6.9 Hz),
1.16 (3H, d, J=6.9 Hz), 3.63 (1H, d, J=13.2 Hz), 4.37 (1H, d,
J=12.6 Hz), 4.78-4.87 (1H, m), 5.10 (1H, s), 5.67 (1H, d, J=13.2
Hz), 5.82 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=2.1 Hz), 6.96-6.99 (1H,
m), 7.08-7.12 (2H, m), 7.17 (1H, d, J=13.5 Hz), 7.25-7.32 (1H, m),
7.35-7.37 (1H, m), 7.42-7.47 (1H, m).
Reference Example 351
##STR00538##
[2079] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08 (3H, d, J=6.9 Hz),
1.16 (3H, d, J=6.9 Hz), 3.68 (1H, d, J=13.2 Hz), 4.37 (1H, d,
J=12.9 Hz), 4.76-4.84 (2H, m), 5.18 (1H, s), 5.72 (1H, d, J=13.5
Hz), 5.81 (1H, dd, J=0.9 Hz, 7.5 Hz), 6.56 (1H, d, J=7.2 Hz),
6.76-6.83 (1H, m), 6.90 (1H, t, J=9.0 Hz), 7.07-7.11 (1H, m), 7.19
(1H, d, J=7.5 Hz), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m).
Reference Example 352
##STR00539##
[2081] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.07 (3H, d, J=6.9 Hz),
1.15 (3H, d, J=7.1 Hz), 3.59 (1H, d, J=13.2 Hz), 4.36 (1H, d, J=9.9
Hz), 4.75-4.85 (2H, m), 5.11 (1H, s), 5.70 (1H, d, J=13.2 Hz), 5.84
(1H, d, J=7.8 Hz), 6.48-6.55 (1H, m), 6.71 (1H, dd, J=5.4 Hz, 8.4
Hz), 6.80 (1H, dd, J=2.4 Hz, 9.3 Hz), 7.11 (1H, d, J=7.8 Hz), 7.18
(1H, dd, J=0.9 Hz), 7.5 Hz), 7.25-7.30 (1H, m), 7.32-7.36 (1H, m),
7.39-7.45 (1H, m).
Reference Example 353
##STR00540##
[2083] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.92 (0.66H, s), 3.01
(2.34H, s), 3.59 (0.78H, d, J=13.5 Hz), 3.67 (0.22H, d, J=13.8 Hz),
4.18 (0.22H, d, J=13.2 Hz), 4.21 (0.78H, d, J=12.9 Hz), 5.03 (1H,
J=12.9 Hz), 5.05 (0.22H, s), 5.10 (0.78H, s), 5.62 (0.78H, d,
J=13.5 Hz), 5.76-5.82 (0.44H, m), 5.87 (0.78H, d, J=7.8 Hz), 6.62
(0.78H, brs), 6.68 (0.22H, d, J=8.1 Hz), 6.85 (0.22H, d, J=7.8 Hz),
6.98-7.04 (1.56H, m), 7.11-7.39 (3H, m), 7.44-7.49 (1H, m).
Reference Example 354
##STR00541##
[2085] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.89 (0.48H, s), 3.00
(2.52H, s), 3.64 (0.84H, d, J=13.5 Hz), 3.71 (0.16H, d, J=13.8 Hz),
4.21 (1H, d, J=12.9 Hz), 4.94 (0.84H, d, J=12.9 Hz), 4.98 (0.16H,
d, J=12.9 Hz), 5.10 (0.16H, s), 5.19 (0.84H, s), 5.65 (0.84H, d,
J=7.5 Hz), 5.77-5.85 (1.32H, m), 6.52 (0.84H, d, J=7.8 Hz), 6.64
(0.16H, d, J=7.8 Hz), 6.77-6.84 (1H, m), 6.89-6.95 (1H, m), 6.99
(1H, d, J=7.8 Hz), 7.07-7.25 (1H, m), 7.29-7.38 (2H, m), 7.42-7.47
(1H, m).
Reference Example 355
##STR00542##
[2087] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.91 (0.48H, s), 3.00
(2.52H, s), 3.56 (d, J=13.8 Hz), 3.62 (0.16H, d, J=13.8 Hz), 4.18
(0.16H, d, J=12.9 Hz), 4.20 (0.84H, d, J=12.9 Hz), 4.96 (0.84H, d,
J=12.9 Hz), 4.98 (0.16H, d, J=13.8 Hz), 5.03 (0.16H, s), 5.12
(0.84H, s), 5.64 (0.84H, d, J=13.5 Hz), 5.78-5.87 (0.32H, m), 5.89
(0.84H, d, J=7.8 Hz), 6.50-6.56 (0.84H, m), 6.63-6.69 (1.16H, m),
6.84 (1H, dd, J=2.4 Hz, 9.3 Hz), 6.94-6.97 (0.16H, m), 7.02 (0.84H,
d, J=7.5 Hz), 7.13-7.23 (1H, m), 7.33-7.38 (2H, m), 7.42-7.47 (1H,
m).
Reference Example 356
##STR00543##
[2089] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08 (3H, d, J=6.9 Hz),
1.15 (3H, d, J=6.9 Hz), 2.24 (3H, s), 3.68 (1H, d, J=13.2 Hz), 4.38
(1H, d, J=13.2 Hz), 4.76-4.85 (1H, m), 4.80 (1H, d, J=12.6 Hz),
5.14 (1H, s), 5.72 (1H, d, J=12.9 Hz), 5.76 (1H, d, J=7.8 Hz), 6.59
(1H, d, J=7.5 Hz), 6.72 (1H, t, J=7.5 Hz), 6.99 (1H, d, J=6.9 Hz),
7.07 (1H, d, J=7.8 Hz), 7.17-7.27 (2H, m), 7.33-7.42 (2H, m).
Reference Example 357
##STR00544##
[2091] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (3H, d, J=6.9 Hz),
1.16 (3H, d, J=6.9 Hz), 3.58 (1H, d, J=13.2 Hz), 4.37 (1H, d,
J=12.9 Hz), 4.76-4.87 (1H, m), 4.85 (1H, d, J=12.6 Hz), 5.06 (1H,
s), 5.65 (1H, d, J=13.2 Hz), 5.79 (1H, d, J=7.5 Hz), 6.54 (1H, s),
6.89 (1H, dd, J=1.5 Hz, 8.4 Hz), 6.95 (1H, d, J=7.8 Hz), 7.14-7.19
(1H, m), 7.22-7.28 (1H, m), 7.33-7.43 (2H, m).
Reference Example 358
##STR00545##
[2093] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.07 (3H, d, J=6.9 Hz),
1.16 (3H, d, J=6.9 Hz), 2.20 (3H, s), 2.23 (3H, s), 3.77 (1H, d,
J=12.6 Hz), 4.47 (1H, d, J=12.9 Hz), 4.78-4.86 (1H, m), 4.88 (1H,
12.9 Hz), 5.49 (1H, d, J=12.9 Hz), 5.83 (1H, d, J=11.1 Hz), 5.85
(1H, d, J=9.0 Hz), 6.64 (1H, d, J=7.8 Hz), 6.86 (1H, J=7.8 Hz),
7.16-7.40 (5H, m).
Reference Example 359
##STR00546##
[2095] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.94 (3H, s), 3.07 (1H,
m), 3.98-4.12 (4H, m), 4.25 (2H, d, J=13.4 Hz), 5.13 (2H, d, J=13.3
Hz), 5.56 (1H, s), 5.66 (1H, d, J=13.5 Hz), 5.68 (1H, t, J=7.8 Hz),
6.87-7.51 (8H, m).
Reference Example 360
##STR00547##
[2097] Compound 325 (46.0 mg, 0.0960 mmol) was dissolved in
methanol (0.5 ml) and tetrahydrofuran (0.5 ml), a 2N aqueous sodium
hydroxide solution (0.241 ml, 0.482 mmol) was added, and the
mixture was stirred for 30 minutes. To the reaction solution was
added dilute hydrochloric acid to make the solution acidic, and the
mixture was extracted with chloroform. The organic layer was dried
with sodium sulfate, and the reaction solution was concentrated
under reduced pressure. To the resulting compound 360 were added
n-hexane-diethyl ether, and the precipitated residue was filtered
to obtain 33 mg of a white solid.
[2098] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.85-2.94 (1H, m), 3.52
(2H, m), 3.89 (1H, d, J=13.4 Hz), 3.98 (1H, td, J=9.1, 4.5 Hz),
4.24 (1H, d, J=13.6 Hz), 4.84 (1H, brs), 5.16 (1H, d, J=13.6 Hz),
5.48 (1H, s), 5.65 (2H, m), 6.86-7.55 (9H, m).
[2099] MS: m/z=436 [M+H].sup.+
[2100] Using ester bodies synthesized according to Reference
examples 107, 246 and 285, and according to the method of Reference
example 320, compounds 361 to 382 were synthesized.
Reference Example 361
##STR00548##
[2102] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.82 (3H, m), 3.49 (1H,
brs), 3.71 (1H, dt, J=16.7, 5.0 Hz), 4.03 (1H, t, J=7.8 Hz),
4.08-4.15 (2H, m), 4.79 (1H, brs), 5.01 (1H, d, J=13.4 Hz), 5.25
(1H, s), 5.51 (1H, d, J=7.6 Hz), 6.72-7.41 (9H, m).
Reference Example 362
##STR00549##
[2104] MS: m/z=432 [M+H].sup.+.
Reference Example 363
##STR00550##
[2106] MS: m/z=450 [M+H].sup.+.
Reference Example 364
##STR00551##
[2108] MS: m/z=448 [M+H].sup.+.
Reference Example 365
##STR00552##
[2110] MS: m/z=466 [M+H].sup.+.
Reference Example 366
##STR00553##
[2112] MS: m/z=466 [M+H].sup.+.
Reference Example 367
##STR00554##
[2114] MS: m/z=512 [M+H].sup.+.
Reference Example 368
##STR00555##
[2116] MS: m/z=406 [M+H].sup.+.
Reference Example 369
##STR00556##
[2118] MS: m/z=420 [M+H].sup.+.
Reference Example 370
##STR00557##
[2120] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (3H, s), 1.24 (3H,
s), 2.43 (1H, d, J=13.7 Hz), 2.81-2.91 (1H, m), 2.96-3.10 (1H, m),
3.61-3.72 (1H, m), 4.02-4.14 (1H, m), 4.15 (1H, d, J=13.7 Hz), 4.42
(1H, d, J=14.0 Hz), 4.95 (1H, s), 5.15 (1H, d, J=13.5 Hz), 5.74
(1H, d, J=7.7 Hz), 6.54-6.61 (2H, m), 6.86-6.94 (1H, m), 7.11-7.39
(8H, m).
[2121] MS: m/z=446 [M+H].sup.+.
Reference Example 371
##STR00558##
[2123] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (3H, s), 1.26 (3H,
s), 2.52 (1H, d, J=14.0 Hz), 3.56 (1H, d, J=13.7 Hz), 4.34 (1H, d,
J=13.5 Hz), 4.36 (1H, d, J=13.5 Hz), 5.04 (1H, s), 5.23 (1H, d,
J=13.7 Hz), 5.63 (1H, d, J=13.5 Hz), 5.84 (1H, d, J=7.7 Hz), 6.65
(1H, d, J=7.7 Hz), 6.76-6.84 (1H, m), 7.03-7.18 (5H, m), 7.27-7.47
(4H, m).
[2124] MS: m/z=464 [M+H].sup.+.
Reference Example 372
##STR00559##
[2126] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21-1.68 (10H, m), 2.47
(1H, d, J=13.7 Hz), 3.55 (1H, d, J=13.5 Hz), 4.34 (1H, d, J=13.6
Hz), 4.35 (1H, d, J=13.6 Hz), 5.03 (1H, s), 5.25 (1H, d, J=13.5
Hz), 5.63 (1H, d, J=13.5 Hz), 5.79 (1H, d, J=7.7 Hz), 6.64 (1H, d,
J=7.4 Hz), 6.76-6.84 (1H, m), 7.03 (1H, d, J=7.7 Hz), 7.06-7.10
(2H, m), 7.15 (1H, d, J=7.1 Hz), 7.28-7.37 (2H, m), 7.37-7.46 (1H,
m).
[2127] MS: m/z=504 [M+H].sup.+.
Reference Example 373
##STR00560##
[2129] MS: m/z=450 [M+H].sup.+.
Reference Example 374
##STR00561##
[2131] MS: m/z=492 [M+H].sup.+.
Reference Example 375
##STR00562##
[2133] MS: m/z=445 [M+H].sup.+.
Reference Example 376
##STR00563##
[2135] MS: m/z=512 [M+H].sup.+.
Reference Example 377
##STR00564##
[2137] MS: m/z=492 [M+H].sup.+.
Reference Example 378
##STR00565##
[2139] MS: m/z=478 [M+H].sup.+
Reference Example 379
##STR00566##
[2141] MS: m/z=478 [M+H].sup.+
Reference Example 380
##STR00567##
[2143] MS: m/z=492 [M+H].sup.+
Reference Example 381
##STR00568##
[2145] MS: m/z=492 [M+H].sup.+
Reference Example 382
##STR00569##
[2147] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.76-2.85 (1H, m), 3.58
(2H, m), 3.92 (1H, m), 3.98 (1H, d, J=13.5 Hz), 4.18 (1H, d, J=13.6
Hz), 4.80 (1H, brs), 5.10 (1H, t, J=8.8 Hz), 5.50-5.68 (3H, m),
6.87-7.52 (8H, m).
Reference Example 383
##STR00570##
[2148] First Step
[2149] Compound 383A (1.00 g, 4.42 mmol) was dissolved in
dichloromethane (50 ml), mCPBA (2.67 g, 15.5 mmol) was added at
0.degree. C., and the mixture was stirred at room temperature for 4
hours. To the reaction solution was added an aqueous sodium sulfite
solution, and the mixture was extracted with dichloromethane. The
organic layer was washed with an aqueous sodium bicarbonate
solution, and dried with sodium sulfate, and the solvent was
distilled off. To the resulting compound were added
n-hexane-dichloromethane, and the precipitated residue was filtered
to obtain 1.06 g of a white solid 383B.
[2150] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.81 (2H, s), 7.29-8.12
(6H, m).
Second Step
[2151] To compound 383B (1.05 g, 4.07 mmol) was added methanol (11
ml), sodium borohydride (185 mg, 4.88 mmol) was added at 0.degree.
C., and the mixture was stirred at room temperature for 30 minutes.
The reaction solution was poured into water, the mixture was
extracted with dichloromethane, the organic layer was dried with
sodium sulfate, and the solvent was distilled off. To the resulting
compound were added n-hexane-dichloromethane, and the precipitated
residue was filtered to obtain 1.01 g of a white solid 383C.
[2152] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.84 (1H, d, J=3.7 Hz),
4.76 (1H, d, J=14.6 Hz), 5.25 (1H, d, J=14.6 Hz), 6.23 (1H, d,
J=3.7 Hz), 7.28-7.96 (8H, m).
Third Step
[2153] According to Reference example 107, compound 383 was
synthesized by the same procedure.
[2154] MS: m/z=466 [M+H].sup.+.
[2155] Using intermediates corresponding to 383A to 383C which are
commercially available or known in the references, and according to
the method of Reference example 383, compounds 384 to 389 were
synthesized.
Reference Example 384
##STR00571##
[2157] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12-1.25 (6H, m),
2.87-3.26 (3H, m), 3.42-3.67 (1H, m), 4.00-4.08 (1H, m), 4.28-4.35
(1H, m), 4.56-4.83 (3H, m), 5.10-5.30 (1H, m), 5.89-6.11 (1H, m),
6.55-6.63 (0.5H, m), 6.71-6.75 (0.5H, m), 6.84-6.94 (1H, m),
7.03-7.47 (4H, m), 8.18-8.20 (0.5H, m), 8.48-8.49 (0.5H, m).
Reference Example 385
##STR00572##
[2159] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.59 (3H, d, J=6.6 Hz),
1.07-1.14 (4H, m), 1.19-1.28 (1H, m), 2.22-2.32 (1H, m), 2.73-3.12
(3H, m), 4.71-4.81 (1H, m), 4.83 (1H, d, J=12.9 Hz), 4.96 (1H, d,
J=12.9 Hz), 5.88 (1H, d, J=7.5 Hz), 5.89 (1H, s), 6.89 (1H, m),
7.00-7.04 (2H, m), 7.08-7.18 (2H, m), 7.22-7.27 (1H, m), 7.38 (1H,
d, J=7.5 Hz), 7.58-7.61 (1H, m), 7.79 (1H, d, J=7.5 Hz).
Reference Example 386
##STR00573##
[2161] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.95 (3H, d, J=6.9 Hz),
1.17 (3H, d, 6.9 Hz), 3.34 (2H, d, J=12.3 Hz), 4.39 (1H, d, J=12.9
Hz), 4.56-4.65 (1H, m), 4.85 (1H, d, J=12.9 Hz), 4.93 (1H, m), 5.77
(1H, d, J=7.5 Hz), 6.77-6.81 (1H, m), 6.79 (1H, d, J=7.5 Hz),
7.00-7.05 (1H, m), 7.21-7.29 (2H, m), 7.32-7.42 (3H, m).
Reference Example 387
##STR00574##
[2163] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.06-1.17 (6H, m),
4.02-4.17 (1H, m), 4.61-4.78 (2H, m), 5.16 (1H, d, J=5.1 Hz), 5.72
(1H, t, J=8.1 Hz), 6.54 (0.5H, d, J=7.8 Hz), 6.84 (0.5H, d, J=7.8
Hz), 6.91-7.08 (2H, m), 7.16-7.47 (4H, m), 7.56-7.59 (1H, m), 8.00
(0.5H, J=6.3 Hz), 8.09-8.12 (0.5H, m), 8.51 (0.5H, s), 8.68 (0.5H,
s).
Reference Example 388
##STR00575##
[2165] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, d, J=6.9 Hz),
1.25 (3H, d, J=6.9 Hz), 2.76-2.91 (2H, m), 3.23-3.31 (1H, m),
4.17-4.33 (2H, m), 4.54-4.84 (2H, m), 5.18 (1H, s), 5.87 (1H, d,
J=7.8 Hz), 6.70 (1H, d, J=5.1 Hz), 6.86 (1H, d, J=7.8 Hz), 7.04
(1H, d, J=5.1 Hz), 7.19-7.25 (2H, m), 7.32-7.38 (2H, m).
Reference Example 389
##STR00576##
[2167] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.04-1.20 (6H, m),
2.83-3.02 (1H, m), 3.46-3.57 (1H, m), 3.75-3.85 (1H, m), 4.13-4.26
(1H, m), 4.32-4.50 (1H, m), 4.56-4.62 (1H, m), 4.89 (1H, d, J=13.2
Hz), 5.36 (1H, s), 5.44-5.50 (1H, m), 6.73 (1H, d, J=7.8 Hz), 6.86
(1H, t, J=7.5 Hz), 6.95-6.98 (1H, m), 7.09-6.54 (5H, m).
Reference Example 390
##STR00577##
[2168] First Step
[2169] Compound 390A (14.8 g, 115 mmol) was added to methanol (200
ml), sodium methoxide (28% methanol solution, 22.2 g, 115 mmol) was
added at room temperature, and the mixture was stirred for 1 hour.
The solvent was distilled off under reduced pressure to obtain 17.3
g of a white solid. To 5.61 g of it was added phthalide (5.00 g,
37.3 mmol), and the mixture was stirred at 200.degree. C. for 1
hour. The reaction solution was poured into water, the mixture was
made acidic with hydrochloric acid, and the generated white
precipitate was filtered. This was dissolved in chloroform, the
solution was dried with sodium sulfate, and the solvent was
distilled off. To the resulting compound were added
n-hexane-chloroform-diisopropyl ether, and the precipitated residue
was filtered to obtain 2.44 g of a pale brown solid 390B.
[2170] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.61 (2H, s), 6.92 (1H,
td, J=7.6, 1.4 Hz), 7.01 (1H, dd, J=8.3, 1.3 Hz), 7.21 (1H, ddd,
J=8.7, 7.0, 1.2 Hz), 7.32-7.54 (2H, m), 7.66 (1H, td, J=7.6, 1.4
Hz), 7.92-7.99 (1H, m), 8.17 (1H, dd, J=7.9, 1.3 Hz).
Second Step
[2171] Compound 390B (2.44 g, 9.29 mmol) was dissolved in
dichloromethane (30 ml), trifluoroacetic anhydride (1.44 ml, 10.2
mmol) and boron trifluoride etherate (0.235 ml, 1.86 mmol) were
added, and the mixture was stirred at room temperature for 3 hours.
The reaction solution was poured into water, the mixture was
extracted with dichloromethane, the organic layer was washed with
1N hydrochloric acid and an aqueous saturated sodium chloride
solution, and the solvent was distilled off. The resulting crude
product was purified by silica gel column chromatography, and
eluted with n-hexane-ethyl acetate (4:1, v/v) to obtain 1.76 g of a
pale yellow solid 390C.
[2172] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.36 (2H, s), 7.11 (1H, t,
J=8.0 Hz), 7.43-7.66 (4H, m), 7.93 (1H, d, J=6.5 Hz), 8.19 (1H, dd,
J=8.1, 1.8 Hz).
Third Step
[2173] To compound 390C (1.76 g, 7.19 mmol) was added methanol (20
ml), sodium borohydride (327 mg, 8.63 mmol) was added at 0.degree.
C., and the mixture was stirred at room temperature for 30 minutes.
The reaction solution was poured into water, the mixture was
extracted with dichloromethane, the organic layer was dried with
sodium sulfate, and the solvent was distilled off. To the resulting
compound were added n-hexane-dichloromethane, and the precipitated
residue was filtered to obtain 1.44 g of a white solid 390D.
[2174] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.75 (1H, d, J=5.0 Hz),
5.18 (1H, d, J=13.6 Hz), 5.69 (1H, d, J=5.0 Hz), 5.89 (1H, d,
J=13.6 Hz), 6.93 (1H, t, J=7.9 Hz), 7.19-7.43 (6H, m).
Fourth Step
[2175] According to the same procedure as that of Reference example
107, compound 390 was synthesized.
[2176] MS: m/z=452 [M+H].sup.+
[2177] Using amines which are commercially available or known in
the references and intermediates corresponding to 390A to 390D
which are commercially available or known in the references, and
according to the method of Reference example 390, compounds 391 to
412 were synthesized.
Reference Example 391
##STR00578##
[2179] MS: m/z=418 [M+H].sup.+.
Reference Example 392
##STR00579##
[2181] MS: m/z=416 [M+H].sup.+.
Reference Example 393
##STR00580##
[2183] MS: m/z=458 [M+H].sup.+.
Reference Example 394
##STR00581##
[2185] MS: m/z=434 [M+H].sup.+.
Reference Example 395
##STR00582##
[2187] MS: m/z=390 [M+H].sup.+.
Reference Example 396
##STR00583##
[2189] MS: m/z=468 [M+H].sup.+
Reference Example 397
##STR00584##
[2191] MS: m/z=452 [M+H].sup.+
Reference Example 398
##STR00585##
[2193] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12-1.32 (6H, m), 4.25
(0.52H, d, J=12.9 Hz), 4.41 (0.48H, d, J=13.2 Hz), 4.58-4.79 (2H,
m), 4.92-5.03 (2H, m), 5.73 (0.48H, d, J=7.8 Hz), 5.89 (0.52H, d,
J=7.8 Hz), 6.12 (0.48H, d, J=12 Hz), 6.46-6.58 (1.52H, m),
6.74-6.78 (1H, m), 6.98 (1H, t, J=7.5 Hz), 7.10-7.14 (1H, m),
7.20-7.50 (4H, m).
Reference Example 399
##STR00586##
[2195] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12-1.31 (6H, m), 4.25
(0.75H. d, J=12.9 Hz), 4.43 (0.25H, d, J=12.9 Hz), 4.53-4.60
(0.50H, m), 4.67-4.78 (1.5H, m), 4.90-5.05 (2H. m), 5.70 (0.25H, d,
J=7.8 Hz, 5.86 (0.75H, d, J=7.5 Hz), 6.18 (0.25H, d, J=13.5 Hz),
6.36-6.42 (0.75H, m), 6.49-6.56 (2H, m), 6.69-6.80 (1H, m), 6.94
(1H, d, J=7.8 Hz), 7.10-7.19 (0.25H, m), 7.21-7.50 (3.75H, m).
Reference Example 400
##STR00587##
[2197] MS: m/z=452 [M+H].sup.+
Reference Example 401
##STR00588##
[2199] MS: m/z=452 [M+H].sup.+
Reference Example 402
##STR00589##
[2201] MS: m/z=470 [M+H].sup.+
Reference Example 403
##STR00590##
[2203] MS: m/z=436 [M+H].sup.+
Reference Example 404
##STR00591##
[2205] MS: m/z=452 [M+H].sup.+
Reference Example 405
##STR00592##
[2207] MS: m/z=452 [M+H].sup.+
Reference Example 406
##STR00593##
[2209] MS: m/z=490 [M+H].sup.+
Reference Example 407
##STR00594##
[2211] MS: m/z=436 [M+H].sup.+
Reference Example 408
##STR00595##
[2213] MS: m/z=452 [M+H].sup.+
Reference Example 409
##STR00596##
[2215] MS: m/z=452 [M+H].sup.+
Reference Example 410
##STR00597##
[2217] MS: m/z=490 [M+H].sup.+
Reference Example 411
##STR00598##
[2219] MS: m/z=506 [M+H].sup.+
Reference Example 412
##STR00599##
[2221] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13-1.31 (12H, m),
3.28-3.37 (0.50H, m), 3.44-3.53 (0.50H, m), 4.29-4.36 (1H, m),
4.65-4.76 (2H, m), 4.98-5.05 (2H, m), 6.37 (0.5H, d, J=12.9 Hz),
6.45 (0.5H, d, J=7.5 Hz), 6.67 (0.5H, t, J=7.8 Hz), 6.81 (0.5H, 7.8
Hz), 6.98-7.08 (2H, m), 7.14 (0.5Hm d, J=7.8 Hz), 7.22-7.45 (2.5H,
m).
Reference Example 413, Reference Example 414
##STR00600##
[2222] First Step
[2223] Compound 413A (200 mg, 0.544 mmol) obtained by the same
procedure as that of Reference example 95, and
6,11-dihydrodibenzo[b,e]thiepin-11-ol (124 mg, 0.554 mmol) were
dissolved in acetic acid (8 ml), and concentrated sulfuric acid (2
ml) was added dropwise under water-cooling. After the mixture was
stirred at room temperature for 30 minutes, water was added, and
the mixture was extracted with ethyl acetate. The organic layer was
dried with sodium sulfate, and the solvent was distilled off under
reduced pressure to obtain a crude product of 413B.
Second Step
[2224] Compound 413B obtained in the first step was dissolved in
dichloromethane (2 ml), acetic acid anhydride (0.154 ml, 1.63
mmol), triethylamine (0.226 ml, 1.63 mmol) and
4-(dimethylamino)pyridine (cat.) were added, and the mixture was
stirred at room temperature for 30 minutes. The solvent was
distilled off, the resulting crude product was purified by silica
gel column chromatography, and eluted with chloroform-methanol
(97:3, v/v), and diastereomers were resolved. They were dissolved
in methanol (1 ml) and tetrahydrofuran (1 ml), respectively, a 2N
aqueous sodium hydroxide solution (0.198 ml, 0.397 mmol) was added,
and the mixture was stirred at room temperature for 30 minutes. The
reaction solution was poured into water, and the mixture was made
acidic with hydrochloric acid, and extracted with ethyl acetate.
The organic layer was dried with sodium sulfate, and the solvent
was distilled off under reduced pressure. To the resulting compound
were added ethyl acetate-diethyl ether, and the
fractionation-precipitated residue was filtered to obtain compound
413 (22 mg) and compound 414 (20 mg), respectively.
Reference Example 413
[2225] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20 (3H, d, J=7.4 Hz),
3.92 (1H, d, J=13.6 Hz), 4.45 (1H, d, J=13.4 Hz), 5.12 (1H, d,
J=12.8 Hz), 5.60 (4H, m), 6.87-7.60 (9H, m).
[2226] MS: m/z=488 [M+H].sup.+
Reference Example 414
[2227] MS: m/z=488 [M+H]
[2228] According to Reference example 413, compounds 414 to 475
were synthesized using the same procedure.
Reference Example 415
##STR00601##
[2230] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.16 (3H, d, J=7.3 Hz),
3.88 (1H, d, J=13.3 Hz), 4.41 (1H, d, J=13.3 Hz), 5.07 (1H, d,
J=13.0 Hz), 5.42-5.52 (1H, m), 5.62 (3H, m), 6.82-7.56 (9H, m).
[2231] MS: m/z=488 [M+H].sup.+
Reference Example 416
##STR00602##
[2233] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35 (3H, d, J=7.3 Hz),
3.88 (1H, d, J=13.3 Hz), 4.44 (1H, d, J=12.7 Hz), 5.15 (1H, d,
J=12.5 Hz), 5.16 (1H, m), 5.29 (1H, s), 5.57 (1H, d, J=13.4 Hz),
5.64 (1H, d, J=7.8 Hz), 6.81-7.45 (9H, m).
[2234] MS: m/z=488 [M+H].sup.+
Reference Example 417
##STR00603##
[2236] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (3H, d, J=7.2 Hz),
4.32 (1H, d, J=13.9 Hz), 4.49 (1H, d, J=13.1 Hz), 4.90 (1H, d,
J=13.3 Hz), 5.15 (1H, s), 5.47-5.65 (2H, m), 5.83 (1H, d, J=8.1
Hz), 6.69 (1H, d, J=6.5 Hz), 6.80-6.87 (1H, m), 7.07-7.24 (5H, m),
7.54 (1H, d, J=7.9 Hz).
[2237] MS: m/z=522 [M+H].sup.+.
Reference Example 418
##STR00604##
[2239] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.48 (3H, d, J=7.1 Hz),
3.63 (1H, d, J=13.2 Hz), 4.49 (1H, d, J=12.6 Hz), 5.03 (1H, s),
5.28-5.45 (2H, m), 5.53 (1H, d, J=13.5 Hz), 5.73 (1H, d, J=7.7 Hz),
6.50 (1H, dd, J=8.7, 2.6 Hz), 6.79-6.86 (1H, m), 6.90 (1H, d, J=9.1
Hz), 7.02 (1H, dd, J=8.8, 5.2 Hz), 7.10 (1H, ddd, J=8.1, 2.5, 1.2
Hz), 7.25 (1H, d, J=7.7 Hz), 7.30 (1H, dd, J=8.5, 5.5 Hz).
[2240] MS: m/z=524 [M+H].sup.+.
Reference Example 419
##STR00605##
[2242] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50 (3H, d, J=7.1 Hz),
4.28 (1H, d, J=13.7 Hz), 4.50 (1H, d, J=12.4 Hz), 5.17 (1H, s),
5.26-5.44 (2H, m), 5.60-5.69 (2H, m), 6.65 (1H, d, J=7.4 Hz),
6.73-6.80 (1H, m), 7.01-7.21 (5H, m), 7.48 (1H, d, J=8.0 Hz).
[2243] MS: m/z=522 [M+H].sup.+.
Reference Example 420
##STR00606##
[2245] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.49 (3H, d, J=7.4 Hz),
3.51 (1H, d, J=13.5 Hz), 4.48 (1H, d, J=12.6 Hz), 5.12 (1H, s),
5.28-5.44 (2H, m), 5.60-5.70 (2H, m), 6.65 (1H, d, J=7.4 Hz),
6.73-6.80 (1H, m), 7.00-7.06 (2H, m), 7.10 (1H, d, J=8.5 Hz), 7.14
(1H, d, J=8.0 Hz), 7.23 (1H, dd, J=8.2, 2.2 Hz), 7.31 (1H, d, J=1.9
Hz).
[2246] MS: m/z=522 [M+H].sup.+.
Reference Example 421
##STR00607##
[2248] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.53 (3H, d, J=7.4 Hz),
3.59 (1H, d, J=13.4 Hz), 4.51 (1H, d, J=12.6 Hz), 5.12 (1H, s),
5.30-5.48 (2H, m), 5.62-5.70 (2H, m), 6.71 (1H, d, J=7.7 Hz),
6.80-6.83 (1H, m), 7.07-7.11 (2H, m), 7.18 (1H, d, J=7.7 Hz), 7.22
(1H, s), 7.28 (1H, d, J=8.4 Hz), 7.39 (1H, d, J=8.1 Hz).
[2249] MS: m/z=522 [M+H].sup.+.
Reference Example 422
##STR00608##
[2251] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.49 (3H, d, J=7.4 Hz),
3.59 (1H, d, J=13.5 Hz), 4.48 (1H, d, J=12.4 Hz), 5.12 (1H, s),
5.29-5.39 (2H, m), 5.66 (1H, d, J=13.5 Hz), 5.73 (1H, d, J=7.7 Hz),
6.61 (1H, d, J=8.2 Hz), 6.73 (1H, dd, J=8.2, 2.2 Hz), 7.04 (1H, d,
J=2.2 Hz), 7.12-7.20 (2H, m), 7.23-7.27 (1H, m), 7.31 (1H, d, J=6.3
Hz), 7.36-7.44 (1H, m).
[2252] MS: m/z=522 [M+H].sup.+.
Reference Example 423
##STR00609##
[2254] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.47 (3H, d, J=7.1 Hz),
3.69 (1H, d, J=13.5 Hz), 4.49 (1H, d, J=12.6 Hz), 5.21 (1H, s),
5.27 (1H, d, J=12.6 Hz), 5.30-5.40 (1H, m), 5.70 (1H, d, J=7.7 Hz),
5.75 (1H, d, J=13.5 Hz), 6.65 (1H, dd, J=7.8, 1.5 Hz), 6.73 (1H, t,
J=7.7 Hz), 7.13 (1H, d, J=7.7 Hz), 7.15-7.22 (2H, m), 7.25-7.29
(1H, m), 7.32 (1H, d, J=8.0 Hz), 7.37-7.45 (1H, m).
[2255] MS: m/z=522 [M+H].sup.+.
Reference Example 424
##STR00610##
[2257] MS: m/z=490 [M+H].sup.+.
Reference Example 425
##STR00611##
[2259] MS: m/z=490 [M+H].sup.+.
Reference Example 426
##STR00612##
[2261] MS: m/z=490 [M+H].sup.+.
Reference Example 427
##STR00613##
[2263] .sup.1HNMR (CDCl.sub.3) .delta.: 1.14 (3H, d, J=6.9 Hz),
3.64 (1H, d, J=13.5 Hz), 4.48 (1H, d, J=12.8 Hz), 4.88 (1H, d,
J=12.8 Hz), 5.08 (1H, s), 5.51 (1H, m), 5.60 (1H, d, J=13.5 Hz),
5.93 (1H, d, J=8.1 Hz), 6.58 (1H, d, J=8.1 Hz), 6.95 (1H, dd,
J=2.0, 8.1 Hz), 7.18 (2H, m), 7.29 (1H, m), 7.37-7.45 (2H, m).
Reference Example 428
##STR00614##
[2265] .sup.1HNMR (CDCl.sub.3) .delta.: 1.41 (3H, d, J=7.5 Hz),
3.61 (1H, d, J=13.4 Hz), 4.55 (1H, d, J=12.5 Hz), 5.06 (1H, d,
J=12.5 Hz), 5.16 (1H, s), 5.34 (1H, m), 5.63 (1H, d, J=13.4 Hz),
5.87 (1H, d, J=8.1 Hz), 6.61 (1H, d, J=8.1 Hz), 6.93 (1H, dd,
J=1.8, 8.1 Hz), 7.16-7.41 (5H, m).
Reference Example 429
##STR00615##
[2267] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, d, J=7.4 Hz),
3.64 (1H, d, J=13.5 Hz), 4.44 (1H, d, J=13.2 Hz), 4.87 (1H, d,
J=13.2 Hz), 5.44-5.57 (1H, m), 5.68 (1H, d, J=13.2 Hz), 5.83 (1H,
d, J=7.7 Hz), 5.94 (1H, s), 6.78-6.91 (2H, m), 7.08-7.18 (3H, m),
7.28-7.38 (3H, m).
[2268] MS: m/z=522 [M+H].sup.+.
Reference Example 430
##STR00616##
[2270] MS: m/z=522 [M+H].sup.+.
Reference Example 431
##STR00617##
[2272] MS: m/z=522 [M+H].sup.+.
Reference Example 432
##STR00618##
[2274] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (3H, d, J=7.4 Hz),
3.70 (1H, d, J=13.5 Hz), 4.43 (1H, d, J=13.2 Hz), 4.93 (1H, d,
J=13.2 Hz), 5.21 (1H, s), 5.46-5.60 (1H, m), 5.70 (1H, d, J=13.5
Hz), 5.84 (1H, d, J=7.7 Hz), 6.73 (1H, d, J=7.1 Hz), 6.82-6.89 (1H,
m), 7.08-7.17 (2H, m), 7.22 (1H, d, J=7.7 Hz), 7.35 (1H, d, J=8.0
Hz), 7.55 (1H, d, J=8.0 Hz), 7.67 (1H, s).
[2275] MS: m/z=071 [M+H].sup.+.
Reference Example 433
##STR00619##
[2277] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (3H, d, J=7.1 Hz),
3.56 (1H, d, J=13.5 Hz), 4.48 (1H, d, J=13.2 Hz), 4.90 (1H, d,
J=13.2 Hz), 5.09 (1H, s), 5.46-5.60 (1H, m), 5.62 (1H, d, J=13.2
Hz), 5.82 (1H, d, J=7.7 Hz), 6.69 (1H, d, J=7.4 Hz), 6.84 (1H, dt,
J=10.0, 3.5 Hz), 7.04-7.14 (3H, m), 7.17 (1H, d, J=7.7 Hz), 7.42
(1H, dd, J=8.0, 1.6 Hz), 7.55 (1H, d, J=1.9 Hz).
[2278] MS: m/z=433 [M+H].sup.+.
Reference Example 434
##STR00620##
[2280] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, d, J=7.3 Hz),
3.54 (1H, d, J=13.4 Hz), 4.54 (1H, d, J=12.5 Hz), 5.10 (1H, d,
J=12.5 Hz), 5.16 (1H, s), 5.31-5.45 (1H, m), 5.65 (1H, d, J=13.3
Hz), 5.73 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=7.8 Hz), 6.77-6.84 (1H,
m), 7.03-7.11 (3H, m), 7.22 (1H, d, J=7.6 Hz), 7.40 (1H, dd, J=8.2,
2.0 Hz), 7.48 (1H, d, J=2.0 Hz).
[2281] MS: m/z=433 [M+H].sup.+.
Reference Example 435
##STR00621##
[2283] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (3H, d, J=7.3 Hz),
3.70 (1H, d, J=13.4 Hz), 4.51 (1H, d, J=13.1 Hz), 4.90 (1H, d,
J=12.8 Hz), 5.19 (1H, s), 5.44-5.58 (1H, m), 5.62 (1H, d, J=13.3
Hz), 5.87 (1H, d, J=7.6 Hz), 6.86 (1H, d, J=7.9 Hz), 7.07 (1H, dd,
J=8.2, 1.4 Hz), 7.15-7.22 (2H, m), 7.27-7.51 (4H, m).
[2284] MS: m/z=433 [M+H].sup.+.
Reference Example 436
##STR00622##
[2286] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.48 (3H, d, J=7.4 Hz),
3.71 (1H, d, J=13.3 Hz), 4.60 (1H, d, J=12.6 Hz), 5.21 (1H, d,
J=12.6 Hz), 5.29 (1H, s), 5.32-5.46 (1H, m), 5.70 (1H, d, J=13.3
Hz), 5.80 (1H, d, J=7.7 Hz), 6.91 (1H, d, J=7.9 Hz), 7.08 (1H, d,
J=7.4 Hz), 7.20-7.29 (2H, m), 7.33-7.51 (4H, m).
[2287] MS: m/z=433 [M+H].sup.+.
Reference Example 437
##STR00623##
[2289] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (3H, d, J=7.3 Hz),
3.60 (1H, d, J=13.6 Hz), 4.46 (1H, d, J=13.1 Hz), 4.90 (1H, d,
J=12.8 Hz), 5.15 (1H, s), 5.47-5.59 (1H, m), 5.68 (1H, d, J=13.4
Hz), 5.83 (1H, d, J=7.6 Hz), 6.70 (1H, d, J=7.3 Hz), 6.80-6.88 (1H,
m), 7.07-7.26 (6H, m).
[2290] MS: m/z=433 [M+H].sup.+.
Reference Example 438
##STR00624##
[2292] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.42 (3H, d, J=7.3 Hz),
3.57 (1H, d, J=13.3 Hz), 4.55 (1H, d, J=12.5 Hz), 5.05 (1H, d,
J=12.5 Hz), 5.23 (1H, s), 5.32-5.47 (1H, m), 5.70 (1H, d, J=13.4
Hz), 5.77 (1H, d, J=7.6 Hz), 6.74 (1H, d, J=7.8 Hz), 6.79-6.87 (1H,
m), 7.04-7.26 (6H, m).
[2293] MS: m/z=433 [M+H].sup.+.
Reference Example 439
##STR00625##
[2295] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (3H, d, J=7.2 Hz),
2.29 (3H, s), 3.76 (1H, d, J=13.3 Hz), 4.54 (1H, d, J=13.1 Hz),
4.92 (1H, d, J=13.1 Hz), 5.18 (1H, s), 5.50-5.62 (1H, m), 5.71 (1H,
d, J=13.4 Hz), 5.84 (1H, d, J=7.7 Hz), 6.63 (1H, d, J=7.4 Hz), 6.78
(1H, t, J=7.6 Hz), 7.06 (1H, d, J=7.6 Hz), 7.17 (1H, d, J=7.7 Hz),
7.23 (1H, d, J=7.6 Hz), 7.28-7.34 (1H, m), 7.39-7.51 (2H, m).
[2296] MS: m/z=433 [M+H].sup.+.
Reference Example 440
##STR00626##
[2298] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (3H, d, J=7.2 Hz),
2.27 (3H, s), 3.74 (1H, d, J=13.3 Hz), 4.61 (1H, d, J=12.4 Hz),
5.07 (1H, d, J=12.4 Hz), 5.27 (1H, s), 5.31-5.44 (1H, m), 5.75 (1H,
d, J=13.3 Hz), 5.80 (1H, d, J=7.7 Hz), 6.67 (1H, d, J=7.1 Hz), 6.77
(1H, t, J=7.6 Hz), 7.04 (1H, d, J=7.1 Hz), 7.21-7.47 (5H, m).
[2299] MS: m/z=433 [M+H].sup.+.
Reference Example 441
##STR00627##
[2301] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.22 (3H, d, J=7.2 Hz),
3.94 (1H, d, J=13.3 Hz), 4.45 (1H, d, J=13.4 Hz), 5.08 (1H, d,
J=12.8 Hz), 5.56 (4H, dm), 6.84-7.54 (8H, m).
Reference Example 442
##STR00628##
[2303] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.37 (3H, d, J=7.2 Hz),
3.98 (1H, d, J=13.4 Hz), 4.48 (1H, d, J=13.1 Hz), 5.21 (1H, d,
J=12.9 Hz), 5.22 (1H, m), 5.38 (1H, s), 5.52 (1H, d, J=13.4 Hz),
5.67 (1H, d, J=7.6 Hz), 6.87-7.57 (8H, m).
Reference Example 443
##STR00629##
[2305] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.19 (3H, d, J=7.2 Hz),
3.92 (1H, d, J=13.4 Hz), 4.43 (1H, d, J=13.1 Hz), 5.05 (1H, d,
J=13.0 Hz), 5.54 (4H, m), 7.29 (8H, m).
[2306] MS: m/z=522 [M+H].sup.+
Reference Example 444
##STR00630##
[2308] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.13 (3H, d, J=7.0 Hz),
4.00 (1H, d, J=14.2 Hz), 4.40 (1H, d, J=13.3 Hz), 5.05 (1H, d,
J=13.3 Hz), 5.44 (1H, m), 5.62-5.71 (3H, m), 6.82-7.56 (8H, m).
[2309] MS: m/z=506 [M+H].sup.+
Reference Example 445
##STR00631##
[2311] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.23 (3H, d, J=7.2 Hz),
4.14 (1H, d, J=13.8 Hz), 4.60 (1H, d, J=13.6 Hz), 5.10 (1H, d,
J=13.3 Hz), 5.48 (1H, d, J=15.6 Hz) 5.49 (1H, m), 5.69 (1H, d,
J=7.9 Hz), 5.70 (1H, s), 6.89-7.47 (8H, m).
[2312] MS: m/z=506 [M+H].sup.+
Reference Example 446
##STR00632##
[2314] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.22 (3H, d, J=6.9 Hz),
3.93 (1H, d, J=13.1 Hz), 4.49 (1H, d, J=13.4 Hz), 5.05 (1H, d,
J=13.7 Hz), 5.57 (4H, m), 6.87-7.61 (8H, m).
[2315] MS: m/z=522 [M+H].sup.+
Reference Example 447
##STR00633##
[2317] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.41 (3H, d, J=7.2 Hz),
3.98 (1H, d, J=13.3 Hz), 4.48 (1H, d, J=12.9 Hz), 5.21 (1H, d,
J=14.4 Hz), 5.22 (1H, m), 5.39 (1H, s), 5.52 (1H, d, J=13.6 Hz),
5.67 (1H, d, J=7.6 Hz), 6.88-7.57 (8H, m).
[2318] MS: m/z=506 [M+H].sup.+
Reference Example 448
##STR00634##
[2320] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.19 (3H, d, J=7.2 Hz),
3.94 (1H, d, J=13.3 Hz), 4.44 (1H, d, J=13.3 Hz), 5.12 (1H, d,
J=13.1 Hz), 5.46-5.68 (3H, m), 5.76 (1H, d, J=7.6 Hz), 7.27 (8H,
m).
[2321] MS: m/z=506 [M+H].sup.+
Reference Example 449
##STR00635##
[2323] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.14 (3H, d, J=7.2 Hz),
3.93 (1H, d, J=13.3 Hz), 4.40 (1H, d, J=13.1 Hz), 5.07 (1H, d,
J=13.0 Hz), 5.46 (1H, m), 5.62 (1H, d, J=15.6 Hz), 5.64 (1H, s),
5.75 (1H, d, J=7.6 Hz), 6.94-7.55 (8H, m).
[2324] MS: m/z=522 [M+H].sup.+
Reference Example 450
##STR00636##
[2326] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.14 (3H, d, J=7.2 Hz),
4.03 (1H, d, J=13.3 Hz), 4.41 (1H, d, J=13.3 Hz), 5.06 (1H, d,
J=13.0 Hz), 5.46 (1H, m), 5.69 (3H, m), 6.88-7.57 (8H, m).
[2327] MS: m/z=522 [M+H].sup.+
Reference Example 451
##STR00637##
[2329] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35 (3H, d, J=7.2 Hz),
4.03 (1H, d, J=13.3 Hz), 4.43 (1H, d, J=13.0 Hz), 5.14 (1H, t,
J=12.6 Hz), 5.15 (1H, m), 5.42 (1H, s), 5.63 (1H, d, J=13.5 Hz),
5.65 (1H, d, J=7.8 Hz), 6.88-7.44 (8H, m).
[2330] MS: m/z=522 [M+H].sup.+
Reference Example 452
##STR00638##
[2332] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.42 (3H, d, J=7.2 Hz),
4.14 (1H, d, J=13.9 Hz), 4.57 (1H, d, J=13.1 Hz), 5.14 (1H, d,
J=13.0 Hz), 5.15 (1H, m), 5.30 (1H, d, J=13.0 Hz), 5.40 (1H, s),
5.68 (1H, d, J=7.7 Hz), 6.89-7.38 (8H, m).
[2333] MS: m/z=506 [M+H].sup.+
Reference Example 453
##STR00639##
[2335] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40 (3H, d, J=7.4 Hz),
4.05 (1H, d, J=13.4 Hz), 4.47 (1H, d, J=13.1 Hz), 5.18 (1H, m),
5.19 (1H, d, J=13.2 Hz), 5.46 (1H, s), 5.65 (1H, d, J=13.4 Hz),
5.74 (1H, d, J=7.6 Hz), 6.89-7.52 (8H, m).
[2336] MS: m/z=506 [M+H].sup.+
Reference Example 454
##STR00640##
[2338] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20 (3H, d, J=7.2 Hz),
3.89 (1H, d, J=13.4 Hz), 4.46 (1H, d, J=13.4 Hz), 5.05 (1H, d,
J=13.4 Hz), 5.44-5.66 (4H, m), 6.83-7.63 (8H, m).
[2339] MS: m/z=506 [M+H].sup.+
Reference Example 455
##STR00641##
[2341] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.16 (3H, d, J=7.3 Hz),
3.92 (1H, d, J=13.3 Hz), 4.39 (1H, d, J=13.1 Hz), 5.07 (1H, d,
J=13.3 Hz), 5.47 (1H, m), 5.60 (1H, d, J=13.3 Hz), 5.68 (1H, s),
5.72 (1H, d, J=7.6 Hz), 7.07-7.54 (8H, m).
[2342] MS: m/z=522 [M+H].sup.+
Reference Example 456
##STR00642##
[2344] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.13 (5H, d, J=6.3 Hz),
4.00 (1H, d, J=13.4 Hz), 4.52 (1H, d, J=13.6 Hz), 5.09 (1H, d,
J=13.3 Hz), 5.49-5.69 (4H, m), 6.84-7.51 (8H, m).
[2345] MS: m/z=506 [M+H]
Reference Example 457
##STR00643##
[2347] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40 (3H, d, J=7.2 Hz),
4.02 (1H, d, J=13.1 Hz), 4.53 (1H, d, J=13.3 Hz), 5.20 (1H, d,
J=12.9 Hz), 5.26 (1H, m), 5.67 (3H, m), 7.18 (8H, m).
[2348] MS: m/z=506 [M+H].sup.+
Reference Example 458
##STR00644##
[2350] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.15 (3H, d, J=7.3 Hz),
3.91 (1H, d, J=13.4 Hz), 4.39 (1H, d, J=13.3 Hz), 5.06 (1H, d,
J=13.3 Hz), 5.45 (1H, m), 5.62 (1H, s), 5.63 (1H, t, J=13.5 Hz),
5.74 (1H, d, J=7.6 Hz), 6.71-7.55 (8H, m).
[2351] MS: m/z=506 [M+H].sup.+
Reference Example 459
##STR00645##
[2353] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.39 (3H, d, J=7.4 Hz),
3.95 (1H, d, J=13.4 Hz), 4.46 (1H, d, J=12.9 Hz), 5.19 (1H, d,
J=13.1 Hz), 5.20 (1H, m), 5.41 (1H, s), 5.62 (1H, d, J=13.4 Hz),
5.76 (1H, d, J=7.7 Hz), 6.72-7.50 (8H, m).
[2354] MS: m/z=506 [M+H].sup.+
Reference Example 460
##STR00646##
[2356] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.42 (3H, d, J=7.2 Hz),
3.94 (1H, d, J=13.3 Hz), 4.50 (1H, d, J=13.1 Hz), 5.17 (1H, d,
J=12.4 Hz), 5.18 (1H, m), 5.39 (1H, s), 5.60-5.69 (2H, m),
6.87-7.42 (8H, m).
[2357] MS: m/z=506 [M+H].sup.+
Reference Example 461
##STR00647##
[2359] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35 (3H, d, J=7.2 Hz),
3.91 (1H, d, J=13.0 Hz), 4.43 (1H, d, J=13.1 Hz), 5.15 (1H, d,
J=12.8 Hz), 5.16 (1H, m), 5.41 (1H, s), 5.47 (1H, d, J=13.0 Hz),
5.69 (1H, d, J=7.6 Hz), 7.00-7.45 (8H, m).
[2360] MS: m/z=506 [M+H].sup.+
Reference Example 462
##STR00648##
[2362] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.21 (3H, d, J=7.3 Hz),
3.97 (1H, d, J=13.3 Hz), 4.46 (1H, d, J=13.1 Hz), 5.09 (1H, d,
J=13.6 Hz), 5.50 (1H, m), 5.51 (1H, d, J=12.8 Hz), 5.65 (1H, s),
5.72 (1H, d, J=7.6 Hz), 6.85-7.55 (7H, m).
[2363] MS: m/z=524 [M+H].sup.+
Reference Example 463
##STR00649##
[2365] MS: m/z=568 [M+H].sup.+
Reference Example 464
##STR00650##
[2367] MS: m/z=502 [M+H].sup.+
Reference Example 465
##STR00651##
[2369] MS: m/z=502 [M+H].sup.+
Reference Example 466
##STR00652##
[2371] MS: m/z=540 [M+H].sup.+
Reference Example 467
##STR00653##
[2373] MS: m/z=540 [M+H].sup.+
Reference Example 468
##STR00654##
[2375] .sup.1HNMR (CDCl.sub.3) .delta.: 1.13 (3H, d, J=5.8 Hz),
4.20 (1H, d, J=13.6 Hz), 4.58 (1H, d, J=12.7 Hz), 4.99 (1H, d,
J=12.7 Hz), 5.29-5.42 (3H, m), 5.84 (1H, d, J=7.8 Hz), 6.60 (1H,
m), 6.79-7.01 (3H, m), 7.19-7.28 (4H, m).
[2376] MS: m/z=524 [M+H].sup.+.
Reference Example 469
##STR00655##
[2378] .sup.1HNMR (CDCl.sub.3) .delta.: 1.19 (3H, d, J=7.6 Hz),
4.21 (1H, d, J=13.9 Hz), 4.48 (1H, d, J=13.3 Hz), 4.89 (1H, d,
J=13.3 Hz), 5.22 (1H, s), 5.37 (1H, dd, J=2.1, 13.9 Hz), 5.52 (1H,
m), 5.86 (1H, d, J=7.6), 6.55 (1H, m), 6.83 (1H, m), 6.96 (1H, m),
7.14 (1H, d, J=7.6 Hz), 7.19-7.30 (4H, m).
[2379] MS: m/z=524 [M+H].sup.+.
Reference Example 470
##STR00656##
[2381] .sup.1HNMR (CDCl.sub.3) .delta.: 1.19 (3H, d, J=7.3 Hz),
3.65 (1H, d, J=13.5 Hz), 4.47 (1H, d, J=13.0 Hz), 4.87 (1H, d,
J=13.0 Hz), 5.18 (1H, s), 5.50 (1H, m), 5.69 (1H, d, J=13.5 Hz),
5.85 (1H, d, J=7.8 Hz), 6.53 (1H, m), 6.83 (1H, m), 6.91-7.01 (2H,
m), 7.11 (1H, d, J=7.6 Hz), 7.10-7.20 (3H, m).
[2382] MS: m/z=524 [M+H].sup.+.
Reference Example 471
##STR00657##
[2384] .sup.1HNMR (CDCl.sub.3) .delta.: 1.13 (3H, d, J=6.1 Hz),
3.63 (1H, d, J=13.5 Hz), 4.56 (1H, d, J=12.5 Hz), 5.02 (1H, d,
J=12.5 Hz), 5.26 (1H, s), 5.38 (1H, m), 5.71 (1H, d, J=13.5 Hz),
5.81 (1H, d, J=7.8 Hz), 6.57 (1H, m), 6.81 (1H, m), 6.91 (1H, m),
6.99 (1H, dd, J=2.6, 8.2 Hz), 7.05 (1H, dd, J=2.6, 8.7 Hz), 7.17
(2H, m), 7.19 (1H, d, J=7.6 Hz).
[2385] MS: m/z=524 [M+H].sup.+.
Reference Example 472
##STR00658##
[2387] .sup.1HNMR (CDCl.sub.3) .delta.: 1.21 (3H, d, J=7.4 Hz),
3.66 (1H, d, J=13.5 Hz), 4.47 (1H, d, J=13.3 Hz), 4.88 (1H, d,
J=13.3 Hz), 5.17 (1H, s), 5.52 (1H, m), 5.66 (1H, d, J=13.5 Hz),
5.85 (1H, d, J=7.7 Hz), 6.54 (1H, m), 6.83 (1H, m), 6.95 (1H, m),
7.11-7.14 (2H, m), 7.23-7.29 (2H, m), 7.41 (1H, d, J=2.0 Hz).
[2388] MS: m/z=540 [M+H].sup.+.
Reference Example 473
##STR00659##
[2390] .sup.1HNMR (CDCl.sub.3) .delta.: 1.13 (3H, d, J=6.2 Hz),
3.63 (1H, d, J=13.5 Hz), 4.55 (1H, d, J=12.6 Hz), 5.04 (1H, d,
J=12.6 Hz), 5.25 (1H, s), 5.38 (1H, m), 5.69 (1H, d, J=13.5 Hz),
5.80 (1H, d, J=7.7 Hz), 6.58 (1H, m), 6.82 (1H, m), 6.92 (1H, m),
7.13 (1H, m), 7.19 (1H, d, J=7.7 Hz), 7.24-7.29 (2H, m), 7.34 (1H,
d, J=2.2 Hz).
[2391] MS: m/z=540 [M+H].sup.+.
Reference Example 474
##STR00660##
[2393] .sup.1HNMR (CDCl.sub.3) .delta.: 1.19 (3H, d, J=7.3 Hz),
4.40 (1H, d, J=13.9 Hz), 4.59 (1H, d, J=13.0 Hz), 5.02 (1H, d,
J=13.0 Hz), 5.31 (1H, s), 5.39 (1H, m), 5.66 (1H, d, J=13.9 Hz),
5.84 (1H, d, J=7.8 Hz), 6.58 (1H, m), 6.82 (1H, m), 6.92 (1H, m),
7.10 (1H, m), 7.19 (1H, dd, J=3.7, 7.9 Hz), 7.20-7.26 (2H, m), 7.51
(1H, m).
[2394] MS: m/z=540 [M+H].sup.+.
Reference Example 475
##STR00661##
[2396] MS: m/z=522 [M+H].sup.+.
Reference Example 476
##STR00662##
[2397] First Step
[2398] Compound 476A (3.00 g, 9.83 mmol) synthesized by the same
procedure as that of Reference example was dissolved in
dimethylformamide (30 ml), copper(I) cyanide (2.64 g, 29.5 mmol)
was added, and the mixture was stirred at 150.degree. C. for 7
hours. The reaction solution was cooled to room temperature, and
filtered with celite. To the filtrate was added water, the mixture
was extracted with ethyl acetate, and the organic layer was washed
with water. The solvent was distilled off under reduced pressure,
and the resulting crude product was purified by silica gel column
chromatography, and eluted with n-hexane-ethyl acetate (1:1, v/v).
To the resulting compound was added n-hexane, and the precipitated
residue was filtered to obtain 1.81 g of a white solid 476B.
[2399] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.29 (2H, s), 7.28-7.48
(4H, m), 7.78 (2H, t, J=7.5 Hz), 8.20 (1H, dd, J=8.1, 1.5 Hz).
Second Step
[2400] According to the same procedure as that of Reference example
107, compound 476 was synthesized.
[2401] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.16 (3H, d, J=7.0 Hz),
4.01 (1H, d, J=14.0 Hz), 4.65 (1H, d, J=13.7 Hz), 5.04 (1H, d,
J=13.3 Hz), 5.45 (1H, t, J=8.1 Hz), 5.66 (1H, d, J=7.6 Hz), 5.74
(1H, s), 5.84 (1H, d, J=14.0 Hz), 6.87-7.93 (7H, m).
[2402] MS: m/z=513 [M+H].sup.+
Reference Example 477
##STR00663##
[2403] First Step
[2404] To compound 476B (859 mg, 3.42 mmol) was added concentrated
sulfuric acid (13 ml), and the mixture was stirred at room
temperature for 18 hours, and at 60.degree. C. for 2 hours. The
reaction solution was added to water, the mixture was extracted
with ethyl acetate, and the organic layer was dried with sodium
sulfate. The solvent was concentrated under reduced pressure to
obtain 387 mg of a pale yellow solid. To the resulting compound was
added methanol (10 ml), a 10N aqueous sodium hydroxide solution (6
ml) was added, and the mixture was stirred at 90.degree. C. for 5
hours. The reaction solution was cooled to room temperature, water
was added, and the mixture was washed with dichloromethane. To the
aqueous layer was added dilute hydrochloric acid, the mixture was
extracted with ethyl acetate, and the organic layer was dried with
sodium sulfate. The solvent was concentrated under reduced pressure
to obtain 296 mg of a yellow solid 477A.
Second Step
[2405] Compound 477A (179 mg, 0.662 mmol) obtained in the first
step was dissolved in dichloromethane (4 ml), dimethylamine
hydrochloride (108 mg, 1.32 mmol), EDCI (190 mg, 0.993 mmol),
1H-benzo[d][1,2,3]triazol-1-ol (89.0 mg, 0.662 mmol) and
triethylamine (0.3 ml) were added, and the mixture was stirred at
room temperature for 2 hours. To the reaction solution was added
water, the mixture was extracted with ethyl acetate, and the
organic layer was washed with an aqueous sodium bicarbonate
solution, and dried with sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting crude product was
purified by silica gel column chromatography, and eluted with
n-hexane-ethyl acetate (1:1, v/v), to obtain 170 mg of a colorless
gummy substance 477B.
[2406] .sup.1H-NMR (CDCl3) .delta.: 2.99 (3H, s), 3.23 (3H, s),
4.08 (2H, s), 7.28-7.44 (5H, m), 7.58 (1H, t, J=4.4 Hz), 8.22 (1H,
dd, J=8.1, 1.5 Hz).
Third Step
[2407] According to the same procedure as that of Reference example
107, compound 477 was synthesized.
[2408] MS: m/z=559 [M+H].sup.+
Reference Example 478
##STR00664## ##STR00665##
[2409] First Step
[2410] Compound 277 (971 mg, 2.11 mmol) was dissolved in
dimethylformamide (10 ml), cesium carbonate (2.75 g, 8.45 mmol) and
benzyl bromide (0.753 ml, 6.34 mmol) were added, and the mixture
was stirred at room temperature for 4 hours. The reaction solution
was poured into water, then extracted with ethyl acetate, and the
organic layer was washed with water, and dried with sodium sulfate.
The solvent was distilled off under reduced pressure, to the
resulting compound were added dichloromethane-diethyl ether, and
the precipitated residue was filtered to obtain 740 mg of a white
solid 478A.
Second Step
[2411] Compound 478A (740 mg, 1.35 mmol) was dissolved in
tetrahydrofuran (7 ml) and methanol (7 ml), a 2N aqueous sodium
hydroxide solution (3.37 ml, 6.73 mmol) was added, and the mixture
was stirred at room temperature for 30 minutes. To the reaction
solution was added dilute hydrochloric acid to make the solution
acidic, the mixture was extracted with chloroform, and the organic
layer was dried with sodium sulfate. The solvent was concentrated
under reduced pressure to obtain 618 mg of a white solid 478B.
[2412] MS: m/z=508 [M+H]
Third Step
[2413] Compound 478B (505 mg, 0.995 mmol) was dissolved in
tetrahydrofuran (10 ml), triphenylphosphine (391 mg, 1.49 mmol),
phthalimide (220 mg, 1.49 mmol) and azodicarboxylic acid
diisopropyl ester (0.290 ml, 1.49 mmol) were added, and the mixture
was stirred at room temperature for 1 hour. The reaction solution
was concentrated under reduced pressure, and the resulting crude
product was purified by silica gel column chromatography, and
eluted with chloroform-methanol (97:3, v/v). To the resulting
compound were added dichloromethane-diethyl ether, and the
precipitated residue was filtered to obtain 578 mg of a white solid
478C.
[2414] MS: m/z=637 [M+H].sup.+
Fourth Step
[2415] To compound 478C (667 mg, 1.05 mmol) was added ethanol (10
ml), hydrazine hydrate (0.254 ml, 5.24 mmol) was added, and the
mixture was stirred at 90.degree. C. for 2 hours. The reaction
solution was cooled to room temperature, chloroform was added,
insolubles were removed by filtration, and the filtrate was
concentrated under reduced pressure. The resulting crude product
was purified by amino column chromatography, and eluted with
chloroform-methanol (97:3, v/v). To the resulting compound were
added dichloromethane-diethyl ether, and the precipitated residue
was filtered to obtain 462 mg of a white solid 478D.
[2416] MS: m/z=507 [M+H].sup.+
Fifth Step
[2417] To compound 478D (100 mg, 0.197 mmol) were added formic acid
(1.0 ml) and an aqueous formalin solution (1.0 ml), and the mixture
was stirred at 80.degree. C. for 1 hour. To the reaction solution
was added a 1N aqueous sodium hydroxide solution, the mixture was
extracted with dichloromethane, and the organic layer was dried
with sodium sulfate. The resulting crude product was purified by
amino column chromatography, and eluted with chloroform-methanol
(97:3, v/v), to obtain 56 mg of a colorless oily substance. This
compound was dissolved in acetic acid (2.0 ml), concentrated
sulfuric acid (0.5 ml) was added dropwise, and the mixture was
stirred at room temperature for 30 minutes. The reaction solution
was poured into an aqueous sodium bicarbonate solution, and was
extracted with chloroform, and the organic layer was dried with
sodium sulfate. The solvent was distilled off under reduced
pressure, to the resulting crude product were added
dichloromethane-ethyl acetate-diethyl ether, and the precipitated
residue was filtered to obtain 12 mg of a white solid 478.
[2418] MS: m/z=445 [M+H].sup.+
Reference Example 479
##STR00666##
[2419] First Step
[2420] To a dichloromethane (50 ml) solution of compound 479A (5.25
g, 11.8 mmol) synthesized according to Reference example 95, DIPEA
(6.20 mL, 35.5 mmol) and Boc2O (5.17 g, 23.7 mmol) was added DMAP
(434 mg, 3.55 mmol), and the mixture was stirred at room
temperature for 4 hours. After the reaction solution was
concentrated under reduced pressure, the residue was dissolved in
ethyl acetate. The solution was sequentially washed with 0.5N
aqueous hydrochloric acid solution and an aqueous saturated sodium
chloride solution, and dried with sodium sulfate. The solvent was
distilled off, and the resulting oil was purified by silica gel
chromatography. The materials were eluted firstly with chloroform
and, then, with chloroform-methanol (97:3, v/v). Concentration of
an objective fraction afforded 5.22 g of compound 479B as an
oil.
[2421] MS: m/z=544 [M+H].sup.+.
Second Step
[2422] To a THF (340 mL) solution of compound 479B (29.7 g, 102
mmol) and acetic acid (29.7 g, 102 mmol) was added TBAF (1M THF
solution, 23.6 g, 310 mmol) under ice-cooling, and the mixture was
stirred at room temperature for 16 hours. To the reaction solution
were added ethyl acetate and water, and the ethyl acetate layer was
separated, washed with water, and dried with sodium sulfate. The
solvent was distilled off, and the resulting oil was solidified by
adding dichloromethane-ether, to obtain 2.76 g of compound
479C.
[2423] MS: m/z=430 [M+H].sup.+.
Third Step
[2424] To an ethyl acetate (20 mL) suspension of compound 479C (500
mg, 1.16 mmol) was added IBX (652 mg, 2.33 mmol), and the mixture
was heated to stir for 3 hours. After the reaction solution was
diluted with ethyl acetate, insolubles were filtered, and the
resulting filtrate was sequentially washed with a 1N aqueous sodium
hydroxide solution and water, and dried with sodium sulfate. After
the solvent was distilled off, and the resulting oil was dissolved
in THF (5 mL), dimethylamine (2M THF solution, 0.873 mL, 1.75 mmol)
and NaBH(OAc).sub.3 (370 mg, 1.75 mmol) were added under
ice-cooling, and the mixture was stirred at room temperature for
1.5 hours. After 2N aqueous hydrochloric acid solution was added to
the reaction solution under ice-cooling, the mixture was made basic
with an aqueous sodium bicarbonate solution. This was extracted
with chloroform, and dried with sodium sulfate. The solvent was
distilled off, and the resulting oil was purified by silica gel
chromatography. The materials were eluted firstly with chloroform
and, then, with chloroform-methanol (93:7, v/v). Concentration of
an objective fraction afforded 437 mg of compound 479D as an
amorphous substance.
[2425] MS: m/z=457 [M+H].sup.+.
Fourth Step
[2426] Compound 479D (430 mg, 0.942 mmol) was dissolved in acetic
acid (10 mL), and the solution was heated to stir for 1 hour. The
solvent was distilled off, and the resulting oil was purified by
silica gel chromatography. The materials were eluted firstly with
chloroform and, then, with chloroform-methanol (95:5, v/v).
Concentration of an objective fraction afforded 330 mg of compound
479E as an oil.
[2427] MS: m/z=357 [M+H].sup.+.
Fifth Step
[2428] To an acetic acid (2 mL) solution of compound 479E (50 mg,
0.140 mmol) and dibenzosuberol (29.5 mg, 0.140 mmol) was added
dropwise sulfuric acid (0.5 mL), and the mixture was stirred for 30
minutes. To the reaction solution were added ethyl acetate and
water, thereafter, the aqueous layer was separated, and neutralized
with an aqueous sodium bicarbonate solution. Extraction was
performed using the ethyl acetate layer, and the extract was washed
with water, and dried with sodium sulfate. The solvent was
distilled off, and the resulting oil was solidified by adding
ether, to obtain 17.0 mg of compound 479.
[2429] MS: m/z=354 [M+H].sup.+.
[2430] According to Reference example 478 or Reference example 479,
compounds were synthesized as compounds of Reference examples 480
to 490 using the same procedure.
Reference Example 480
##STR00667##
[2432] MS: m/z=477 [M+H].sup.+.
Reference Example 481
##STR00668##
[2434] MS: m/z=512 [M+H].sup.+.
Reference Example 482
##STR00669##
[2436] MS: m/z=501 [M+H].sup.+.
Reference Example 483
##STR00670##
[2438] MS: m/z=519 [M+H].sup.+.
Reference Example 484
##STR00671##
[2440] MS: m/z=514 [M+H].sup.+.
Reference Example 485
##STR00672##
[2442] MS: m/z=532 [M+H].sup.+
Reference Example 486
##STR00673##
[2444] MS: m/z=499 [M+H].sup.+.
Reference Example 487
##STR00674##
[2446] MS: m/z=517 [M+H].sup.+.
Reference Example 488
##STR00675##
[2448] MS: m/z=517 [M+H].sup.+.
Reference Example 489
##STR00676##
[2450] MS: m/z=535 [M+H].sup.+.
Reference Example 490
##STR00677##
[2452] MS: m/z=473 [M+H].sup.+
Reference Example 491
##STR00678##
[2454] According to Reference example 65 and Reference example 107,
compound 491 was synthesized by the same procedure.
[2455] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.10 (3H, d, J=4.0 Hz),
1.12 (3H, d, J=4.6 Hz), 2.82-3.06 (2H, m), 3.56 (1H, d, J=17.8 Hz),
4.26 (1H, d, J=13.2 Hz), 4.31 (1H, m), 4.51-4.60 (1H, m), 4.97 (1H,
d, J=13.1 Hz), 5.39 (1H, s), 6.74-7.52 (8H, m).
[2456] MS: m/z=460 [M+H].sup.+
Reference Example 492
##STR00679##
[2458] According to Reference example 65 and Reference example 107,
compound 492 was synthesized by the same procedure.
[2459] MS: m/z=478 [M+H].sup.+
Reference Example 493
##STR00680##
[2460] First Step
[2461] A dichloromethane (5 mL) solution of compound 493A (258 mg,
1.30 mmol) was cooled to -50.degree. C., and a toluene solution
(1M, 1.96 mL) of DIBAL-H was added dropwise over 5 minutes while
the same temperature was retained. After the reaction solution was
stirred at the same temperature for 1 hour, temperature was raised
to room temperature, and the mixture was stirred for 2.5 hours. To
the reaction solution was added an aqueous saturated ammonium
chloride solution, thereafter, the mixture was stirred at room
temperature for 1 hour, and insolubles were removed by filtration.
The dichloromethane layer was separated, and the aqueous layer was
extracted with dichloromethane once. The combined extracts were
washed with water three times, washed with an aqueous saturated
sodium chloride solution, and dried. The solvent was distilled off,
and the resulting oil was subjected to silica gel column
chromatography, and eluted with n-hexane-ethyl acetate.
Concentration of an objective fraction afforded 148 mg of compound
493B as an oil.
[2462] .sup.1HNMR (CDCl.sub.3) .delta.: 1.03-1.44 (5H, m),
1.63-1.83 (5H, m), 2.05-2.13 (1H, m), 3.25 (1H, dd, J=9.5 Hz, 3.4
Hz), 7.16-7.19 (2H, ms), 7.27-7.38 (3H, m), 9.69 (1H, d, J=3.5
Hz).
Second Step
[2463] According to Reference example 177, compound 493 was
synthesized by the same procedure.
[2464] MS: m/z=410 [M+H].sup.+
[2465] Using aldehydes which are commercially available or known in
the references and hydrazines which are commercially available or
known in the references, and according to Reference example 493,
compounds 494 to 505 were synthesized.
Reference Example 494
##STR00681##
[2467] MS: m/z=428 [M+H].sup.+
Reference Example 495
##STR00682##
[2469] MS: m/z=420 [M+H].sup.+.
Reference Example 496
##STR00683##
[2471] MS: m/z=376 [M+H].sup.+.
Reference Example 497
##STR00684##
[2473] MS: m/z=500 [M+H].sup.+.
Reference Example 498
##STR00685##
[2475] MS: m/z=404 [M+H].sup.+.
Reference Example 499
##STR00686##
[2477] MS: m/z=382 [M+H].sup.+.
Reference Example 500
##STR00687##
[2479] MS: m/z=382 [M+H].sup.+.
Reference Example 501
##STR00688##
[2481] MS: m/z=368 [M+H].sup.+.
Reference Example 502
##STR00689##
[2483] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.94 (3H, t, J=7.2 Hz),
1.26 (3H, t, J=7.3 Hz), 2.87-2.94 (2H, m), 3.10-3.22 (1H, m),
3.79-3.89 (1H, m), 3.98 (1H, d, J=16.9 Hz), 4.17 (1H, d, J=16.8
Hz), 4.28 (1H, d, J=9.8 Hz), 6.04 (1H, d, J=7.2 Hz), 6.54 (2H, t,
J=8.1 Hz), 6.73 (1H, d, J=9.8 Hz), 6.95-7.33 (6H, m), 7.66 (1H, dd,
J=5.3, 3.6 Hz).
[2484] MS: m/z=448 [M+H].sup.+.
Reference Example 503
##STR00690##
[2486] MS: m/z=374 [M+H].sup.+.
Reference Example 504
##STR00691##
[2488] MS: m/z=374 [M+H].sup.+.
Reference Example 505
##STR00692##
[2490] MS: m/z=342 [M+H].sup.+.
Reference Example 506
##STR00693##
[2492] According to Reference example 177, using compound 65B,
compound 506 was synthesized by the same procedure.
[2493] MS: m/z=470 [M+H].sup.+.
Reference Example 507
##STR00694##
[2495] According to Reference example 65, using compound 506,
compound 507 was synthesized by the same procedure.
[2496] MS: m/z=446 [M+H].sup.+.
Reference Example 508
##STR00695## ##STR00696##
[2497] First Step
[2498] Compound 508A (261 mg, 0.475 mmol) which is a synthetic
intermediate of Reference example 491 was dissolved in
dimethylformamide (3 ml), triethylamine (0.132 ml, 0.950 mmol) and
ethyl chloroformate (0.0910 ml, 0.950 mmol) were added at 0.degree.
C., and the mixture was stirred at room temperature for 20 minutes.
An aqueous solution (0.5 ml) of sodium borohydride (71.9 mg, 1.90
mmol) was added at 0.degree. C., and the mixture was stirred for 30
minutes. The reaction solution was poured into water, the mixture
was extracted with ethyl acetate, and the organic layer was dried
with sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting crude product was purified by silica
gel column chromatography, and eluted with chloroform-methanol
(97:3, v/v). Diethyl ether was added, and the precipitated residue
was filtered to obtain 107 mg of a white solid 508B.
[2499] MS: m/z=536 [M+H].sup.+
Second Step
[2500] Compound 508B (100 mg, 0.187 mmol) obtained in the first
step was dissolved in dichloromethane (1 ml), DAST (33.1 mg, 0.205
mmol) was added at 0.degree. C., and the mixture was stirred for 30
minutes. The reaction solution was poured into water, the mixture
was extracted with chloroform, and the organic layer was dried with
sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting crude product was purified by silica
gel column chromatography, and eluted with chloroform-methanol
(97:3, v/v), to obtain 28 mg of a pale yellow gummy substance
508C.
[2501] MS: m/z=538 [M+H].sup.+
Third Step
[2502] To compound 508C obtained in the second step were added
acetic acid (2 ml) and concentrated sulfuric acid (0.5 ml), and the
mixture was stirred at room temperature for 20 minutes. The
reaction solution was poured into water, the mixture was extracted
with ethyl acetate, and the organic layer was dried with sodium
sulfate. Diethyl ether was added, and the precipitated residue was
filtered to obtain 4.5 mg of a white solid 508.
[2503] MS: m/z=448 [M+H].sup.+
Reference Example 509
##STR00697##
[2505] According to Reference example 508, compound 509 was
synthesized by the same procedure.
[2506] MS: m/z=466 [M+H].sup.+
Reference Example 510
##STR00698## ##STR00699##
[2507] First Step
[2508] Compound 510A (36.8 g, 259 mmol) was dissolved in
dimethylformamide (380 ml), potassium carbonate (39.3 g, 285 mmol)
and benzyl bromide (30.7 ml, 259 mmol) were added, and the mixture
was stirred at 80.degree. C. for 8 hours. The reaction was cooled
to room temperature, insolubles were removed by filtration, and the
solvent was distilled off under reduced pressure. Water was added,
and the precipitated residue was filtered, and dried under reduced
pressure to obtain 46.21 g of a pale brown solid 510B.
Second Step
[2509] To compound 510B (4.79 g, 20.6 mmol) obtained in the first
step was added dichloromethane (70 ml), triethylamine (4.29 ml,
30.9 mmol) and methanesulfonyl chloride (1.93 ml, 24.8 mmol) were
added at 0.degree. C., and the mixture was stirred for 30 minutes.
The reaction solution was poured into an aqueous saturated sodium
chloride solution, the mixture was extracted with dichloromethane,
the extract was dried with sodium sulfate, and the solvent was
distilled off under reduced pressure. To the resulting compound
were added n-hexane-dichloromethane, and the precipitated residue
was filtered to obtain 6.56 g of a white solid. This compound was
dissolved in acetonitrile (40 ml), tetrabutylammonium fluoride (75%
aqueous solution, 21.6 g, 61.9 mmol) was added, and the mixture was
stirred at room temperature for 18 hours. The solvent was distilled
off under reduced pressure, ethyl acetate was added, and the
mixture was washed with an aqueous sodium bicarbonate solution. The
organic layer was dried with sodium sulfate, and distilled off
under reduced pressure, and the resulting crude product was
purified by silica gel column chromatography, and eluted with
n-hexane-ethyl acetate (1:1, v/v), to obtain 2.51 g of a white
solid 510C.
[2510] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.96 (3H, s), 5.30 (3H,
d, J=46.4 Hz), 6.56 (1H, d, J=1.8 Hz), 7.39 (5H, m), 8.30 (1H,
s).
Third Step
[2511] Compound 510C (2.40 g, 10.3 mmol) obtained in the second
step was dissolved in dichloromethane (40 ml), boron tribromide (1M
dichloromethane solution, 10.3 ml, 10.3 mmol) was added dropwise at
0.degree. C., and the mixture was stirred for 30 minutes. Methanol
was added, the solvent was distilled off under reduced pressure,
ethyl acetate was added, and the mixture was washed with an aqueous
saturated sodium chloride solution. The organic layer was dried
with sodium sulfate, the solvent was distilled off under reduced
pressure, and the resulting solid was washed with diethyl ether to
obtain 940 mg of 510D.
[2512] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.20 (2H, d, J=46.3 Hz),
6.40 (1H, s), 6.62 (1H, s), 7.91 (1H, s).
Fourth Step
[2513] Compound 510D (940 mg, 6.52 mmol) obtained in the third step
was dissolved in methanol (8 ml), a 2N aqueous sodium hydroxide
solution (3.26 ml, 6.52 mmol) and a 37% aqueous formaldehyde
solution (1.46 ml, 19.6 mmol) were added at 0.degree. C., and the
mixture was stirred at room temperature for 20 hours. To the
reaction solution was added an aqueous saturated ammonium chloride
solution, and the solvent was distilled off under reduced pressure.
Hydrochloric acid was added, the mixture was extracted with
chloroform, and the organic layer was dried with sodium sulfate.
The solvent was distilled off under reduced pressure, to the
resulting compound were added n-hexane-dichloromethane-ethyl
acetate, and the precipitated residue was filtered to obtain 858 mg
of a pale yellow solid 510E.
[2514] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.73 (2H, s), 5.19 (2H, d,
J=46.1 Hz), 6.55 (1H, s).
Fifth Step
[2515] Compound 510E (855 mg, 4.91 mmol) obtained in the fourth
step was dissolved in dimethylformamide (10 ml), potassium
carbonate (746 mg, 5.40 mmol) and benzyl bromide (0.583 ml, 4.91
mmol) were added, and the mixture was stirred at 80.degree. C. for
5 hours. Insolubles were removed by filtration, and the filtrate
was distilled off under reduced pressure. The resulting crude
product was purified by silica gel column chromatography, and
eluted with chloroform-methanol (97:3, v/v), to obtain 887 mg of a
pale orange solid 510F.
[2516] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39 (1H, t, J=7.1 Hz),
4.31 (2H, d, J=7.2 Hz), 5.12 (2H, dd, J=46.3, 0.7 Hz), 5.23 (2H,
s), 6.50 (1H, s), 7.33-7.43 (5H, m).
Sixth Step
[2517] Compound 510F (887 mg, 3.36 mmol) obtained in the fifth step
was dissolved in chloroform, manganese dioxide (2.00 g, 23.0 mmol)
was added, and the mixture was stirred at 80.degree. C. for 2
hours. After cooled to room temperature, the mixture was filtered
with celite, and the solvent was distilled off under reduced
pressure to obtain 812 mg of a white solid 510G.
[2518] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.18 (2H, dd, J=45.8, 0.8
Hz), 5.52 (2H, s), 6.60 (1H, d, J=0.8 Hz), 7.32-7.38 (5H, m), 9.86
(1H, s).
Seventh Step
[2519] To compound 510G (884 mg, 3.37 mmol) obtained in the sixth
step were added acetonitrile and water, monosodium dihydrogen
phosphate (809 mg, 6.74 mmol) and sodium hypochlorite (1.01 g, 11.1
mmol) were added, and the mixture was stirred at room temperature
for 1 hour. The reaction solution was concentrated, pH was adjusted
to 3 with hydrochloric acid, the mixture was extracted with
chloroform, and the extract was dried with sodium sulfate. The
solvent was distilled off under reduced pressure to obtain 404 mg
of a white solid 510H.
[2520] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 5.17 (2H, s), 5.38 (2H,
d, J=46.2 Hz), 6.73 (1H, d, J=1.5 Hz), 7.34-7.51 (5H, m).
Eighth Step
[2521] Compound 51OH (402 mg, 1.45 mmol) obtained in the seventh
step was dissolved in dimethylformamide,
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (554 mg, 2.89 mmol) and
1H-benzo[d][1,2,3]triazol-1-ol (195 mg, 1.45 mmol) were added, and
the mixture was stirred at room temperature for 5 minutes. After
propan-2-amine (0.149 ml, 1.73 mmol) was added, the mixture was
stirred at room temperature for 1 hour. The reaction solution was
concentrated under reduced pressure, water was added, the mixture
was extracted with ethyl acetate, and the organic layer was washed
with an aqueous sodium bicarbonate solution, and dried with sodium
sulfate. The reaction solution was distilled off under reduced
pressure, to the resulting compound was added n-hexane, and the
precipitated residue was filtered to obtain 3.56 g of a white solid
5101.
[2522] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.98 (6H, d, J=6.6 Hz),
4.05 (1H, m), 5.24 (2H, dd, J=45.9, 0.9 Hz), 5.41 (2H, s), 6.59
(1H, q, J=0.9 Hz), 7.40 (5H, m), 7.56 (1H, brs).
Ninth Step
[2523] Compound 510I (392 mg, 1.23 mmol) obtained in the eighth
step was dissolved in ethanol (6 ml), aqueous ammonia (4 ml) was
added, and the mixture was stirred at room temperature for 15
hours. The reaction solution was concentrated under reduced
pressure, and the resulting crude product was purified by silica
gel column chromatography, and eluted with chloroform-methanol
(97:3, v/v), to obtain 333 mg of a white solid 510J.
[2524] MS: m/z=319 [M+H].sup.+
Tenth Step
[2525] Compound 510 was synthesized by the same procedure as that
of Reference example 95.
[2526] MS: m/z=422 [M+H].sup.+
Reference Example 511
##STR00700##
[2527] First Step
[2528] A dichloromethane (90 mL) solution of compound 511A (200 mg,
0.664 mmol) and 1,1,3-trimethoxypropane (178.2 mg, 1.33 mmol) was
cooled to 1 to 3.degree. C., and a boron trifluoride diethyl ether
complex (113 mg, 0.797 mmol) was added dropwise while the same
temperature was retained. After the reaction solution was stirred
at the same temperature for 30 minutes, saturated sodium
bicarbonate water was added. The dichloromethane layer was
separated, and the aqueous layer was extracted with dichloromethane
three times. After the combined extracts were dried with sodium
sulfate, the solvent was distilled off, and the resulting oil was
purified by silica gel column chromatography. The materials were
eluted firstly with ethyl acetate and, then, with ethyl
acetate-methanol (3:2, v/v). Concentration of an objective fraction
afforded 179.2 mg of compound 511B as an oil.
[2529] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (6H, d, J=6.3 Hz),
2.71 (2H, dd, J=6.0 Hz), 3.34 (3H, s), 3.64 (2H, t, J=6.0 Hz),
4.06-4.17 (1H, m), 5.23 (2H, s), 6.34 (1H, brs), 6.37 (1H, d, J=7.8
Hz), 7.26-7.43 (6H, m), 7.90 (1H, t, J=5.4 Hz).
Second Step
[2530] A dimethylformamide (3 ml) solution of compound 511B (179.2
mg, 0.482 mmol) was cooled to 1 to 3.degree. C., cesium carbonate
(786 mg, 2.41 mmol) was added while the same temperature was
retained, and the mixture was stirred at the same temperature for
15 minutes. The reaction solution was diluted with water, and
extracted with chloroform three times. After the combined extracts
were dried with sodium sulfate, the solvent was distilled off to
obtain 130 mg of compound 511C as a solid.
[2531] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (3H, d, J=6.9 Hz),
1.28 (3H, d, J=6.9 Hz), 1.59 (2H, brs), 3.22-3.41 (2H, m), 3.12
(3H, s), 4.57-4.70 (2H, m), 5.19 (1H, d, J=10.5 Hz), 5.38 (1H,
brs), 5.54 (1H, d, J=10.5 Hz), 6.34 (1H, d, J=7.8 Hz), 7.26-7.32
(4H, m), 7.49-7.52 (2H, m).
Third Step
[2532] To an acetic acid (2 ml) solution of compound 511C (130 mg,
0.350 mmol) and dibenzosuberol (368 mg, 1.75 mmol) was added
dropwise sulfuric acid (0.4 ml) at room temperature, and the
mixture was stirred at the same temperature for 30 minutes. The
reaction solution was diluted with water, and the mixture was
extracted with ethyl acetate three times. The extract was washed
with water once, and dried with sodium sulfate, thereafter, the
solvent was distilled off, and the resulting solid was washed with
diisopropyl ether to obtain 65 mg of compound 511 as a solid.
[2533] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27 (3H, d, J=6.9 Hz),
1.49 (3H, d, J=6.6 Hz), 1.64-1.74 (1H, m), 1.88-1.99 (1H, m), 2.83
(1H, d, J=4.5 Hz, 4.5 Hz, 9.3 Hz), 3.06 (1H, ddd, J=5.6 Hz, 13.2
Hz, 13.2 Hz), 3.19 (3H, s), 3.30-3.44 (1H, m), 3.50-3.57 (1H, m),
3.78-3.92 (1H, m), 4.28 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 4.53
(1H, dd, J=3.3 Hz, 10.8 Hz), 4.96 (1H, s), 5.73 (1H, d, J=7.5 Hz),
6.61 (1H, d, J=7.5 Hz), 6.65 (1H, d, J=7.5 Hz), 6.89-6.93 (1H, m),
7.08-7.36 (6H, m).
[2534] Using amines which are commercially available or known in
the references and acetals which are commercially available or
known in the references, and according to Reference example 511,
compounds 512 to 515 were synthesized.
Reference Example 512
##STR00701##
[2536] MS: m/z=528 [M+H].sup.+
Reference Example 513
##STR00702##
[2538] MS: m/z=528 [M+H].sup.+
Reference Example 514
##STR00703##
[2540] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.27 (1H, 3H, d, J=6.9
Hz), 1.48 (3H, d, J=6.6 Hz), 1.95 (3H, s), 2.63-2.68 (2H, m), 2.84
(1H, ddd, J=4.8 Hz, 9.3 Hz, 9.3 Hz), 3.05 (1H, ddd, J=4.2 Hz, 13.2
Hz, 13.2 Hz), 3.60 (1H, ddd, J=4.8 Hz, 4.8 Hz, 17.4 Hz), 3.87-3.98
(1H, m), 4.42 (1H, dd, J=6.6 Hz, 8.1 Hz), 4.59 (1H, ddd, J=4.2 Hz,
13.5 Hz, 13.5 Hz), 4.93 (1H, s), 5.77 (1H, d, J=7.8 Hz), 6.64 (1H,
d, J=6.9 Hz), 6.69 (1H, d, J=7.8 Hz), 6.91 (1H, t, J=6.0 Hz),
7.09-7.38 (6H, m).
Reference Example 515
##STR00704##
[2542] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (3H, d, J=6.9 Hz),
1.44 (3H, d, J=6.9 Hz), 2.80 (1H, ddd, J=4.5 Hz, 4.5 Hz, 9.3 Hz),
3.07 (1H, ddd, J=4.5 Hz, 13.5 Hz, 13.5 Hz), 3.25 (3H, s), 3.22-3.43
(2H, m), 3.55 (1H, ddd, J=4.2 Hz, 4.2 Hz, 8.7 Hz), 3.85-3.94 (1H,
m), 4.36 (1H, dd, J=5.1 Hz, 14.1 Hz), 4.42-4.48 (1H, m), 4.92 (1H,
s), 5.78 (1H, d, J=7.5 Hz), 6.59 (1H, d, J=7.8 Hz), 6.64 (1H, d,
J=7.5 Hz), 6.91 (1H, t, J=6.9 Hz), 7.09-7.36 (6H, m).
Reference Example 516
##STR00705##
[2543] First Step
[2544] To a toluene (3 ml) solution of compound 516A (100 mg, 0.332
mmol) and 3-(methylthio)propanal (52 mg, 0.498 mmol) was added
acetic acid (30 mg, 0.500 mmol), and the mixture was refluxed for
30 minutes. After cooled to room temperature, the solvent was
distilled off, and the resulting crude product was dissolved in
dimethylformamide (3 ml). The solution was cooled to 1 to 3.degree.
C., cesium carbonate (541 mg, 1.66 mmol) was added while the same
temperature was retained, and the mixture was stirred at the same
temperature for 30 minutes. The reaction solution was diluted with
water, and the mixture was extracted with ethyl acetate three
times. The combined extracts were washed with water three times,
and dried with sodium sulfate, and the solvent was distilled off.
The resulting oil was purified by silica gel column chromatography.
The materials were eluted firstly with ethyl acetate and, then,
with ethyl acetate-methanol (7:3, v/v). Concentration of an
objective fraction afforded 84.7 mg of compound 516B as an oil.
[2545] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (3H, J=6.9 Hz), 1.28
(3H, d, J=6.9 Hz), 1.31-1.56 (2H, m), 2.05 (3H, s), 2.46 (2H, dd,
J=5.4 Hz, 7.8 Hz), 4.57-4.71 (2H, m), 5.18 (1H, d, J=10.5 Hz), 5.51
(1H, d, J=10.5 Hz), 5.66 (1H, brs), 6.33 (1H, d, J=7.8 Hz),
7.19-7.35 (4H, m), 7.46-7.49 (2H, m).
Second Step
[2546] Compound 516 was synthesized by the same procedure as that
of Reference example 511.
[2547] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, d, J=6.9 Hz),
1.49 (3H, d, J=6.6 Hz), 1.82-1.89 (2H, m), 1.99 (3H, s), 2.41-2.58
(2H, m), 2.86 (1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz), 2.99-3.11 (1H,
m), 3.53 (1H, ddd, J=4.5 Hz, 4.5 Hz, 17.7 Hz), 4.87-3.96 (1H, m),
4.21 (1H, ddd, J=3.9 Hz, 12.9 Hz, 12.9 Hz), 4.53 (1H, dd, J=5.1 Hz,
8.7 Hz), 4.96 (1H, s), 5.74 (1H, d, J=7.5 Hz), 6.62 (1H, d, J=7.5
Hz), 6.64 (1H, d, J=9.0 Hz), 6.89-6.94 (1H, m), 7.07-7.37 (6H,
m).
[2548] Using amines which are commercially available or known in
the references and aldehydes which are commercially available or
known in the references, and according to Reference example 516,
compounds 517 to 526 were synthesized.
Reference Example 517
##STR00706##
[2550] MS: m/z=500 [M+H].sup.+
Reference Example 518
##STR00707##
[2552] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.78 (3H, t, J=6.9 Hz),
1.19-1.30 (1H, m), 1.29 (3H, d, J=6.9 Hz), 1.43-1.62 (3H, m), 1.50
(3H, d, J=6.9 Hz), 2.84 (1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz),
3.00-3.11 (1H, ddd, J=3.9 Hz, 12.9 Hz, 12.9 Hz), 3.52 (1H, ddd,
J=4.5 Hz, 4.5 Hz, 17.4 Hz), 3.79-3.88 (1H, m), 4.23-4.35 (2H, m),
4.96 (1H, s), 5.74 (1H, d, J=7.8 Hz), 6.61 (1H, d, J=7.5 Hz), 6.65
(1H, dd, J=1.2 Hz, 7.8 Hz), 6.91 (1H, ddd, J=1.5 Hz, 7.5 Hz, 7.5
Hz), 7.08-7.37 (6H, m).
Reference Example 519
##STR00708##
[2554] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, d, J=6.9 Hz),
1.54 (3H, d, J=6.6 Hz), 1.88 (1H, ddd, J=3.9 Hz, 3.9 Hz, 14.4 Hz),
2.72 (1H, ddd, J=3.6 Hz, 14.1 Hz, 14.1 Hz), 3.15 (1H, ddd, J=4.2
Hz, 4.2 Hz, 16.5 Hz), 3.54 (1H, dd, J=3.0 Hz, 14.4 Hz), 3.66 (1H,
ddd, J=3.9 Hz, 13.8 Hz, 13.8 Hz), 4.03 (1H, dd, J=10.5 Hz, 14.1
Hz), 4.27-4.26 (1H, m), 4.64 (1H, dd, J=2.7 Hz, 10.5 Hz), 4.92 (1H,
s), 5.80 (1H, d, J=7.8 Hz), 6.62-6.70 (2H, m), 6.69 (1H, d, J=7.8
Hz), 6.89 (1H, t, J=7.5 Hz), 6.96 (1H, d, J=7.5 Hz), 7.09-7.25 (4H,
m), 7.77-7.89 (4H, m).
Reference Example 520
##STR00709##
[2556] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, d, J=6.6 Hz),
1.54 (3H, d, J=6.6 Hz), 2.83 (1H, ddd, J=4.8 Hz, 4.8 Hz, 14.1 Hz),
3.03-3.14 (1H, m), 3.21 (3H, s), 3.30 (3H, s), 3.53 (1H, ddd, J=4.5
Hz, 4.5 Hz, 17.7 Hz), 3.61-3.70 (1H, m), 4.18 (1H, d, J=5.4 Hz),
4.26 (1H, d, J=5.4 Hz), 4.45 (1H, ddd, J=4.5 Hz, 13.8 Hz, 13.8 Hz),
4.92 (1H, s), 5.72 (1H, d, J=7.8 Hz), 6.63 (1H, d, J=7.8 Hz), 6.65
(1H, d, J=6.6 Hz), 6.91 (1H, t, J=6.0 Hz), 7.08-7.36 (6H, m).
Reference Example 521
##STR00710##
[2558] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (2.52H, d, J=6.9 Hz),
1.36 (0.48H, d, J=6.9 Hz), 1.42 (0.48H, d, J=6.9 Hz), 1.50 (2.52H,
d, J=6.9 Hz), 1.74-1.98 (1H, m), 2.00-2.12 (1H, m), 2.16-2.35 (1H,
m), 2.89 (1H, ddd, J=5.1 Hz, 5.1 Hz, 13.5 Hz), 3.06 (1H, ddd, J=3.9
Hz, 12.9 Hz, 12.9H), 3.52 (1H, d, J=4.2 Hz, 4.2 Hz, 17.4 Hz),
3.86-3.96 (1H, m), 4.15 (1H, ddd, J=3.9 Hz, 13.5 Hz, 13.5 Hz), 4.32
(1H, dd, J=3.9 Hz, 10.8 Hz), 4.48-4.64 (1H, m), 4.97 (0.84H, s),
5.30 (0.16H, s), 5.73 (0.84H, d, J=7.8 Hz), 6.20 (0.16H, d, J=7.5
Hz), 6.45 (0.16H, brs), 6.61 (1H, d, J=7.5 Hz), 6.64 (0.84H, d,
J=8.7 Hz), 6.92 (1H, t, J=6.3 Hz), 7.10 (1H, d, J=7.5 Hz),
7.15-7.39 (3H, m).
Reference Example 522
##STR00711##
[2560] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.28 (3H, d, J=6.9 Hz),
1.49 (3H, d, J=6.9 Hz), 1.54-1.79 (4H, m), 2.84 (1H, ddd, J=4.8 Hz,
4.8 Hz, 14.1 Hz), 3.05 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 3.17
(3H, s), 3.17-3.21 (2H, m), 3.52 (1H, ddd, J=4.2 Hz, 4.2 Hz, 17.7
Hz), 3.83-3.92 (1H, m), 4.22-4.32 (2H, m), 4.96 (1H, s), 5.73 (1H,
d, J=7.5 Hz), 6.62 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=8.1 Hz), 6.92
(1H, t, J=7.2 Hz), 7.07-7.37 (6H, m).
Reference Example 523
##STR00712##
[2562] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19-1.28 (1H, m), 1.28
(3H, d, J=6.9 Hz), 1.40-1.82 (4H, m), 1.48 (3H, d, J=6.6 Hz),
2.89-3.00 z81H, m), 3.17 (3H, s), 3.20-3.27 (2H, m), 3.31-3.40 (1H,
m), 3.44-3.53 (1H, m), 3.86-3.98 (2H, m), 4.38 (1H, dd, J=3.6 Hz,
10.5 Hz), 5.05 (1H, s), 5.84 (1H, d, 7.5 Hz), 6.48-6.50 (1H, m),
6.66-6.69 (1H, m), 6.89-7.00 (2H, m), 7.05 (1H, d, 7.2 Hz),
7.11-7.24 (2H, m).
Reference Example 524
##STR00713##
[2564] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, d, J=6.9 Hz),
1.42-1.83 (4H, m), 1.48 (3H, d, J=6.6 Hz), 2.80 (1H, ddd, J=4.5 Hz,
4.5 Hz), 14.4H), 2.94-3.11 (1H, m), 3.18 (3H, s), 3.21-3.26 (2H,
m), 3.49 (1H, ddd, J=4.2 Hz, 4.2 Hz, 18.0 Hz), 3.82-3.91 (1H, m),
4.20-4.33 (2H, m), 5.83 (1H, s), 5.84 (1Hm d, J=7.8 Hz), 6.58-6.72
(2H, m), 6.91-6.94 (1H, m), 7.11-7.30 (4H, m).
Reference Example 525
##STR00714##
[2566] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, d, J=6.9 Hz),
1.47 (3H, d, J=6.6 Hz), 2.10 (3H, s), 2.78 (1H, ddd, J=4.2 Hz, 4.2
Hz, 13.8 Hz), 2.97 (3H, s), 3.01-3.13 (2H, m), 3.47 (1H, ddd, J=4.2
Hz, 4.2 Hz, 17.7 Hz), 3.65 (1H, dd, J=3.3 Hz, 14.1 Hz), 3.99-4.23
(2H, m), 4.70 (1H, dd, J=3.3 Hz, 10.2 Hz), 4.95 (1H, s), 5.78 (1H,
d, J=7.8 Hz), 6.61 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=7.5 Hz), 6.93
(1H, t, J=6.6 Hz), 7.09 (1H, d, J=7.5 Hz), 7.15-7.27 (4H, m),
7.30-7.37 (1H, m).
Reference Example 526
##STR00715##
[2568] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.57-1.34 (1H, m), 1.29
(3H, d, J=6.9 Hz), 1.41-1.52 (1H, m), 1.48 (3H, d, J=6.6 Hz),
1.59-1.81 (2H, m), 2.80 (1H, ddd, 4.5 Hz, 4.5 Hz, 14.4 Hz), 3.04
(1H, ddd, J=4.2 Hz, 13.2 Hz, 13.2 Hz), 3.14-3.26 (2H, m), 3.18 (3H,
s), 3.49 (1H, ddd, J=4.8 Hz, 4.8 Hz, 17.7 Hz), 3.84-3.93 (1H, m),
4.23-4.34 (2H, m), 4.96 (1H, s), 5.81 (1H, d, J=7.5 Hz), 6.60-6.79
(3H, m), 6.81 (1Hm d, J=9.3 Hz), 6.92 (1H, ddd, J=2.7 Hz, 8.4 Hz,
8.4 Hz), 7.19-7.24 (1H, m).
Reference Example 527
##STR00716##
[2569] First Step
[2570] A DMF (0.2 mL) solution of compound 527A (36 mg, 0.09 mmol)
synthesized according to the method of synthesizing compound 516
was cooled to 1 to 3.degree. C., 5-chlorodibenzosuberane (97 mg,
0.43 mmol) and cesium carbonate (138 mg, 0.43 mmol) were added, and
the mixture was stirred at room temperature overnight. To the
reaction solution was added water, and the mixture was distributed
between ethyl acetate and water. The organic layer was washed with
an aqueous saturated sodium chloride solution, and dried. The
solvent was distilled off, and the resulting oil was subjected to
silica gel column chromatography, and eluted with
chloroform-methanol. Concentration of an objective fraction
afforded 19 mg of compound 527B as an oil.
[2571] MS: m/z=616 [M+H].sup.+.
Second Step
[2572] Compound 527B (19 mg, 0.03 mmol) was dissolved in MeOH (0.6
mL), 10% Pd--C (3 mg) was added, and the mixture was subjected to a
catalytic reduction reaction under hydrogen stream. The catalyst
was removed by filtration, and the filtrate was concentrated. The
resulting oil was subjected to diol silica gel column
chromatography, and eluted with chloroform-methanol. Concentration
of an objective fraction afforded 7 mg of compound 527 as an
oil.
[2573] MS: m/z=526 [M+H].sup.+.
[2574] Using halides which are commercially available or known in
the references and aldehydes which are commercially available or
known in the references, and according to the method of Reference
example 527, compounds 528 to 531 were synthesized.
Reference Example 528
##STR00717##
[2576] MS: m/z=418 [M+H].sup.+
Reference Example 529
##STR00718##
[2578] MS: m/z=432 [M+H].sup.+
Reference Example 530
##STR00719##
[2580] MS: m/z=459 [M+H].sup.+
Reference Example 531
##STR00720##
[2582] MS: m/z=466 [M+H].sup.+
Reference Example 532
##STR00721##
[2583] First Step
[2584] To a methanol (5 ml) solution of compound 519 (440 mg, 0.766
mmol) was added hydrazine hydrate (383 mg, 7.66 mmol), and the
mixture was refluxed for 1 hour. After cooled to room temperature,
the precipitated insolubles were filtered off. After the solvent
was distilled off, the residue was suspended in ethyl acetate, the
insolubles were filtered off, and the solvent was distilled off.
The resulting crude product was suspended in chloroform, and
insolubles were filtered off. The solvent was distilled off, and
the resulting crude product was washed with ethyl
acetate-diisopropyl ether to obtain 190 mg of compound 532 as a
solid.
[2585] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (3H, d, J=6.9H), 1.46
(3H, d, J=6.6 Hz), 2.73-2.90 (3H, m), 3.08 (1H, ddd, J=4.2 Hz, 12.9
Hz, 12.9 Hz), 3.54 (1H, ddd, J=4.5 Hz, 4.5 Hz, 17.7 Hz), 3.85-3.94
(1H, m), 4.19 (1H, dd, J=7.2 Hz, 11.1 Hz), 4.35 (1H, ddd, J=4.5 Hz,
13.8 Hz, 13.8 Hz), 4.97 (1H, s), 5.74 (1H, d, J=7.5 Hz), 6.60 (1H,
d, J=7.8 Hz), 6.65 (1H, d, J=7.2 Hz), 6.92 (1H, t, J=6.3 Hz),
7.09-7.45 (6H, m).
Reference Example 533
##STR00722##
[2587] Compound 533 was synthesized by the same procedure as that
of Reference example 532.
[2588] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.22 (3H, d, J=6.6 Hz),
1.40 (3H, d, J=6.6 Hz), 0.1.45-1.58 (1H, m), 1.62-1.75 (1H, m),
2.61-2.69 (1H, m), 2.71-2.84 (1H, m), 2.88-2.95 (1H, m), 3.16-3.34
(1H, m), 3.60-3.64 (1H, m), 3.92-4.00 (1H, m), 4.24-4.33 (1H, m),
4.42-4.46 (1H, dd, J=3.3 Hz, 10.8 Hz), 5.10 (1H, s), 5.47 (1H, d,
J=7.5 Hz), 6.70 (1H, d, J=7.5 Hz), 6.88 (1H, t, J=7.5 Hz), 7.02
(1H, d, J=10.8 Hz), 7.09-7.16 (2H, m), 7.19-7.25 (1H, m), 7.33 (2H,
d, 4.2 Hz), 7.42 (1H, d, J=7.5 Hz).
Reference Example 534
##STR00723##
[2590] Compound 534 was synthesized by the same procedure as that
of Reference example 532.
[2591] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.25 (3H, d, J=6.9 Hz),
1.44 (3H, d, J=6.6 Hz), 1.32-1.58 (2H, m), 1.77-1.79 (2H, m),
2.64-2.73 (1H, m), 2.79-3.00 (2H, m), 3.88-3.97 (2H, m), 4.19-4.28
(2H, m), 5.15 (1H, s), 5.67 (1H, d, J=7.5 Hz), 5.73 (1H, d, J=7.5
Hz), 6.90 (1H, t, J=6.6 Hz), 7.03 (1H, d, J=7.5 Hz), 7.13-7.32 (3H,
m), 7.36 (2H, d, J=4.2 Hz), 7.44 (1H, J=7.2 Hz), 7.75 (1H,
brs).
Reference Example 535
##STR00724##
[2593] Compound 535 was synthesized by the same procedure as that
of Reference example 532.
[2594] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-1.52 (1H, m),
1.61-1.72 (1H, m), 2.40-2.49 (1H, m), 2.58-2.62 (1H, m), 2.78-2.86
(1H, m), 2.89-2.95 (1H, m), 2.95 (3H, m), 3.66-3.74 (1H, m),
4.01-4.13 (1H, m), 4.28-4.32 (1H, m), 5.14 (1H, m), 5.51 (1H, d,
J=7.8 Hz), 6.72 (1H, d, J=7.5 Hz), 6.91-6.94 (2H, m), 7.14-7.40
(6H, m).
Reference Example 536
##STR00725##
[2595] First Step
[2596] A dichloromethane (1 ml) solution of compound 532 (30 mg,
0.0675 mmol) and a 38% aqueous formalin solution (53.5 mg, 0.675
mmol) was cooled to 1 to 3.degree. C., sodium triacetoxyhydroborate
(42.9 mg, 0.293 mmol) and acetic acid (10 mg, 0.166 mmol) were
added while the same temperature was retained. After the reaction
solution was stirred at the same temperature for 30 minutes,
saturated sodium bicarbonate water was added, and the mixture was
extracted with ethyl acetate three times. The combined extracts
were washed with water once, and dried with sodium sulfate, and the
solvent was distilled off. The resulting crude product was washed
with ethyl acetate-diisopropyl ether to obtain 20 mg of compound
536 as a solid.
[2597] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (3H, d, J=6.6 Hz),
1.44 (3H, d, J=6.9 Hz), 2.06 (6H, s), 2.29 (1H, dd, J=4.5 Hz, 13.2
Hz), 4.23 (1H, dd, J=8.4 Hz, 13.2 Hz), 2.78 (1H, ddd, J=4.5 Hz, 4.5
Hz, 14.1 Hz, 3.06 (1H, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 3.55 (1H, ddd,
J=4.2 Hz, 4.2 Hz, 17.7 Hz), 3.83-3.92 (1H, m), 4.34 (1H, dd, J=4.5
Hz, 8.4 Hz), 4.54 (1H, ddd, J=4.5 Hz, 13.8 Hz, 13.8 Hz), 4.91 (1H,
s), 5.74 (1H, d, J=7.5 Hz), 6.63 (1H, d, J=7.8 Hz), 6.64 (1H, d,
J=7.8 Hz), 6.88-6.93 (1H, m), 7.08-7.45 (6H, m).
Reference Example 537
##STR00726##
[2599] Compound 537 was synthesized by the same procedure as that
of Reference example 536.
[2600] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.25 (3H, d, J=6.6 Hz),
1.40 (3H, d, J=6.6 Hz), 1.46-1.57 (1H, m), 1.68-1.79 (1H, m), 1.98
(6H, s), 2.04-2.11 (1H, m), 2.27-2.41 (1H, m), 2.72-2.94 (2H, m),
3.55-3.64 (1H, m), 3.91-4.00 (1H, m), 4.29-4.44 (2H, m), 5.10 (1H,
s), 5.48 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=7.8 Hz), 6.86-6.90 (1H,
m), 7.05-7.24 (4H, m), 7.33 (2H, d, J=4.2 Hz), 7.40 (1H, d, J=7.5
Hz).
Reference Example 538
##STR00727##
[2602] Compound 538 was synthesized by the same procedure as that
of Reference example 536.
[2603] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.75 (6H, t, J=6.6 Hz),
1.28 (3H, d, J=6.6 Hz), 1.41 (3H, d, J=6.6 Hz), 1.45-1.56 (1H, m),
1.67-1.78 (1H, m), 2.22-2.49 (4H, m), 2.74-2.97 (2H, m), 3.94-4.03
(1H, m), 4.29-4.41 (2H, m), 5.11 (1H, s), 5.48 (1H, d, J=7.8 Hz),
6.71 (1H, d, J=6.9 Hz), 6.87 (1H, t, J=7.2 Hz), 7.06-7.25 (4H, m),
7.33 (2H, d, J=7.2 Hz), 7.35 (1H, m).
Reference Example 539
##STR00728##
[2605] Compound 539 was synthesized by the same procedure as that
of Reference example 536.
[2606] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.25 (3H, d, J=6.6 Hz),
1.44 (3H, d, J=6.6 Hz), 1.42-1.51 (2H, m), 1.75-1.91 (2H, m),
2.62-2.67 (1H, m), 2.65 (6H, s), 2.74-2.97 (3H, m), 3.57-3.63 (1H,
m), 3.91-3.26 (4H, m), 5.16 (1H, s), 5.73 (1H, d, J=7.5 Hz), 6.71
(1H, d, J=7.2 Hz), 6.89 (1H, t, J=6.9 Hz), 7.12-7.28 (4H, m),
7.33-7.45 (3H, m).
Reference Example 540
##STR00729##
[2608] Compound 540 was synthesized by the same procedure as that
of Reference example 536.
[2609] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.58-1.78 (2H, m), 2.06
(6H, s), 2.15-2.35 (2H, m), 2.84-2.93 (1H, m), 2.96-3.11 (1H, m),
3.00 (3H, s), 3.65-3.74 (1H, m), 3.99-4.14 (1H, m), 4.28-4.33 (1H,
m), 4.94 (1H, s), 5.78 (1H, d, J=7.5 Hz), 6.56 (1H, d, J=7.8 Hz),
8.66 (1H, d, J=7.2 Hz), 6.95 (t, J=7.2 Hz), 7.13-7.38 (6H, m).
Reference Example 541
##STR00730##
[2611] Compound 541 was synthesized by the same procedure as that
of Reference example 536.
[2612] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.846 (6H, t, J=7.2 Hz),
1.49-1.75 (2H, m), 2.30-2.41 (5H, m), 2.43-2.53 (1H, m), 2.85-2.93
(1H, m), 2.98-3.08 (1H, m), 3.01 (3H, s), 3.63-3.74 (1H, m),
3.97-4.07 (1H, m), 4.30 (1H, dd, J=5.1 Hz, 8.1 Hz), 4.95 (1H, s),
5.77 (1H, d, J=6.0 Hz), 6.56 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=7.8
Hz), 6.95 (1H, t, J=6.3 Hz), 7.13-7.38 (6H, m).
Reference Example 542
##STR00731##
[2613] First Step
[2614] A dichloromethane (1 ml) solution of compound 532 (30 mg,
0.0675 mmol) and triethylamine (20.5 mg, 0.202 mmol) was cooled to
1 to 3.degree. C., and acetic acid anhydride (10.3 mg, 0.101 mmol)
was added while the same temperature was retained. After the
reaction solution was stirred at the same temperature for 30
minutes, water was added, and the mixture was extracted with ethyl
acetate three times. The combined extracts were washed with water
once, and dried with sodium sulfate, and the solvent was distilled
off. The resulting crude product was washed with ethyl
acetate-diisopropyl ether to obtain 15 mg of compound 542 as a
solid.
[2615] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.30 (3H, d, J=6.9 Hz),
1.47 (3H, d, J=6.6 Hz), 2.00 (3H, s), 2.78-2.94 (2H, m), 3.04 (1H,
ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 3.48-3.60 (1H, m), 3.98-3.07 (1H,
m), 4.36 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 4.64 (1H, dd, J=3.9
Hz, 9.3 Hz), 4.87 (1H, s), 5.43 (1H, d, J=7.5 Hz), 6.57 (1H, d,
J=7.5 Hz), 6.68 (1H, d, J=7.5 Hz), 6.85 (1H, t, J=6.0 Hz),
7.09-7.36 (6H, m), 7.41 (1H, brs).
Reference Example 543
##STR00732##
[2617] Compound 543 was synthesized by the same procedure as that
of Reference example 542.
[2618] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.32 (3H, d, J=6.9 Hz),
1.50 (3H, d, J=6.9 Hz), 2.79 (1H, ddd, J=4.2 Hz, 4.2 Hz, 14.4 Hz),
3.01 (1H, ddd, J=3.9 Hz, 13.5 Hz, 13.5 Hz), 3.18-3.28 (1H, m),
3.46-3.59 (2H, m), 4.04-4.18 (1H, m), 4.27 (1H, ddd, J=3.9 Hz, 13.5
Hz, 13.5 Hz), 4.69 (1H, dd, J=3.3 Hz, 9.9 Hz), 4.87 (0.9H, s), 5.17
(0.1H, s), 5.37 (0.9H, d, J=7.8 Hz), 4.50 (0.1H, d, J=7.8H), 6.32
(0.1H, d, J=7.8 Hz), 6.54 (1H, d, J=7.5 Hz), 6.78 (0.9H, d, J=7.5
Hz), 6.84 (1H, t, J=6.6 Hz), 6.91 (0.1H, d, J=6.0 Hz), 7.06-7.51
(6H, m), 9.29 (1H, brs).
Reference Example 544
##STR00733##
[2620] Compound 544 was synthesized by the same procedure as that
of Reference example 542.
[2621] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, d, J=6.9 Hz),
1.46 (3H, d, J=6.3 Hz), 2.78 (1H, ddd, J=4.5 Hz, 4.5 Hz, 15.9 Hz),
2.94-3.10 (2H, m), 3.19-3.54 (2H, m), 3.64 (3H, s), 3.96-3.11 (1H,
m), 4.28 (1H, ddd, J=4.2 Hz, 13.5 Hz, 13.5 Hz), 4.57 (1H, dd, J=3.3
Hz, 9.9 Hz), 4.91 (1H, s), 5.57 (1H, brs), 5.70 (1H, d, J=7.5 Hz),
6.60 (1H, d, J=7.5 Hz), 6.66 (1H, d, J=7.8 Hz), 6.89 (1H, t, J=7.2
Hz), 7.08-7.47 (6H, m).
Reference Example 545
##STR00734##
[2622] First Step
[2623] A dichloromethane (1 ml) solution of compound 532 (30 mg,
0.0675 mmol) and pyridine (16 mg, 0.203 mmol) was cooled to 1 to
3.degree. C., and 2-methoxyacetyl chloride (11 mg, 0.101 mmol) was
added while the same temperature was retained. After the reaction
solution was stirred at the same temperature for 30 minutes, water
was added, and the mixture was extracted with ethyl acetate three
times. The combined extracts were washed with water once, and dried
with sodium sulfate, and the solvent was distilled off. The
resulting crude product was washed with ethyl acetate-diisopropyl
ether to obtain 22 mg of compound 545 as a solid.
[2624] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.31 (3H, d, J=6.9 Hz),
1.49 (3H, d, J=6.9 Hz), 2.77 (1H, ddd, J=4.8 Hz, 4.8 Hz, 14.1 Hz),
2.99-3.11 (2H, m), 3.47 (3H, s), 3.47-3.55 (1H, m), 3.64-3.72 (1H,
m), 3.77-3.88 (2H, m), 4.02-4.11 (1H, m), 4.23 (1H, ddd, J=4.2 Hz,
13.8 Hz, 13.8 Hz), 4.47 (1H, dd, J=3.3 Hz, 9.9 Hz), 4.94 (1H, s),
5.75 (1H, d, J=7.8 Hz), 6.64 (1H, d, J=9.0 Hz), 6.67 (1H, 7.8 Hz),
6.80 (1H, brt), 6.91 (1H, t, J=7.5 Hz), 7.08-7.23 (5H, m),
7.29-7.36 (1H, m).
Reference Example 546
##STR00735##
[2625] First Step
[2626] To a dimethylformamide (1 ml) solution of
2-(methylthio)acetic acid (15.7 mg, 0.148 mmol) were added EDCI
(28.5 mg, 0.148 mmol) and 1-hydroxy benzotriazole (11.4 mg, 0.0742
mmol) at room temperature, the mixture was stirred at the same
temperature for 5 minutes, and compound 532 was added. The reaction
solution was stirred at room temperature for 1 hour, and diluted
with methanol (3 ml). The solution was cooled to 1 to 3.degree. C.,
a 2N aqueous sodium hydroxide solution (1 ml) was added, the
mixture was stirred at the same temperature for 30 minutes, and the
mixture was neutralized with 2N hydrochloric acid (1 ml). The
reaction solution was extracted with ethyl acetate three times, the
combined extracts were washed with water once, and dried with
sodium sulfate, and the solvent was distilled off. The resulting
crude product was washed with ethyl acetate-diisopropyl ether to
obtain 15 mg of compound 546 as a solid.
[2627] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.32 (3H, d, J=6.9 Hz),
1.50 (3H, J=6.6 Hz), 2.11 (3, s), 2.79 (1H, ddd, J=4.2 Hz, 4.2 Hz,
14.1 Hz), 2.99-3.16 (4H, m), 3.50 (1H, ddd, J=4.5 Hz, 4.5 Hz, 12.9
Hz), 3.68 (1H, d, J=10.2 Hz), 3.97-4.11 (1H, m), 4.26 (1H, ddd,
J=4.5 Hz, 13.8 Hz, 13.8 Hz), 4.94 (3H, s), 5.69 (1H, d, J=7.5 Hz),
6.63 (1H, d, J=7.5 Hz), 6.70 (1H, d, J=7.8 Hz), 6.90 (1H, t, J=6.0
Hz), 7.09 (1H, d, J=7.5 Hz), 7.20-7.25 (3H, m), 7.29-7.36 (1H, m),
7.36-7.49 (1H, m).
Reference Example 547
##STR00736##
[2628] First Step
[2629] To an acetic acid (3 ml) solution of compound 547A (367 mg,
0.812 mmol) synthesized by the same procedure as that of Reference
example 516 and dibenzosuberol (205 mg, 0.974 mmol) was added
dropwise sulfuric acid (0.6 ml) at room temperature, and the
mixture was stirred at the same temperature for 30 minutes. The
reaction solution was diluted with water, and the mixture was
extracted with ethyl acetate three times. The extract was washed
with water once, and dried with sodium sulfate, and the solvent was
distilled off. The resulting crude product was dissolved in
methanol (3 ml), a 2N aqueous sodium hydroxide solution (1 ml) was
added at room temperature, and the mixture was stirred for 30
minutes. The reaction solution was neutralized with 2N aqueous
hydrochloric acid solution (1 ml), and extracted with ethyl acetate
three times. The combined extracts were dried with sodium sulfate,
and the solvent was distilled off. The resulting crude product was
washed with ethyl acetate-diisopropyl ether to obtain 75 mg of
compound 547 as a solid.
[2630] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (3H, d, J=6.9 Hz),
1.45 (3H, d, J=6.3 Hz), 2.80 (1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz),
2.99-3.11 (1H, m), 3.53 (1H, ddd, J=3.9 Hz, 3.9 Hz, 17.7 Hz), 3.64
(1H, dd, J=6.9 Hz), 12.3 Hz), 3.82 (1H, dd, J=3.3 Hz, 12.3 Hz),
3.86-3.97 (1H, m), 4.34-4.44 (2H, m), 4.88 (1H, s), 5.35 (1H, d,
J=7.5 Hz), 6.52-6.58 (2H, m), 6.82 (1H, dt, J=1.8 Hz, 7.2 Hz),
7.06-7.35 (6H, m).
Reference Example 548
##STR00737##
[2632] Compound 548 was synthesized by the same procedure as that
of Reference example 547.
[2633] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.29 (3H, d, J=6.6 Hz),
1.50 (3H, d, J=6.6 Hz), 1.70-1.81 (1H, m), 1.88-2.00 (1H, m), 2.85
(1H, ddd, J=4.5 Hz, 4.5 Hz, 14.1 Hz), 2.99-3.11 (1H, m), 3.48-3.57
(1H, m), 3.68-3.73 (2H, m), 3.83-3.92 (1H, m), 4.30 (1H, ddd, J=4.2
Hz, 13.8 Hz, 13.8 Hz), 4.54 (1H, dd, J=3.6 Hz, 11.1 Hz), 4.67 (1H,
s), 5.69 (1H, d, J=7.8 Hz), 6.62 (1H, d, J=7.5 Hz), 6.64 (1H, d,
J=5.7 Hz), 6.90 (1H, t, J=6.9 Hz), 7.07-7.36 (6H, m).
Reference Example 549
##STR00738##
[2634] First Step
[2635] To an acetic acid (3 ml) solution of compound 549A (997 mg,
1.69 mmol) synthesized by the same procedure as that of Reference
example 516 and dibenzosuberol (1.07 g, 5.08 mmol) was added
dropwise sulfuric acid (0.6 ml) at room temperature, and the
mixture was stirred at the same temperature for 30 minutes. The
reaction solution was diluted with water, and the mixture was
extracted with ethyl acetate three times. The extract was washed
with water once, and dried with sodium sulfate, and the solvent was
distilled off. The resulting crude product was washed with ethyl
acetate-diisopropyl ether to obtain 513 mg of compound 549B.
[2636] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.09 (3H, s), 2.71 (1H,
ddd, J=3.6 Hz, 13.5 Hz, 13.5 Hz), 3.18-3.27 (1H, m), 3.42-3.56 (2H,
m), 3.80 (1H, dd, J=2.7 Hz, 14.1 Hz), 4.03 (1H, dd, J=10.2 Hz, 14.1
Hz), 4.15 (1H, ddd, J=4.2 Hz, 4.2 Hz, 9.3 Hz), 4.32-4.40 (1H, m),
4.49-4.53 (2H, m), 4.94 (1H, s), 5/83 (1H, d, J=7.8 Hz), 6.63 (1H,
d, J=7.5 Hz), 6.69 (1H, d, J=7.8 Hz), 6.76 (1H, d, J=6.6 Hz), 6.91
(1H, t, J=7.5 Hz), 7.00 (1H, d, J=8.1 Hz), 7.12-7.17 (2H, m),
7.20-7.32 (2H, m), 7.82-7.89 (4H, m).
Second Step
[2637] To a methanol (5 ml) solution of compound 549B (513 mg,
0.829 mmol) was added hydrazine hydrate (124.5 mg, 2.49 mmol), and
the mixture was refluxed for 2 hours. After cooled to room
temperature, to the reaction solution were added 2N hydrochloric
acid (30 ml) and ethyl acetate (30 ml). After the layers were
separated, the organic layer was extracted with 2N hydrochloric
acid two times. The combined aqueous layers were neutralized with
sodium bicarbonate water, and extracted with chloroform-methanol
three times. The combined organic layers were dried with sodium
sulfate, and the solvent was distilled off. The resulting crude
product was washed with ethyl acetate-diisopropyl ether to obtain
135 mg of compound 549.
[2638] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.40-2.50 (1H, m),
2.72-2.80 (1H, m), 2.83-2.98 (2H, m), 3.03-3.66 (4H, m), 3.79-3.87
(1H, m), 4.11 (1H, 4.2 Hz), 4.32-4.44 (1H, m), 5.12 (1H, s), 5.51
(1H, 7.5 Hz), 6.69 (d, J=7.5 Hz), 6.84-6.90 (1H, m), 7.07-7.24 (4H,
m), 7.30-7.34 (2H, m), 7.39-7.42 (1H, m).
Reference Example 550
##STR00739##
[2640] According to Reference example 536, compound 550 was
synthesized from compound 549 by the same procedure.
[2641] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.77 (6H, t, 6.9 Hz),
1.99-2.36 (3H, m), 2.38-2.56 (1H, m), 2.64 (1H, dd, J=3.9 Hz, 14.1
Hz), 2.75 z81H, ddd, J=4.5 Hz, 4.5 Hz, 14.4 Hz), 2.89-3.00 (1H, m),
3.09-3.68 (4H, m), 3.74-3.82 (1H, m), 4.09 (1H, brs), 4.17 (1H, dd,
J=3.6 Hz, 8.4 Hz), 5.03 (1H, brs), 5.17 (1H, s), 5.53 (1H, d, J=7.5
Hz), 6.73 (1H, d, J=7.5 Hz), 6.84 (1H, d, J=7.8 Hz), 6.91 (1H, t,
J=7.2 Hz), 7.12-7.26 (4H, m), 7.31-7.44 (4H, m), 7.45 (1H, d, J=7.2
Hz).
Reference Example 551
##STR00740##
[2643] According to Reference example 536, compound 551 was
synthesized from compound 549 by the same procedure.
[2644] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.99 (6H, s), 2.27 (1H,
brs), 2.51-2.27 (3H, m), 3.56-3.70 (4H, m), 4.03 (2H, brs), 4.36
(1H, brs), 4.94 (2H, brs), 5.29 (1H, brs), 6.54-6.83 (3H, m),
7.11-7.33 (6H, m).
Reference Example 552
##STR00741##
[2645] First Step
[2646] To an acetic acid (2 ml) solution of compound 552A (137 mg,
0.367 mmol) synthesized by the same procedure as that of Reference
example 516 and dibenzosuberol (386 mg, 1.83 mmol) was added
dropwise sulfuric acid (0.4 ml) at room temperature, and the
mixture was stirred at the same temperature for 30 minutes. The
reaction solution was diluted with water, and the mixture was
extracted with ethyl acetate three times. The extract was washed
with water once, and dried with sodium sulfate, and the solvent was
distilled off. The resulting crude product was dissolved in
methanol (5 ml), a 2N aqueous sodium hydroxide solution (2 ml) was
added at room temperature, and the mixture was stirred for 30
minutes. The reaction solution was neutralized with 2N aqueous
hydrochloric acid solution (2 ml), and extracted with ethyl acetate
two times. The combined extracts were dried with sodium sulfate,
and the solvent was distilled off. The resulting crude product was
washed with ethyl acetate to obtain 62 mg of compound 552.
[2647] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.71-1.82 (1H, m),
2.09-2.21 (1H, m), 2.82-2.90 (1H, m), 3.06 (1H, ddd, J=4.2 Hz, 13.2
Hz, 13.2 Hz), 3.19 (3H, s), 3.22-3.43 (3H, m), 3.60 (1H, ddd,
J=10.5 Hz, 10.5 Hz, 17.4 Hz), 3.79-3.96 (3H, m), 4.12-4.21 (1H, m),
4.46 (1H, dd, J=3.3 Hz, 10.2 Hz), 4.98 (1H, s), 5.89 (1H, d, J=7.5
Hz), 6.62 (1H, d, J=6.9 Hz), 6.64 (1H, d, J=7.5 Hz), 6.88-6.93 (1H,
m), 7.11-7.37 (6H, m).
Reference Example 553
##STR00742##
[2649] Compound 553 was synthesized by the same procedure as that
of Reference example 552.
[2650] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.80 (3H, d, J=6.6 Hz),
0.94 (3H, d, J=6.9 Hz), 1.94-2.00 (1H, m), 2.82-2.90 (1H, m),
3.00-3.11 (1H, m), 5.31-3.59 (2H, m), 3.64-3.74 (1H, m), 3.94-4.04
(3H, m), 4.25-4.36 (1H, m), 5.04 (1H, s), 5.87 (1H, d, J=7.2 Hz),
6.65 (1H, d, J=7.2 Hz), 7.12 (1H, d, J=7.5 Hz), 6.92 (1H, t, J=8.1
Hz), 7.10 (1H, d, J=7.2 Hz), 7.15-7.38 (5H, m).
Reference Example 554
##STR00743##
[2651] First Step
[2652] To an acetic acid (2 ml) solution of compound 554A (100 mg,
0.177 mmol) synthesized by the same procedure as that of Reference
example 516 and dibenzosuberol (186 mg, 0.885 mmol) was added
dropwise sulfuric acid (0.4 ml) at room temperature, and the
mixture was stirred at the same temperature for 30 minutes. The
reaction solution was diluted with water, and the mixture was
extracted with ethyl acetate three times. The extract was washed
with water once, and dried with sodium sulfate, and the solvent was
distilled off. The resulting crude product was dissolved in
methanol (5 ml), a 2N aqueous sodium hydroxide solution (2 ml) was
added at room temperature, and the mixture was stirred for 30
minutes. The reaction solution was neutralized with an aqueous
citric acid solution, and extracted with ethyl acetate two times.
The combined extracts were washed with sodium bicarbonate water,
and dried with sodium sulfate, and the solvent was distilled off.
The resulting crude product was washed with ethyl acetate to obtain
24 mg of compound 554.
[2653] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.81-2.91 (2H, m),
2.98-3.09 (1H, m), 3.60-3.75 (2H, m), 3.91-4.04 (2H, m), 4.08-4.17
(2H, m), 4.22-4.33 (2H, m), 4.80 (1H, s), 5.69 (1H, d, J=7.8 Hz),
6.48 (1H, d, J=7.5 Hz), 6.59 (1H, d, J=7.5 Hz), 6.80-6.85 (1H, m),
7.13-7.35 (6H, m).
Reference Example 555
##STR00744##
[2655] To an acetic acid (4 ml) solution of compound 555A (380 mg,
1.11 mmol) synthesized according to Reference example 516 and
dibenzosuberol (1.16 g, 5.52 mmol) was added dropwise sulfuric acid
(0.8 ml) at room temperature, and the mixture was stirred at the
same temperature for 30 minutes. The reaction solution was diluted
with water, and the mixture was extracted with ethyl acetate three
times. The extract was washed with water once, and dried with
sodium sulfate, and the solvent was distilled off. The resulting
crude product was dissolved in methanol (5 ml), a 2N aqueous sodium
hydroxide solution (2 ml) was added at room temperature, and the
mixture was stirred for 30 minutes. The reaction solution was
neutralized with an aqueous citric acid solution, and extracted
with ethyl acetate three times. The combined extracts were dried
with sodium sulfate, and the solvent was distilled off. To the
resulting crude product were added ethyl acetate-diisopropyl ether,
and the precipitated residue was filtered to obtain 22 mg of
compound 555.
[2656] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.62 (3H, d, J=6.9 Hz),
2.81 (1H, ddd, J=4.2 Hz, 4.2 Hz, 14.4 Hz), 3.09 (1H, ddd, J=4.5 Hz,
13.8 Hz, 13.8 Hz), 3.37 (3H, s), 3.37-3.53 (2H, m), 3.70 (1H, d,
J=5.4 Hz), 4.23-4.30 (2H, m), 4.33-4.44 (1H, m), 4.94 (1H, s), 5.70
(1H, d, J=7.8 Hz), 6.59 (1H, d, J=7.5 Hz), 6.64 (1H, d, J=7.8 Hz),
6.88-6.92 (1H, m), 7.08-7.37 (6H, m).
Reference Example 556
##STR00745##
[2658] According to Reference example 65 and Reference example 516,
compound 556 was synthesized by the same procedure.
[2659] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.66-1.78 (2H, m), 1.97
(3H, s), 2.19-2.31 (1H, m), 2.35-2.44 (1H, m), 2.49-2.57 (1H, m),
2.85-2.93 (1H, m), 3.06 (1H, J=3.9 Hz, 12.9 Hz, 12.9 Hz), 3.27-3.39
(2H, m), 3.34 (3H, s), 3.58-3.73 (3H, m), 3.96-4.04 (1H, m),
4.08-4.18 (1H, m), 4.60 (1H, dd, J=3.0 Hz, 11.1 Hz), 4.96 (1H, s),
6.52 (1H, d, J=7.5 Hz), 6.87-6.92 (1H, m), 7.18-7.28 (4H, m),
7.31-7.40 (2H, m), 7.65 (1H, s), 12.04 (1H, s), 14.33 (1H, s).
Reference Example 557
##STR00746##
[2661] Compound 557 was synthesized by the same procedure as that
of Reference example 149.
[2662] MS: m/z=419 [M+H].sup.+.
Reference Example 558
##STR00747##
[2664] To a DMSO (2 mL) solution of compound 63B (68.8 mg, 0.120
mmol) was added copper chloride (39.2 mg, 0.396 mmol), and the
mixture was stirred at 110.degree. C. for 2 hours and, further, at
120.degree. C. for 1 hour. Thereafter, copper chloride (50.0 mg,
0.505 mmol) was added, and the mixture was stirred at 200.degree.
C. for 1 hour. The reaction solution was purified using an LCMS
fractionating device, the eluted solvent was distilled off, to the
concentrated residue was added diethyl ether, and the precipitated
white solid was filtered. Washing with diethyl ether, and drying
afforded 20.9 mg of compound 558.
[2665] MS: m/z=439 [M+H].sup.+.
Reference Example 559
##STR00748##
[2666] First Step
[2667] Compound 48A (43 mg, 0.083 mmol) was dissolved in
dichloromethane (6.0 mL), manganese dioxide (120 mg, 1.38 mmol) was
added, and the mixture was stirred at room temperature for 3 hours.
After the reaction solution was filtered with celite, the filtrate
was concentrated to obtain 22.3 mg of compound 559B as a pale
yellow solid.
[2668] .sup.1HNMR (CDCl.sub.3) .delta.: 3.17 (3H, s), 3.41-3.55
(4H, m), 3.95-4.07 (2H, m), 4.28 (1H, d, J=16.1 Hz), 4.53 (1H, d,
J=11.8 Hz), 5.49 (2H, d, J=2.0 Hz), 6.97-7.66 (16H, m), 10.07 (1H,
s).
Second Step
[2669] Compound 559B (22 mg, 0.043 mmol) was dissolved in THF (6.0
mL), a 40% methanamine methanol solution (6.5 ul, 0.064 mmol) and
acetic acid (3.7 ul, 0.064 mmol) were added, and the mixture was
stirred at room temperature for 5 minutes. The reaction solution
was ice-cooled, NaBH(OAc).sub.3 (14 mg, 0.064 mmol) was added, and
the mixture was stirred at room temperature overnight. To the
reaction solution were added water and chloroform, and the
chloroform layer was separated. The aqueous layer was extracted
with chloroform, and sodium sulfate was added to the combined
extracts to dry them. The solvent was distilled off to obtain 24 mg
of compound 559C as a pale yellow solid.
[2670] MS: m/z=538 [M+H].sup.+.
Third Step
[2671] Compound 559 was synthesized by the same procedure as that
of Reference example 1.
[2672] MS: m/z=448 [M+H].sup.+.
Reference Example 560
##STR00749## ##STR00750## ##STR00751##
[2673] First Step
[2674] A dioxane (20 mL) mixed solution of
(methoxymethyl)triphenylphosphonium chloride (6.73 g, 19.0 mmol)
was cooled to 0.degree. C., and a 1.06M NaHMDS toluene solution
(18.0 ml, 19.0 mmol) was added dropwise while the same temperature
was retained. After the reaction solution was stirred at the same
temperature for 30 minutes, compound 383A was added, and the
mixture was refluxed for 1 hour and 30 minutes. The reaction
solution was returned to room temperature, and water and ethyl
acetate were added. The ethyl acetate layer was separated, and the
aqueous layer was extracted with ethyl acetate. To the combined
extracts was added sodium sulfate to dry them. The solvent was
distilled off, and the resulting oil was purified by silica gel
column chromatography, and eluted with n-hexane-ethyl acetate
(95:5, v/v). Concentration of an objective fraction afforded 2.22 g
of compound 560B as an oil.
[2675] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.68 (3H, s), 3.73 (3H,
s), 4.20 (4H, brs), 6.17 (1H, s), 6.39 (1H, s), 6.96-7.07 (6H, m),
7.18-7.32 (9H, m), 7.32-7.46 (1H, m).
Second Step
[2676] Compound 560B (1.98 g, 7.78 mmol) was dissolved in
dichloromethane (30 mL), a 70% aqueous perchloric acid solution
(8.0 ml, 93 mmol) was added, and the mixture was stirred at room
temperature overnight. To the reaction solution was added an
aqueous saturated sodium carbonate solution, and the
dichloromethane layer was separated. The aqueous layer was
extracted with dichloromethane, and magnesium sulfate was added to
the combined extracts to dry them. The solvent was distilled off,
and the resulting oil was purified by silica gel column
chromatography, and eluted with n-hexane-ethyl acetate (90:10,
v/v). Concentration of an objective fraction afforded 1.80 g of
compound 560C as an oil.
[2677] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.93 (1H, d, J=16.1 Hz),
4.06 (1H, d, J=16.1 Hz), 4.53 (1H, s), 7.11-7.50 (8H, m), 9.89 (1H,
s).
[2678] MS: m/z=241 [M+H].sup.+.
Third Step
[2679] To a dichloromethane (30 mL) solution of compound 560C (2.87
g, 11.9 mmol) were added tetraisopropoxytitanium (17.5 mL, 59.7
mmol) and (S)-4-methylbenzenesulfinamide (2.27 g, 14.3 mmol) at
room temperature, then the mixture was refluxed for 3 hours and 30
minutes. The reaction solution was ice-cooled, ice water (30 ml)
was added, the mixture was stirred for 1 hour while temperature was
retained at the same temperature, and the precipitated solid was
filtered using celite. The resulting filtrate was extracted with
dichloromethane, and magnesium sulfate was added to the combined
extracts to dry them. The solvent was distilled off, and the
resulting oil was purified by silica gel column chromatography, and
eluted with n-hexane-ethyl acetate (70:30, v/v). Concentration of
an objective fraction afforded 3.16 g of compound 560D as a yellow
solid.
[2680] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.39 (6H, s), 3.60 (1H, d,
J=15.2 Hz), 3.68 (1H, d, J=14.9 Hz), 3.97 (1H, d, J=15.0 Hz), 4.07
(1H, d, J=15.0 Hz), 4.90 (1H, d, J=2.7 Hz), 4.92 (1H, d, J=2.9 Hz),
7.08-7.26 (20H, m), 7.46-7.51 (4H, m), 8.62 (1H, d, J=2.8 Hz), 8.65
(1H, d, J=2.7 Hz).
[2681] MS: m/z=378 [M+H].sup.+.
Fourth Step
[2682] A THF (30 mL) suspension of a 1M cyanodiethylaluminum
toluene solution (16.7 mL, 16.7 mmol) was cooled to 0.degree. C.,
2-propanol (1.29 mL, 16.7 mmol) was added and, thereafter, the
mixture was stirred for 1 hour while temperature was retained at
the same temperature. Thereafter, the reaction solution was cooled
to -60.degree. C., a THF (12 mL) solution of compound 560D (3.16 g,
8.37 mmol) was added dropwise, the mixture was stirred for 15
minutes while temperature was retained at the same temperature,
thereafter, temperature was raised to room temperature, and the
mixture was stirred overnight. The reaction solution was
ice-cooled, an aqueous saturated ammonium chloride solution was
added, the mixture was stirred at room temperature for 1 hour and
30 minutes and, thereafter, the precipitated solid was filtered
using celite, and washed with dichloromethane. The dichloromethane
layer of the filtrate was separated, and the aqueous layer was
extracted with dichloromethane and, thereafter, sodium sulfate was
added to the combined extracts to dry them. The solvent was
distilled off, and the resulting oil was purified by silica gel
column chromatography, and eluted with chloroform-methanol (97:3,
v/v). Concentration of an objective fraction afforded 1.88 g of
compound 560E as a white solid.
[2683] MS: m/z=427 [M+Na].sup.+.
Fifth Step
[2684] A methanol (4 mL) solution of compound 560E (235 mg, 0.581
mmol) was cooled to 0.degree. C., cobalt(II) chloride hexahydrate
(55.3 mg, 0.232 mmol) was added, and the mixture was stirred at
room temperature for 30 minutes. Thereafter, the reaction solution
was ice-cooled, a DMF (4 mL) solution of sodium borohydride (88 mg,
2.3 mmol) was added dropwise, and the mixture was stirred at the
same temperature for 5 minutes, and at room temperature for 1 hour.
Then, Boc.sub.2O (0.674 mL, 2.90 mmol) was added, and the mixture
was stirred for 30 minutes. To the reaction solution was added
water, the mixture was extracted with ethyl acetate, and sodium
sulfate was added to the combined extracts to dry them. The solvent
was distilled off, and the resulting oil was subjected to silica
gel column chromatography, and eluted with chloroform-methanol
(98:2, v/v). Concentration of an objective fraction afforded a
crude product (211 mg) of compound 560F.
[2685] MS: m/z=509 [M+Na].sup.+.
Sixth Step
[2686] To a methanol (6 mL) solution of the crude product (211 mg)
of compound 560F was added TFA (0.128 mL, 1.66 mmol), and the
mixture was stirred at room temperature for 2.5 hours. To the
reaction solution was added triethylamine (0.230 mL, 1.66 mmol),
the solvent was distilled off, and the resulting crude product of
compound 560G was used in a next reaction without purification.
[2687] MS: m/z=371 [M+H].sup.+.
Seventh Step
[2688] To a toluene (4 mL) solution of the crude product of
compound 560G was added dimethyl
3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (132 mg, 0.416
mmol), and the mixture was refluxed for 1 hour and 30 minutes. The
reaction solution was subjected to silica gel column
chromatography, and eluted with chloroform-methanol
(100:0.fwdarw.90:10, v/v). Concentration of an objective fraction
afforded a crude product (287 mg) of compound 560H.
[2689] MS: m/z=671 [M+H].sup.+.
Eighth Step
[2690] To the crude product of compound 560H obtained in the
seventh step was added a 4N hydrochloric acid ethyl acetate
solution (3 mL), and the mixture was stirred at room temperature
for 30 minutes. The solvent was distilled off, to the resulting
concentrated residue were added THF (2 mL) and an aqueous saturated
sodium bicarbonate solution (2 mL), and the mixture was stirred at
room temperature for 45 minutes. To the reaction solution was added
water, the mixture was extracted with chloroform, and sodium
sulfate was added to the combined extracts to dry them. The solvent
was distilled off, and the resulting oil was subjected to silica
gel column chromatography, and eluted with chloroform-methanol
(100:0.fwdarw.94:6, v/v). Concentration of an objective fraction
afforded 27 mg of compound 560I as a yellow solid.
[2691] MS: m/z=539 [M+H].sup.+.
Ninth Step
[2692] Compound 560I (27 mg, 0.050 mmol) was dissolved in DMF (2
mL), cesium carbonate (82 mg, 0.25 mmol) and methyl iodide (0.010
mL, 0.16 mmol) were added, and the mixture was stirred at room
temperature for 1 hour and 30 minutes. To the reaction solution was
added water, the mixture was extracted with ethyl acetate, and
sodium sulfate was added to the combined extracts to dry them. The
solvent was distilled off, and the resulting oil was subjected to
silica gel column chromatography, and eluted with
chloroform-methanol (100:0.fwdarw.94:6, v/v). Concentration of an
objective fraction afforded a crude product of compound 560J.
[2693] MS: m/z=553 [M+H].sup.+.
Tenth Step
[2694] To an EtOH (2 mL) solution of the crude product of compound
560J obtained in the ninth step was added 2N NaOH (1 mL), and the
mixture was stirred at room temperature for 40 minutes. To the
reaction solution was added a 2N aqueous HCl solution, the mixture
was extracted with ethyl acetate, and sodium sulfate was added to
the combined extracts to dry them. The solvent was distilled off to
obtain 17 mg of compound 560K as a white oil.
[2695] MS: m/z=539 [M+H].sup.+.
Eleventh Step
[2696] To compound 560K (17 mg, 0.032 mmol) was added TFA (2.0 mL),
and the mixture was stirred at room temperature for 35 minutes. The
reaction solution was subjected to toluene azeotropy, to the
resulting concentrated residue was added isopropyl ether, and the
precipitated solid was filtered and washed to obtain 7.1 mg of
compound 560 as a pink solid.
[2697] MS: m/z=449 [M+H].sup.+.
Reference Example 561
##STR00752## ##STR00753##
[2698] First Step
[2699] To a crude product (433 mg) of compound 560H was added a 4N
hydrochloric acid ethyl acetate solution (3 mL), and the mixture
was stirred at room temperature for 1 hour. The solvent was
distilled off, to a THF (2 mL) solution of the resulting residue
was added acetone (2 mL), the mixture was stirred at room
temperature for 20 minutes, NaBH(OAc).sub.3 (70 mg, 0.32 mmol) was
added, and the mixture was stirred at room temperature for 1 hour
and 30 minutes. Thereafter, to the reaction solution was added an
aqueous saturated sodium bicarbonate solution (3 mL), and the
mixture was stirred at room temperature overnight. To the reaction
solution was added water, the mixture was extracted with
chloroform, and sodium sulfate was added to the combined extracts
to dry them. The solvent was distilled off, and the resulting oil
was subjected to silica gel column chromatography, and eluted with
chloroform-methanol (100:0.fwdarw.94:6, v/v). Concentration of an
objective fraction afforded a crude product (79 mg) of compound
561A.
[2700] MS: m/z=581 [M+H].sup.+.
Second Step
[2701] To an EtOH (4 mL) solution of the crude product (79 mg) of
compound 561A was added 2N NaOH (2 mL), and the mixture was stirred
at room temperature for 1 hour. To the reaction solution was added
a 2N aqueous HCl solution, the mixture was extracted with ethyl
acetate, and sodium sulfate was added to the combined extracts to
dry them. The solvent was distilled off, and the resulting oil was
subjected to silica gel column chromatography, and eluted with
chloroform-methanol (100:0.fwdarw.94:6, v/v). Concentration of an
objective fraction afforded compound 561B (53 mg).
[2702] MS: m/z=567 [M+H].sup.+.
Third Step
[2703] A DMF (2 mL) solution of compound 561B (53 mg, 0.093 mmol)
was cooled to 0.degree. C., triethylamine (0.039 mL, 0.28 mmol) and
ethyl chloroformate (0.018 mL, 0.187 mmol) were added, and the
mixture was stirred at room temperature for 10 minutes. Thereafter,
the reaction solution was cooled to 0.degree. C., sodium azide (18
mg, 0.28 mmol) was added, and the mixture was stirred for 50
minutes while temperature was retained at the same temperature. To
the reaction solution was added water, the mixture was extracted
with dichloromethane, and the combined extracts were concentrated
to obtain a crude product of compound 561C.
[2704] MS: m/z=592 [M+H].sup.+.
Fourth Step
[2705] The crude product (55 mg) of compound 561C was dissolved in
methanol (2 mL), and the mixture was stirred at 50.degree. C. for 1
hour. The reaction solution was subjected to silica gel column
chromatography, and eluted with chloroform-methanol
(100:0.fwdarw.94:6, v/v). Concentration of an objective fraction
afforded a crude product (43 mg) of compound 561D.
[2706] MS: m/z=596 [M+H].sup.+.
Fifth Step
[2707] To an EtOH (2 mL) solution of the crude product (43 mg) of
compound 561D was added 2N NaOH (4 mL), and the mixture was stirred
at 60.degree. C. for 1 hour. The solvent was distilled off, water
was added, the mixture was extracted with ethyl acetate and,
thereafter, sodium sulfate was added to the combined extracts to
dry them. The solvent was distilled off, the resulting oil was
subjected to amino column chromatography, and eluted with
chloroform-methanol (100:0.fwdarw.80:20, v/v). Concentration of an
objective fraction afforded 16 mg of compound 561E as a pale yellow
solid.
[2708] MS: m/z=538 [M+H].sup.+.
Sixth Step
[2709] Compound 561E (16 mg, 0.029 mmol) was dissolved in EtOH (1
mL) and a 48% aqueous tetrafluoroboric acid (1 mL), the reaction
solution was cooled to 0.degree. C., sodium nitrite (15 mg, 0.22
mmol) was added, and the mixture was stirred for 1 hour and 30
minutes while temperature was retained at the same temperature and,
further, at room temperature for 2 hours and 30 minutes. To the
reaction solution was added water, the mixture was extracted with
chloroform, and sodium sulfate was added to the combined extracts
to dry them. The solvent was distilled off, to the resulting
concentrated residue were added ethyl acetate and isopropyl ether,
and the precipitated solid was filtered and washed to obtain 5 mg
of compound 561 as a white solid.
[2710] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, d, J=6.9 Hz),
1.17 (3H, d, J=6.8 Hz), 3.37 (1H, d, J=13.3 Hz), 3.88 (1H, dd,
J=13.4, 4.3 Hz), 3.99 (1H, d, J=14.9 Hz), 4.08 (1H, d, J=11.3 Hz),
4.52 (1H, d, J=14.9 Hz), 4.81-4.90 (1H, m), 5.67 (1H, dd, J=11.3,
3.1 Hz), 5.94 (1H, d, J=7.4 Hz), 6.59 (1H, d, J=6.4 Hz), 6.72 (1H,
d, J=7.3 Hz), 6.86 (1H, t, J=7.1 Hz), 7.09 (1H, t, J=7.6 Hz),
7.16-7.31 (5H, m).
Reference Example 562
##STR00754##
[2712] Compound 562 was synthesized by the same procedure as that
of Reference example 561.
[2713] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.07 (3H, s), 3.21 (1H, d,
J=12.3 Hz), 4.00-4.31 (4H, m), 5.78 (1H, d, J=10.5 Hz), 5.94 (1H,
d, J=7.4 Hz), 6.54 (1H, d, J=7.3 Hz), 6.69 (1H, d, J=7.5 Hz), 6.98
(1H, t, J=7.6 Hz), 7.14-7.41 (6H, m).
[2714] MS: m/z=405 [M+H].sup.+.
Reference Example 563
##STR00755## ##STR00756##
[2715] First Step
[2716] Compound 563A (Tetrahedron Letters, 34, 953-956, 1993, 41.1
g, 154 mmol) was dissolved in THF (300 mL), 1M BH.sub.3-THF (770
mL) was slowly added at room temperature, and the mixture was
stirred for 18 hours. 3N aqueous hydrochloric acid solution (513
mL) was slowly added, and the mixture was refluxed for 1 hour, and
was progressed to a next step without purification.
[2717] LC-MS: m/z=254 [M+H].sup.+.
Second Step
[2718] Using a solution containing compound 563B, according to
Reference example 12, compound 563C was synthesized.
[2719] LC-MS: m/z=353 [M+H].sup.+.
[2720] .sup.1H-NMR (DMSO-d.sub.6): 1.40 (9H, s), 2.65-2.72 (1H, m),
2.86-2.92 (3H, m), 3.47-3.56 (3H, m), 3.56-3.69 (1H, m), 6.63 (1H,
s), 7.11-7.26 (8H, m).
Third Step
[2721] A toluene (30 mL) solution of compound 563C (2.16 g, 6.79
mmol) and dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate
(2.38 g, 6.75 mmol) was stirred at 100.degree. C. for 4 hours. The
reaction solution was distilled off under reduced pressure, and the
resulting crude product of compound 563D was used in a next
reaction without purification.
[2722] MS: m/z=653.05 [M+H].sup.+.
Fourth Step
[2723] To an ethyl acetate (20 mL) solution of the crude product of
compound 563D was added hydrogen chloride (4N ethyl acetate
solution, 20 mL) at room temperature, and the mixture was stirred
for 30 minutes. The reaction solution was distilled off under
reduced pressure, and the resulting crude product of compound 563E
was used in a next reaction without purification.
[2724] MS: m/z=553.05 [M+H].sup.+.
Fifth Step
[2725] To a tetrahydrofuran (40 mL) solution of the crude product
of compound 563E was added saturated sodium bicarbonate water (5
mL) at room temperature, and the mixture was stirred for 16 hours.
To the reaction solution was added water (50 mL), the mixture was
extracted with chloroform three times, and the extracts were
combined, and dried with sodium sulfate. The solvent was distilled
off under reduced pressure, and diethyl ether and chloroform were
added to the resulting residue to covert them into a powder, to
obtain compound 563F (2.90 g, 70.2%) as a white solid.
[2726] MS: m/z=521.05 [M+H].sup.+.
Sixth Step
[2727] To a methanol (7.5 mL) suspension of compound 563F (523 mg,
1.01 mmol) was added an aqueous sodium hydroxide solution (2M, 1.5
mL) at room temperature, and the mixture was stirred for 3 hours.
To the reaction solution were added hydrochloric acid (2N, 1.5 mL)
and water (3 mL) at room temperature and, thereafter, the mixture
was stirred at 0.degree. C. for 15 minutes. The precipitated solid
was filtered, and washed with water and diethyl ether to obtain
compound 563G (418 mg, 82.0%) as a white solid.
[2728] MS: m/z=507.00 [M+H].sup.+.
Seventh Step
[2729] A diphenyl ether (5 mL) suspension of compound 563G (107 mg,
0.211 mmol) was stirred at 240.degree. C. for 1 hour under
microwave irradiation. The reaction solution was purified by silica
gel column chromatography (methanol/chloroform=0%-5%) to obtain
compound 563H (64.4 mg, 65.9%) as a white solid.
[2730] MS: m/z=463.05 [M+H].sup.+.
Eighth Step
[2731] A methanol (30 mL) solution of compound 563H (64.4 mg, 0.139
mmol) was hydrogenated by passing through 10% Pd--C CatCart
(H-cube, Full-H.sub.2 mode, 25.degree. C.) for 3 hours. The
reaction solution was distilled off under reduced pressure, and
ethyl acetate and methanol were added to the resulting residue to
convert it into a powder, to obtain compound 563 (31.1 mg, 60.0%)
as a gray white solid.
[2732] .sup.1HNMR (DMSO-d.sub.6) .delta.: 2.50-3.03 (3H, m),
3.50-3.72 (3H, m), 4.29 (1H, d, J=11.4 Hz), 5.12 (1H, m), 5.69 (1H,
d, J=7.2 Hz), 6.50 (1H, d, J=7.7 Hz), 6.75 (1H, d, J=7.7 Hz), 6.84
(1H, m), 7.14-7.30 (6H, m), 9.16 (1H, d, J=4.8 Hz).
[2733] MS: m/z=372.90 [M+H].sup.+.
Reference Example 564
##STR00757##
[2734] First Step
[2735] To a dimethylformamide (2 mL) suspension of compound 563H
(64.2 mg, 0.139 mmol) and cesium carbonate (220 mg, 0.675 mmol) was
added methyl iodide (0.0430 mL, 0.688 mmol) at room temperature,
and the mixture was stirred for 3 hours. To the reaction solution
was added water (10 mL) at room temperature, and the mixture was
extracted with ethyl acetate (30 mL). The organic layer was washed
with water (10 mL) and an aqueous saturated sodium chloride
solution (10 mL), and dried with sodium sulfate. The solvent was
distilled off under reduced pressure, and the residue was purified
by silica gel column chromatography
(methanol/chloroform=2.5%.fwdarw.10%) to obtain compound 564A (56.0
mg, 85.0%) as a colorless gummy substance.
[2736] MS: m/z=477.00 [M+H].sup.+.
Second Step
[2737] A solution of compound 564A (56.0 mg, 0.118 mmol) in
methanol (10 mL), ethyl acetate (5 mL) and tetrahydrofuran (5 mL)
was hydrogenated by passing through 10% Pd--C CatCart (H-cube,
Full-H.sub.2 mode, 25.degree. C.) for 75 minutes. The reaction
solution was distilled off under reduced pressure, and ethyl
acetate and methanol were added to the resulting residue to convert
it into a powder, to obtain compound 564 (22.0 mg, 48.4%) as a gray
white solid.
[2738] .sup.1HNMR (DMSO-d.sub.6) .delta.: 2.86-2.98 (6H, m),
3.51-3.58 (2H, m), 3.94 (1H, m), 4.30 (1H, d, J=11.1 Hz), 5.19 (1H,
d, J=10.2 Hz), 5.79 (1H, d, J=6.9 Hz), 6.49 (1H, d, J=7.4 Hz), 6.74
(1H, d, J=7.4 Hz), 6.85 (1H, m), 7.14 (2H, m), 7.25 (4H, m), 12.50
(1H, brs).
[2739] MS: m/z=387.05 [M+H].sup.+.
Reference Example 565
##STR00758##
[2741] Compound 565 was synthesized by the same procedure as that
of Reference example 564.
[2742] MS: m/z=443.95 [M+H].sup.+.
Reference Example 566
##STR00759##
[2743] First Step
[2744] A dimethylformamide (2 mL) suspension of compound 563H (75.4
mg, 0.163 mmol), 3-iodobenzonitrile (124 mg, 0.541 mmol), copper(I)
iodide (33.2 mg, 0.174 mmol), potassium carbonate (74.7 mg, 0.540
mmol) and N,N'-dimethylethylenediamine (0.0200 ml, 0.186 mmol) was
stirred at 140.degree. C. for 2 hours under microwave irradiation.
To the reaction solution were added water (10 mL) and hydrochloric
acid (2M, 2 mL) at room temperature, and the mixture was extracted
with ethyl acetate. The extract was filtered with celite, and the
filtrate was washed with water (10 mL.times.2) and an aqueous
saturated sodium chloride solution (10 mL), and dried with sodium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting crude product of compound 566A was used in a next
reaction without purification.
[2745] MS: m/z=564.05 [M+H].sup.+.
Second Step
[2746] To a methylene chloride (10 mL) solution of the crude
product of compound 566A obtained in the first step was added
trifluoroacetic acid (2 mL) at room temperature, and the mixture
was stirred for 1 hour. The reaction solution was concentrated
under reduced pressure, and the resulting residue was purified by
preparative LCMS to obtain compound 566 (30.3 mg, 39.3%) as a
yellow solid.
[2747] .sup.1HNMR (DMSO-d.sub.6) .delta.: 2.81-2.94 (2H, m),
3.38-3.58 (2H, m), 4.54 (1H, d, J=10.5 Hz), 4.64 (1H, d, J=10.5
Hz), 5.35 (1H, d, J=10.5 Hz), 5.76 (1H, m), 6.66-6.71 (3H, m), 6.90
(1H, m), 7.06-7.15 (6H, m), 7.76 (2H, m), 7.90 (2H, m).
[2748] MS: m/z=473.90 [M+H].sup.+.
Reference Example 567
##STR00760##
[2750] Compound 567 was synthesized by the same procedure as that
of Reference example 566.
[2751] .sup.1HNMR (DMSO-d.sub.6) .delta.: 2.80-3.00 (2H, m),
3.40-3.70 (2H, m), 4.52 (1H, m), 4.64 (1H, m), 5.38 (1H, m), 5.76
(1H, m), 6.60-7.20 (10H, m), 7.60-7.90 (3H, m), 8.11 (1H, m).
[2752] MS: m/z=474.00 [M+H].sup.+.
Reference Example 568
##STR00761##
[2754] Compound 568 was synthesized by the same procedure as that
of Reference example 566.
[2755] .sup.1HNMR (DMSO-d.sub.6) .delta.: 2.87-2.96 (2H, m),
3.34-3.73 (2H, m), 4.64 (2H, m), 5.33 (1H, m), 5.71 (1H, d, J=7.2
Hz), 6.61 (1H, d, J=7.8 Hz), 6.87-6.95 (3H, m), 7.00-7.27 (6H, m),
7.62 (2H, m), 7.86 (1H, m), 8.07 (1H, m).
[2756] MS: m/z=474.00 [M+H].sup.+.
Reference Example 569
##STR00762##
[2758] Compound 569 was synthesized by the same procedure as that
of Reference example 566.
[2759] MS: m/z=449.95 [M+H].sup.+.
Reference Example 570
##STR00763##
[2761] Compound 570 was synthesized by the same procedure as that
of Reference example 566.
[2762] .sup.1HNMR (DMSO-d.sub.6) .delta.: 2.83-2.97 (3H, m),
3.16-3.62 (2H, m), 3.56 (1H, m), 3.66 (1H, d, J=11.1 Hz), 5.35 (1H,
d, J=11.1 Hz), 5.73 (1H, d, J=7.4 Hz), 6.68 (1H, d, J=7.4 Hz), 6.92
(1H, m), 7.06-7.21 (5H, m), 7.49 (1H, m), 7.97 (1H, d, J=8.4 Hz),
8.14 (1H, s), 8.50 (1H, d, J=3.6 Hz), 8.81 (1H, d, J=2.1 Hz).
[2763] MS: m/z=449.95 [M+H].sup.+.
Reference Example 571
##STR00764##
[2764] First Step
[2765] To a DMF (1 mL) solution of compound 563H (50.0 mg, 0.108
mmol) was added cesium carbonate (176 mg, 0.540 mmol), and the
mixture was stirred at room temperature for 10 minutes. To the
reaction solution was added O-(2,4-dinitrophenyl)hydroxylamine
(64.6 mg, 0.324 mmol), and the mixture was stirred at room
temperature for 9 hours. To the reaction solution was added
chloroform, and the mixture was washed with water, and dried with
sodium sulfate. The solvent was distilled off, and the resulting
oil was purified by silica gel column chromatography. The materials
were eluted firstly with chloroform and, then, with
chloroform-methanol (98:2, v/v). Concentration of an objective
fraction afforded 28.3 mg of compound 571A as an amorphous
substance.
[2766] MS: m/z=478 [M+H].sup.+.
Second Step
[2767] Compound 571A (27.0 g, 0.057 mmol) was dissolved in a
THF-methanol (1 mL, 1:1, v/v) solution, 10% palladium carbon (15.0
mg) was added, and the mixture was stirred at room temperature for
2 hours under hydrogen atmosphere. After dilution with chloroform,
insolubles were removed by celite filtration. After the filtrate
was concentrated under reduced pressure, the residue was solidified
with dichloromethane-ether to obtain 12.0 mg of compound 571.
[2768] MS: m/z=388 [M+H].sup.+.
Reference Example 572
##STR00765##
[2770] Using compound 12H, and according to Reference example 571,
compound 572 was synthesized by the same procedure.
[2771] MS: m/z=420 [M+H].sup.+.
Reference Example 573
##STR00766##
[2772] First Step
[2773] To a dimethylformamide (1.5 mL) solution of compound 563H
(83.2 mg, 0.160 mmol) was added sodium hydride (60%, 13.2 mg, 0.330
mmol) under ice-cooling, the mixture was stirred for 30 minutes,
thereafter, bromoacetonitrile (0.0190 mL, 0.270 mmol) was added,
and the mixture was stirred at room temperature for 1 hour. To the
reaction solution was added an aqueous ammonium chloride solution
(10%, 3 mL), and the mixture was extracted with ethyl acetate. The
organic layer was washed with water (10 mL) and an aqueous
saturated sodium chloride solution (10 mL), and dried with sodium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting crude product of compound 573A was used in a next
reaction without purification.
[2774] MS: m/z=502.00 [M+H].sup.+.
Second Step
[2775] To an acetonitrile (4 mL) suspension of the crude product of
compound 573A obtained in the first step and sodium iodide (111 mg,
0.741 mmol) was added chlorotrimethylsilane (0.0920 mL, 0.720 mmol)
at room temperature, and the mixture was stirred for 24 hours. To
the reaction solution was added an aqueous sodium hydrogen sulfite
solution (10%, 10 mL) and, thereafter, the mixture was extracted
with chloroform. After the extracts were combined, and dried with
sodium sulfate, the solvent was concentrated under reduced
pressure, and the resulting residue was purified by preparative
LCMS to obtain compound 573 (22.0 mg, 29.7%) as a gray white
solid.
[2776] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.86-2.95 (2H, m),
3.45-3.63 (2H, m), 4.01 (1H, m), 4.30 (1H, d, J=10.8 Hz), 4.35 (1H,
d, J=17.4 Hz), 4.74 (1H, d, J=17.4 Hz), 5.20 (1H, m), 5.66 (1H, d,
J=7.5 Hz), 6.52 (1H, d, J=7.8 Hz), 6.73 (1H, d, J=7.5 Hz), 6.83
(1H, m), 7.11-7.28 (6H, m).
[2777] MS: m/z=502.00 [M+H].sup.+.
Reference Example 574
##STR00767##
[2779] Compound 574 was synthesized by the same procedure as that
of Reference example 573.
[2780] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.16 (1H, dd, J=13.26,
3.53 Hz), 4.36 (1H, d, J=11.58 Hz), 4.52 (2H, dd, J=20.73, 17.54
Hz), 5.44 (1H, d, J=11.41 Hz), 5.65 (1H, d, J=7.39 Hz), 6.99 (1H,
d, J=7.55 Hz), 7.11-7.32 (6H, m), 7.36-7.45 (2H, m), 7.58 (2H, d,
J=7.39 Hz).
Reference Example 575
##STR00768##
[2782] Compound 575 was synthesized by the same procedure as that
of Reference example 573.
[2783] MS: m/z=425.95 [M+H].sup.+.
Reference Example 576
##STR00769## ##STR00770##
[2784] First Step
[2785] A dichloromethane (30 mL) solution of compound 576A (Bioorg.
Med. Chem., 2003, 11, 197-206) (2.26 g, 10.2 mmol) were added
tetraisopropoxytitanium (10.0 mL, 33.1 mmol) and
(S)-4-methylbenzenesulfinamide (1.29 g, 8.13 mmol) at room
temperature, and the mixture was refluxed for 2 hours. The reaction
solution was ice-cooled, ice water (40 ml) was added, the mixture
was stirred for 1 hour while temperature was retained at the same
temperature, and the precipitated solid was filtered using celite.
The resulting filtrate was extracted with dichloromethane, and
magnesium sulfate was added to the combined extracts to dry them.
The solvent was distilled off, and the resulting oil was purified
by silica gel column chromatography, and eluted with n-hexane-ethyl
acetate (100:0.fwdarw.70:30, v/v). Concentration of an objective
fraction afforded 1.35 g of compound 576B as a yellow solid.
[2786] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.32 (3H, s), 2.72-2.85
(2H, m), 3.03-3.16 (2H, m), 4.89 (1H, d, J=3.5 Hz), 7.09-7.25 (10H,
m), 7.39-7.42 (2H, m), 8.49 (1H, d, J=3.6 Hz).
[2787] MS: m/z=360 [M+H].sup.+.
Second Step
[2788] A THF (20 mL) solution of a 1M cyanodiethylaluminum toluene
solution (7.51 mL, 7.51 mmol) was cooled to 0.degree. C.,
2-propanol (0.579 mL, 7.51 mmol) was added and, thereafter, the
mixture was stirred for 1 hour while temperature was retained at
the same temperature. Thereafter, the reaction solution was cooled
to -60.degree. C., a THF (14 mL) solution of compound 576B was
added dropwise, the mixture was stirred for 15 minutes while
temperature was retained at the same temperature, thereafter,
temperature was raised to room temperature, and the mixture was
stirred overnight. The reaction solution was ice-cooled, an aqueous
saturated ammonium chloride solution was added, the mixture was
stirred at room temperature for 1 hour and 30 minutes and,
thereafter, the precipitated solid was filtered using celite, and
washed with dichloromethane. The dichloromethane layer of the
filtrate was separated, and the aqueous layer was extracted with
dichloromethane and, thereafter, sodium sulfate was added to the
combined extracts to dry them. The solvent was distilled off, to
the resulting oil were added ethyl acetate and hexane, and the
precipitated solid was filtered and washed to obtain 976 mg of
compound 576C as a white solid.
[2789] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.38 (3H, s), 2.92-3.055
(2H, m), 3.41-3.52 (2H, m), 4.25 (1H, d, J=10.8 Hz), 4.28 (1H, d,
J=5.6 Hz), 4.94 (1H, dd, J=10.6, 5.7 Hz), 7.14-7.41 (12H, m).
Third Step
[2790] A methanol (8 mL) suspension of compound 576C (500 mg, 1.29
mmol) was cooled to 0.degree. C., cobalt(II) chloride hexahydrate
(123 mg, 0.517 mmol) was added, and the mixture was stirred at room
temperature for 30 minutes. To the reaction solution was added
chloroform (5 mL), thereafter, the mixture was ice-cooled, a DMF (4
mL) solution of sodium borohydride (196 mg, 5.17 mmol) was added
dropwise, and the mixture was stirred at the same temperature for 5
minutes, and at room temperature for 2 hours. Then, Boc.sub.2O (1.0
mL, 4.3 mmol) was added, and the mixture was stirred at room
temperature overnight. To the reaction solution was added water,
the mixture was extracted with ethyl acetate, and sodium sulfate
was added to the combined extracts to dry them. The solvent was
distilled off, and the resulting oil was subjected to silica gel
column chromatography, and eluted with chloroform-methanol
(100:0.fwdarw.98:2, v/v). Concentration of an objective fraction
afforded a crude product (200 mg) of compound 576D.
[2791] MS: m/z=491 [M+Na].sup.+.
Fourth Step
[2792] To a methanol (6 mL) solution of the crude product (200 mg)
of compound 576D obtained in the third step was added TFA (0.188
mL, 2.45 mmol), and the mixture was stirred at room temperature for
2.5 hours. To the reaction solution was added triethylamine (0.399
mL, 2.45 mmol), the solvent was distilled off, and the resulting
crude product of compound 576E was used in a next reaction without
purification.
[2793] MS: m/z=353 [M+H].sup.+.
Fifth Step
[2794] To a toluene (4 mL) solution of the crude product of
compound 576E obtained in the fourth step was added dimethyl
3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (130 mg, 0.409
mmol), and the mixture was refluxed for 2 hours. The reaction
solution was subjected to silica gel column chromatography, and
eluted with chloroform-methanol (100:0.fwdarw.90:10, v/v).
Concentration of an objective fraction afforded a crude product
(268 mg) of compound 576F.
[2795] MS: m/z=653 [M+H].sup.+.
Sixth Step
[2796] To the crude product (263 mg) of compound 576F obtained in
the fifth step was added a 4N hydrochloric acid ethyl acetate
solution (3 mL), and the mixture was stirred at room temperature
for 1 hour and 30 minutes. The solvent was distilled off, to a THF
(4 mL) solution of the resulting concentrated residue was added
acetone (1 mL), the mixture was stirred at room temperature for 25
minutes, thereafter, NaBH(OAc).sub.3 (180 mg, 0.807 mmol) was
added, and the mixture was stirred at room temperature for 1 hour
and 15 minutes. Thereafter, to the reaction solution was added an
aqueous saturated sodium bicarbonate solution (7 mL), and the
mixture was stirred at room temperature overnight. To the reaction
solution was added water, the mixture was extracted with
chloroform, and sodium sulfate was added to the combined extracts
to dry them. The solvent was distilled off, and the resulting oil
was subjected to silica gel column chromatography, and eluted with
chloroform-methanol (100:0.fwdarw.94:6, v/v). Concentration of an
objective fraction afforded a crude product (160 mg) of compound
576G.
[2797] MS: m/z=563 [M+H].sup.+.
Seventh Step
[2798] To an EtOH (4 mL) solution of the crude product (160 mg) of
compound 576G obtained in the sixth step was added 2N NaOH (2 mL),
and the mixture was stirred at room temperature for 3 hours. To the
reaction solution was added a 2N aqueous HCl solution, the mixture
was extracted with ethyl acetate, and sodium sulfate was added to
the combined extracts to dry them. The solvent was distilled off,
and the resulting oil was subjected to silica gel column
chromatography, and eluted with chloroform-methanol
(100:0.fwdarw.94:6, v/v). Concentration of an objective fraction
afforded 78 mg of compound 576H as a yellow solid.
[2799] MS: m/z=549 [M+H].sup.+.
Eighth Step
[2800] To compound 576H (78 mg, 0.14 mmol) was added diphenyl ether
(3 mL), and the mixture was stirred at 245.degree. C. for 1 hour
under microwave irradiation. The reaction solution was subjected to
silica gel column chromatography, and eluted with
chloroform-methanol (100:0.fwdarw.90:10, v/v). Concentration of an
objective fraction afforded 43 mg of compound 576I as a bronzed
oil.
[2801] MS: m/z=505 [M+H].sup.+.
Ninth Step
[2802] To compound 576I (42 mg, 0.083 mmol) was added TFA (1.0 mL),
and the mixture was stirred at room temperature for 35 minutes. The
reaction solution was subjected to toluene azeotropy, to the
resulting concentrated residue was added an aqueous saturated
sodium bicarbonate solution, and the mixture was extracted with
ethyl acetate. To the combined extracts was added sodium sulfate to
dry them. The solvent was distilled off, to the resulting oil were
added ethyl acetate and isopropyl ether, and the precipitated solid
was filtered and washed to obtain 14 mg of compound 576 as a pale
brown solid.
[2803] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (3H, d, J=6.7 Hz),
1.20 (3H, d, J=6.7 Hz), 2.95-3.13 (2H, m), 3.28 (1H, d, J=13.1 Hz),
3.37-3.59 (2H, m), 3.75 (1H, d, J=10.3 Hz), 4.10 (1H, d, J=10.8
Hz), 4.80-4.87 (2H, m), 5.91 (1H, d, J=5.8 Hz), 6.41 (2H, t, J=6.5
Hz), 6.85 (1H, t, J=6.4 Hz), 7.05-7.35 (6H, m).
[2804] MS: m/z=415 [M+H].sup.+.
Reference Example 577
##STR00771##
[2805] First Step
[2806] To a dimethylformamide (3 mL) solution of a crude product
(140 mg) of compound 159A was added potassium cyanide (21.0 mg,
0.323 mmol) at room temperature, and the mixture was stirred at
80.degree. C. for 30 minutes, and at 100.degree. C. for 30 minutes.
The reaction solution was concentrated under reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (ethyl acetate/n-hexane=80%-100%) to obtain compound
577B (41.5 mg, 33.5%) as a pale orange foam.
[2807] MS: m/z=535.25 [M+H].sup.+.
Second Step
[2808] To an acetonitrile (4 mL) solution of compound 577B (41.5
mg, 0.078 mmol) and sodium iodide (45.5 mg, 0.304 mmol) was added
chlorotrimethylsilane (0.0400 mL, 0.313 mmol) at room temperature,
and the mixture was stirred for 2 hours. To the reaction solution
was added water (1 mL), the reaction solution was concentrated
under reduced pressure, and the resulting residue was purified by
preparative LCMS. Diethyl ether was added to the resulting residue
to convert it into a powder, to obtain compound 577 (20.7 mg,
60.0%) as a gray white solid.
[2809] .sup.1HNMR (DMSO-d.sub.6) .delta.: 3.10 (3H, s), 3.51 (2H,
m), 3.70 (1H, d, J=18.9 Hz), 4.03 (1H, d, J=18.9 Hz), 4.46 (1H, d,
J=13.4 Hz), 5.04 (1H, d, J=13.4 Hz), 5.56 (1H, s), 5.69 (1H, s),
7.09-7.21 (5H, m), 7.39-7.63 (3H, m), 7.64 (2H, m).
[2810] MS: m/z=445.20 [M+H].sup.+.
Reference Example 578
##STR00772##
[2812] Compound 578 was synthesized by the same procedure as that
of Reference example 157.
[2813] .sup.1HNMR (CDCl.sub.3) .delta.: 0.97 (3H, d, J=6.6 Hz),
1.19 (3H, d, J=6.9 Hz), 3.29 (3H, s), 3.97 (1H, d, J=16.1 Hz), 4.56
(1H, d, J=13.7 Hz), 4.82 (1H, m), 4.96 (1H, d, J=16.1 Hz), 5.34
(1H, s), 5.97 (1H, d, J=13.7 Hz), 6.78 (2H, m), 7.12 (2H, m),
7.44-7.51 (6H, m).
[2814] MS: m/z=434.10 [M+H].sup.+.
Reference Example 579
##STR00773##
[2816] Compound 579 was synthesized by the same procedure as that
of Reference example 163.
[2817] MS: m/z=477.25 [M+H].sup.+.
Reference Example 580
##STR00774## ##STR00775##
[2818] First Step
[2819] To a solution of compound 155A (10.5 g, 26.9 mmol),
diisopropylethylamine (11.0 mL, 63.0 mmol), 1-methylimidazole (2.60
mL, 32.6 mmol) and isopropylamine (2.80 mL, 32.7 mmol) in toluene
(100 mL) and acetonitrile (20 mL) was added dropwise
diphenylphosphoric acid chloride (6.80 mL, 32.7 mmol) over 5
minutes under ice-cooling, and the mixture was stirred under
ice-cooling for 90 minutes, at room temperature for 90 minutes. To
the reaction solution were added tert-butyldimethylsilyl chloride
(4.05 g, 26.9 mmol) and triethylamine (4.10 mL, 29.6 mmol) under
ice-cooling, the mixture was stirred at room temperature for 80
minutes, 4-dimethylaminopyridine (164 mg, 1.35 mmol) and methylene
chloride (100 mL) were added at room temperature, and the mixture
was stirred for 15.5 hours. To the reaction solution was added
tert-butyldimethylsilyl chloride (2.04 g, 26.9 mmol) at room
temperature, and the mixture was stirred for 24 hours. To the
reaction solution was added a 10% aqueous acetic acid solution (100
mL) at room temperature. The mixture was extracted with chloroform,
the extracts were combined, washed with saturated sodium
bicarbonate water (100 mL), and dried with sodium sulfate. The
solvent was concentrated under reduced pressure, and the resulting
residue was purified by silica gel column chromatography (ethyl
acetate/n-hexane=15%.fwdarw.40%) to obtain compound 580B (6.96 g,
59.9%) as a pale yellow oil.
[2820] MS: m/z=432.25 [M+H].sup.+.
Second Step
[2821] To an ethanol (50 mL) solution of compound 580B (6.96 g,
16.1 mmol) was added aqueous ammonia (35 mL) at room temperature,
and the mixture was stirred for 4 days. The reaction solution was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (ethyl
acetate/n-hexane=75%-100%, methanol/chloroform=0%-15%) to obtain
compound 580C (4.50 g, 64.8%) as a pale orange gummy substance.
[2822] MS: m/z=431.25 [M+H].sup.+.
Third Step
[2823] To a dimethylformamide (90 mL) solution of compound 580C
(4.50 g, 10.5 mmol) and potassium carbonate (7.27 g, 52.6 mmol) was
added O-(2,4-dinitrophenyl)hydroxylamine (6.29 g, 31.6 mmol) at
room temperature, and the mixture was stirred for 2 days. To the
reaction solution was added chloroform (180 mL) at room
temperature, the precipitated insolubles were filtered off, the
filtrate was concentrated under reduced pressure, and the resulting
residue was purified by silica gel column chromatography
(methanol/chloroform=0%-10%) to obtain compound 580D (5.28 g,
quant) as a yellow solid.
[2824] MS: m/z=446.25 [M+H].sup.+.
Fourth Step
[2825] To an ethanol (15 ml) solution of compound 580D (1.29 g,
2.89 mmol) was added paraformaldehyde (261 mg, 8.68 mmol) at room
temperature, and the mixture was stirred at 140.degree. C. for 3
hours under microwave irradiation. The reaction solution was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (ethyl
acetate/n-hexane=50%.fwdarw.100%) to obtain compound 580E (2.47 g,
93.0%) as a pale orange solid.
[2826] MS: m/z=458.20 [M+H].sup.+.
Fifth Step
[2827] To a DMF (25 mL) solution of compound 580E (2.47 g, 5.40
mmol) were added cesium carbonate (5.28 g, 16.2 mmol) and
bromodiphenylmethane (4.02 g, 16.3 mmol) under ice-cooling, and the
mixture was stirred at room temperature for 2 days. To the reaction
solution was added water (50 mL) under ice-cooling and, thereafter,
the mixture was extracted with ethyl acetate (150 mL.times.2). The
extracts were combined, sequentially washed with water (50
mL.times.2) and an aqueous saturated sodium chloride solution (50
mL), and dried with sodium sulfate. The solvent was concentrated
under reduced pressure, and the resulting residue was purified by
silica gel column chromatography (ethyl acetate/n-hexane=50%-100%,
methanol/chloroform=10%.fwdarw.20%) to obtain compound 580F (1.60
g, 47.5%) as a yellow form.
[2828] MS: m/z=624.30 [M+H].sup.+.
Sixth Step
[2829] To a methanol (40 mL) solution of compound 580F (1.60 g,
2.56 mmol) was added hydrogen chloride (4N ethyl acetate solution,
20 mL) at room temperature, and the mixture was stirred for 2
hours. The reaction solution was concentrated under reduced
pressure, to the resulting residue was added saturated sodium
bicarbonate water (20 mL) at room temperature and, thereafter, the
mixture was extracted with chloroform three times. The extracts
were combined, and dried with sodium sulfate, the solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (ethyl acetate) to
obtain compound 580G (920 mg, 70.4%) as a white foam.
[2830] MS: m/z=510.25 [M+H].sup.+.
Seventh Step
[2831] To a THF (80 mL) solution of compound 580G (816 mg, 1.60
mmol) was added manganese dioxide (2.39 g, 27.5 mmol) at room
temperature, and the mixture was stirred for 19 hours. After the
reaction solution was filtered, the filtrate was distilled off
under reduced pressure, and the resulting crude product (785 mg) of
compound 580H was used in a next reaction without purification.
[2832] MS: m/z=508.20 [M+H].sup.+.
Eighth Step
[2833] To a solution of the crude product (635 mg, 1.25 mmol) of
compound 580H obtained in the seventh step and amidosulfuric acid
(425 mg, 4.38 mmol) in methanol (30 mL) and water (10 mL) was added
dropwise a solution of sodium chlorite (396 mg, 4.38 mmol) in water
(4 mL) over 10 minutes under ice-cooling, the mixture was stirred
at room temperature for 30 minutes, and a 5% aqueous sodium
hydrogen sulfite solution (10 mL) was added. Methanol was distilled
off under reduced pressure, and the resulting residue was extracted
with ethyl acetate two times. The extracts were combined, washed
with an aqueous saturated sodium chloride solution (10 mL), and
dried with sodium sulfate. The filtrate was distilled off under
reduced pressure, and the resulting crude product of compound 580I
was used in a next reaction without purification.
[2834] MS: m/z=524.25 [M+H].sup.+.
Ninth Step
[2835] To a methylene chloride (20 mL) solution of the crude
product (164 mg, 0.313 mmol) of compound 580I obtained in the
eighth step, diisopropylethylamine (0.131 mL, 0.751 mmol),
1-methylimidazole (0.0300 mL, 0.376 mmol) and methylamine (2.0M
tetrahydrofuran solution, 0.188 mL, 0.376 mmol) was added
diphenylphosphoric acid chloride (0.0780 mL, 0.375 mmol) at room
temperature, the mixture was stirred for 3.5 hours, methylamine
hydrochloride (25.0 mg, 0.370 mmol) was added, and the mixture was
stirred for 6 days. The reaction solution was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (ethyl acetate/n-hexane=75%-100%) to
obtain compound 580J (45.7 mg, 27.2%) as a white foam.
[2836] MS: m/z=537.30 [M+H].sup.+.
Tenth Step
[2837] To an acetonitrile (4 mL) solution of compound 580J (45.7
mg, 0.0850 mmol) and sodium iodide (103 mg, 0.687 mmol) was added
chlorotrimethylsilane (0.0870 mL, 0.681 mmol) at room temperature,
and the mixture was stirred for 20 hours. To the reaction solution
was added a 5% aqueous sodium hydrogen sulfite solution (4 mL), and
the mixture was extracted with chloroform two times. After the
extracts were combined, and dried with sodium sulfate, the residue
obtained by concentration under reduced pressure was purified by
preparative LCMS. Diethyl ether and n-hexane were added to the
resulting residue to convert it into a powder, to obtain compound
580 (17.1 mg, 45.0%) as a white solid.
[2838] .sup.1HNMR (CDCl.sub.3) .delta.: 0.93 (3H, d, J=6.9 Hz),
1.11 (3H, d, J=6.9 Hz), 2.83 (3H, d, J=4.8 Hz), 4.53 (1H, d, J=13.4
Hz), 4.85 (1H, m), 4.97 (1H, d, J=13.4 Hz), 5.07 (1H, brd), 5.25
(1H, s), 5.86 (1H, s), 6.97 (2H, m), 7.15-7.24 (2H, m), 7.38-7.46
(6H, m).
[2839] MS: m/z=447.20 [M+H].sup.+.
Reference Example 581
##STR00776##
[2840] First Step
[2841] To a tert-butanol (4 mL) solution of compound 580I (398 mg,
0.760 mmol) were added triethylamine (0.158 mL, 1.14 mmol) and
diphenylphosphoric acid azide (0.196 mL, 0.912 mmol) at room
temperature, and the mixture was heated to reflux for 20 hours. To
the reaction solution was added water (20 mL) at room temperature,
and the mixture was extracted with chloroform three times. The
extracts were combined, and dried with sodium sulfate. The solvent
was distilled off under reduced pressure, and the resulting residue
was purified by silica gel column chromatography
(methanol/chloroform=0%.fwdarw.10%) to obtain compound 581A (167
mg, 36.9%) as a gray white solid.
[2842] MS: m/z=595.10 [M+H].sup.+.
Second Step
[2843] To a methylene chloride (2 mL) solution of compound 581A
(167 mg, 0.281 mmol) was added trifluoroacetic acid (2 mL) at room
temperature, and the mixture was stirred for 1.5 hours. The
reaction solution was concentrated under reduced pressure, and the
resulting residue was purified by preparative LCMS. Ethyl acetate,
diethyl ether, and methanol were added to the resulting residue to
convert it into a powder, to obtain compound 581 (29.4 mg, 25.9%)
as a white solid.
[2844] .sup.1HNMR (DMSO-d.sub.6) .delta.: 0.81 (3H, d, J=6.5 Hz),
0.98 (3H, d, J=6.5 Hz), 4.35 (1H, d, J=12.6 Hz), 4.63 (1H, m), 4.68
(1H, d, J=12.6 Hz), 4.80 (1H, s), 5.28 (1H, s), 6.34 (2H, s),
7.10-7.43 (8H, m), 7.81-7.83 (2H, m).
[2845] MS: m/z=404.95 [M+H].sup.+.
Reference Example 582
##STR00777##
[2846] First Step
[2847] To an ethanol (4 mL) solution of compound 582A (200 mg,
0.470 mmol) synthesized according to the synthesis method of
Reference example 65 was added paraformaldehyde (14.8 mg, 0.493
mmol) at room temperature, and the mixture was stirred at
140.degree. C. for 45 minutes under microwave irradiation. The
reaction solution was distilled off under reduced pressure, and the
resulting residue was purified by silica gel column chromatography
(ethyl acetate/n-hexane=90%-100%) to obtain compound 582B (173 mg,
84.0%) as a white solid.
[2848] MS: m/z=438.15 [M+H].sup.+.
Second Step
[2849] To a methylene chloride (4 mL) solution of compound 582B
(173 mg, 0.396 mmol), 4-dimethylaminopyridine (5.6 mg, 0.046 mmol)
and triethylamine (0.164 mL, 1.18 mmol) was added
2-fluorobenzenesulfonyl chloride (0.0790 mL, 0.597 mmol) at room
temperature, and the mixture was stirred for 3 days. The reaction
solution was distilled off under reduced pressure, and the
resulting residue was purified by silica gel column chromatography
(ethyl acetate/n-hexane=60%-80%) to obtain compound 582C (199 mg,
84.0%) as a white solid.
[2850] MS: m/z=596.15 [M+H].sup.+.
Third Step
[2851] To an acetic acid (2 mL) solution of compound 582C (162 mg,
0.272 mmol) was added 48% aqueous hydrogen bromide (2 mL) at room
temperature, and the mixture was stirred at 100.degree. C. for 20
minutes under microwave irradiation. The solvent was distilled off
under reduced pressure, and diethyl ether and methanol were added
to the resulting residue to convert it into a powder, to obtain
compound 582 (160 mg, quant) as a yellow solid.
[2852] .sup.1HNMR (DMSO-d.sub.6) .delta.: 4.34 (1H, d, J=14.7 Hz),
4.59 (1H, d, J=14.7 Hz), 5.50 (1H, d, J=14.3 Hz), 5.81 (1H, d,
J=14.3 Hz), 7.15-7.21 (2H, m), 7.35-7.40 (2H, m), 7.45-7.61 (2H,
m), 7.78 (1H, m), 7.93 (1H, m), 8.42 (1H, s).
[2853] MS: m/z=492.10 [M+H].sup.+.
Reference Example 583, Reference Example 584
##STR00778##
[2854] First Step
[2855] Compound 583A (3.0 g, 0.99 mmol) synthesized according to
Reference example 95 was added to toluene (300 ml) and acetic acid
(30.0 ml) to dissolve, and TsOH H2O (0.1 g, 0.526 mmol) was added
at room temperature. The reaction mixture was stirred for 3 hours
under heat-refluxing. After concentration under reduced pressure,
the residue was purified by amino silica gel column chromatography
(CHCl3/MeOH 50:1) to obtain compound 583B (1.8 g, 72.4%).
[2856] MS: m/z=312 [M+H].sup.+.
Second Step
[2857] Compound 583B (233 mg, 0.748 mmol) and compound 403C (197
mg, 0.8 mmol) were suspended in THF (7.5 ml), and NaHMDS (1.123 ml,
1.123 mmol, 1M-THF solution) was added at room temperature under
nitrogen stream. After stirring at room temperature for 3 hours,
water was added, and the mixture was extracted with ethyl acetate
(2.times.30 mL). The ethyl acetate layer was washed with an aqueous
saturated sodium chloride solution, and dried with sodium sulfate,
and the solvent was distilled off under reduced pressure. The
residue was purified by silica gel column chromatography
(CHCl3/MeOH 20:1) to obtain compound 583D (90 mg, 23.1%).
[2858] MS: m/z=522 [M+H].sup.+.
Third Step
[2859] Compound 583D (90 mg, 0.173 mmol) was dissolved in a mixed
solvent of MeOH (3 ml) and THF (3.00 ml), and 10% palladium-carbon
(90 mg, 0.846 mmol) was added. The mixture was stirred for 24 hours
under hydrogen (2 atm) stream, and insolubles were filtered. The
residue was purified using HPLC (MeCN--H2O), and diastereomers were
resolved.
First Fraction (Compound 583)
[2860] (15 mg, 20.1%)
[2861] MS: m/z=432 [M+H].sup.+.
Second Fraction (Compound 584) (45 mg, 60.4%)
[2862] MS: m/z=432 [M+H].sup.+.
Reference Example 585
##STR00779##
[2864] Compound 585 was synthesized by the same procedure as that
of Reference example 403.
[2865] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.87-2.28 (4H, m),
3.40-3.80 (3H, m), 4.32 (1H, d, J=12.96 Hz), 5.34 (1H, t, J=7.32
Hz), 5.65 (1H, d, J=7.63 Hz), 6.90 (1H, d, J=7.78 Hz), 7.10-7.35
(5H, m).
[2866] MS: m/z=312 [M+H].sup.+.
Reference Example 586
##STR00780## ##STR00781## ##STR00782##
[2867] First Step
[2868] Compound 95B (2.29 g, 8.12 mmol) was dissolved in pyridine
(10 ml), iso-propyl-D.sub.7-amine hydrochloride (1.00 g, 9.75
mmol), 1H-benzo[d][1,2,3]triazol-1-ol (1.10 g, 8.12 mmol) and
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (3.11 g, 16.2 mmol) were added, and the mixture was
stirred at room temperature for 20 hours. The reaction solution was
poured into water, the mixture was extracted with ethyl acetate,
and the extract was dried with sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting crude
product was purified by silica gel column chromatography, and
eluted with chloroform-methanol (97:3, v/v). To the resulting
compound was added diethyl ether, and the precipitated residue was
filtered to obtain 1.36 g of a white solid 586B.
Second Step
[2869] Compound 586B (1.36 g, 4.64 mmol) obtained in the first step
was dissolved in dimethylformamide (20 ml), potassium carbonate
(3.20 g, 23.2 mmol) was added, and the mixture was stirred at room
temperature for 50 minutes. O-(2,4-dinitrophenyl)hydroxylamine
(1.85 g, 9.27 mmol) was added, and the mixture was stirred at room
temperature for 18 hours. To the reaction solution was added
chloroform, the generated precipitate was removed by filtration,
and the filtrate was concentrated under reduced pressure. The
resulting crude product was purified by amino column
chromatography, and eluted with chloroform-methanol (97:3, v/v) to
obtain 835 mg of a colorless solid 586C.
[2870] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.28 (2H, s), 5.63 (2H,
s), 6.32 (1H, d, J=7.7 Hz), 7.10 (1H, brs), 7.42 (6H, m).
Third Step
[2871] Compound 586C (581 mg, 1.88 mmol) obtained in the second
step and paraformaldehyde-D.sub.2 (181 mg, 5.65 mmol) were added to
ethanol (12 ml), and the mixture was stirred at 140.degree. C. for
30 minutes under microwave irradiation. The reaction solution was
concentrated under reduced pressure, and the resulting crude
product was purified by amino column chromatography, and eluted
with chloroform-methanol (97:3, v/v). To the resulting compound was
added diethyl ether, and the precipitated residue was filtered to
obtain 140 mg of white solid 586D.
[2872] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.39 (2H, d, J=8.1 Hz),
5.36 (2H, s), 5.42 (1H, t, J=8.0 Hz), 6.37 (1H, d, J=7.6 Hz), 7.48
(6H, m).
Fourth Step
[2873] Compound 586E (972 mg, 5.78 mmol) was dissolved in
tetrahydrofuran (10 ml), sodium hydride (60%, 231 mg, 5.78 mmol)
and benzyl bromide-D.sub.2 (1.00 g, 5.78 mmol) were added at
0.degree. C., and the mixture was stirred at 60.degree. C. for 30
minutes. The reaction solution was added to dilute hydrochloric
acid, the mixture was extracted with ethyl acetate, and the organic
layer was washed with an aqueous sodium bicarbonate solution. The
solvent was distilled off under reduced pressure to obtain 1.48 g
of a white solid 586F.
[2874] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.95 (3H, s), 7.17-7.48
(8H, m), 8.00 (1H, dd, J=7.8, 1.3 Hz).
Fifth Step
[2875] Compound 586F (1.50 g, 5.76 mmol) obtained in the fourth
step was dissolved in methanol (20 ml) and tetrahydrofuran (20 ml),
a 2N aqueous sodium hydroxide solution (14.4 ml, 28.8 mmol) was
added, and the mixture was stirred at room temperature for 3 hours.
To the reaction solution was added dilute hydrochloric acid to make
the solution acidic, the mixture was extracted with ethyl acetate,
and the organic layer was washed with an aqueous saturated sodium
chloride solution, and dried with sodium sulfate. The solvent was
distilled off under reduced pressure, to the resulting compound
were added n-hexane-ethyl acetate, and the precipitated residue was
filtered to obtain 1.17 g of a white solid 586G.
[2876] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.18-7.48 (8H, m), 8.11
(1H, dd, J=7.9, 1.6 Hz).
Sixth Step
[2877] To compound 586G (1.15 g, 4.67 mmol) obtained in the fifth
step was added toluene (10 ml), dimethylformamide (0.100 ml, 1.29
mmol) and thionyl chloride (0.410 ml, 5.60 mmol) were added, and
the mixture was stirred at 130.degree. C. for 1.5 hours. After
cooled to room temperature, the reaction solution was concentrated
under reduced pressure. To the resulting compound was added
n-hexane, and the precipitated residue was filtered to obtain 1.16
g of a white solid. To aluminum chloride (718 mg, 5.38 mmol) were
added dichloromethane (10 ml) and nitromethane (0.5 ml), a
dichloromethane solution (5 ml) of 500 mg of the compound obtained
above was added at 0.degree. C., and the mixture was stirred at
room temperature for 5 hours. To the reaction solution was added an
aqueous sodium hydroxide solution, the mixture was extracted with
methylene chloride, and the organic layer was dried with sodium
sulfate. The solvent was concentrated under reduced pressure, and
the resulting crude product was purified by silica gel column
chromatography, and eluted with n-hexane-ethyl acetate (4:1, v/v).
To the resulting compound was added n-hexane, and the precipitated
residue was filtered to obtain 155 mg of a pale yellow solid
586H.
[2878] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.21-7.39 (6H, m), 7.46
(1H, td, J=7.5, 1.4 Hz), 7.59 (1H, dd, J=7.5, 1.4 Hz), 8.21 (1H,
dd, J=8.0, 1.0 Hz).
Seventh Step
[2879] Compound 586H (150 mg, 0.657 mmol) obtained in the sixth
step was dissolved in tetrahydrofuran (3 ml), lithium aluminum
hydride-D.sub.4 (13.8 mg, 0.329 mmol) was added at 0.degree. C.,
and the mixture was stirred at room temperature for 2 hours. To the
reaction solution was added dilute hydrochloric acid, the mixture
was extracted with ethyl acetate, and dried with sodium sulfate,
and the solvent was distilled off under reduced pressure. To the
resulting compound were added n-hexane-dichloromethane, and the
precipitated residue was filtered to obtain 114 mg of a white solid
5861.
[2880] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.17 (6H, m), 7.40-7.52
(2H, m).
Eighth Step
[2881] Compound 586D (76.0 mg, 0.236 mmol) and 5861 (54.5 mg, 0.236
mmol) were dissolved in acetic acid (3.2 ml), and concentrated
sulfuric acid (0.8 ml) was added dropwise under water-cooling.
After the mixture was stirred at room temperature for 30 minutes,
the mixture was poured into water, and extracted with ethyl
acetate. The organic layer was dried with sodium sulfate, the
solvent was distilled off under reduced pressure, to the resulting
crude product were added ethyl acetate-diethyl ether, and the
precipitated residue was filtered to obtain 32 mg of a white solid
586.
[2882] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 5.57 (1H, d, J=7.3 Hz),
6.82-7.44 (9H, m).
[2883] MS: m/z=446 [M+H].sup.+
[2884] Using a commercially available heavy hydrogen reagent, and
according to Reference example 586, compounds 587 to 591 were
synthesized.
Reference Example 587
##STR00783##
[2886] MS: m/z=436 [M+H].sup.+
Reference Example 588
##STR00784##
[2888] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.87 (1H, d, J=13.4 Hz),
5.58 (1H, d, J=7.8 Hz), 5.60 (1H, d, J=12.6 Hz), 6.81-7.48 (9H,
m).
Reference Example 589
##STR00785##
[2890] MS: m/z=441 [M+H].sup.+
Reference Example 590
##STR00786##
[2892] MS: m/z=435 [M+H].sup.+
Reference Example 591
##STR00787##
[2894] MS: m/z=436 [M+H].sup.+
Reference Example 592
##STR00788##
[2895] First Step
[2896] Compound 592A (22.8 g, 64.1 mmol) and
7-(trifluoromethyl)-6,11-dihydrodibenzo[b,e]thiepin-11-ol (19 g,
64.1 mmol) were suspended in 1,2-dichloroethane, dichloroacetic
acid (13.2 mL, 160 mmol) was added, and the mixture was stirred for
2.5 hours under heat-refluxing. The mixture was cooled to room
temperature and diluted with dichloromethane, then washed with an
aqueous saturated sodium bicarbonate solution and an aqueous
saturated sodium chloride solution, and dried. The solvent was
distilled off, and the resulting solid was solidified by adding
ethyl acetate-diisopropylether to obtain 32 g (containing 10% of
592A) of compound 592B.
[2897] MS: m/z=634 [M+H].sup.+.
[2898] Rf: 0.56 (AcOEt only).
Second Step
[2899] To an N,N-dimethylacetoamide (120 mL) solution of compound
592B (6.0 g, 9.47 mmol) were added
2-tert-butylimino2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphori-
ne (16.5 mL, 56.8 mmol) and paraformaldehyde (569 mg, 18.9 mmol),
and the mixture was stirred at room temperature for 3 hours.
Subsequently, TsCl (3.61 g, 18.9 mmol) was slowly added, and the
mixture was stirred for further 2 hours. To the reaction solution
was added a 1N aqueous HCl solution, and the mixture was extracted
with ethyl acetate two times. The organic layer was washed with
water and an aqueous saturated sodium chloride solution, and dried.
After the solvent was distilled off, the resulting solid was
purified by silica gel column chromatography. The materials were
eluted firstly with hexane-ethyl acetate (2:3, v/v) and, then
eluted with hexane-ethyl acetate (1:9, v/v). Concentration of an
objective fraction afforded 1.74 g of compound 592C as a pale
yellow solid.
[2900] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (3H, d, J=7.2 Hz),
3.96 (1H, d, J=14.6 Hz), 4.34 (1H, d, J=13.2 Hz), 4.81 (1H, d,
J=13.2 Hz), 5.17 (1H, s), 5.46 (1H, d, J=10.8 Hz), 5.56 (1H, d,
J=10.8 Hz), 5.60 (1H, m), 5.82 (1H, d, J=14.6 Hz), 5.87 (1H, d,
J=7.7 Hz), 6.56 (1H, d, J=7.2 Hz), 6.73 (1H, m), 7.04-7.11 (2H, m),
7.09 (1H, d, J=7.7 Hz), 7.29-7.38 (5H, m), 7.56 (2H, m), 7.78 (1H,
m).
[2901] MS: m/z=646 [M+H].sup.+.
[2902] Rf: 0.65 (AcOEt only).
Third Step
[2903] To an N,N-dimethylacetoamide (34 mL) solution of compound
592C (1.7 g, 2.63 mmol) were added anhydrous LiCl (1.3 g, 31.6
mmol) and paraformaldehyde (569 mg, 18.9 mmol), and the mixture was
stirred at 100.degree. C. for 3 hours. To the reaction solution was
added a 1N aqueous HCl solution, and the mixture was extracted with
ethyl acetate two times. The organic layer was washed with water
and an aqueous saturated sodium chloride solution, and dried. After
the solvent was distilled off, the resulting solid was purified by
silica gel column chromatography. The materials were eluted firstly
with chloroform-methanol (99:1, v/v) and, then, with
chloroform-methanol (96:4, v/v). An objective fraction was
concentrated, and the resulting solid was solidified by adding
ethyl acetate-diisopropylether to obtain 1.33 g of compound 592 as
a colorless solid.
[2904] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (3H, d, J=7.2 Hz),
2.90 (1H, brs), 3.99 (1H, d, J=14.5 Hz), 4.45 (1H, d, J=13.2 Hz),
4.92 (1H, d, J=13.2 Hz), 5.24 (1H, s), 5.54 (1H, m), 5.83 (1H, d,
J=7.72 Hz), 5.87 (1H, d, J=14.5 Hz), 6.70 (1H, d, J=7.1 Hz), 6.84
(1H, m), 7.07-7.16 (2H, m), 7.13 (1H, d, J=7.7 Hz), 7.36-7.42 (2H,
m), 7.80 (1H, m).
[2905] MS: m/z=556 [M+H].sup.+.
[2906] Rf: 0.46 (CHCl3:MeOH=9:1).
Reference Example 593
##STR00789##
[2908] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35 (3H, d, J=7.0 Hz),
4.12 (1H, d, J=13.7 Hz), 4.49 (1H, d, J=13.1 Hz), 5.14 (1H, d,
J=13.0 Hz), 5.20 (1H, m), 5.68 (3H, m), 6.74 (1H, d, J=7.5 Hz),
6.93 (1H, m), 7.12-7.46 (5H, m).
Reference Example 594
##STR00790##
[2910] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.21 (3H, d, J=7.2 Hz),
4.27 (1H, d, J=14.1 Hz), 4.61 (1H, d, J=13.4 Hz), 5.08 (1H, d,
J=13.4 Hz), 5.47 (1H, m), 5.55 (1H, d, J=15.8 Hz), 5.75 (1H, d,
J=7.6 Hz), 5.83 (1H, s), 6.97 (1H, t, J=7.8 Hz), 7.06 (1H, dd,
J=7.8, 1.6 Hz), 7.21 (1H, d, J=7.7 Hz), 7.41 (4H, m).
[2911] MS: m/z=540 [M+H].sup.+.
Reference Example 595
##STR00791##
[2913] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.42 (3H, d, J=7.2 Hz),
4.08 (1H, d, J=13.3 Hz), 4.49 (1H, d, J=13.1 Hz), 5.12 (1H, m),
5.16 (1H, d, J=13.1 Hz), 5.51 (1H, s), 5.70 (2H, m), 6.93 (1H, t,
J=7.8 Hz), 7.05 (1H, dd, J=7.9, 1.3 Hz), 7.18 (2H, m), 7.37-7.43
(3H, m).
[2914] MS: m/z=540 [M+H].sup.+.
Reference Example 596
##STR00792##
[2916] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35 (3H, d, J=7.2 Hz),
3.90 (1H, d, J=12.8 Hz), 4.42 (1H, d, J=13.1 Hz), 5.12 (1H, m),
5.14 (1H, d, J=12.5 Hz), 5.36 (1H, s), 5.58 (1H, d, J=13.4 Hz),
5.71 (1H, d, J=7.5 Hz), 6.70 (1H, td, J=8.3, 2.6 Hz), 6.96-7.06
(2H, m), 7.21 (1H, d, J=7.6 Hz), 7.26 (2H, d, J=3.5 Hz), 7.42 (2H,
m).
[2917] MS: m/z=506 [M+H].sup.+.
Reference Example 597
##STR00793##
[2919] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.38 (3H, d, J=7.2 Hz),
4.23 (1H, d, J=13.9 Hz), 4.52 (1H, d, J=13.1 Hz), 5.10 (1H, m),
5.12 (1H, d, J=12.8 Hz), 5.44 (1H, d, J=14.2 Hz), 5.52 (1H, s),
5.69 (1H, d, J=7.6 Hz), 6.91 (1H, t, J=7.8 Hz), 7.04 (1H, d, J=7.2
Hz), 7.15 (2H, m), 7.28-7.40 (3H, m).
[2920] MS: m/z=540 [M+H].sup.+.
Reference Example 598
##STR00794##
[2922] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.12 (3H, d, J=7.3 Hz),
4.02 (1H, d, J=13.1 Hz), 4.50 (1H, d, J=13.4 Hz), 5.07 (1H, d,
J=13.4 Hz), 5.50 (1H, m), 5.64 (1H, d, J=13.4 Hz), 5.69 (1H, s),
5.75 (1H, d, J=7.5 Hz), 6.73 (1H, td, J=8.5, 2.6 Hz), 7.02 (2H, m),
7.21 (2H, m), 7.35 (1H, d, J=7.0 Hz), 7.47 (1H, t, J=6.8 Hz).
[2923] MS: m/z=524 [M+H].sup.+.
Reference Example 599
##STR00795##
[2925] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.10 (3H, d, J=7.5 Hz),
4.11 (1H, d, J=13.6 Hz), 4.51 (1H, d, J=13.4 Hz), 5.05 (1H, d,
J=13.3 Hz), 5.49 (1H, m), 5.67 (3H, m), 6.80 (1H, d, J=7.8 Hz),
6.92 (1H, dd, J=13.6, 7.7 Hz), 7.11-7.24 (3H, m), 7.36 (1H, d,
J=7.5 Hz), 7.47 (1H, t, J=6.9 Hz).
[2926] MS: m/z=524 [M+H].sup.+.
Reference Example 600
##STR00796##
[2928] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.19 (3H, d, J=7.2 Hz),
3.86 (3H, s), 4.22 (1H, d, J=13.3 Hz), 4.49 (1H, d, J=13.1 Hz),
5.06 (1H, d, J=13.3 Hz), 5.34 (1H, d, J=13.3 Hz), 5.46 (1H, m),
5.55 (1H, s), 5.65 (1H, d, J=7.8 Hz), 6.84 (1H, t, J=7.2 Hz), 6.94
(1H, d, J=7.8 Hz), 7.14 (6H, m).
[2929] MS: m/z=518 [M+H].sup.+.
Reference Example 601
##STR00797##
[2931] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.09 (3H, d, J=7.1 Hz),
4.15 (1H, d, J=13.6 Hz), 4.53 (1H, d, J=13.6 Hz), 5.07 (1H, d,
J=14.0 Hz), 5.48 (1H, m), 5.70 (3H, m), 6.93 (2H, m), 7.14-7.26
(2H, m), 7.35-7.51 (3H, m).
[2932] MS: m/z=540 [M+H].sup.+.
Reference Example 602
##STR00798##
[2934] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.18 (3H, d, J=7.0 Hz),
4.03 (1H, d, J=14.5 Hz), 4.47 (1H, d, J=13.6 Hz), 5.03 (1H, d,
J=13.1 Hz), 5.46 (1H, m), 5.68-5.74 (3H, m), 6.94 (2H, m),
7.10-7.17 (2H, m), 7.34-7.40 (2H, m), 7.63 (1H, m).
[2935] MS: m/z=540 [M+H].sup.+.
Reference Example 603
##STR00799##
[2937] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.14 (3H, t, J=6.3 Hz),
3.90 (1H, d, J=13.6 Hz), 4.39 (1H, d, J=13.4 Hz), 5.06 (1H, d,
J=13.0 Hz), 5.46 (1H, m), 5.63 (1H, s), 5.64 (1H, d, J=13.2 Hz),
5.73 (1H, d, J=7.6 Hz), 6.73 (1H, td, J=8.3, 2.7 Hz), 6.96-7.04
(2H, m), 7.21 (1H, d, J=7.6 Hz), 7.27 (1H, dt, J=10.3, 3.7 Hz),
7.43 (2H, m), 7.53 (1H, d, J=7.3 Hz).
[2938] MS: m/z=506 [M+H].sup.+.
Reference Example 604
##STR00800##
[2940] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35 (3H, d, J=7.2 Hz),
4.01 (1H, d, J=13.4 Hz), 4.47 (1H, d, J=13.1 Hz), 5.17 (1H, d,
J=12.7 Hz), 5.20 (1H, m), 5.63 (1H, d, J=13.7 Hz), 5.66 (1H, s),
5.72 (1H, d, J=7.6 Hz), 6.72 (1H, td, J=8.3, 2.8 Hz), 6.92 (1H, dd,
J=8.6, 6.0 Hz), 7.04 (1H, dd, J=10.0, 2.5 Hz), 7.19 (2H, m), 7.30
(1H, d, J=7.0 Hz), 7.43 (1H, m).
[2941] MS: m/z=524 [M+H].sup.+.
Reference Example 605
##STR00801##
[2943] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.37 (3H, d, J=7.3 Hz),
3.85 (3H, s), 4.23 (1H, d, J=13.6 Hz), 4.50 (1H, d, J=12.8 Hz),
5.13 (1H, d, J=12.8 Hz), 5.14 (1H, m), 5.28 (1H, s), 5.30 (1H, d,
J=12.4 Hz), 5.63 (1H, d, J=7.8 Hz), 6.80-7.25 (8H, m).
[2944] MS: m/z=518 [M+H].sup.+.
Reference Example 606
##STR00802##
[2946] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35 (3H, d, J=7.5 Hz),
4.13 (1H, d, J=13.9 Hz), 4.48 (1H, d, J=13.1 Hz), 5.14 (1H, d,
J=12.5 Hz), 5.20 (1H, m), 5.69 (3H, m), 6.90 (2H, m), 7.18 (2H, m),
7.32 (1H, d, J=8.1 Hz), 7.43 (2H, m).
[2947] MS: m/z=540 [M+H].sup.+.
Reference Example 607
##STR00803##
[2949] MS: m/z=524 [M+H].sup.+.
Reference Example 608
##STR00804##
[2951] MS: m/z=524 [M+H].sup.+.
Reference Example 609
##STR00805##
[2953] MS: m/z=448 [M+H].sup.+. RT=1.54 min.
Reference Example 610
##STR00806##
[2955] MS: m/z=522 [M+H].sup.+. RT=1.84 min.
Reference Example 611
##STR00807##
[2957] MS: m/z=522 [M+H].sup.+. RT=1.76 min.
Reference Example 612
##STR00808##
[2959] MS: m/z=536 [M+H].sup.+
Reference Example 613
##STR00809##
[2961] MS: m/z=516 [M+H].sup.+
Reference Example 614
##STR00810##
[2963] MS: m/z=520 [M+H].sup.+
Reference Example 615
##STR00811##
[2965] MS: m/z=536 [M+H].sup.+
Reference Example 616
##STR00812##
[2967] MS: m/z=516 [M+H].sup.+
Reference Example 617
##STR00813##
[2969] MS: m/z=520 [M+H].sup.+
Reference Example 618
##STR00814##
[2971] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, d, J=7.5 Hz),
3.82 (1H, d, J=13.7 Hz), 4.49 (1H, d, J=13.1 Hz), 4.91 (1H, d,
J=13.7 Hz), 5.18 (1H, s), 5.51 (1H, m), 5.71 (1H, d, J=13.1 Hz),
5.88 (1H, d, J=7.5 Hz), 6.94 (2H, m), 7.14-7.52 (6H, m).
[2972] MS: m/z=513.20 [M+H].sup.+.
Reference Example 619
##STR00815##
[2974] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, d, J=7.3 Hz),
2.00 (1H, brs), 3.65 (1H, d, J=13.6 Hz), 4.46 (1H, d, J=13.3 Hz),
4.87 (1H, d, J=13.3 Hz), 5.17 (1H, s), 5.51 (1H, m), 5.74 (1H, d,
J=13.6 Hz), 5.86 (1H, d, J=7.7 Hz), 6.68-6.75 (2H, m), 6.98 (1H,
dt, J=2.6, 8.3 Hz), 7.10 (1H, d, J=7.7 Hz), 7.11 (1H, dd, J=2.6,
8.3 Hz), 7.17 (1H, dd, J=5.3, 8.3 Hz), 7.45 (1H, dd, J=2.6, 6.9
Hz).
[2975] MS: m/z=585 [M+H].sup.+.
Reference Example 620
##STR00816##
[2977] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.42 (3H, d, J=7.3 Hz),
2.00 (1H, brs), 3.63 (1H, d, J=13.6 Hz), 4.54 (1H, d, J=12.6 Hz),
5.05 (1H, d, J=12.6 Hz), 5.24 (1H, s), 5.37 (1H, m), 5.77 (1H, d,
J=13.6 Hz), 5.79 (1H, d, J=7.6 Hz), 6.68 (1H, d, J=7.3 Hz), 6.73
(1H, dd, J=2.1, 7.3 Hz), 6.97 (1H, dt, J=2.6, 8.4 Hz), 7.04 (1H,
dd, J=2.6, 8.4 Hz), 7.16 (1H, d, J=7.6 Hz), 7.16 (1H, m), 7.42 (1H,
dd, J=2.1, 7.3 Hz).
[2978] MS: m/z=585 [M+H].sup.+.
Reference Example 621
##STR00817##
[2980] MS: m/z=540 [M+H].sup.+.
Reference Example 622
##STR00818##
[2982] MS: m/z=540 [M+H].sup.+.
Reference Example 623
##STR00819##
[2984] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, d, J=7.3 Hz),
2.10 (1H, brs), 2.25 (3H, s), 4.21 (1H, d, J=13.6 Hz), 4.48 (1H, d,
13.3 Hz), 4.89 (1H, d, J=13.3 Hz), 5.18 (1H, s), 5.37 (1H, dd,
J=2.0, 13.6 Hz), 5.52 (1H, s), 5.80 (1H, d, J=7.8 Hz), 6.57 (1H, d,
J=7.2 Hz), 6.75 (1H, t, J=7.6 Hz), 6.97-7.04 (2H, m), 7.12 (1H, d,
J=7.8 Hz), 7.17-7.24 (2H, m).
[2985] MS: m/z=520 [M+H].sup.+.
Reference Example 624
##STR00820##
[2986] First Step
[2987] Compound 624A (14.7 g, 87.0 mmol) and methyl
2-(bromomethyl)benzoate (20.0 g, 87.0 mmol) were dissolved in DMF
(200 ml), cesium carbonate (42.7 g, 131 mmol) was added, and the
mixture was stirred at room temperature for 2 hours. The reaction
solution was filtered, ethyl acetate was added to the filtrate, and
the mixture was washed with water and an aqueous saturated sodium
bicarbonate solution. After the organic layer was dried with sodium
sulfate, the solvent was distilled off under reduced pressure. The
resulting solid was crushed by adding hexane, and filtered out to
obtain 26.2 g of a white solid 624B.
[2988] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.89 (6H, s), 4.64 (2H,
s), 7.14-7.52 (6H, m), 7.94 (2H, t, J=7.1 Hz).
Second Step
[2989] Compound 624B (26.2 g, 83.0 mmol) was dissolved in methanol
(200 ml) and THF (200 ml), a 2N aqueous sodium hydroxide solution
(207 ml, 414 mmol) was added at room temperature, and the mixture
was stirred at room temperature for 3 days. To the reaction
solution was added dilute hydrochloric acid to make the solution
acidic, and the generated white precipitate was filtered and dried
to obtain 23.1 g of a white solid 624C.
[2990] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.58 (2H, s), 7.20 (1H,
td, J=7.2, 1.3 Hz), 7.35-7.54 (5H, m), 7.85 (2H, t, J=6.9 Hz).
Third Step
[2991] To compound 624C (2.66 g, 9.23 mmol) was added
polyphosphoric acid (30 g), and the mixture was stirred at
120.degree. C. for 3 hours. After the reaction solution was cooled
to room temperature, water was added, the mixture was extracted
with ethyl acetate, and the organic layer was dried with sodium
sulfate. The solvent was distilled off under reduced pressure to
obtain 2.37 g of a pale brown solid 624D.
[2992] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.05 (2H, s), 7.27 (1H, d,
J=7.4 Hz), 7.36-7.42 (2H, m), 7.52 (1H, td, J=7.6, 1.3 Hz), 7.62
(1H, dd, J=7.5, 1.1 Hz), 8.23 (1H, dd, J=7.6, 1.7 Hz), 8.52 (1H,
dd, J=8.1, 1.7 Hz).
Fourth Step
[2993] To compound 624D (96.0 mg, 0.355 mmol) was added toluene (2
ml), DMF (0.028 mmol) and thionyl chloride (0.131 ml, 1.80 mmol)
were added, and the mixture was stirred at 130.degree. C. for 1
hour. After the solvent was distilled off under reduced pressure,
the substance was dissolved in methanol (1 ml) and THF (1 ml),
sodium borohydride (100 mg, 2.64 mmol) was added, and the mixture
was stirred at room temperature for 1 hour. To the reaction
solution was added an aqueous ammonium chloride solution, the
mixture was extracted with ethyl acetate, and the organic layer was
dried with sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting crude product was purified by
silica gel column chromatography and eluted with n-hexane-ethyl
acetate (1:1, v/v) to obtain 41 mg of a white solid 624E.
[2994] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.09 (1H, t, J=6.3 Hz),
2.79 (1H, d, J=3.7 Hz), 4.43 (2H, d, J=1.3 Hz), 4.76 (2H, m), 6.33
(1H, d, J=3.0 Hz), 7.18-7.34 (5H, m), 7.52-7.56 (2H, m).
Fifth Step
[2995] Compound 624E (40.0 mg, 0.155 mmol) was dissolved in
dichloromethane (2 ml), pyridine (61.2 mg, 0.774 mmol) and benzoyl
chloride (21.8 mg, 0.155 mmol) were added, and the mixture was
stirred at room temperature for 2 hours. To the reaction solution
was added water, the mixture was extracted with ethyl acetate, and
the organic layer was dried with sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting crude
product was purified by silica gel column chromatography and eluted
with n-hexane-ethyl acetate (1:1, v/v) to obtain 30 mg of a white
solid 624F.
[2996] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.83 (1H, d, J=3.4 Hz),
4.27 (1H, d, J=13.9 Hz), 4.41 (1H, d, J=14.0 Hz), 5.42 (2H, s),
6.35 (1H, d, J=2.9 Hz), 7.12-7.58 (5H, m), 8.06 (2H, dd, J=8.2, 1.4
Hz).
[2997] Hereinbelow, according to Reference example 592, compound
624 was synthesized by the same procedure.
[2998] MS: m/z=518 [M+H].sup.+.
Reference Example 625
##STR00821##
[2999] First Step
[3000] To a toluene (3.3 ml) solution of compound 625A (700 mg,
2.29 mmol) were added 2-pyrrolidone (264 .mu.L, 3.44 mmol),
N,N'-dimethylethylene diamine (49 .mu.L, 0.46 mmol), copper iodide
(87 mg, 0.46 mmol), and potassium carbonate (634 mg, 4.59 mmol)
under nitrogen stream, and the mixture was stirred at 110.degree.
C. for 8 hours. After cooled to room temperature, the reaction
solution was directly purified by silica gel column chromatography.
Elution with chloroform-methanol (19:1, v/v) and concentration of
an objective fraction afforded 620 mg of compound 625B as a gray
white solid.
[3001] MS: m/z=310 [M+H].sup.+.
[3002] Rf: 0.50 (CHCl3:MeOH=19:1).
Second Step
[3003] A THF (8 mL) solution of compound 625B (620 mg, 2.0 mmol)
was added to an ice-cooled MeOH (4 ml) solution of NaBH4 (227 mg,
6.0 mmol), and the mixture was stirred for 1 hour. After water was
added, followed by extraction with ethyl acetate two times, the
organic layer was washed with an aqueous saturated sodium chloride
solution, and dried. The solvent was distilled off, and the
resulting solid was purified by silica gel column chromatography.
Elution with chloroform-methanol (19:1, v/v) and concentration of
an objective fraction afforded 621 mg of compound 625C as a
colorless solid.
[3004] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.26 (2H, m, J=6.9, 7.2,
8.0 Hz), 2.61 (2H, t, J=8.0 Hz), 2.89 (1H, d, J=2.9 Hz), 3.77 (2H,
m, J=6.9, 7.2, 9.7 Hz), 4.24 (1H, brs), 6.13 (1H, s), 7.02-7.14
(4H, m), 7.29 (1H, t, J=7.8 Hz), 7.46 (1H, d, J=7.2 Hz), 7.56 (1H,
d, J=6.0 Hz).
[3005] Rf: 0.30 (CHCl3:MeOH=19:1).
[3006] Hereinbelow, according to Reference example 592, compound
625 was synthesized by the same procedure.
[3007] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=7.32), 2.33
(2H, m), 2.65 (2H, t, J=8.1 Hz), 3.65 (1H, d, J=14.2 Hz), 3.77-3.95
(2H, m), 4.60 (1H, d, J=13.4 Hz), 4.87 (1H, d, J=13.4 Hz), 5.16
(1H, s), 5.48 (1H, m), 5.50 (1H, d, J=14.2 Hz), 5.82 (1H, d, J=7.7
Hz), 6.70 (1H, dd, J=1.2, 7.6 Hz), 6.83 (1H, dt, J=7.6, 10.2 Hz),
7.04-7.17 (4H, m), 7.13 (1H, d, J=7.7 Hz), 7.31 (1H, d, J=5.3 Hz),
7.31 (1H, d, J=3.7 Hz).
[3008] MS: m/z=571 [M+H].sup.+.
Reference Example 626
##STR00822##
[3009] First Step
[3010] A N,N-dimethylformamide (200 mL) solution of compound 626A
(20.0 g, 114 mmol) and phenylmethanethiol (14.19 g, 114 mmol) was
cooled to 1 to 3.degree. C., and t-butoxypotassium (14.11 g, 126
mmol) was put over 20 minutes while the same temperature was
retained. After the reaction solution was stirred at the same
temperature for 30 minutes, temperature was gradually raised to
room temperature, and the mixture was stirred at the same
temperature for 2 hours. Ice water was added, and the mixture was
extracted with ethyl acetate. The extract was washed with water
three times, washed with an aqueous saturated sodium chloride
solution, and dried. The solvent was distilled off, and the
resulting oil was solidified by adding diisopropyl ether to obtain
15.0 g of compound 626B.
[3011] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.16 (2H, s), 7.19-7.41
(8H, m), 10.61 (1H, s).
[3012] MS: m/z=263 [M+H].sup.+.
Second Step
[3013] Compound 626B (6.9 g, 26.3 mmol) was suspended in
1,4-dioxane (60 mL), SULFAMIC ACID (5.61 g, 57.8 mmol) was added,
and the mixture was cooled to 1 to 3.degree. C. To the reaction
solution was added dropwise an aqueous solution (20 ml) of sodium
hypochlorite (5.23 g, 57.8 mmol) over 10 minutes while temperature
was retained at the same temperature. After the reaction solution
was stirred at the same temperature for 30 minutes, temperature was
gradually raised to room temperature, and the mixture was stirred
at the same temperature for 2 hours. To the reaction solution was
added ice water, and the mixture was extracted with ethyl acetate.
The extract was washed with an aqueous saturated sodium chloride
solution, and dried. The solvent was distilled off, and the
resulting oil was solidified by adding diisopropyl ether to obtain
7.1 g of compound 626C.
[3014] .sup.1H-NMR (DMSO-d6) .delta.: 3.99 (1H, d, J=11.2 Hz), 4.41
(1H, d, J=11.2 Hz), 7.11 (2H, brs), 7.33 (3H, brs), 7.49 (1H, d,
J=7.2 Hz), 7.60 (1H, t, J=7.2 Hz), 7.73 (1H, d, J=7.2 Hz), 10.4
(1H, brs).
[3015] MS: m/z=295 [M+H].sup.+.
Third Step
[3016] Compound 626C (8.0 g, 27.1 mmol) was suspended in
acetonitrile (40 mL), and sodium iodide (12.1 g, 81.0 mmol) was
added. Into the reaction solution was put BF3 etherate (5.16 ml,
40.7 mmol) at once, and the mixture was stirred at the same
temperature for 30 minutes. To the reaction solution was added ice
water and a 10% aqueous sodium sulfite solution, and the mixture
was extracted with ethyl acetate. The extract was washed with an
aqueous saturated sodium chloride solution, and dried. The solvent
was distilled off, and the resulting oil was solidified by adding
diisopropyl ether to obtain 5.0 g of compound 626D.
[3017] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.11 (2H, s), 7.22-7.34
(8H, m).
[3018] MS: m/z=277 [M-H].sup.+.
Fourth Step
[3019] Compound 626D (2.5 g, 9.0 mmol) was put into 20 g of
polyphosphoric acid heated to 120.degree. C. over 60 minutes.
Thereafter, the mixture was stirred at the same temperature for 6
hours. After the reaction solution was cooled to room temperature,
and the mixture was put into ice water and extracted with ethyl
acetate. The extract was washed with an aqueous saturated sodium
chloride solution, and dried. The solvent was distilled off, and
the resulting oil was purified by silica gel column chromatography.
The materials were eluted firstly with n-hexane and, then, with
n-hexane-ethyl acetate (1:1, v/v). An objective fraction was
concentrated, and solidified by adding hexane to obtain 710 mg of
compound 626E as a white solid.
[3020] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.05 (2H, s), 7.20-7.25
(2H, m), 7.32-7.37 (2H, m), 7.46 (1H, d, J=7.2 Hz), 7.59 (1H, d,
J=7.2 Hz), 8.16 (1H, d, J=7.2 Hz).
[3021] MS: m/z=261 [M-H].sup.+.
Fifth Step
[3022] A tetrahydrofuran (10 mL) solution of compound 626E (730 mg,
2.80 mmol) was cooled to 1 to 3.degree. C., and lithium borohydride
(61 mg, 2.80 mmol) was put while the same temperature was retained.
The mixture was stirred at the same temperature for 30 minutes. To
the reaction solution was added ice water and a 10% aqueous
ammonium chloride solution, and the mixture was extracted with
ethyl acetate. The extract was washed with an aqueous saturated
sodium chloride solution, and dried. The solvent was distilled off,
and the resulting oil was solidified by adding diisopropyl ether to
obtain 530 mg of compound 626F.
[3023] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.48 (1H, d, J=5.3 Hz),
4.31 (1H, d, J=11.2 Hz), 4.48 (1H, d, J=11.2 Hz), 6.14 (1H, d,
J=5.3 Hz), 7.03-7.46 (7H, m).
[3024] Hereinbelow, according to Reference example 592, compound
626 was synthesized by the same procedure.
[3025] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (3H, d, J=6.9 Hz),
3.92 (1H, d, J=7.8 Hz), 4.40 (1H, d, J=7.8 Hz), 5.08 (1H, d, J=7.8
Hz), 5.39-5.52 (1H, m), 5.60-5.65 (2H, m), 5.76 (1H, d, J=6.9 Hz),
6.96-7.01 (1H, m), 7.17-7.55 (7H, m), 8.31 (1H, s).
Reference Example 627
##STR00823##
[3027] MS: m/z=530 [M+H].sup.+. RT=2.08 min.
Reference Example 628
##STR00824##
[3029] MS: m/z=530 [M+H].sup.+. RT=2.21 min.
Reference Example 629
##STR00825##
[3031] MS: m/z=430 [M+H].sup.+. RT=1.64 min.
Reference Example 630
##STR00826##
[3033] MS: m/z=498 [M+H].sup.+. RT=2.43 min.
Reference Example 631
##STR00827##
[3035] MS: m/z=484 [M+H].sup.+. RT=2.24 min.
Reference Example 632
##STR00828##
[3037] MS: m/z=498 [M+H].sup.+. RT=2.35 min.
Reference Example 633
##STR00829##
[3039] MS: m/z=488 [M+H].sup.+. RT=2.12 min.
Reference Example 634
##STR00830##
[3041] MS: m/z=488 [M+H].sup.+. RT=2.17 min.
Reference Example 635
##STR00831##
[3043] MS: m/z=498 [M+H].sup.+. RT=2.40 min.
Reference Example 636
##STR00832##
[3045] MS: m/z=506 [M+H].sup.+. RT=2.17 min.
Reference Example 637
##STR00833##
[3047] MS: m/z=538 [M+H].sup.+ RT=2.46 min.
Reference Example 638
##STR00834##
[3049] MS: m/z=506 [M+H].sup.+ RT=2.21 min.
Reference Example 639
##STR00835##
[3051] MS: m/z=504 [M+H].sup.+ RT=2.36 min.
Reference Example 640
##STR00836##
[3053] MS: m/z=506 [M+H].sup.+ RT=2.17 min.
Reference Example 641
##STR00837##
[3055] MS: m/z=504 [M+H].sup.+ RT=2.36 min.
Reference Example 642
##STR00838##
[3057] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.47-1.58 (1H, m),
1.62-1.75 (2H, m), 1.82-1.92 (1H, m), 2.83-2.91 (1H, m), 3.00-3.11
(1H, m), 3.15 (3H, s), 3.18-3.24 (1H, m), 3.47-3.72 (2H, m),
4.08-4.23 (2H, m), 4.36-4.54 (2H, m), 4.92 (1H, s), 5.79 (1H, d,
J=7.5 Hz), 6.60-6.68 (2H, m), 6.93 (1H, t, J=7.2 Hz), 7.10-7.39
(6H, m).
Reference Example 643
##STR00839##
[3059] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.47-1.56 (1H, m),
1.59-1.72 (2H, m), 1.81-1.91 (1H, m), 2.83 (1H, ddd, J=4.2 Hz, 4.2
Hz, 14.7 Hz), 3.00-3.11 (1H, m), 3.16 (3H, s), 3.19-3.26 (2H, m),
3.47-3.57 (1H, m), 3.77-3.91 (1H, m), 4.16-4.34 (2H, m), 4.40-4.45
(1H, m), 4.96 (1H, s), 5.86 (1H, d, J=7.8 Hz), 6.63-6.71 (2H, m),
6.82-6.85 (1H, m), 6.91-6.98 (1H, m), 7.00-7.04 (1H, m), 7.11-7.15
(1H, m).
Reference Example 644
##STR00840##
[3061] MS: m/z=517 [M+H].sup.+.
Reference Example 645
##STR00841##
[3063] MS: m/z=528 [M+H].sup.+
Reference Example 646
##STR00842##
[3064] First Step
[3065] Compound 646A (100 mg, 0.33 mmol) was dissolved in acetone
(1 mL)-toluene (1 mL), acetic acid (0.02 mL, 0.33 mmol) was added,
and the mixture was heated to reflux for 2 hours. The reaction
solution was concentrated under reduced pressure, and the residue
was purified by silica gel column chromatography. The materials
were eluted firstly with chloroform and, then, with
chloroform-methanol (10:1, v/v). Concentration of an objective
fraction afforded 117 mg of compound 646B as an oil.
[3066] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (6H, d, J=6.6 Hz),
1.95 (3H, s), 2.17 (3H, s), 4.01 (1H, q, J=14.3 Hz), 5.30 (2H, s),
6.36 (1H, brs), 6.45 (1H, d, J=7.6 Hz), 6.92 (1H, d, J=7.6 Hz),
7.29-7.40 (5H, m).
Second Step
[3067] A DMF (170 mL) solution of compound 646B was ice-cooled to 1
to 3.degree. C., and benzyl bromide (0.11 mL, 0.92 mmol) and cesium
carbonate (301 mg, 0.92 mmol) were added. After the reaction
solution was stirred at room temperature for 3 hours, the mixture
was distributed between ethyl acetate and water. The ethyl acetate
layer was separated, and the aqueous layer was extracted with ethyl
acetate once. The combined extracts were sequentially washed with
water two times and an aqueous saturated sodium chloride solution,
and dried. The solvent was distilled off, and the resulting oil was
purified by silica gel column chromatography. The materials were
eluted firstly with chloroform and, then, with chloroform-methanol
(10:1, v/v). Concentration of an objective fraction afforded 10 mg
of compound 646C as an oil.
[3068] MS: m/z=432 [M+H].sup.+
Third Step
[3069] Compound 646C (10 mg, 0.023 mmol) was dissolved in MeOH (0.5
mL), 10% Pd--C (2.5 mg) was added, and the mixture was subjected to
a catalytic reduction reaction under hydrogen stream. The catalyst
was removed by filtration, and the filtrate was concentrated. The
resulting residue was purified by diol silica gel column
chromatography. The materials were eluted firstly with chloroform
and, then, with chloroform-methanol (10:1, v/v). Concentration of
an objective fraction afforded 3.4 mg of compound 646 as an
oil.
[3070] MS: m/z=342 [M+H].sup.+.
Reference Example 647
##STR00843##
[3072] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.03-1.30 (3H, m), 4.51
(1H, t, J=14.41 Hz), 5.12-5.55 (4H, m), 7.18-7.46 (9H, m),
7.58-7.69 (2H, m).
[3073] MS: m/z=444.15 [M+H].sup.+.
Reference Example 648
##STR00844##
[3075] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.12-1.35 (2H, m),
4.46-4.55 (1H, m), 5.24-5.61 (3H, m), 6.33-6.42 (1H, m), 7.23-7.67
(8H, m), 8.22-8.29 (1H, m).
[3076] MS: m/z=512.15 [M+H].sup.+.
Reference Example 649
##STR00845##
[3078] MS: m/z=480.15 [M+H].sup.+.
Reference Example 650
##STR00846##
[3080] MS: m/z=520 [M+H].sup.+. RT=2.21 min.
Reference Example 651
##STR00847##
[3082] MS: m/z=487 [M+H].sup.+. RT=2.04 min.
Reference Example 652
##STR00848##
[3084] MS: m/z=478 [M+H].sup.+. RT=2.04 min.
LCMS Method
[3085] Column: ACQUITY UPLC registered trademark BEH C18 (1.7 .mu.m
i.d. 2.1.times.50 mm) (Waters) Flow rate: 0.8 mL/min. UV detection
wavelength: 254 nm Mobile phase: an aqueous solution containing
0.1% formic acid for [A], an acetonitrile solution containing 0.1%
formic acid for [B] Gradient: a linear gradient of 10% to 100%
solvent [B] over 3.5 minutes was performed, and 100% solvent [B]
was retained for 0.5 minutes.
Reference Example 653
##STR00849##
[3087] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (3H, d, J=7.4 Hz),
3.69 (1H, d, J=13.7 Hz), 4.52 (1H, d, J=12.6 Hz), 5.14-5.20 (2H,
m), 5.32-5.45 (1H, m), 5.64 (1H, d, J=13.5 Hz), 5.74 (1H, d, J=7.7
Hz), 6.56 (1H, d, J=7.7 Hz), 6.81 (1H, ddd, J=7.8, 7.8, 3.9 Hz),
6.87-6.96 (2H, m), 7.11 (1H, ddd, J=8.2, 8.2, 2.6 Hz), 7.17 (1H, d,
J=7.7 Hz), 7.32 (1H, dd, J=8.4, 5.4 Hz).
[3088] MS: m/z=524 [M+H].sup.+.
Reference Example 654
##STR00850##
[3090] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, d, J=7.4 Hz),
3.62 (1H, d, J=13.5 Hz), 4.44 (1H, d, J=12.9 Hz), 4.86 (1H, d,
J=13.2 Hz), 5.43-5.56 (1H, m), 5.68 (1H, d, J=13.5 Hz), 5.83 (1H,
d, J=7.7 Hz), 5.94 (1H, s), 6.81-6.91 (2H, m), 7.07-7.18 (3H, m),
7.26 (1H, t, J=7.7 Hz), 7.34 (1H, d, J=7.4 Hz), 7.55 (1H, d, J=8.0
Hz).
[3091] MS: m/z=566, 568 [M+H].sup.+.
Reference Example 655
##STR00851##
[3093] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44 (3H, d, J=7.4 Hz),
4.07 (1H, d, J=14.6 Hz), 4.52 (1H, d, J=12.6 Hz), 5.13 (1H, d,
J=12.6 Hz), 5.34-5.47 (2H, m), 5.79 (1H, d, J=7.7 Hz), 5.93 (1H, d,
J=14.6 Hz), 6.58 (1H, d, J=7.7 Hz), 6.82 (1H, ddd, J=7.9, 7.9, 5.6
Hz), 6.89-6.97 (1H, m), 7.14 (1H, d, J=7.7 Hz), 7.40 (2H, d, J=5.2
Hz), 7.76-7.83 (1H, m).
[3094] MS: m/z=573 [M+H].sup.+.
Reference Example 656
##STR00852##
[3096] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (3H, d, J=7.4 Hz),
3.72 (1H, d, J=13.7 Hz), 4.48 (1H, d, J=13.2 Hz), 4.90 (1H, d,
J=13.2 Hz), 5.13 (1H, s), 5.50-5.58 (1H, m), 5.61 (1H, d, J=14.0
Hz), 5.86 (1H, d, J=7.7 Hz), 6.56 (1H, d, J=7.7 Hz), 6.84 (1H, ddd,
J=7.9, 7.9, 5.6 Hz), 6.91-7.00 (2H, m), 7.11-7.19 (2H, m), 7.40
(1H, dd, J=8.4, 5.4 Hz).
[3097] MS: m/z=524 [M+H].sup.+.
Reference Example 657
##STR00853##
[3099] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (3H, d, J=7.3 Hz),
3.97 (1H, d, J=14.5 Hz), 4.53 (1H, d, J=12.7 Hz), 5.12 (1H, d,
J=12.7 Hz), 5.32 (1H, s), 5.35-5.49 (1H, m), 5.76 (1H, d, J=7.6
Hz), 5.90 (1H, d, J=14.5 Hz), 6.73 (1H, d, J=7.6 Hz), 6.78-6.86
(1H, m), 7.03-7.14 (2H, m), 7.19 (1H, dd, J=7.7, 0.8 Hz), 7.36-7.43
(2H, m), 7.77 (1H, dd, J=6.3, 2.9 Hz).
[3100] MS: m/z=556 [M+H].sup.+.
Reference Example 658
##STR00854##
[3102] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (3H, d, J=7.1 Hz),
3.74 (1H, d, J=13.7 Hz), 4.47 (1H, d, J=12.9 Hz), 4.90 (1H, d,
J=13.2 Hz), 5.13 (1H, s), 5.47-5.60 (1H, m), 5.65 (1H, d, J=13.7
Hz), 5.86 (1H, d, J=7.7 Hz), 6.68 (1H, d, J=7.7 Hz), 6.81 (1H, dd,
J=7.8, 7.8 Hz), 6.94 (1H, dd, J=8.5, 2.5 Hz), 7.10-7.20 (2H, m),
7.27-7.31 (1H, m), 7.39 (1H, dd, J=8.4, 5.4 Hz).
[3103] MS: m/z=540 [M+H].sup.+.
Reference Example 659
##STR00855##
[3105] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (3H, d, J=7.1 Hz),
4.31 (1H, d, J=14.0 Hz), 4.53 (1H, d, J=12.6 Hz), 5.15 (1H, d,
J=12.6 Hz), 5.21 (1H, s), 5.31-5.45 (1H, m), 5.64 (1H, d, J=14.0
Hz), 5.80 (1H, d, J=7.7 Hz), 6.51 (1H, ddd, J=8.0, 8.0, 2.6 Hz),
6.70 (1H, dd, J=8.4, 5.6 Hz), 6.80 (1H, dd, J=9.3, 2.5 Hz), 7.10
(1H, d, J=7.7 Hz), 7.15-7.25 (2H, m), 7.51 (1H, d, J=8.0 Hz).
[3106] MS: m/z=540 [M+H].sup.+.
Reference Example 660
##STR00856##
[3108] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (3H, d, J=7.4 Hz),
4.09 (1H, d, J=14.6 Hz), 4.44 (1H, d, J=13.2 Hz), 4.92 (1H, d,
J=13.5 Hz), 5.32 (1H, s), 5.48-5.60 (1H, m), 5.85-5.95 (2H, m),
6.56 (1H, d, J=7.7 Hz), 6.85 (1H, ddd, J=8.0, 8.0, 5.6 Hz),
6.92-7.00 (1H, m), 7.11 (1H, d, J=7.7 Hz), 7.39-7.44 (2H, m),
7.80-7.87 (1H, m).
[3109] MS: m/z=574 [M+H].sup.+.
Reference Example 661
##STR00857##
[3111] MS: m/z=566, 568 [M+H].sup.+.
Reference Example 662
##STR00858##
[3113] MS: m/z=502 [M+H].sup.+.
Reference Example 663
##STR00859##
[3115] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (3H, d, J=7.1 Hz),
4.33 (1H, d, J=14.0 Hz), 4.48 (1H, d, J=13.2 Hz), 4.90 (1H, d,
J=12.6 Hz), 5.16 (1H, s), 5.46-5.59 (1H, m), 5.62 (1H, d, J=13.7
Hz), 5.90 (1H, d, J=7.7 Hz), 6.54 (1H, ddd, J=7.7, 7.7, 2.5 Hz),
6.69 (1H, dd, J=8.7, 5.6 Hz), 6.84 (1H, dd, J=9.3, 2.5 Hz), 7.11
(1H, d, J=7.7 Hz), 7.15 (1H, d, J=7.7 Hz), 7.23 (1H, dd, J=7.8, 7.8
Hz), 7.55 (1H, d, J=8.0 Hz).
[3116] MS: m/z=540 [M+H].sup.+.
Reference Example 664
##STR00860##
[3118] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45 (3H, d, J=7.1 Hz),
3.71 (1H, d, J=13.7 Hz), 4.52 (1H, d, J=12.6 Hz), 5.13-5.19 (2H,
m), 5.32-5.45 (1H, m), 5.68 (1H, d, J=13.7 Hz), 5.74 (1H, d, J=7.7
Hz), 6.68 (1H, dd, J=7.7, 1.4 Hz), 6.78 (1H, dd, J=7.8, 7.8 Hz),
6.92 (1H, d, J=9.1 Hz), 7.07-7.18 (2H, m), 7.24 (1H, dd, J=8.0, 1.4
Hz), 7.32 (1H, dd, J=8.2, 5.5 Hz).
[3119] MS: m/z=540 [M+H].sup.+.
Reference Example 665
##STR00861##
[3121] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.92 (3H, d, J=7.1 Hz),
2.35 (3H, s), 3.60 (1H, d, J=13.5 Hz), 4.49 (1H, d, J=12.9 Hz),
4.82 (1H, d, J=12.4 Hz), 5.39-5.51 (2H, m), 5.60 (1H, d, J=13.5
Hz), 5.85 (1H, d, J=7.7 Hz), 6.69 (1H, d, J=7.4 Hz), 6.79-6.87 (1H,
m), 7.05 (1H, d, J=7.7 Hz), 7.10-7.15 (3H, m), 7.22 (1H, d, J=7.1
Hz), 7.27-7.33 (1H, m).
[3122] MS: m/z=502 [M+H].sup.+.
[3123] Methods for synthesizing intermediate compounds i-1 to i-72
for synthesizing parent compounds are shown below.
Synthesis of Intermediate Compound i-3
##STR00862##
[3124] Step 1
[3125] Compound i-1 (50.0 g, 136 mmol) was dissolved in
dichloromethane (500 mL), Boc.sub.2O (34.8 mL, 150 mmol) and DMAP
(831 mg, 6.81 mmol) were added, and the mixture was stirred at room
temperature for 2 hours. Thereafter, NBS (29.1 g, 163 mmol) was
added, and the mixture was further stirred at room temperature
overnight.
[3126] The organic layer was washed with water and aqueous
saturated sodium chloride solution, and then dried with anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (hexane-ethyl acetate) to obtain compound i-2
(64.0 g, yield 86%).
[3127] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.62 (s, 1H), 7.58 (t,
J=8.6 Hz, 2H), 7.38 (brs, 3H), 5.44 (brs, 1H), 5.23 (d, J=10.6 Hz,
2H), 5.14 (d, J=11.9 Hz, 1H), 3.40 (s, 1H), 1.47-1.43 (m, 12H).
Step 2
[3128] A methanol (600 mL) solution of compound i-2 (64.0 g, 117
mmol) was cooled to 0.degree. C. with ice water. A 2 mol/L aqueous
sodium hydroxide solution (76 mL, 152 mmol) was added thereto, and
the mixture was stirred at 0.degree. C. for 1 hour. Under an ice
bath, the mixture was neutralized with 2 mol/L hydrochloric acid,
and the precipitated solid was separated by filtration. The solid
was washed with water, and dried to obtain compound i-3 (40.5 g,
yield 78%).
[3129] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.38 (s, 1H), 7.62 (t,
J=6.6 Hz, 1H), 7.53 (d, J=7.1 Hz, 2H), 7.35-7.33 (m, 3H), 5.29
(brs, 1H), 5.11 (q, J=12.5 Hz, 2H), 4.75 (t, J=6.9 Hz, 1H), 4.65
(t, J=11.1 Hz, 1H), 1.45 (d, J=7.1 Hz, 3H).
Synthesis of Intermediate Compound i-5
##STR00863##
[3130] Step 1
[3131] To compound i-4 (6.60 g, 9.55 mmol), dioxane (66 mL),
Pd.sub.2(PPh.sub.3).sub.2 (670 mg, 0.955 mmol), and
tributyl(1-ethoxy-vinyl)tin (4.84 mL, 14.3 mmol) were added under
nitrogen atmosphere, and the mixture was heated to reflux for 2
hours and 30 minutes. After cooling the mixture to room
temperature, 1 mol/L hydrochloric acid (20 mL) was added, and the
mixture was stirred at room temperature for 20 minutes. Water was
added, and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and aqueous saturated sodium
chloride solution, and then dried with anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the
resulting residue was purified by silica gel column chromatography
(hexane-ethyl acetate) to obtain compound i-5 (5.50 g, yield
88%).
[3132] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.75 (s, 1H), 7.59 (d,
J=6.6 Hz, 2H), 7.50 (s, 1H), 7.42-7.39 (m, 5H), 7.11 (s, 2H), 6.80
(s, 1H), 6.54 (d, J=7.1 Hz, 1H), 5.74 (s, 1H), 5.64 (d, J=13.4 Hz,
1H), 5.57 (brs, 1H), 5.45 (d, J=10.6 Hz, 1H), 5.25 (d, J=10.6 Hz,
1H), 5.12 (d, J=13.6 Hz, 1H), 4.52 (d, J=13.6 Hz, 1H), 3.96 (d,
J=13.6 Hz, 1H), 2.37 (s, 3H), 1.02 (d, J=6.3 Hz, 3H).
Synthesis of Intermediate Compound i-7
##STR00864##
[3133] Step 1
[3134] To compound i-6 (40 mg, 0.058 mmol) were added
dimethylacetamide (0.5 mL) and copper(I) cyanide (52 mg, 0.579
mmol), and the mixture was heated to stir in a sealed tube at
140.degree. C. for 26 hours. 1 mol/L hydrochloric acid (20 mL) was
added, and the mixture was extracted with ethyl acetate. The
organic layer was washed with aqueous saturated sodium chloride
solution, and then dried with anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure, and the resulting residue
was purified by preparative LCMS (method 14) to obtain compound i-7
(8.0 mg, yield 25%).
[3135] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.58 (s, 1H), 7.51 (s,
1H), 7.46 (s, 2H), 7.21 (brs, 2H), 6.92-6.88 (m, 2H), 5.86 (s, 1H),
5.65 (d, J=12.6 Hz, 1H), 5.48 (brs, 1H), 4.95 (brs, 1H), 4.49 (brs,
1H), 3.97 (d, J=13.4 Hz, 2H), 1.02 (s, 3H).
Synthesis of Intermediate Compound i-10
##STR00865##
[3136] Step 1
[3137] To compound i-8 (110 mg, 0.164 mmol) were added methanol (1
mL), tetrahydrofuran (1 mL), and 2 mol/L aqueous sodium hydroxide
solution (0.246 mL, 0.492 mmol), and the mixture was stirred at
60.degree. C. for 3 hours, then 2 mol/L aqueous sodium hydroxide
solution (0.164 mL, 0.328 mmol) was further stirred at 60.degree.
C. for 4 hours. The mixture was neutralized with 2 mol/L
hydrochloric acid, and then extracted with chloroform. The organic
layer was washed with aqueous saturated sodium chloride solution,
and then dried with anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure to obtain compound i-9 (91 mg,
98%).
[3138] MS: m/z=566 [M+H].sup.+. RT=2.30 min.
Step 2
[3139] To compound i-9 (20 mg, 0.035 mmol) were added
dimethylformamide (0.5 mL), 2 mol/L ammonia-methanol solution
(0.053 mL, 0.106 mmol),
[4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
chloride] (29.3 mg, 0.106 mmol), and the mixture was stirred at
room temperature overnight. Thereafter, a 28% sodium
methoxide-methanol solution (34.1 mg, 0.177 mmol) was added, and
the mixture was further stirred at room temperature for 1 hour.
After adding 0.5 mol/L hydrochloric acid, the mixture was extracted
with ethyl acetate. The organic layer was washed with aqueous
saturated sodium chloride solution, and then dried with anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by preparative
LCMS (method 14) to obtain compound i-10 (4.0 mg, yield 20%).
[3140] MS: m/z=565 [M+H].sup.+. RT=2.03 min.
Synthesis of Intermediate Compound i-12
##STR00866##
[3141] Step 1
[3142] To compound i-11 (1.00 g, 3.28 mmol) were added
tetrahydrofuran (25 mL),
[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride
(214 mg, 4.91 mmol), potassium cyclopropyltrifluoroborate (727 mg,
4.91 mmol), and a 2 mol/L aqueous sodium carbonate solution (4.91
mL, 9.83 mmol) under nitrogen atmosphere, and the mixture was
heated to reflux for 20 hours. After adding water, the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and aqueous saturated sodium chloride solution, and then
dried with anhydrous magnesium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel column chromatography (hexane-chloroform) to obtain
compound i-12 (350 mg, yield 24%).
[3143] MS: m/z=267 [M+H].sup.+. RT=2.46 min.
Synthesis of Intermediate Compound i-14
##STR00867##
[3144] Step 1
[3145] To compound i-13 (200 mg, 0.305 mmol) were added
tetrahydrofuran (3 mL), bis(pinacolato)diboron (232 mg, 0.914
mmol), PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (24.9 mg, 0.030 mmol), and
potassium acetate (90 mg, 0.914 mmol), and the mixture was stirred
at 80.degree. C. for 3 hours and 30 minutes. After cooled to room
temperature, the mixture was filtered with celite, and the solvent
was distilled off under reduced pressure. After adding 1 mol/L
hydrochloric acid, the mixture was extracted with ethyl acetate.
The organic layer was washed with aqueous saturated sodium chloride
solution, and then dried with anhydrous sodium sulfate. To the
obtained brown substance were added dimethylacetamide (2 mL) and
lithium chloride (64.5 mg, 1.53 mmol), and the mixture was stirred
at 100.degree. C. for 4 hours. After cooled to room temperature, 1
mol/L hydrochloric acid was added, and the mixture was extracted
with ethyl acetate. The organic layer was washed with aqueous
saturated sodium chloride solution, and then dried with anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by preparative
LCMS (method 14) to obtain compound i-14 (59 mg, yield 37%).
[3146] MS: m/z=532 [M+H].sup.+. RT=2.02 min.
Synthesis of Intermediate Compound i-16
##STR00868##
[3147] Step 1
[3148] To compound i-15 (20 mg, 0.030 mmol) were added
tetrahydrofuran (0.5 mL), PEPPSI-IPr (2.07 mg, 3.05 .mu.mol), and 2
mol/L methyl zinc chloride-tetrahydrofuran solution (0.076 mL,
0.152 mmol), and the mixture was heated to stir in a sealed tube at
100.degree. C. for 3 hours under nitrogen stream. After cooled to
room temperature, 2 mol/L hydrochloric acid was added, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with aqueous saturated sodium chloride solution, and then
dried with anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel column chromatography (DIOL, hexane-ethyl acetate) to
obtain compound i-16 (4.0 mg, yield 26%).
[3149] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.54 (s, 1H), 7.46 (s,
1H), 7.41 (s, 1H), 7.25 (s, 2H), 7.08 (s, 2H), 6.91 (s, 1H), 6.81
(s, 1H), 5.68 (d, J=13.1 Hz, 1H), 5.56 (s, 1H), 5.48 (s, 1H), 5.05
(d, J=13.6 Hz, 1H), 4.41 (d, J=12.6 Hz, 1H), 3.87 (d, J=12.9 Hz,
1H), 1.52 (s, 3H), 1.18 (d, J=6.3 Hz, 3H).
Synthesis of Intermediate Compound i-18
##STR00869##
[3150] Step 1
[3151] Compound i-17 (50 mg, 0.076 mmol) was dissolved in
tetrahydrofuran (1 mL), and the mixture was cooled to -78.degree.
C. with dry ice-acetone. A 1.06 mol/L diisobutylaluminum
hydride-hexane solution (0.108 mL, 0.115 mmol) was added thereto,
and the mixture was stirred at -78.degree. C. for 1 hour. A
saturated Rochelle salt solution was added, and the mixture was
stirred at room temperature for 20 minutes and then extracted with
ethyl acetate. The organic layer was washed with aqueous saturated
sodium chloride solution, and then dried with anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (hexane-ethyl acetate) to obtain compound i-18 (35
mg, yield 70%).
[3152] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.53 (s, 3H), 7.46 (s,
2H), 7.36 (d, J=7.3 Hz, 3H), 7.29 (s, 1H), 7.15 (s, 2H), 6.80 (brs,
1H), 6.47 (d, J=7.1 Hz, 1H), 5.70 (s, 1H), 5.61 (d, J=14.4 Hz, 1H),
5.53 (brs, 1H), 5.33 (d, J=11.1 Hz, 1H), 5.13 (d, J=11.4 Hz, 1H),
5.01 (d, J=12.9 Hz, 1H), 4.92 (s, 1H), 4.57 (s, 1H), 4.47 (d,
J=13.9 Hz, 1H), 3.98 (d, J=13.9 Hz, 1H), 0.98 (d, J=6.8 Hz, 3H),
0.71 (d, J=5.3 Hz, 3H).
Synthesis of Intermediate Compound i-20
##STR00870##
[3153] Step 1
[3154] To compound i-19 (560 mg, 1.43 mmol) were added toluene (250
mL), acetic acid (25 mL), and tosyl acid monohydrate (54.4 mg,
0.286 mmol), and the mixture was heated to reflux for 16 hours. The
solvent was distilled off under reduced pressure, and the resulting
residue was purified by silica gel column chromatography
(hexane-ethyl acetate) to obtain compound i-20 (210 mg, yield
45%).
[3155] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.56 (d, J=6.8 Hz, 2H),
7.36-7.27 (m, 5H), 6.23 (d, J=7.3 Hz, 1H), 5.06 (s, 2H), 4.79 (t,
J=11.7 Hz, 1H), 4.14 (d, J=13.4 Hz, 1H), 4.02 (brs, 2H), 3.43 (t,
J=13.0 Hz, 1H), 3.13 (t, J=10.5 Hz, 1H), 2.95 (t, J=11.1 Hz,
1H).
Synthesis of Intermediate Compound i-25
##STR00871##
[3156] Step 1
[3157] Compound i-21 (30.0 g, 104 mmol) was suspended in methanol
(450 mL), and dissolved by heating to 65.degree. C. Manganese
dioxide (75 g, 863 mmol) was added, and the mixture was stirred at
65.degree. C. for 2 hours. The solid was removed by filtration, and
the filtrate was distilled off under reduced pressure. To the
resulting residue were added tetrahydrofuran-diisopropyl ether to
precipitate a solid, then the solid was filtered to obtain compound
i-22 (27.55 g, yield 93%).
[3158] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.99 (s, 3H), 5.43 (s,
2H), 7.27-7.45 (m, 6H), 8.62 (s, 1H), 10.05 (s, 1H).
Step 2
[3159] Sodium chlorite (34.6 g, 383 mmol) was dissolved in water
(150 mL), and the mixture was cooled to 0.degree. C. with ice
water. Amidosulfuric acid (37.2 mg, 383 mmol) was added thereto,
and the mixture was stirred for 40 minutes. Compound i-22 (27.5 g,
96 mmol) was dissolved in tetrahydrofuran (450 mL) and DMF (45 mL)
in another flask, and the mixture was cooled to 0.degree. C. with
ice water. The aqueous solution prepared as above was added
dropwise thereto, and the mixture was stirred at 0.degree. C. for 1
hour. The solvent was concentrated under reduced pressure, water
and diisopropyl ether were added, and the solid was filtered to
obtain compound i-23 (19.49 g, yield 67%).
[3160] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.74 (s, 3H), 5.11 (s,
2H), 7.27-7.40 (m, 4H), 7.44-7.50 (m, 2H), 8.11 (s, 1H).
Step 3
[3161] Compound i-23 (14.0 g, 46.2 mmol) was dissolved in DMF (140
mL), and the solution was ice-cooled.
(R)-1,1,1-trifluoroisopropylamine hydrochloride (10.36 g, 69.2
mmol), EDC (11.50 g, 60.0 mmol), HOBt (8.11 g, 60.0 mmol), and
triethylamine (19.2 mL, 138 mmol) were added, and the mixture was
stirred at room temperature for 4 hours. Water was added to the
reaction solution to stop the reaction. The solution was extracted
with ethyl acetate, and the organic layer was washed with water and
aqueous saturated sodium chloride solution, and then dried with
anhydrous magnesium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel chromatography (chloroform-methanol) to obtain compound i-24
(12.87 g, yield 70%).
[3162] MS: m/z=399.1 [M+H].sup.+.
Step 4
[3163] Compound i-24 (12.55 g, 31.5 mmol) was dissolved in DMF (130
mL). Potassium carbonate (21.77 g, 158 mmol) was added, and the
mixture was stirred for 15 minutes. 2,4-dinitrophenylhydroxylamine
(9.41 g, 47.3 mmol) was added, and the mixture was stirred for 3
hours. To the reaction solution was added chloroform, the
precipitated solid was removed by filtration, and the filtrate was
distilled off under reduced pressure. To the resulting DMF solution
were added paraformaldehyde (851 mg, 28.3 mmol) and acetic acid
(0.09 mL, 1.58 mmol), and the mixture was stirred at 110.degree. C.
for 3 hours and 30 minutes. The reaction solution was allowed to
cool, the solvent was distilled off under reduced pressure, and the
resulting residue was purified by silica gel chromatography
(chloroform-methanol) to obtain compound i-25 (8.15 g, yield
61%).
[3164] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.32 (d, J=7.2 Hz, 3H),
3.79 (s, 3H), 4.39-4.54 (m, 2H), 5.14 (d, J=10.2 Hz, 1H), 5.24 (m,
1H), 5.28 (d, J=10.2 Hz, 1H), 6.54 (m, 1H), 7.25-7.33 (m, 3H),
7.45-7.52 (m, 2H), 8.18 (s, 1H).
Synthesis of Intermediate Compound i-29
##STR00872##
[3165] Step 1
[3166] Compound i-25 (1.5 g, 3.5 mmol) was suspended in
dichloromethane. Boc.sub.2O (0.86 mL, 3.7 mmol) and DMAP (43 mg,
0.35 mmol) were added, and the mixture was stirred at room
temperature for 1 hour. Water was added, and the mixture was
extracted with chloroform. The organic layer was washed with water
and aqueous saturated sodium chloride solution, and then dried with
anhydrous magnesium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel chromatography (hexane-ethyl acetate) to obtain compound i-26
(1.59 g, yield 86%).
[3167] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33-1.50 (m, 12H), 3.91
(s, 3H), 4.71 (m, 0.6H), 4.88 (m, 0.4H), 5.13-5.60 (m, 4H),
7.27-7.37 (m, 3H), 7.49-7.66 (m, 2H), 8.16 (s, 1H).
Step 2
[3168] Compound i-26 (1.5 g, 2.9 mmol) was suspended in toluene (30
mL) under nitrogen atmosphere, and the mixture was cooled to
-78.degree. C. with dry ice-acetone. A DIBAL-hexane solution (3.0
mL, 3.1 mmol) was added dropwise thereto, and the mixture was
stirred at -78.degree. C. for 1 hour. To the reaction solution was
added ethyl acetate to stop the reaction, and the mixture was
heated to room temperature. An aqueous potassium sodium tartrate
solution was added, and the mixture was stirred vigorously at room
temperature for 1 hour. Two layers were separated, and the organic
layer was washed with water and aqueous saturated sodium chloride
solution, and then dried with anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure, and the resulting residue
was purified by silica gel chromatography (hexane-ethyl acetate) to
obtain compound i-27 (568 mg, yield 40%).
[3169] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38-1.49 (m, 12H),
4.58-4.81 (m, 1H), 5.23-5.70 (m, 4H), 7.27-7.40 (m, 3H), 7.47-7.65
(m, 2H), 7.95 (s, 1H), 10.32 (s, 1H).
Step 3
[3170] Compound i-27 (550 mg, 1.1 mmol) was dissolved in
dichloromethane (11 mL). The solution was ice-cooled,
bis(2-methoxyethyl)aminosulfur trifluoride (0.72 mL, 3.9 mmol) was
added, and the mixture was heated to room temperature and stirred
for 2 hours. Water was added to the reaction solution to stop the
reaction, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated sodium bicarbonate water,
water, and aqueous saturated sodium chloride solution, and then
dried with anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel chromatography (hexane-ethyl acetate) to obtain compound
i-28 (408 mg, yield 71%).
[3171] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.36-1.52 (m, 12H), 4.68
(m, 0.7H), 4.78 (m, 0.3H), 5.18-5.59 (m, 4H), 6.89 (t, J=54.9 Hz,
1H), 7.27-7.38 (m, 3H), 7.47-7.63 (m, 2H), 7.64 (s, 1H).
Step 4
[3172] Compound i-28 (400 mg, 0.77 mmol) was dissolved in methanol
(6 mL). The solution was ice-cooled, a 2 mol/L aqueous sodium
hydroxide solution (0.5 mL, 1.0 mmol) was added, and the mixture
was stirred at 0.degree. C. for 1 hour. The reaction solution was
diluted by adding water, and the mixture was extracted with
chloroform. The organic layer was washed with water and aqueous
saturated sodium chloride solution, and then dried with anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure to obtain compound i-29 (286 mg, yield 89%).
[3173] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38 (d, J=7.2 Hz, 3H),
4.47 (d, J=7.8 Hz, 2H), 5.22 (d, J=10.2 Hz, 1H), 5.29 (m, 1H), 5.34
(d, J=10.2 Hz, 1H), 5.82 (m, 1H), 6.80 (t, J=55.2 Hz, 1H),
7.28-7.37 (m, 3H), 7.48-7.55 (m, 2H), 7.71 (s, 1H).
Synthesis of Intermediate Compound i-32
##STR00873##
[3174] Step 1
[3175] Compound i-30 (13.3 g, 69.9 mmol) was dissolved in DMF (60
mL). The solution was ice-cooled, sodium hydride (3.3 g, 83 mmol)
was added, and the mixture was stirred at 0.degree. C. for 15
minutes. Bromoacetaldehyde dimethyl acetal (12.3 mL, 104 mmol) and
potassium iodide (1.16 g, 7.0 mmol) were added thereto, and the
mixture was stirred at room temperature for 3 hours. Water was
added to the reaction solution to stop the reaction, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and aqueous saturated sodium chloride solution,
and then dried with anhydrous magnesium sulfate. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel chromatography (hexane-ethyl acetate) to
obtain compound i-31 (8.8 g, yield 45%).
[3176] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.34 (s, 6H), 3.53 (d,
J=5.1 Hz, 2H), 3.76 (t, J=5.7 Hz, 2H), 3.91 (t, J=5.7 Hz, 2H), 4.44
(t, J=5.1 Hz, 1H), 7.72 (m, 2H), 7.85 (m, 2H).
Step 2
[3177] Compound i-31 (8.79 g, 31.5 mmol) was dissolved in ethanol
(100 mL). Hydrazine monohydrate (3.0 mL, 62.9 mmol) was added, and
the mixture was stirred at 60.degree. C. for 2 hours. After
cooling, the precipitated solid was removed by filtration, and the
filtrate was distilled off under reduced pressure. The
reprecipitated solid was removed by filtration, and the filtrate
was distilled off under reduced pressure to obtain compound i-32
(4.37 g, yield 93%).
[3178] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.87 (m, 2H), 3.40 (s,
6H), 3.49-3.57 (m, 4H), 4.53 (m, 1H).
Synthesis of Intermediate Compounds i-36 and i-37
##STR00874##
[3179] Step 1
[3180] Compound i-33 (1.00 g, 4.09 mmol) was dissolved in DMF (5
mL), dimethylamine hydrochloride (384 mg, 4.71 mmol), potassium
carbonate (651 mg, 4.71 mmol), and triethylamine (0.653 mL, 4.71
mmol) were added, and the mixture was stirred in a sealed tube at
160.degree. C. for 17.5 hours. Water was added, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and aqueous saturated sodium chloride solution, and then
dried with anhydrous magnesium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel chromatography (hexane-ethyl acetate) to obtain
compound i-34 (587 mg, yield 53%).
[3181] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.71 (s, 6H), 3.96 (s,
2H), 6.68 (d, J=7.3 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 7.18-7.36 (m,
4H), 7.99 (dd, J=7.9, 1.5 Hz, 1H).
Step 2
[3182] Compound i-34 (587 mg, 2.18 mmol) was dissolved in
tetrahydrofuran (20 mL), sodium
bis(2-methoxyethoxy)aluminumhydride-toluene solution (3.39 mL, 10.9
mmol) was added dropwise under ice-cooling, and the mixture was
stirred at room temperature for 3.5 hours. Under ice-cooling, an
aqueous Rochelle salt (7.06 g, 25.0 mmol) solution (50 mL) was
added, and the mixture was heated to room temperature. The solution
was extracted with ethyl acetate, and the organic layer was washed
with aqueous saturated sodium chloride solution, and then dried
with anhydrous magnesium sulfate. The solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel chromatography (hexane-ethyl acetate) to obtain compound
i-35 (460 mg, yield 78%).
[3183] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.61 (s, 6H), 3.67 (d,
J=13.7 Hz, 1H), 4.95 (d, J=13.7 Hz, 1H), 6.61 (d, J=7.1 Hz, 1H),
6.96-7.18 (m, 4H), 7.24-7.28 (m, 2H), 7.79 (d, J=7.7 Hz, 1H), 9.88
(d, J=6.6 Hz, 1H).
Step 3
[3184] Compound i-35 (100 mg, 0.368 mmol) was dissolved in ethyl
acetate (3 mL), compound i-A (222 mg, 0.553 mmol) and chloroacetic
acid (104 mg, 1.11 mmol) were added, and the mixture was stirred in
a sealed tube at 120.degree. C. for 4 hours. The mixture was
diluted with ethyl acetate, washed with an aqueous saturated sodium
bicarbonate solution and water, and then dried with anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
chromatography (hexane-ethyl acetate) to obtain compound i-36 (107
mg, yield 44%) and compound i-37 (42.7 mg, yield 18%).
[3185] 4: .sup.1H-NMR (CDCl.sub.3) .delta.: 0.96 (d, J=7.1 Hz, 3H),
2.48 (s, 6H), 3.49 (d, J=14.0 Hz, 1H), 4.18 (d, J=13.2 Hz, 1H),
4.66 (d, J=13.2 Hz, 1H), 5.35-5.52 (m, 2H), 5.59 (d, J=10.4 Hz,
1H), 5.79 (d, J=14.0 Hz, 1H), 5.99 (s, 1H), 6.57 (d, J=7.7 Hz, 1H),
6.72 (t, J=7.1 Hz, 1H), 7.03-7.15 (m, 4H), 7.26-7.38 (m, 5H),
7.58-7.64 (m, 2H).
[3186] 5: MS: m/z=655.15 [M+H].sup.+.
Synthesis of Intermediate Compound i-42
##STR00875##
[3187] Step 1
[3188] Compound i-38 (12.0 g, 49.1 mmol) was dissolved in
tetrahydrofuran (20 mL), a sodium methoxide-methanol solution (60.0
mL, 311 mmol) was added, and the mixture was refluxed for 4 hours.
An aqueous hydrochloric acid solution was added, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
water and aqueous saturated sodium chloride solution, and then
dried with anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure, and to the resulting residue were added
dichloromethane-hexane to precipitate a solid, then the solid was
filtered to obtain compound i-39 (10.5 g, yield 84%).
[3189] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79 (s, 3H), 3.99 (s,
2H), 6.85 (dd, J=7.8, 6.2 Hz, 2H), 7.19-7.26 (m, 2H), 7.30-7.39 (m,
2H), 7.95 (dd, J=8.2, 1.4 Hz, 1H).
Step 2
[3190] Compound i-39 was suspended in dichloromethane (100 mL)
under nitrogen atmosphere, and a 1 mol/L
tribromoborane-dichloromethane solution (82.0 mL, 82.0 mmol) was
added dropwise under ice-cooling, then the mixture was stirred at
room temperature for 2 hours. An aqueous sodium bicarbonate
solution was added under ice-cooling, and then the mixture was
heated to room temperature. An aqueous saturated sodium chloride
solution was added, and the mixture was extracted with
dichloromethane. The organic layer was washed with aqueous
saturated sodium chloride solution, and then dried with anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and to the resulting residue were added
dichloromethane-hexane to precipitate a solid, then the solid was
filtered to obtain compound i-40 (8.42 g, yield 85%).
[3191] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.05 (s, 2H), 6.72 (d,
J=6.9 Hz, 1H), 6.98 (dd, J=8.2, 1.1 Hz, 1H), 7.32-7.48 (m, 4H),
8.29 (dd, J=7.6, 2.1 Hz, 1H), 12.35 (s, 1H).
Step 3
[3192] Compound i-40 (500 mg, 2.06 mmol) was dissolved in
tetrahydrofuran (10 mL), sodium
bis(2-methoxyethoxy)aluminumhydride-toluene solution (3.21 mL, 10.3
mmol) was added dropwise under ice-cooling, and the mixture was
stirred for 1 hour under ice-cooling. Under ice-cooling, an aqueous
Rochelle salt (2.82 g, 10.0 mmol) solution (20 mL) was added, and
the mixture was heated to room temperature. The solution was
extracted with ethyl acetate, and the organic layer was washed with
water and aqueous saturated sodium chloride solution, and then
dried with anhydrous magnesium sulfate. The solvent was distilled
off under reduced pressure, and to the resulting residue were added
dichloromethane-hexane to precipitate a solid, then the solid was
filtered to obtain compound i-41 (389 mg, yield 77%).
[3193] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.28 (s, 1H), 3.77 (d,
J=13.2 Hz, 1H), 4.73 (d, J=13.2 Hz, 1H), 6.69 (s, 1H), 6.73-6.78
(m, 2H), 7.06-7.17 (m, 4H), 7.60-7.65 (m, 1H), 8.45 (s, 1H).
Step 4
[3194] Compound i-41 (150 mg, 0.614 mmol) was suspended in
acetonitrile (1.5 mL), triethylamine (0.426 mL, 3.07 mmol), acetic
acid anhydride (0.290 mL, 3.07 mmol) and DMAP (37.5 mg, 0.307 mmol)
were added, and the mixture was stirred at room temperature for 1.5
hours. Water was added, and the mixture was extracted with ethyl
acetate. The organic layer was washed with an aqueous hydrochloric
acid solution and aqueous saturated sodium chloride solution, and
then dried with anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel chromatography (hexane-ethyl acetate) to obtain
compound i-42 (171 mg, yield 85%).
[3195] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.03 (s, 3H), 2.41 (s,
3H), 3.55 (d, J=14.0 Hz, 1H), 5.38 (d, J=13.9 Hz, 1H), 6.97-7.16
(m, 5H), 7.24 (s, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.40 (d, J=7.8 Hz,
1H).
Synthesis of Intermediate Compound i-49
##STR00876##
[3196] Step 1
[3197] Compound i-43 (4.06 g, 16.7 mmol) was dissolved in DMSO (40
mL), potassium phosphate (7.11 g, 33.5 mmol) and allyl bromide
(2.18 mL, 25.1 mmol) were added, and the mixture was stirred at
room temperature for 6 hours. Water was added, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and aqueous saturated sodium chloride solution, and then
dried with anhydrous magnesium sulfate. The solvent was distilled
off under reduced pressure, and to the resulting residue was added
hexane to precipitate a solid, then the solid was filtered to
obtain compound i-44 (4.28 g, yield 91%).
[3198] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.00 (s, 2H), 4.50-4.55
(m, 2H), 5.20-5.26 (m, 1H), 5.32-5.41 (m, 1H), 5.89-6.03 (m, 1H),
6.84 (d, J=8.0 Hz, 2H), 7.19-7.26 (m, 2H), 7.29-7.37 (m, 2H), 7.92
(dd, J=8.2, 1.4 Hz, 1H).
Step 2
[3199] Compound i-44 (50.0 mg, 0.177 mmol) was dissolved in DMA (1
mL), and the solution was stirred in a sealed tube at 230.degree.
C. for 6 hours. An aqueous hydrochloric acid solution was added,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with an aqueous hydrochloric acid solution and aqueous
saturated sodium chloride solution, and then dried with anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
chromatography (hexane-ethyl acetate) to obtain compound i-45 (37.1
mg, yield 74%).
[3200] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.43 (d, J=6.6 Hz, 2H),
4.01 (s, 2H), 5.05-5.15 (m, 2H), 6.01 (ddt, J=17.3, 10.1, 6.8 Hz,
1H), 6.65 (d, J=7.4 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.29-7.46 (m,
3H), 8.27 (dd, J=8.0, 1.6 Hz, 1H), 12.69 (s, 1H).
Step 3
[3201] Compound i-45 (600 mg, 2.13 mmol) was dissolved in DMSO (6
mL), potassium phosphate (902 mg, 4.25 mmol) and allyl bromide
(0.276 mL, 3.19 mmol) were added, and the mixture was stirred at
room temperature for 2 hours. Water was added, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and aqueous saturated sodium chloride solution, and then
dried with anhydrous magnesium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel chromatography (hexane-ethyl acetate) to obtain
compound i-46 (642 mg, yield 88%).
[3202] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.40 (d, J=6.3 Hz, 2H),
3.99 (s, 2H), 4.27-4.32 (m, 2H), 5.03-5.07 (m, 1H), 5.08-5.12 (m,
1H), 5.15-5.21 (m, 1H), 5.25-5.33 (m, 1H), 5.85-6.04 (m, 2H), 6.95
(d, J=8.0 Hz, 1H), 7.18-7.27 (m, 4H), 7.30-7.37 (m, 1H), 7.88-7.94
(m, 1H).
Step 4
[3203] Compound i-46 (560 mg, 1.74 mmol) was dissolved in
dichloromethane (56 mL) under nitrogen atmosphere, a second
generation Grubbs catalyst (147 mg, 0.174 mmol) was added, and the
mixture was stirred at room temperature for 14 hours. The solvent
was distilled off under reduced pressure, and the resulting residue
was purified by silica gel chromatography (hexane-ethyl acetate) to
obtain compound i-47 (366 mg, yield 72%).
[3204] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.22-3.28 (m, 2H), 3.82
(s, 2H), 4.42-4.47 (m, 2H), 5.23-5.31 (m, 1H), 5.57-5.67 (m, 1H),
6.72 (d, J=7.7 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 7.00-7.07 (m, 2H),
7.11-7.19 (m, 1H), 7.74-7.79 (m, 1H).
Step 5
[3205] Compound i-47 (362 mg, 1.23 mmol) was dissolved in
tetrahydrofuran (7 mL), sodium
bis(2-methoxyethoxy)aluminumhydride-toluene solution (1.15 mL, 3.69
mmol) was added dropwise under ice-cooling, and the mixture was
stirred for 45 minutes under ice-cooling. Under ice-cooling, an
aqueous Rochelle salt (2.11 g, 7.50 mmol) solution (30 mL) was
added, and the mixture was heated to room temperature. The solution
was extracted with ethyl acetate, and the organic layer was washed
with aqueous saturated sodium chloride solution, then dried with
anhydrous magnesium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel chromatography (hexane-ethyl acetate) to obtain compound i-48
(352 mg, yield 97%).
[3206] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.29-3.40 (m, 1H),
3.43-3.55 (m, 1H), 3.95 (d, J=5.5 Hz, 1H), 4.06 (d, J=13.7 Hz, 1H),
4.47-4.52 (m, 2H), 4.82 (d, J=13.7 Hz, 1H), 5.33-5.41 (m, 1H),
5.74-5.84 (m, 1H), 6.43 (d, J=5.8 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H),
6.99 (d, J=7.7 Hz, 1H), 7.06-7.14 (m, 3H), 7.46-7.52 (m, 1H).
Step 6
[3207] To a tetrahydrofuran-methanol (1:1, 3 mL) solution of
compound i-48 (215 mg, 0.725 mmol) was added 10% palladium carbon
(77.0 mg, 0.073 mmol), and the mixture was stirred at room
temperature for 1.5 hours under hydrogen atmosphere. The solid was
removed by filtration, and the filtrate was distilled off under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (hexane-ethyl acetate) to obtain compound
i-49 (139 mg, yield 64%).
[3208] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.45-1.55 (m, 1H),
1.67-1.80 (m, 1H), 1.85-2.01 (m, 2H), 2.65-2.85 (m, 2H), 3.63-3.74
(m, 1H), 4.06-4.16 (m, 1H), 4.29 (d, J=13.5 Hz, 1H), 4.49 (d,
J=13.5 Hz, 1H), 4.58-4.70 (m, 1H), 6.44 (d, J=6.9 Hz, 1H), 6.88 (d,
J=7.4 Hz, 1H), 7.02 (d, J=7.7 Hz, 1H), 7.07-7.11 (m, 3H), 7.49-7.55
(m, 1H).
Synthesis of Intermediate Compounds i-51 and i-54
##STR00877##
[3209] Step 1
[3210] Compound i-51 (676 mg, 2.39 mmol) was dissolved in dioxane
(10 mL), dichlorobis(acetonitrile)palladium (155 mg, 0.599 mmol),
sodium carbonate (254 mg, 2.39 mmol) and benzoquinone (259 mg, 2.39
mmol) were added, and the mixture was stirred in a sealed tube at
100.degree. C. for 27 hours. The mixture was diluted with ethyl
acetate, and the solid was removed by filtration. The filtrate was
washed with water and aqueous saturated sodium chloride solution,
and then dried with anhydrous magnesium sulfate. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel chromatography (hexane-ethyl acetate) to
obtain compound i-51 (166 mg, yield 25%) and compound i-52 (280 mg,
yield 41%). 16: MS: m/z=280.95 [M+H].sup.+. 17: .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.92 (dd, J=6.6, 1.6 Hz, 3H), 4.01 (s, 2H),
6.25 (dq, J=15.8, 6.6 Hz, 1H), 6.66 (d, J=7.7 Hz, 1H), 6.77 (d,
J=15.8 Hz, 1H), 7.30-7.51 (m, 4H), 8.26-8.31 (m, 1H), 12.67 (s,
1H).
Step 2
[3211] Compound i-52 (250 mg, 0.885 mmol) was dissolved in DMSO
(2.5 mL), potassium phosphate (376 mg, 1.77 mmol) and allyl bromide
(0.115 mL, 1.33 mmol) were added, and the mixture was stirred at
room temperature for 2 hours. Water was added, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and aqueous saturated sodium chloride solution, and then
dried with anhydrous magnesium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel chromatography (hexane-ethyl acetate) to obtain
compound i-53 (285 mg, yield 100%).
[3212] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.88 (dd, J=6.6, 1.5 Hz,
3H), 3.98 (s, 2H), 4.31 (dt, J=5.5, 1.3 Hz, 2H), 5.17 (dd, J=10.5,
1.2 Hz, 1H), 5.29 (dq, J=17.9, 1.5 Hz, 1H), 5.90-6.02 (m, 1H), 6.21
(dq, J=17.9, 6.6 Hz, 1H), 6.57 (dd, J=15.9, 1.2 Hz, 1H), 6.94 (d,
J=7.9 Hz, 1H), 7.17-7.24 (m, 2H), 7.28-7.36 (m, 1H), 7.45 (d, J=7.9
Hz, 1H), 7.88 (dd, J=8.2, 1.4 Hz, 1H).
Step 3
[3213] Compound i-53 (310 mg, 0.961 mmol) was dissolved in
dichloromethane (31 mL) under nitrogen atmosphere, a second
generation Grubbs catalyst (82.0 mg, 0.096 mmol) was added, and the
mixture was stirred at room temperature for 14 hours. The solvent
was distilled off under reduced pressure, and the resulting residue
was purified by silica gel chromatography (hexane-ethyl acetate) to
obtain compound i-54 (170 mg, yield 63%).
[3214] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.95 (s, 2H), 4.82 (dd,
J=3.4, 1.8 Hz, 2H), 5.75 (dt, J=9.9, 3.4 Hz, 1H), 6.38 (d, J=9.9
Hz, 1H), 6.72 (d, J=7.4 Hz, 1H), 6.97 (d, J=7.4 Hz, 1H), 7.19-7.26
(m, 2H), 7.30-7.38 (m, 1H), 7.95-8.00 (m, 1H).
Synthesis of Intermediate Compound i-56
##STR00878##
[3215] Step 1
[3216] Compound i-55 (100 mg, 0.328 mmol) was suspended in DMF (1
mL), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.124 mL, 0.983
mmol) and copper iodide (68.6 mg, 0.360 mmol) were added, and the
mixture was stirred at 130.degree. C. for 4 hours. Water was added,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with aqueous saturated sodium chloride solution, and
then dried with anhydrous magnesium sulfate. The solvent was
distilled off under reduced pressure to obtain compound i-56 (96
mg, yield 100%).
[3217] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.04 (s, 2H), 7.17-7.26
(m, 2H), 7.29-7.36 (m, 1H), 7.41-7.53 (m, 2H), 7.57-7.62 (m, 1H),
7.78 (d, J=7.8 Hz, 1H).
Synthesis of Intermediate Compound i-60
##STR00879##
[3218] Step 1
[3219] Compound i-55 (3.00 g, 9.83 mmol) was suspended in DMF (30
mL), copper cyanide (2.64 g, 29.5 mmol) was added, and the mixture
was refluxed for 8 hours. Water was added, and the mixture was
extracted with chloroform. The organic layer was washed with water,
and then dried with anhydrous magnesium sulfate. The solvent was
distilled off under reduced pressure, and to the resulting residue
were added dichloromethane-diethyl ether-hexane to precipitate a
solid, then the solid was filtered to obtain compound i-57 (1.72 g,
yield 70%).
[3220] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.06 (s, 2H), 7.27-7.35
(m, 2H), 7.40-7.57 (m, 3H), 7.68 (dd, J=7.4, 1.4 Hz, 1H), 8.16-8.21
(m, 1H).
Step 2
[3221] Compound i-57 (25.0 mg, 0.099 mmol) was suspended in
methanol (0.5 mL), trimethylsilyl chloride (0.051 mL, 0.398 mmol)
was added, and the mixture was stirred at 50.degree. C. for 4.5
hours. An aqueous sodium bicarbonate solution was added, the
mixture was extracted with chloroform, and the organic layer was
dried with anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel chromatography (hexane-ethyl acetate) to obtain compound
i-58 (11.4 mg, yield 40%).
[3222] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.87 (s, 3H), 4.09 (s,
2H), 7.25-7.53 (m, 5H), 7.86-7.91 (m, 1H), 7.98 (dd, J=7.8, 1.6 Hz,
1H).
Step 3
[3223] Compound i-58 (600 mg, 2.11 mmol) was added to
tetrahydrofuran (8 mL) under nitrogen atmosphere, lithium aluminum
hydride (481 mg, 12.66 mmol) was added under ice-cooling, and the
mixture was stirred for 45 minutes under ice-cooling. Under
ice-cooling, an aqueous saturated ammonium chloride solution (1.5
mL) was added dropwise, and the mixture was heated to room
temperature. The solution was extracted with ethyl acetate, and the
organic layer was washed with an aqueous hydrochloric acid solution
and aqueous saturated sodium chloride solution, then dried with
anhydrous magnesium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel chromatography (hexane-ethyl acetate) to obtain compound i-59
(415 mg, yield 76%).
[3224] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.48-3.70 (m, 1H),
4.34-4.49 (m, 2H), 4.95 (t, J=5.4 Hz, 1H), 5.18-5.47 (m, 1H),
5.79-5.88 (m, 2H), 6.78-6.95 (m, 3H), 6.99-7.11 (m, 3H), 7.22 (d,
J=6.0 Hz, 1H).
Step 4
[3225] Compound i-59 (70.0 mg, 0.271 mmol) was suspended in
acetonitrile (1 mL), triethylamine (0.188 mL, 1.36 mmol), acetic
acid anhydride (0.128 mL, 1.36 mmol) and DMAP (16.6 mg, 0.135 mmol)
were added, and the mixture was stirred at room temperature for 30
minutes. Water was added, and the mixture was extracted with ethyl
acetate. The organic layer was washed with an aqueous hydrochloric
acid solution and aqueous saturated sodium chloride solution, and
then dried with anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to obtain compound i-60 (93.0 mg, yield
100%).
[3226] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.92 (s, 3H), 2.08 (s,
3H), 3.53 (d, J=14.0 Hz, 1H), 5.38 (d, J=1.4 Hz, 2H), 5.47 (d,
J=14.0 Hz, 1H), 7.03-7.20 (m, 4H), 7.24-7.31 (m, 2H), 7.48 (dd,
J=7.6, 1.2 Hz, 1H).
Synthesis of Intermediate Compound i-61
##STR00880##
[3227] Step 1
[3228] Compound i-59 (100 mg, 0.387 mmol) was added to
tetrahydrofuran under nitrogen atmosphere, sodium hydride (37.2 mg,
0.929 mmol) was added under ice-cooling, and the mixture was
stirred for 5 minutes under ice-cooling. Thereafter, methyl iodide
(0.145 mL, 2.32 mmol) was added, and the mixture was stirred at
room temperature for 2 hours. Water was added, and the mixture was
extracted with ethyl acetate. The organic layer was washed with an
aqueous hydrochloric acid solution and aqueous saturated sodium
chloride solution, and then dried with anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the
resulting residue was purified by silica gel chromatography
(hexane-ethyl acetate) to obtain compound i-61 (106 mg, yield
96%).
[3229] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.29 (s, 3H), 3.34 (s,
3H), 3.40 (d, J=13.1 Hz, 1H), 4.45-4.58 (m, 2H), 5.63 (s, 1H), 5.70
(d, J=13.1 Hz, 1H), 7.00-7.24 (m, 6H), 7.35 (d, J=7.4 Hz, 1H).
Synthesis of Intermediate Compound i-65
##STR00881##
[3230] Step 1
[3231] Compound i-55 (2.10 g, 6.88 mmol) was suspended in DMF (10.5
mL), copper iodide (262 mg, 1.38 mmol),
dichlorobis(triphenylphosphine)palladium (966 mg, 1.38 mmol),
trimethylsilylacetylene (4.86 mL, 34.4 mmol), and triethylamine
(14.0 mL, 101 mmol) were added, and the mixture was stirred in a
sealed tube at 140.degree. C. for 11 hours. The mixture was diluted
with ethyl acetate, and the solid was removed by filtration. The
filtrate was washed with an aqueous hydrochloric acid solution and
aqueous saturated sodium chloride solution, and then dried with
anhydrous magnesium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel chromatography (hexane-ethyl acetate) to obtain compound i-62
(1.34 g, yield 60%).
[3232] MS: m/z=323.05 [M+H].sup.+.
Step 2
[3233] Compound i-62 (1.34 g, 4.16 mmol) was dissolved in methanol
(40 mL), potassium carbonate (1.72 g, 12.5 mmol) was added, and the
mixture was stirred at room temperature for 1.5 hours. Water was
added, and the mixture was extracted with ethyl acetate. The
organic layer was washed with aqueous saturated sodium chloride
solution, and then dried with anhydrous magnesium sulfate. The
solvent was distilled off under reduced pressure, and the resulting
residue was purified by silica gel chromatography (hexane-ethyl
acetate) to obtain compound i-63 (967 mg, yield 93%).
[3234] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.20 (s, 1H), 4.05 (s,
2H), 7.14-7.30 (m, 4H), 7.40 (t, J=7.8 Hz, 1H), 7.51 (d, J=7.6 Hz,
1H), 7.79 (dt, J=7.7, 0.8 Hz, 1H).
Step 3
[3235] Compound i-63 (619 mg, 2.47 mmol) was added to
tetrahydrofuran (12 mL) under nitrogen atmosphere, lithium aluminum
hydride (282 mg, 7.42 mmol) was added under ice-cooling, and the
mixture was stirred for 1 hour under ice-cooling. Under
ice-cooling, an aqueous saturated ammonium chloride solution (15
mL) was added dropwise, and the mixture was heated to room
temperature. The solution was extracted with ethyl acetate, and the
organic layer was washed with an aqueous hydrochloric acid solution
and aqueous saturated sodium chloride solution, then dried with
anhydrous magnesium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel chromatography (hexane-ethyl acetate) to obtain compound i-64
(554 mg, yield 89%).
[3236] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.73 (d, J=3.4 Hz, 1H),
3.41 (s, 1H), 3.57 (d, J=13.6 Hz, 1H), 5.63 (d, J=13.6 Hz, 1H),
6.55 (d, J=3.4 Hz, 1H), 7.04-7.26 (m, 5H), 7.37-7.44 (m, 2H).
Step 4
[3237] A tetrahydrofuran (2 mL) solution of compound i-64 (50.0 mg,
0.198 mmol) was cooled to -78.degree. C. with dry ice-acetone under
nitrogen atmosphere. A 1.65 mol/L n-butyllithium-hexane solution
(0.312 mL, 0.515 mmol) was added dropwise thereto, and the mixture
was stirred at room temperature for 20 minutes. The mixture was
again cooled to -78.degree. C. with dry ice-acetone, then methyl
iodide (0.248 mL, 3.96 mmol) was added dropwise, and the mixture
was stirred for 1.5 hours while the mixture was heated to room
temperature. An aqueous saturated ammonium chloride solution (1.5
mL) was added, and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and aqueous saturated
sodium chloride solution, and then dried with anhydrous magnesium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (hexane-ethyl acetate) to obtain compound i-65 (44.9
mg, yield 81%).
[3238] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.14 (s, 3H), 3.34 (s,
3H), 3.38 (d, J=13.5 Hz, 1H), 5.62 (d, J=13.5 Hz, 1H), 5.97 (s,
1H), 7.01-7.23 (m, 5H), 7.29 (dd, J=7.3, 1.8 Hz, 1H), 7.36 (d,
J=7.4 Hz, 1H).
Synthesis of Intermediate Compound i-67
##STR00882##
[3239] Step 1
[3240] To a tetrahydrofuran-methanol (1:1, 6 mL) solution of
compound i-66 (520 mg, 1.92 mmol) was added 10% palladium carbon
(205 mg, 0.192 mmol), and the mixture was stirred at room
temperature for 1 hour under hydrogen atmosphere. The solid was
removed by filtration, and the filtrate was distilled off under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (hexane-ethyl acetate) to obtain compound
i-67 (370 mg, yield 70%).
[3241] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (t, J=7.5 Hz, 3H),
2.48 (d, J=1.7 Hz, 1H), 2.82 (dq, J=2.7, 7.5 Hz, 2H), 3.63 (d,
J=13.6 Hz, 1H), 5.79 (d, J=13.6 Hz, 1H), 6.25 (s, 1H), 6.97-7.32
(m, 7H).
Synthesis of Intermediate Compound i-69
##STR00883##
[3242] Step 1
[3243] A tetrahydrofuran (40 mL) solution of compound i-68 (1.00 g,
3.81 mmol) was cooled to -78.degree. C. with dry ice-acetone under
nitrogen atmosphere. A 1.65 mol/L n-butyllithium-hexane solution
(6.92 mL, 11.4 mmol) was added dropwise thereto, and the mixture
was stirred at room temperature for 30 minutes. The mixture was
again cooled to -78.degree. C. with dry ice-acetone, then methyl
iodide (2.38 mL, 38.1 mmol) was added dropwise, and the mixture was
stirred for 2.5 hours while the mixture was heated to room
temperature. After the reaction solution was concentrated, water
was added, and the mixture was extracted with ethyl acetate. The
organic layer was washed with aqueous saturated sodium chloride
solution, and then dried with anhydrous magnesium sulfate. The
solvent was distilled off under reduced pressure, and the resulting
residue was purified by silica gel column chromatography
(hexane-ethyl acetate) to obtain compound i-69 (522 mg, yield
50%).
[3244] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.74 (d, J=6.9 Hz, 3H),
4.96-5.09 (m, 2H), 6.65 (d, J=10.7 Hz, 1H), 7.10-7.28 (m, 6H),
7.49-7.52 (m, 1H).
Synthesis of Intermediate Compound i-72
##STR00884##
[3245] Step 1
[3246] Compound i-70 (500 mg, 1.36 mmol) was dissolved in
dichloromethane (10 mL), Boc.sub.2O (0.348 mL, 1.50 mmol) and DMAP
(16 mg, 0.136 mmol) were added, and the mixture was stirred at room
temperature for 1 hour. Thereafter, NCS (273 mg, 2.04 mmol) was
added, and the mixture was heated to reflux for 7 hours, and then
stirred at room temperature for 4 days.
[3247] The reaction solution was concentrated, and the resulting
residue was purified by silica gel column chromatography
(chloroform-methanol) to obtain compound i-71 (670 mg, yield
98%).
[3248] MS: m/z=502.12 [M+H].sup.+
Step 2
[3249] To an ethanol solution of compound i-71 (670 mg, 1.34 mmol)
was added a 2M aqueous hydrochloric acid solution (3.34 mL, 6.67
mmol), and the mixture was stirred at 60.degree. C. for 3 hours.
Saturated sodium bicarbonate water was added, the mixture was
extracted with chloroform. The organic layer was washed with water
and aqueous saturated sodium chloride solution, and then dried with
anhydrous magnesium sulfate. The solvent was distilled off under
reduced pressure to obtain compound i-72 (452 mg, 1.13 mmol).
[3250] MS: m/z=402.08 [M+H].sup.+
[3251] Hereinbelow, Reference examples 666 to 775 were synthesized
using the above intermediate compounds.
Synthesis of Reference Example 666
##STR00885##
[3252] First Step
[3253] Compound 666A (1.0 g, 2.4 mmol),
10-chloro-6,11-dihydrodibenzo[b,e]thiepin-11-ol (741 mg, 2.8 mmol),
and a propanephosphonic acid anhydride-50% ethyl acetate solution
(10 mL, 16.8 mmol) were mixed, and the mixture was stirred at
100.degree. C. for 5 hours. To the reaction solution was added
ethyl acetate, the solution was diluted, and the solution was
washed with water and aqueous saturated sodium chloride solution,
and then dried with anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel chromatography (hexane-ethyl acetate) to
obtain compound 666B (451 mg, yield 29%).
[3254] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09 (d, J=7.5 Hz, 3H),
3.62 (d, J=13.5 Hz, 1H), 3.76 (s, 3H), 4.37 (d, J=13.2 Hz, 1H),
4.80 (d, J=13.2 Hz, 1H), 5.43 (d, 10.5 Hz, 1H), 5.53-5.66 (m, 3H),
5.86 (s, 1H), 6.58 (m, 1H), 6.76 (m, 1H), 7.04-7.13 (m, 2H),
7.26-7.38 (m, 6H), 7.58-7.63 (m, 2H), 7.99 (s, 1H).
Second Step
[3255] Compound 666B (570 mg, 0.85 mmol) was dissolved in
tetrahydrofuran (6 mL) and methanol (1.5 mL). The solution was
ice-cooled, a 2 mol/L aqueous sodium hydroxide solution (0.64 mL,
1.28 mmol) was added thereto, and the mixture was stirred at
0.degree. C. for 30 minutes. Hydrochloric acid was added to the
reaction solution to stop the reaction, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and aqueous saturated sodium chloride solution, and then
dried with anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel chromatography (hexane-ethyl acetate) to obtain compound
666C (433 mg, yield 78%).
[3256] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09 (d, J=7.2 Hz, 3H),
3.62 (d, J=13.8 Hz, 1H), 4.42 (d, J=13.2 Hz, 1H), 4.82 (d, J=13.2
Hz, 1H), 5.50-5.62 (m, 3H), 5.66 (d, J=10.8 Hz, 1H), 5.82 (s, 1H),
6.38 (m, 1H), 6.70 (m, 1H), 7.05-7.16 (m, 2H), 7.26-7.39 (m, 6H),
7.51-7.56 (m, 2H), 8.12 (s, 1H), 14.31 (s, 1H).
Third Step
[3257] Compound 666C (289 mg, 0.44 mmol) was dissolved in
tetrahydrofuran (5 mL). The solution was ice-cooled, triethylamine
(0.18 mL, 1.3 mmol) and ethyl chloroformate (0.11 mL, 1.1 mmol)
were added, and the mixture was stirred for 15 minutes. The mixture
was cooled to -78.degree. C. with dry ice-acetone, a DIBAL-hexane
solution (2.1 mL, 2.2 mmol) was added, and the mixture was stirred
at -78.degree. C. for 40 minutes. To the reaction solution was
added ethyl acetate to stop the reaction, and the mixture was
heated to room temperature. An aqueous potassium sodium tartrate
solution was added, and the mixture was stirred vigorously at room
temperature for 2 hours. The organic layer was dried with anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was dissolved in DMF (2 ml).
Lithium chloride (70 mg, 1.7 mmol) was added, and the mixture was
stirred at 100.degree. C. for 2 hours. The mixture was allowed to
cool, diluted with ethyl acetate, and washed with 2 mol/L
hydrochloric acid, water, and aqueous saturated sodium chloride
solution. The solvent was distilled off under reduced pressure, and
to the resulting residue were added ethyl acetate-diisopropyl ether
to precipitate a solid, then the solid was filtered to obtain
compound 666 (40.5 mg, yield 17%).
[3258] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (d, J=7.2 Hz, 3H),
3.63 (d, J=13.5 Hz, 1H), 4.06 (d, J=13.2 Hz, 1H), 4.24 (d, J=13.2
Hz, 1H), 4.44 (d, J=12.9 Hz, 1H), 4.87 (d, J=12.9 Hz, 1H), 5.50 (m,
1H), 5.72 (d, J=13.5 Hz, 1H), 5.93 (s, 1H), 6.75 (m, 1H), 6.83 (m,
1H), 7.09-7.14 (m, 2H), 7.22 (s, 1H), 7.27-7.39 (m, 1H).
[3259] MS: m/z=552.2 [M+H].sup.+.
Reference Example 667
##STR00886##
[3261] MS: m/z=480.15 [M+H].sup.+.
Reference Example 668
##STR00887##
[3263] MS: m/z=524 [M+H].sup.+.
Reference Example 669
##STR00888##
[3265] MS: m/z=524 [M+H].sup.+.
Reference Example 670
##STR00889##
[3267] MS: m/z=520 [M+H].sup.+.
Reference Example 671
##STR00890##
[3269] MS: m/z=520 [M+H].sup.+.
Reference Example 672
##STR00891##
[3271] MS: m/z=520 [M+H].sup.+.
Reference Example 673
##STR00892##
[3273] MS: m/z=522.19 [M+H].sup.+.
Reference Example 674
##STR00893##
[3275] MS: m/z=566.98 [M+H].sup.+.
Reference Example 675
##STR00894##
[3277] MS: m/z=532.22 [M+H].sup.+.
Reference Example 676
##STR00895##
[3279] MS: m/z=532.22 [M+H].sup.+.
Reference Example 677
##STR00896##
[3281] MS: m/z=488 [M+H].sup.+. RT=2.11 min.
Reference Example 678
##STR00897##
[3283] MS: m/z=542 [M+H].sup.+. RT=2.23 min.
Reference Example 679
##STR00898##
[3285] MS: m/z=506 [M+H].sup.+. RT=2.21 min.
Reference Example 680
##STR00899##
[3287] MS: m/z=534 [M+H].sup.+. RT=2.06 min.
Reference Example 681
##STR00900##
[3289] MS: m/z=500 [M+H].sup.+. RT=2.05 min.
Reference Example 682
##STR00901##
[3291] MS: m/z=482 [M+H].sup.+. RT=1.76 min.
Reference Example 683
##STR00902##
[3293] MS: m/z=600 [M+H].sup.+. RT=2.32 min. ()
Reference Example 684
##STR00903##
[3295] MS: m/z=482 [M+H].sup.+. RT=1.82 min.
Reference Example 685
##STR00904##
[3297] MS: m/z=564 [M+H].sup.+. RT=2.23 min.
Reference Example 686
##STR00905##
[3299] MS: m/z=[M+H].sup.+. RT=. min.
Reference Example 687
##STR00906##
[3301] MS: m/z=547 [M+H].sup.+. RT=2.20 min.
Reference Example 688
##STR00907##
[3303] MS: m/z=565 [M+H].sup.+. RT=2.03 min.
Reference Example 689
##STR00908##
[3305] MS: m/z=486 [M+H].sup.+. RT=1.96 min.
Reference Example 690
##STR00909##
[3307] MS: m/z=486 [M+H].sup.+. RT=1.96 min.
Reference Example 691
##STR00910##
[3309] MS: m/z=529 [M+H].sup.+. RT=2.21 min.
Reference Example 692
##STR00911##
[3311] MS: m/z=566 [M+H].sup.+. RT=2.23 min.
Reference Example 693
##STR00912##
[3313] MS: m/z=566 [M+H].sup.+. RT=2.16 min.
Reference Example 694
##STR00913##
[3315] MS: m/z=564 [M+H].sup.+. RT=2.33 min.
Reference Example 695
##STR00914##
[3317] MS: m/z=548 [M+H].sup.+. RT=2.20 min.
Reference Example 696
##STR00915##
[3319] MS: m/z=548 [M+H].sup.+. RT=2.17 min.
Reference Example 697
##STR00916##
[3321] MS: m/z=558 [M+H].sup.+. RT=2.31 min.
Reference Example 698
##STR00917##
[3323] MS: m/z=578 [M+H].sup.+. RT=2.35 min.
Reference Example 699
##STR00918##
[3325] MS: m/z=598 [M+H].sup.+. RT=2.37 min.
Reference Example 700
##STR00919##
[3327] MS: m/z=532 [M+H].sup.+. RT=2.02 min.
Reference Example 701
##STR00920##
[3329] MS: m/z=536 [M+H].sup.+. RT=2.14 min.
Reference Example 702
##STR00921##
[3331] MS: m/z=570 [M+H].sup.+. RT=2.35 min.
Reference Example 703
##STR00922##
[3333] MS: m/z=520 [M+H].sup.+. RT=2.13 min.
Reference Example 704
##STR00923##
[3335] MS: m/z=538 [M+H].sup.+. RT=2.24 min.
Reference Example 705
##STR00924##
[3337] MS: m/z=502 [M+H].sup.+. RT=2.13 min.
Reference Example 706
##STR00925##
[3339] MS: m/z=566 [M+H].sup.+. RT=2.27 min.
Reference Example 707
##STR00926##
[3341] MS: m/z=566 [M+H].sup.+. RT=2.11 min.
Reference Example 708
##STR00927##
[3343] MS: m/z=550 [M+H].sup.+. RT=2.06 min.
Reference Example 709
##STR00928##
[3345] MS: m/z=568 [M+H].sup.+. RT=2.14 min.
Reference Example 710
##STR00929##
[3347] MS: m/z=566 [M+H].sup.+. RT=2.00 min.
Reference Example 711
##STR00930##
[3349] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (d, J=7.5 Hz, 3H),
4.11 (d, J=13.8 Hz, 1H), 4.48 (d, J=12.9 Hz, 1H), 4.90 (d, J=12.9
Hz, 1H), 5.13 (s, 1H), 5.41 (dd, J=13.8, 3.0 Hz, 1H), 5.54 (m, 1H),
5.82 (d, J=7.8 Hz, 1H), 6.69 (d, J=7.2 Hz, 1H), 6.85 (m, 1H), 6.96
(m, 1H), 7.03-7.14 (m, 3H), 7.16 (d, J=7.2 Hz, 1H).
Reference Example 712
##STR00931##
[3351] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (d, J=6.9 Hz, 3H),
3.61 (d, J=13.5 Hz, 1H), 4.07 (d, J=13.2 Hz, 1H), 4.24 (d, J=13.2
Hz, 1H), 4.50 (d, J=13.2 Hz, 1H), 4.88 (d, J=13.2 Hz, 1H), 5.09 (s,
1H), 5.51 (m, 1H), 5.67 (d, J=13.5 Hz, 1H), 6.66 (m, 1H), 6.79 (m,
1H), 7.04-7.12 (m, 2H), 7.18 (m, 1H), 7.24-7.30 (m, 2H), 7.35-7.46
(m, 2H).
[3352] MS: m/z=518.3 [M+H].sup.+.
Reference Example 713
##STR00932##
[3354] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (d, J=7.2 Hz, 3H),
4.07 (d, J=13.2 Hz, 1H), 4.10 (d, J=13.8 Hz, 1H), 4.29 (d, J=13.2
Hz, 1H), 4.48 (d, J=13.2 Hz, 1H), 4.90 (d, J=13.2 Hz, 1H), 5.12 (s,
1H), 5.44 (dd, J=13.8, 3.0 Hz, 1H), 5.52 (m, 1H), 6.64 (m, 1H),
6.82 (m, 1H), 6.95 (m, 1H), 7.02-7.13 (m, 3H), 7.25 (s, 1H).
[3355] MS: m/z=554.2 [M+H].sup.+.
Reference Example 714
##STR00933##
[3357] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.98 (m, 1H), 3.46 (m,
1H), 3.57 (t, J=10.5 Hz, 1H), 3.58 (d, J=13.5 Hz, 1H), 3.79 (dd,
J=12.3, 3.0 Hz, 1H), 3.96 (dd, J=11.4, 3.0 Hz, 1H), 4.63 (m, 2H),
5.25 (s, 1H), 5.52 (d, J=13.5 Hz, 1H), 5.75 (d, J=7.8 Hz, 1H), 6.70
(m, 1H), 6.81 (m, 1H), 7.04-7.10 (m, 3H), 7.19-7.37 (m, 3H), 7.43
(m, 1H).
[3358] MS: m/z=448.1 [M+H].sup.+.
Reference Example 715
##STR00934##
[3360] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.83 (m, 1H), 3.43 (m,
1H), 3.55 (t, J=10.5 Hz, 1H), 3.61 (d, J=13.8 Hz, 1H), 3.78 (dd,
J=12.0, 3.0 Hz, 1H), 4.04 (dd, J=11.1, 3.0 Hz, 1H), 4.50 (m, 1H),
4.60 (m, 1H), 5.13 (s, 1H), 5.64 (d, J=13.8 Hz, 1H), 5.73 (d, J=7.8
Hz, 1H), 6.59 (d, J=7.8 Hz, 1H), 6.81 (m, 1H), 7.07-7.15 (m, 2H),
7.20-7.37 (m, 5H).
[3361] MS: m/z=448.1 [M+H].sup.+.
Reference Example 716
##STR00935##
[3363] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26 (d, J=7.2 Hz, 3H),
4.13 (d, J=13.8 Hz, 1H), 4.49 (d, J=13.2 Hz, 1H), 4.94 (d, J=13.2
Hz, 1H), 5.13 (s, 1H), 5.38 (dd, J=13.8, 2.4 Hz, 1H), 5.52 (m, 1H),
6.68 (m, 1H), 6.86 (m, 1H), 6.97 (m, 1H), 7.03-7.20 (m, 3H), 7.50
(s, 1H).
[3364] MS: m/z=558.0 [M+H].sup.+.
Reference Example 717
##STR00936##
[3366] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (d, J=7.2 Hz, 3H),
3.65 (d, J=13.5 Hz, 1H), 4.47 (d, J=12.9 Hz, 1H), 4.90 (d, J=12.9
Hz, 1H), 5.49 (m, 1H), 5.66 (d, J=13.5 Hz, 1H), 5.93 (s, 1H), 6.60
(t, J=54.9 Hz, 1H), 6.77 (m, 1H), 6.86 (m, 1H), 7.11-7.16 (m, 2H),
7.28-7.37 (m, 3H), 7.49 (s, 1H).
Reference Example 718
##STR00937##
[3368] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (d, J=7.2 Hz, 3H),
4.11 (d, J=13.8 Hz, 1H), 4.51 (d, J=13.2 Hz, 1H), 4.93 (d, J=13.2
Hz, 1H), 5.11 (s, 1H), 5.38 (dd, J=13.8, 3.0 Hz, 1H), 5.52 (m, 1H),
6.58 (t, J=54.6 Hz, 1H), 6.65 (m, 1H), 6.84 (m, 1H), 6.95 (m, 1H),
7.02-7.15 (m, 3H), 7.52 (s, 1H).
Reference Example 719
##STR00938##
[3370] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.23 (d, J=7.2 Hz, 3H),
4.08 (d, J=12.9 Hz, 1H), 4.24 (d, J=13.5 Hz, 1H), 4.32 (d, J=14.1
Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 4.90 (d, J=13.5 Hz, 1H), 5.13 (s,
1H), 5.53 (m, 1H), 5.64 (d, J=14.1 Hz, 1H), 6.64 (m, 1H), 6.80 (m,
1H), 7.06-7.12 (m, 3H), 7.20 (m, 1H), 7.24 (s, 1H), 7.53 (m,
1H).
[3371] MS: m/z=552.2 [M+H].sup.+.
Reference Example 720
##STR00939##
[3373] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.90 (d, J=7.4 Hz, 3H),
2.25 (s, 3H), 2.34 (s, 3H), 3.70 (d, J=13.5 Hz, 1H), 4.49 (d,
J=12.9 Hz, 1H), 4.81 (d, J=12.9 Hz, 1H), 5.38-5.50 (m, 2H), 5.62
(d, J=13.5 Hz, 1H), 5.84 (d, J=7.7 Hz, 1H), 6.56 (d, J=7.7 Hz, 1H),
6.75 (t, J=7.6 Hz, 1H), 6.98 (d, J=7.7 Hz, 1H), 7.05 (d, J=7.7 Hz,
1H), 7.12 (d, J=7.1 Hz, 1H), 7.21 (d, J=6.6 Hz, 1H), 7.26-7.32 (m,
1H).
Reference Example 721
##STR00940##
[3375] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.93 (d, J=7.2 Hz, 3H),
2.38 (s, 3H), 3.75 (d, J=13.6 Hz, 1H), 4.52 (d, J=12.9 Hz, 1H),
4.85 (d, J=12.9 Hz, 1H), 5.41-5.54 (m, 2H), 5.69 (d, J=13.6 Hz,
1H), 5.93 (d, J=7.7 Hz, 1H), 6.68 (d, J=7.6 Hz, 1H), 6.84 (t, J=7.8
Hz, 1H), 7.04 (d, J=7.7 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.25-7.40
(m, 3H).
Reference Example 722
##STR00941##
[3377] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.90 (d, J=7.4 Hz, 3H),
2.34 (s, 3H), 3.69 (d, J=13.5 Hz, 1H), 4.48 (d, J=12.6 Hz, 1H),
4.82 (d, J=12.6 Hz, 1H), 5.38-5.50 (m, 2H), 5.62 (d, J=13.5 Hz,
1H), 5.88 (d, J=7.7 Hz, 1H), 6.53 (d, J=7.7 Hz, 1H), 6.83 (td,
J=8.0, 5.5 Hz, 1H), 6.92-7.00 (m, 1H), 7.03 (d, J=7.7 Hz, 1H), 7.15
(d, J=7.4 Hz, 1H), 7.23 (d, J=7.1 Hz, 1H), 7.32 (t, J=7.6 Hz,
1H).
Reference Example 723
##STR00942##
[3379] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (d, J=7.4 Hz, 3H),
2.24 (s, 3H), 4.09 (d, J=14.3 Hz, 1H), 4.44 (d, J=12.9 Hz, 1H),
4.91 (d, J=12.9 Hz, 1H), 5.27 (s, 1H), 5.49-5.59 (m, 1H), 5.81 (d,
J=7.7 Hz, 1H), 5.91 (d, J=14.3 Hz, 1H), 6.58 (d, J=7.7 Hz, 1H),
6.76 (t, J=7.6 Hz, 1H), 7.02-7.10 (m, 2H), 7.34-7.43 (m, 2H),
7.70-7.83 (m, 1H).
Reference Example 724
##STR00943##
[3381] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.89 (d, J=7.2 Hz, 3H),
1.08 (t, J=7.5 Hz, 3H), 2.62-2.77 (m, 2H), 3.68 (d, J=13.6 Hz, 1H),
4.44 (d, J=12.7 Hz, 1H), 4.79 (d, J=12.7 Hz, 1H), 5.37-5.47 (m,
1H), 5.58 (s, 1H), 5.69 (d, J=13.6 Hz, 1H), 5.87 (d, J=7.6 Hz, 1H),
6.53 (d, J=7.3 Hz, 1H), 6.82 (td, J=7.8, 5.8 Hz, 1H), 6.90-6.98 (m,
1H), 7.00 (d, J=7.6 Hz, 1H), 7.17-7.23 (m, 2H), 7.36 (t, J=7.5 Hz,
1H).
Reference Example 725
##STR00944##
[3383] MS: m/z=534.20 [M+H].sup.+.
Reference Example 726
##STR00945##
##STR00946##
[3385] MS: m/z=530.10 [M+H].sup.+.
Reference Example 728
##STR00947##
[3387] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09 (d, J=7.1 Hz, 3H),
3.59 (d, J=13.5 Hz, 1H), 3.79 (s, 3H), 4.51 (d, J=12.9 Hz, 1H),
4.84 (d, J=12.9 Hz, 1H), 5.43-5.56 (m, 1H), 5.67 (d, J=13.5 Hz,
1H), 5.83 (d, J=7.7 Hz, 1H), 5.92 (s, 1H), 6.74 (d, J=7.7 Hz, 1H),
6.77-6.86 (m, 2H), 6.95 (d, J=7.7 Hz, 1H), 7.05-7.10 (m, 2H), 7.19
(d, J=7.7 Hz, 1H), 7.35 (t, J=8.1 Hz, 1H).
Reference Example 729
##STR00948##
[3389] MS: m/z=512.10 [M+H].sup.+.
Reference Example 730
##STR00949##
[3391] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (d, J=7.1 Hz, 3H),
3.55 (s, 1H), 3.63 (d, J=13.2 Hz, 1H), 4.46 (d, J=11.5 Hz, 1H),
4.94 (d, J=11.5 Hz, 1H), 5.44-5.54 (m, 1H), 5.63 (d, J=13.2 Hz,
1H), 6.01 (d, J=4.4 Hz, 1H), 6.07 (s, 1H), 6.77 (d, J=7.4 Hz, 1H),
6.83-6.85 (m, 1H), 7.07-7.16 (m, 2H), 7.17-7.24 (m, 1H), 7.36-7.40
(m, 2H), 7.44-7.50 (m, 1H).
Reference Example 731
##STR00950##
[3393] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.91 (d, J=7.4 Hz, 3H),
1.08 (t, J=7.4 Hz, 3H), 2.62-2.79 (m, 2H), 3.59 (d, J=13.2 Hz, 1H),
4.46 (d, J=12.6 Hz, 1H), 4.82 (d, J=12.6 Hz, 1H), 5.38-5.48 (m,
1H), 5.51 (s, 1H), 5.68 (d, J=13.2 Hz, 1H), 5.92 (d, J=6.9 Hz, 1H),
6.68 (d, J=8.0 Hz, 1H), 6.78-6.87 (m, 1H), 7.05 (d, J=7.1 Hz, 1H),
7.09-7.14 (m, 2H), 7.19 (d, J=7.7 Hz, 1H), 7.23 (d, J=7.4 Hz, 1H),
7.36 (t, J=7.7 Hz, 1H).
Reference Example 732
##STR00951##
[3395] MS: m/z=516.75 [M+H].sup.+.
Reference Example 733
##STR00952##
[3397] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.23 (d, J=7.1 Hz, 3H),
3.75 (d, J=13.5 Hz, 1H), 4.47 (d, J=12.9 Hz, 1H), 4.84 (d, J=12.9
Hz, 1H), 5.23-5.33 (m, 1H), 5.91 (d, J=7.7 Hz, 1H), 5.97 (d, J=13.5
Hz, 1H), 6.19 (s, 1H), 6.81-6.93 (m, 2H), 7.07-7.12 (m, 2H), 7.21
(d, J=7.7 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.52 (d, J=7.4 Hz, 1H),
7.57-7.64 (m, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H),
8.07 (d, J=8.8 Hz, 1H).
Reference Example 734
##STR00953##
[3399] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (d, J=5.8 Hz, 6H),
1.43 (d, J=6.0 Hz, 3H), 3.58 (d, J=13.5 Hz, 1H), 4.43-4.57 (m, 2H),
4.84 (d, J=12.9 Hz, 1H), 5.41-5.52 (m, 1H), 5.61 (d, J=13.5 Hz,
1H), 5.88 (d, J=7.7 Hz, 1H), 5.94 (s, 1H), 6.67 (d, J=7.7 Hz, 1H),
6.77-6.87 (m, 2H), 6.91 (d, J=7.1 Hz, 1H), 7.09 (d, J=3.6 Hz, 2H),
7.16 (d, J=7.7 Hz, 1H), 7.31 (t, J=8.0 Hz, 1H).
Reference Example 735
##STR00954##
[3401] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.93 (d, J=7.4 Hz, 3H),
3.59 (d, J=13.5 Hz, 1H), 4.27 (d, J=12.9 Hz, 1H), 4.84 (d, J=12.9
Hz, 1H), 5.24-5.35 (m, 1H), 5.38 (d, J=13.5 Hz, 1H), 5.48 (d, J=7.4
Hz, 1H), 5.59 (s, 1H), 6.50 (d, J=7.4 Hz, 1H), 6.57-6.71 (m, 4H),
6.86-7.03 (m, 5H), 9.98 (s, 1H).
Reference Example 736
##STR00955##
[3403] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00-1.10 (m, 6H),
1.74-1.87 (m, 2H), 3.59 (d, J=13.2 Hz, 1H), 3.78-3.95 (m, 2H), 4.55
(d, J=12.4 Hz, 1H), 4.92 (d, J=12.4 Hz, 1H), 5.39-5.52 (m, 1H),
5.65 (d, J=13.2 Hz, 1H), 5.97 (s, 1H), 6.01-6.11 (m, 1H), 6.66 (d,
J=7.4 Hz, 1H), 6.81 (d, J=8.2 Hz, 2H), 6.93 (d, J=7.4 Hz, 1H),
7.07-7.11 (m, 2H), 7.21-7.25 (m, 1H), 7.32 (t, J=8.0 Hz, 1H).
Reference Example 737
##STR00956##
[3405] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09 (d, J=7.1 Hz, 3H),
1.40 (t, J=6.9 Hz, 3H), 3.59 (d, J=13.2 Hz, 1H), 3.87-4.07 (m, 2H),
4.53 (d, J=13.2 Hz, 1H), 4.86 (d, J=13.2 Hz, 1H), 5.43-5.53 (m,
1H), 5.64 (d, J=13.2 Hz, 1H), 5.91 (d, J=7.4 Hz, 1H), 5.96 (s, 1H),
6.70 (d, J=7.7 Hz, 1H), 6.78-6.84 (m, 2H), 6.93 (d, J=7.4 Hz, 1H),
7.06-7.10 (m, 2H), 7.20 (d, J=7.7 Hz, 1H), 7.32 (t, J=8.0 Hz,
1H).
Reference Example 738
##STR00957##
[3407] MS: m/z=532.5 [M+H].sup.+.
Reference Example 739
##STR00958##
[3409] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.93 (d, J=6.9 Hz, 3H),
3.73 (d, J=13.7 Hz, 1H), 4.58 (d, J=12.9 Hz, 1H), 4.64 (d, J=11.8
Hz, 1H), 4.82-4.90 (m, 2H), 5.31-5.43 (m, 1H), 5.62 (d, J=13.7 Hz,
1H), 5.90 (d, J=7.7 Hz, 1H), 6.09 (s, 1H), 6.65 (d, J=6.6 Hz, 1H),
6.69-6.78 (m, 1H), 6.90-6.98 (m, 1H), 7.00 (d, J=7.7 Hz, 1H),
7.27-7.41 (m, 3H).
Reference Example 740
##STR00959##
[3411] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (d, J=7.1 Hz, 3H),
3.49 (s, 1H), 3.60 (d, J=13.2 Hz, 1H), 4.49-4.62 (m, 2H), 4.74 (dd,
J=15.9, 2.2 Hz, 1H), 4.85 (d, J=13.5 Hz, 1H), 5.44-5.57 (m, 1H),
5.67 (d, J=13.2 Hz, 1H), 5.82 (d, J=7.7 Hz, 1H), 5.89 (s, 1H), 6.74
(d, J=8.0 Hz, 1H), 6.78-6.85 (m, 1H), 7.01 (dd, J=8.1, 3.7 Hz, 2H),
7.05-7.12 (m, 2H), 7.20 (d, J=7.7 Hz, 1H), 7.36 (t, J=8.1 Hz,
1H).
Reference Example 741
##STR00960##
[3413] MS: m/z=556.15 [M+H].sup.+.
Reference Example 742
##STR00961##
[3415] MS: m/z=556.15 [M+H].sup.+.
Reference Example 743
##STR00962##
[3417] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (d, J=7.4 Hz, 3H),
2.14 (s, 3H), 3.59 (d, J=13.5 Hz, 1H), 4.45 (d, J=12.9 Hz, 1H),
4.85 (d, J=12.9 Hz, 1H), 5.43-5.53 (m, 1H), 5.58 (d, J=13.5 Hz,
1H), 5.83 (d, J=7.7 Hz, 1H), 6.08 (s, 1H), 6.71 (d, J=7.4 Hz, 1H),
6.80-6.87 (m, 1H), 7.07-7.14 (m, 3H), 7.26-7.38 (m, 3H).
Reference Example 744
##STR00963##
[3419] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (d, J=7.1 Hz, 3H),
1.78 (d, J=6.9 Hz, 3H), 2.14 (s, 3H), 4.43 (d, J=12.9 Hz, 1H), 4.83
(d, J=12.9 Hz, 1H), 5.42-5.54 (m, 1H), 5.84 (d, J=7.7 Hz, 1H), 5.99
(q, J=7.1 Hz, 1H), 6.22 (s, 1H), 6.69 (d, J=7.1 Hz, 1H), 6.79-6.86
(m, 1H), 7.03-7.14 (m, 3H), 7.31-7.42 (m, 3H).
Reference Example 745
##STR00964##
[3421] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.03 (d, J=6.7 Hz, 3H),
1.21 (d, J=6.4 Hz, 3H), 1.78 (d, J=6.4 Hz, 3H), 4.34 (d, J=12.3 Hz,
1H), 4.70-4.84 (m, 1H), 5.03 (d, J=12.3 Hz, 1H), 6.08-6.27 (m, 3H),
6.70-6.86 (m, 2H), 7.01-7.22 (m, 3H), 7.30-7.42 (m, 3H).
Reference Example 746
##STR00965##
[3423] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.88 (d, J=7.1 Hz, 3H),
3.43 (s, 3H), 3.62 (d, J=13.5 Hz, 1H), 4.27 (d, J=11.0 Hz, 1H),
4.38 (d, J=11.0 Hz, 1H), 4.52 (d, J=13.2 Hz, 1H), 4.84 (d, J=13.2
Hz, 1H), 5.25-5.35 (m, 1H), 5.60 (d, J=13.5 Hz, 1H), 5.70 (s, 1H),
5.91 (d, J=7.1 Hz, 1H), 6.64 (d, J=7.4 Hz, 1H), 6.80-6.88 (m, 1H),
6.96 (d, J=7.7 Hz, 1H), 7.10-7.16 (m, 2H), 7.22 (dd, J=6.3, 2.5 Hz,
1H), 7.32-7.39 (m, 2H).
Reference Example 747
##STR00966##
[3425] MS: m/z=532.20 [M+H].sup.+.
Reference Example 748
##STR00967##
[3427] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (d, J=7.4 Hz, 3H),
1.80 (d, J=6.9 Hz, 3H), 4.42 (d, J=13.2 Hz, 1H), 4.86 (d, J=13.2
Hz, 1H), 5.46-5.57 (m, 1H), 5.83 (d, J=7.7 Hz, 1H), 6.07 (s, 1H),
6.12 (q, J=7.1 Hz, 1H), 6.77-6.89 (m, 2H), 7.04-7.17 (m, 3H),
7.33-7.45 (m, 3H).
Reference Example 749
##STR00968##
[3429] MS: m/z=536.05 [M+H].sup.+.
Reference Example 750
##STR00969##
[3431] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.96 (d, J=7.4 Hz, 3H),
3.64 (d, J=13.7 Hz, 1H), 4.58 (d, J=13.2 Hz, 1H), 4.64 (d, J=11.8
Hz, 1H), 4.82-4.91 (m, 2H), 5.33-5.43 (m, 1H), 5.60 (d, J=13.7 Hz,
1H), 5.86 (d, J=7.4 Hz, 1H), 6.01 (s, 1H), 6.71-6.83 (m, 2H), 7.02
(d, J=7.7 Hz, 1H), 7.11 (d, J=3.6 Hz, 2H), 7.27-7.39 (m, 3H).
Reference Example 751
##STR00970##
[3433] MS: m/z=557.20 [M+H].sup.+.
Reference Example 752
##STR00971##
[3435] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.05 (d, J=7.1 Hz, 3H),
2.49 (s, 6H), 3.50 (d, J=13.7 Hz, 1H), 4.24 (d, J=13.2 Hz, 1H),
4.72 (d, J=13.2 Hz, 1H), 5.35-5.48 (m, 1H), 5.80 (d, J=8.0 Hz, 1H),
5.91 (d, J=13.7 Hz, 1H), 6.05 (s, 1H), 6.75-6.86 (m, 2H), 7.02-7.15
(m, 5H), 7.36 (t, J=7.8 Hz, 1H).
Reference Example 753
##STR00972##
[3437] MS: m/z=531.25 [M+H].sup.+.
Reference Example 754
##STR00973##
[3439] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (d, J=7.4 Hz, 3H),
1.24-1.34 (m, 1H), 1.80 (d, J=14.8 Hz, 1H), 1.88-2.04 (m, 2H),
2.60-2.70 (m, 1H), 2.70-2.82 (m, 1H), 3.09 (t, J=11.8 Hz, 1H), 3.59
(d, J=13.5 Hz, 1H), 4.37 (d, J=11.5 Hz, 1H), 4.45 (d, J=13.2 Hz,
1H), 4.81 (d, J=13.2 Hz, 1H), 5.44-5.54 (m, 1H), 5.58 (d, J=13.5
Hz, 1H), 5.83 (d, J=7.7 Hz, 1H), 6.00 (s, 1H), 6.73 (d, J=7.7 Hz,
1H), 6.78-6.85 (m, 1H), 6.95 (d, J=7.7 Hz, 1H), 7.07-7.21 (m,
4H).
Reference Example 755
##STR00974##
[3441] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08 (d, J=7.4 Hz, 3H),
2.50 (s, 6H), 3.53 (d, J=14.0 Hz, 1H), 4.26 (d, J=13.2 Hz, 1H),
4.74 (d, J=13.2 Hz, 1H), 5.35-5.45 (m, 1H), 5.87 (d, J=14.0 Hz,
1H), 6.05 (s, 1H), 6.75 (d, J=7.7 Hz, 1H), 6.84 (t, J=6.5 Hz, 1H),
7.07-7.18 (m, 4H), 7.33-7.40 (m, 2H).
Reference Example 756
##STR00975##
[3443] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (d, J=6.7 Hz, 3H),
3.49-3.60 (m, 1H), 4.50-4.61 (m, 1H), 4.71 (d, J=14.8 Hz, 1H), 4.90
(d, J=11.6 Hz, 1H), 5.40-5.65 (m, 2H), 5.75-5.82 (m, 2H), 6.03-6.16
(m, 1H), 6.37 (d, J=9.8 Hz, 1H), 6.69 (d, J=7.3 Hz, 1H), 6.78-6.87
(m, 2H), 6.97 (d, J=7.3 Hz, 1H), 7.07-7.14 (m, 2H).
Reference Example 757
##STR00976##
[3445] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.70 (d, J=7.1 Hz, 3H),
2.46 (s, 3H), 3.73 (d, J=13.5 Hz, 1H), 4.51 (d, J=13.2 Hz, 1H),
4.87 (d, J=13.2 Hz, 1H), 5.41-5.52 (m, 1H), 5.70 (d, J=13.5 Hz,
1H), 5.85 (d, J=7.7 Hz, 1H), 5.92 (s, 1H), 6.38 (s, 1H), 6.79-6.90
(m, 2H), 7.07-7.11 (m, 2H), 7.17 (d, J=8.0 Hz, 1H), 7.22 (d, J=7.7
Hz, 1H), 7.45 (d, J=8.0 Hz, 1H).
Reference Example 758
##STR00977##
[3447] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09 (d, J=7.1 Hz, 3H),
2.50 (s, 6H), 2.52 (s, 3H), 3.51 (d, J=13.7 Hz, 1H), 4.27 (d,
J=13.2 Hz, 1H), 4.73 (d, J=13.2 Hz, 1H), 5.35-5.48 (m, 1H), 5.93
(d, J=13.7 Hz, 1H), 6.04 (s, 1H), 6.70-6.83 (m, 2H), 7.00-7.16 (m,
4H), 7.36 (t, J=7.7 Hz, 1H), 7.84 (s, 1H).
Reference Example 759
##STR00978##
[3448] First Step
[3449] Compound 759A (124 mg, 0.35 mmol) was suspended in
dichloromethane. 4,9-dihydrobenzo[e]thieno[2,3-b]thiepin-ol (82 mg,
0.35 mmol) and dichloroacetic acid (87 .mu.L, 1.05 mmol) were
added, and the mixture was stirred at room temperature for 1 hour.
Water was added, and the mixture was extracted with chloroform. The
organic layer was washed with water and aqueous saturated sodium
chloride solution, and then dried with anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the
resulting residue was purified by silica gel chromatography
(chloroform-methanol) to obtain compound 759B (180 mg, yield
90%).
[3450] MS: m/z=572.29 [M+H].sup.+.
Second Step
[3451] Compound 759B (108 mg, 0.18 mmol) was suspended in DMA.
Paraformaldehyde (113 mg, 0.38 mmol) and BEMP (0.33 mL, 1.13 mmol),
and the mixture was stirred for 5 minutes under ice-cooling, and
then stirred at room temperature for 2 days. Thereafter, tosyl
chloride (72 mg, 0.38 mmol) was added, and the mixture was stirred
for 3 days. A saturated ammonia chloride water was added, and the
precipitated solid was filtered. The resulting residue was purified
by silica gel column chromatography (chloroform-methanol) to obtain
compound 759C (16 mg, yield 15%).
[3452] MS: m/z=584.25 [M+H].sup.+
Third Step
[3453] Compound 759C (16 mg, 0.03 mmol) was suspended in DMF.
Lithium chloride (17 mg, 0.41 mmol) was added, and the mixture was
stirred at 90.degree. C. for 7 hours. A 1M aqueous hydrochloric
acid solution was added, and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and aqueous
saturated sodium chloride solution, and then dried with anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by diol silica gel
chromatography (chloroform-methanol) to obtain compound 759 (9 mg,
0.02 mmol).
[3454] MS: m/z=494.18 [M+H].sup.+
Reference Example 760
##STR00979##
[3456] MS: m/z=505.11 [M+H].sup.+
Reference Example 761
##STR00980##
[3458] MS: m/z=507.09 [M+H]
Reference Example 762
##STR00981##
[3460] MS: m/z=556.18 [M+H].sup.+
Reference Example 763
##STR00982##
[3462] MS: m/z=540.12 [M+H].sup.+
Reference Example 764
##STR00983##
[3464] MS: m/z=522.05 [M+H].sup.+
Reference Example 765
##STR00984##
[3465] First Step
[3466] Compound 765A (722 mg, 2.43 mmol) was suspended in DMF.
N-Boc azetidinone (1.25 g, 7.30 mmol) and cesium carbonate (2.96 g,
12.16 mmol) were added, and the mixture was stirred for 30 minutes
under ice-cooling, and then stirred at room temperature for 30
minutes. Thereafter, 5-chlorodibenzosuberane (1.67 g, 7.30 mmol)
was added, and the mixture was stirred for 3 hours. Insolubles were
separated by filtration, then a 0.5M aqueous hydrochloric acid
solution was added, and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and aqueous
saturated sodium chloride solution, and then dried with anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
chromatography (chloroform-methanol) to obtain compound 765B (176
mg, yield 11%).
[3467] MS: m/z=663.33 [M+H].sup.+.
Second Step
[3468] Compound 765B (176 mg, 0.27 mmol) was suspended in DMA.
Lithium chloride (113 mg, 2.66 mmol) was added, and the mixture was
stirred at 100.degree. C. for 2 hours. A 0.5M aqueous hydrochloric
acid solution was added, and the precipitated solid was filtered to
obtain compound 765C (92 mg, 0.16 mmol).
[3469] MS: m/z=573.29 [M+H].sup.+
Third Step
[3470] To compound 765C (45 mg, 0.08 mmol) was added 4N HCl/dioxane
(0.68 mL, 2.75 mmol), and the mixture was stirred for 3 hours under
ice-cooling. The reaction solution was diluted with diisopropyl
ether, and the generated solid was filtered to obtain compound 765D
(29 mg, 0.057 mmol).
[3471] MS: m/z=474.19 [M+H].sup.+
Fourth Step
[3472] Compound 765D (31 mg, 0.06 mmol) was suspended in
dichloromethane. 37% formaldehyde (25 .mu.L, 0.91 mmol),
triethylamine (10 .mu.L, 0.07 mmol), acetic acid (5 .mu.L, 0.09
mmol), and NaBH(OAc).sub.3 (25 mg, 0.12 mmol) were added, and the
mixture was stirred at room temperature for 1 hour. Saturated
sodium bicarbonate water was added, the mixture was extracted with
chloroform. The organic layer was washed with water and aqueous
saturated sodium chloride solution, and then dried with anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure, then the residue was solidified with hexane to obtain
compound 765 (15 mg, 0.03 mmol).
[3473] MS: m/z=487.25 [M+H].sup.+
Reference Example 766
##STR00985##
[3475] MS: m/z=461.23 [M+H].sup.+
Reference Example 767
##STR00986##
[3476] First Step
[3477] Compound 767A (87 mg, 0.37 mmol) was suspended in
dichloromethane.
[3478] Thionyl chloride (54 .mu.L, 0.75 mmol) was added, and the
mixture was heated to reflux for 2 hours. After concentration of
the reaction solution, the resulting residue was solidified with
hexane to obtain compound 767B (48 mg, yield 51%).
Second Step
[3479] Compound 767B (70 mg, 0.19 mmol) was suspended in DMF.
Compound 12 (48 mg, 0.19 mmol) and cesium carbonate (186 mg, 0.57
mmol) were added, and the mixture was stirred at room temperature
for 2 hours. Insolubles were separated by filtration, then water
was added to the filtrate, and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and aqueous
saturated sodium chloride solution, and then dried with anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
chromatography (chloroform-methanol) to obtain compound 767C (32
mg, 0.06 mmol).
[3480] MS: m/z=583.16 [M+H].sup.+
Third Step
[3481] Compound 767C (31 mg, 0.05 mmol) was suspended in
THF-methanol. 10% palladium carbon (15 mg) was added, and the
mixture was stirred at room temperature for 24 hours under hydrogen
atmosphere. Insolubles were separated by filtration, then the
filtrate was concentrated, and the resulting residue was purified
by diol silica gel chromatography (chloroform-methanol) to obtain
compound 767 (6 mg, 0.01 mmol).
[3482] MS: m/z=493.16 [M+H].sup.+
Reference Example 768
##STR00987##
[3484] MS: m/z=536.19 [M+H].sup.+
Reference Example 769
##STR00988##
[3486] MS: m/z=531.49 [M+H].sup.+
Reference Example 770
##STR00989##
[3488] MS: m/z=584.09 [M+H].sup.+
Reference Example 771
##STR00990##
[3490] MS: m/z=586.07 [M+H].sup.+
Reference Example 772
##STR00991##
[3492] MS: m/z=540.14 [M+H].sup.+
Reference Example 773
##STR00992##
[3494] MS: m/z=540.14 [M+H].sup.+
Reference Examples 774 and 775
##STR00993##
[3495] First Step
[3496] Compound 774A (111 mg, 0.20 mmol) was suspended in DMA.
Paraformaldehyde (11 mg, 0.39 mmol) and BEMP (0.34 mL, 1.17 mmol),
and the mixture was stirred at room temperature for 1.5 hours.
Thereafter, tosyl chloride (74 mg, 0.39 mmol) was added, and the
mixture was stirred for 2 hours. A saturated chloride ammonia water
was added, and the precipitated solid was filtered. The resulting
solid was purified by silica gel chromatography (hexane-ethyl
acetate) to obtain compound 774B (16 mg, yield 14%).
[3497] MS: m/z=595.18 [M+H].sup.+
Second Step
[3498] Compound 774B (16 mg, 0.03 mmol) was suspended in DMA.
Lithium chloride (11 mg, 0.27 mmol) was added, and the mixture was
stirred at 100.degree. C. for 3 hours. A 0.5M aqueous hydrochloric
acid solution was added, and the generated solid was filtered to
obtain compound 774 (3 mg, 0.006 mmol).
[3499] MS: m/z=505.11 [M+H].sup.+
Third Step
[3500] Compound 774B (21 mg, 0.04 mmol) was suspended in methanol.
10% palladium carbon (15 mg) was added, and the mixture was stirred
at room temperature for 20 hours under hydrogen atmosphere.
Insolubles were separated by filtration, then the filtrate was
concentrated, and the resulting residue was suspended in DMA.
Lithium chloride (12 mg, 0.28 mmol) was added, and the mixture was
stirred at 100.degree. C. for 3 hours. A 0.5M aqueous hydrochloric
acid solution was added, and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and aqueous
saturated sodium chloride solution, and then dried with anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was solidified with diisopropyl
ether to obtain compound 775 (9 mg, 0.02 mmol).
[3501] MS: m/z=507.13 [M+H].sup.+
[3502] The following EX-1 to EX-29 can be also synthesized like the
Reference examples, and are a preferable embodiment of the parent
compound.
##STR00994## ##STR00995## ##STR00996##
##STR00997## ##STR00998## ##STR00999## ##STR01000##
[3503] Hereinbelow, compounds of Examples 1 to 241 in connection
with the present invention are shown.
Example 1
##STR01001##
[3504] First Step
[3505] To a dichloromethane (1 ml) solution of compound 1-a (50 mg,
0.0900 mmol) and triethylamine (46 mg, 0.45 mmol) were added acetic
acid anhydride (28 mg, 0.27 mmol) and DMAP (11 mg, 0.0090 mmol) at
room temperature, and the mixture was stirred for 3 hours while the
same temperature was retained. The reaction solution was diluted
with dichloromethane (10 ml), and then water was added. The
dichloromethane layer was separated, and the aqueous layer was
extracted with dichloromethane once. After the combined extracts
were dried with sodium sulfate, the solvent was distilled off, and
the resulting solid was washed with ethyl acetate-diisopropyl ether
to obtain 27 mg of compound of Example 1.
[3506] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=7.5 Hz),
2.44 (3H, s), 3.98 (1H, d, J=14.7 Hz), 4.41 (1H, d, J=13.5 Hz),
4.95 (1H, d, J=13.2 Hz), 5.25 (1H, s), 5.46-5.57 (1H, m), 5.86 (1H,
d, J=14.7 Hz), 5.97 (1H, d, J=7.8 Hz), 6.89-6.94 (2H, m), 7.06-7.21
(3H, m), 7.39 (2H, d, J=3.9 Hz), 7.78-7.82 (1H, m).
Example 2
##STR01002##
[3508] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.02 (3H, d, J=6.6 Hz),
1.06 (3H, d, J=6.9 Hz), 3.58-3.62 (1H, m), 4.36 (1H, d, J=13.2 Hz),
4.70 (1H, brs), 4.82-4.91 (1H, m), 5.19 (1H, d, J=8.4 Hz),
5.67-5.75 (1H, m), 6.02 (1H, brs), 6.86 (1H, brs), 7.00-7.08 (3H,
m), 7.13-7.51 (4H, m), 7.55-7.63 (2H, m), 8.07 (1H, d, J=7.5 Hz),
8.26 (2H, d, J=7.5 Hz).
Example 3
##STR01003##
[3510] .sup.1H-NMR (CDCl.sub.3) .delta.:1.03 (3H, d, J=6.6 Hz),
1.08 (3H, d, J=8.4 Hz), 1.45 (9H, s), 3.56-3.60 (1H, m), 4.33 (1H,
d, J=13.2 Hz), 4.79 (2H, brs), 5.15 (1H, brs), 5.68 (1H, brs), 5.90
(1H, brs), 6.84 (1H, brs), 6.94 (1H, brs), 7.05-7.06 (2H, m),
7.15-7.27 (3H, m), 7.33-7.43 (2H, m).
Example 4
##STR01004##
[3512] MS: m/z=566 [M+H].sup.+,
[3513] Rf: 0.56 (CHCl3:MeOH=9:1).
Example 5
##STR01005##
[3515] MS: m/z=566 [M+H].sup.+,
[3516] Rf: 0.52 (CHCl3:MeOH=9:1).
Example 6
##STR01006##
[3518] MS: m/z=582 [M+H].sup.+,
[3519] Rf: 0.56 (CHCl3:MeOH=9:1).
Example 7
##STR01007##
[3521] MS: m/z=582 [M+H].sup.+,
[3522] Rf: 0.52 (CHCl3:MeOH=9:1).
Example 8
##STR01008##
[3524] MS: m/z=582 [M+H].sup.+,
[3525] Rf: 0.56 (CHCl3:MeOH=9:1).
Example 9
##STR01009##
[3527] MS: m/z=582 [M+H].sup.+,
[3528] Rf: 0.52 (CHCl3:MeOH=9:1).
Example 10
##STR01010##
[3530] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (3H, d, J=7.3 Hz),
2.43 (3H, s), 3.64 (1H, d, J=13.6 Hz), 4.42 (1H, d, J=12.9 Hz),
4.91 (1H, d, J=12.9 Hz), 5.18 (1H, s), 5.49 (1H, m), 5.74 (1H, d,
J=13.6 Hz), 6.00 (1H, d, J=7.7 Hz), 6.79 (1H, t, J=7.7 Hz), 6.87
(1H, m), 6.97 (1H, dt, J=2.6, 8.0 Hz), 7.08-7.18 (3H, m), 7.45 (1H,
dd, J=1.5, 8.0 Hz).
[3531] MS: m/z=627 [M+H].sup.+.
[3532] Rf: 0.53 (CHCl.sub.3:MeOH=9:1).
Example 11
##STR01011##
[3534] MS: m/z=627 [M+H].sup.+,
[3535] Rf: 0.46 (CHCl.sub.3:MeOH=9:1).
Example 12
##STR01012##
[3537] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (3H, d, J=7.2 Hz),
2.32 (2H, m), 2.43 (3H, s), 2.65 (2H, t, J=8.1 Hz), 3.64 (1H, d,
J=14.2 Hz), 3.86 (2H, m), 4.56 (1H, d, J=13.5 Hz), 4.91 (1H, d,
J=13.5 Hz), 5.17 (1H, s), 5.44 (1H, m), 5.50 (1H, d, J=14.2 Hz),
5.96 (1H, d, J=7.8 Hz), 6.88 (1H, m), 7.03-7.16 (3H, m), 7.20 (1H,
d, J=7.8 Hz), 7.30 (3H, m).
[3538] MS: m/z=613 [M+H].sup.+.
[3539] Rf: 0.5 (CHCl.sub.3:MeOH=9:1).
Example 13
##STR01013##
[3541] MS: m/z=613 [M+H].sup.+,
[3542] Rf: 0.4 (CHCl.sub.3:MeOH=9:1).
Example 14
##STR01014##
[3544] MS: m/z=582 [M+H].sup.+,
[3545] Rf: 0.56 (CHCl.sub.3:MeOH=9:1).
Example 15
##STR01015##
[3547] MS: m/z=582 [M+H].sup.+,
[3548] Rf: 0.46 (CHCl.sub.3:MeOH=9:1).
Example 16
##STR01016##
[3550] MS: m/z=562 [M+H].sup.+,
[3551] Rf: 0.53 (CHCl.sub.3:MeOH=9:1).
Example 17
##STR01017##
[3553] MS: m/z=562 [M+H].sup.+,
[3554] Rf: 0.46 (CHCl.sub.3:MeOH=9:1).
Example 18
##STR01018##
[3556] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (3H, d, J=6.1 Hz),
2.42 (3H, s), 4.31 (1H, d, J=13.9 Hz), 4.57 (1H, d, J=12.6 Hz),
4.97 (1H, d, J=12.6 Hz), 5.26 (1H, s), 5.28 (1H, m), 5.62 (1H, d,
J=13.9 Hz), 5.96 (1H, d, J=7.8 Hz), 6.87 (1H, m), 7.04-7.12 (3H,
m), 7.19 (1H, t, J=7.9 Hz), 7.32 (1H, d, J=7.5 Hz), 7.49 (1H, dd,
J=1.2, 7.9 Hz).
[3557] MS: m/z=564 [M+H].sup.+.
Example 19
##STR01019##
[3559] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.97-1.09 (9H, m), 1.68
(2H, m), 2.55 (2H, t, J=7.2 Hz), 3.88 (1H, d, J=13.3 Hz), 4.27 (1H,
d, J=13.7 Hz), 4.59 (1H, m), 4.99 (1H, d, J=13.6 Hz), 5.33 (1H, s),
5.73 (2H, dd, J=53.9, 10.8 Hz), 6.83-7.48 (9H, m).
[3560] MS: m/z=504 [M+H].sup.+.
Example 20
##STR01020##
[3562] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, d, J=7.3 Hz),
2.44 (3H, s), 3.61 (1H, d, J=13.4 Hz), 4.46 (1H, d, J=13.1 Hz),
4.91 (1H, d, J=13.3 Hz), 5.12 (1H, s), 5.42-5.57 (1H, m), 5.64 (1H,
d, J=13.4 Hz), 5.98 (1H, d, J=7.8 Hz), 6.87 (2H, s), 6.99-7.61 (7H,
m).
[3563] MS: m/z=530 [M+H].sup.+.
Example 21
##STR01021##
[3564] Example 22
##STR01022##
[3565] Example 23
##STR01023##
[3567] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, d, J=7.3 Hz),
2.44 (3H, s), 3.61 (1H, d, J=13.4 Hz), 4.46 (1H, d, J=13.1 Hz),
4.91 (1H, d, J=13.3 Hz), 5.12 (1H, s), 5.42-5.57 (1H, m), 5.64 (1H,
d, J=13.4 Hz), 5.98 (1H, d, J=7.8 Hz), 6.87 (2H, s), 6.99-7.61 (7H,
m).
Example 24
##STR01024##
[3569] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.34 (3H, d, J=7.3 Hz),
2.43 (3H, s), 3.60 (1H, d, J=13.3 Hz), 4.57 (1H, d, J=12.5 Hz),
4.97 (1H, d, J=12.5 Hz), 5.23 (1H, s), 5.29 (1H, m), 5.66 (1H, d,
J=13.1 Hz), 5.97 (1H, d, J=7.9 Hz), 6.87 (2H, s), 7.05-7.42 (8H,
m).
Example 25
##STR01025##
[3570] Example 26
##STR01026##
[3571] Example 27
##STR01027##
[3573] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (3H, d, J=7.4 Hz),
2.46 (3H, s), 3.63 (1H, d, J=13.5 Hz), 4.46 (1H, d, J=13.2 Hz),
4.93 (1H, d, J=13.2 Hz), 5.14 (1H, s), 5.51 (1H, m), 5.68 (1H, d,
J=13.5 Hz), 6.07 (1H, d, J=8.0 Hz), 6.63 (1H, t, J=8.0 Hz), 6.84
(2H, m), 7.18-7.49 (6H, m).
[3574] MS: m/z=541 [M+H].sup.+.
Example 28
##STR01028##
[3576] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (3H, d, J=7.2 Hz),
2.41 (3H, d, J=15.1 Hz), 3.62 (1H, d, J=13.6 Hz), 4.44 (1H, d,
J=13.3 Hz), 4.93 (1H, d, J=13.1 Hz), 5.06 (1H, s), 5.50 (1H, m),
5.58 (1H, d, J=13.4 Hz), 5.98 (1H, d, J=7.8 Hz), 6.88-7.39 (8H,
m).
Example 29
##STR01029##
[3578] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.35 (3H, d, J=7.5 Hz),
2.42 (3H, s), 3.61 (1H, d, J=13.4 Hz), 4.56 (1H, d, J=12.8 Hz),
4.99 (1H, d, J=12.8 Hz), 5.16 (1H, s), 5.23-5.38 (1H, m), 5.59 (1H,
d, J=13.6 Hz), 5.97 (1H, d, J=7.8 Hz), 6.91-7.38 (8H, m).
Example 30
##STR01030##
[3579] Example 31
##STR01031##
[3580] Example 32
##STR01032##
[3581] Example 33
##STR01033##
[3582] Example 34
##STR01034##
[3583] Example 35
##STR01035##
[3584] Example 36
##STR01036##
[3585] Example 37
##STR01037##
[3586] Example 38
##STR01038##
[3587] Example 39
##STR01039##
[3589] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.35 (3H, d, J=7.5 Hz),
2.42 (3H, s), 3.61 (1H, d, J=13.4 Hz), 4.56 (1H, d, J=12.8 Hz),
4.99 (1H, d, J=12.8 Hz), 5.16 (1H, s), 5.23-5.38 (1H, m), 5.59 (1H,
d, J=13.6 Hz), 5.97 (1H, d, J=7.8 Hz), 6.91-7.38 (8H, m).
Example 40
##STR01040##
[3590] Example 41
##STR01041##
[3591] Example 42
##STR01042##
[3592] Example 43
##STR01043##
[3593] Example 44
##STR01044##
[3594] Example 45
##STR01045##
[3595] Example 46
##STR01046##
[3596] Example 47
##STR01047##
[3597] Example 48
##STR01048##
[3598] Example 49
##STR01049##
[3599] Example 50
##STR01050##
[3601] MS: m/z=548 [M+H].sup.+.
Example 51
##STR01051##
[3602] Example 52
##STR01052##
[3603] Example 53
##STR01053##
[3604] Example 54
##STR01054##
[3605] Example 55
##STR01055##
[3606] Example 56
##STR01056##
[3607] Example 57
##STR01057##
[3608] Example 58
##STR01058##
[3609] Example 59
##STR01059##
[3610] Example 60
##STR01060##
[3611] Example 61
##STR01061##
[3612] Example 62
##STR01062##
[3613] Example 63
##STR01063##
[3614] Example 64
##STR01064##
[3616] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.07 (4H, m), 1.17 (3H,
d, J=6.9 Hz), 1.88 (1H, m), 3.88 (1H, d, J=13.6 Hz), 4.38 (1H, d,
J=13.6 Hz), 5.11 (1H, d, J=13.4 Hz), 5.46 (1H, m), 5.51 (1H, s),
5.63 (1H, d, J=13.3 Hz), 5.87 (1H, d, J=7.8 Hz), 6.84-7.60 (9H,
m).
[3617] MS: m/z=556 [M+H].sup.+.
Example 65
##STR01065##
[3618] Example 66
##STR01066##
[3619] Example 67
##STR01067##
[3621] MS: m/z=614 [M+H].sup.+.
Example 68
##STR01068##
[3622] Example 69
##STR01069##
[3623] Example 70
##STR01070##
[3624] Example 71
##STR01071##
[3625] Example 72
##STR01072##
[3626] Example 73
##STR01073##
[3627] Example 74
##STR01074##
[3628] Example 75
##STR01075##
[3629] Example 76
##STR01076##
[3631] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.17 (3H, d, J=7.2 Hz),
2.44 (3H, s), 4.22 (1H, d, J=13.7 Hz), 4.44 (1H, d, J=13.3 Hz),
4.93 (1H, d, J=13.6 Hz), 5.23 (1H, s), 5.42 (1H, d, J=15.7 Hz),
5.50 (1H, m), 6.00 (1H, d, J=7.9 Hz), 6.85-7.29 (7H, m).
[3632] MS: m/z=582 [M+H].sup.+.
Example 77
##STR01077##
[3633] Example 78
##STR01078##
[3634] Example 79
##STR01079##
[3635] Example 80
##STR01080##
[3636] Example 81
##STR01081##
[3637] Example 82
##STR01082##
[3638] Example 83
##STR01083##
[3640] MS: m/z=609.90 [M+H].sup.+
Example 84
##STR01084##
[3642] MS: m/z=609.90 [M+H].sup.+.
Example 85
##STR01085##
[3644] MS: m/z=555.20 [M+H].sup.+.
Example 86
##STR01086##
[3646] MS: m/z=555.20 [M+H].sup.+.
Example 87
##STR01087##
[3648] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.34 (3H, d, J=7.4 Hz),
2.42 (3H, s), 3.60 (1H, d, J=13.3 Hz), 4.56 (1H, d, J=12.7 Hz),
4.96 (1H, d, J=12.4 Hz), 5.20-5.34 (2H, m), 5.65 (1H, d, J=13.5
Hz), 5.97 (1H, d, J=7.9 Hz), 6.76-7.41 (9H, m).
[3649] MS: m/z=530 [M+H].sup.+.
Example 88
##STR01088##
[3651] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.34 (3H, d, J=7.5 Hz),
1.39 (6H, d, J=6.8 Hz), 2.92-3.00 (1H, m), 3.59 (1H, d, J=13.1 Hz),
4.56 (1H, d, J=12.7 Hz), 4.97 (1H, d, J=12.2 Hz), 5.22-5.30 (2H,
m), 5.65 (1H, d, J=13.7 Hz), 6.00 (1H, d, 7.9 Hz), 6.90-7.39 (9H,
m).
[3652] MS: m/z=558 [M+H].sup.+.
Example 89
##STR01089##
[3654] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26-1.35 (6H, m), 2.76
(2H, q, J=7.3 Hz), 3.59 (1H, d, J=13.2 Hz), 4.56 (1H, d, J=12.6
Hz), 4.96 (1H, d, J=12.8 Hz), 5.22-5.30 (2H, m), 5.66 (1H, d,
J=13.4 Hz), 5.95 (1H, d, J=7.7 Hz), 6.89-7.42 (9H, m).
[3655] MS: m/z=544 [M+H].sup.+.
Example 90
##STR01090##
[3657] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (3H, d, J=7.2 Hz),
1.40 (6H, d, J=6.9 Hz), 2.93-3.02 (1H, m), 3.60 (1H, d, J=13.1 Hz),
4.44 (1H, d, J=13.1 Hz), 4.90 (1H, d, J=12.9 Hz), 5.12 (1H, s),
5.46-5.66 (2H, m), 5.93 (1H, d, J=7.7 Hz), 6.89 (2H, brs),
7.06-7.28 (5H, m), 7.35-7.44 (2H, m).
[3658] MS: m/z=558 [M+H].sup.+.
Example 91
##STR01091##
[3660] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (3H, d, J=6.1 Hz),
1.31 (3H, t, J=7.5 Hz), 2.77 (2H, q, J=7.6 Hz), 3.60 (1H, d, J=13.4
Hz), 4.45 (1H, d, J=13.2 Hz), 4.90 (1H, d, J=13.3 Hz), 5.12 (1H,
s), 5.44-5.66 (2H, m), 5.95 (1H, d, J=7.9 Hz), 6.89 (2H, brs),
7.06-7.45 (7H, m).
[3661] MS: m/z=544 [M+H].sup.+.
Example 92
##STR01092##
[3663] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09-1.14 (9H, m),
2.26-2.35 (1H, m), 2.60 (2H, d, J=6.6 Hz), 3.60 (1H, d, J=13.5 Hz),
4.44 (1H, d, J=13.0 Hz), 4.90 (1H, d, J=12.7 Hz), 5.11 (1H, s),
5.46-5.65 (2H, m), 5.94 (1H, d, J=8.1 Hz), 6.88 (2H, brs),
7.07-7.44 (7H, m).
[3664] MS: m/z=572 [M+H].sup.+.
Example 93
##STR01093##
[3666] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.05-1.14 (6H, m),
1.81-1.88 (2H, m), 2.71 (2H, t, J=7.4 Hz), 3.61 (1H, d, J=13.4 Hz),
4.45 (1H, d, J=13.4 Hz), 4.91 (1H, d, J=13.3 Hz), 5.12 (1H, s),
5.47-5.66 (2H, m), 5.95 (1H, d, J=8.0 Hz), 6.89 (2H, brs),
7.07-7.45 (7H, m).
[3667] MS: m/z=558 [M+H].sup.+.
Example 94
##STR01094##
[3669] MS: m/z=572 [M+H].sup.+.
Example 95
##STR01095##
[3671] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.03 (3H, d, J=8.0 Hz),
2.29 (3H, s), 3.98 (1H, d, J=12.0 Hz), 4.53 (1H, d, 12.0 Hz), 5.13
(1H, d, 12.0 Hz), 5.47 (1H, m), 5.66 (1H, d, J=12.0 Hz), 5.79 (1H,
s), 5.92 (1H, d, J=8.0 Hz), 6.81 (1H, d, 8.0 Hz), 6.91 (1H, m),
7.13-7.22 (2H, m), 7.27 (1H, d, J=8.0 Hz), 7.45 (2H, m), 7.51 (1H,
m).
[3672] MS: m/z=564 [M+H].sup.+. RT=2.10 min.
Example 96
##STR01096##
[3674] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40 (3H, d, J=8.0 Hz),
2.42 (3H, s), 3.62 (1H, d, J=12.0 Hz), 4.48 (1H, d, 12.0 Hz), 5.02
(2H, m), 5.64 (1H, m), 5.97 (1H, d, J=8.0 Hz), 6.05 (1H, s), 6.91
(1H, m), 7.05-7.15 (2H, m), 7.20-7.35 (5H, m)
[3675] MS: m/z=564 [M+H].sup.+. RT=2.11 min.
Example 97
##STR01097##
[3677] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.94-1.02 (6H, m), 3.89
(1H, d, J=13.42 Hz), 4.29 (1H, d, J=13.57 Hz), 4.54 (1H, t, J=6.79
Hz), 5.04 (1H, d, J=13.42 Hz), 5.50 (2H, t, J=51.02 Hz), 5.91 (1H,
d, J=7.78 Hz), 6.87-7.26 (5H, m), 7.42 (4H, dt, J=21.66, 7.66 Hz),
7.64-7.68 (1H, m), 8.40-8.43 (1H, m), 8.90 (1H, dd, J=4.73, 1.68
Hz), 9.20 (1H, d, J=1.68 Hz).
[3678] MS: m/z=539.00 [M+H].sup.+.
Example 98
##STR01098##
[3680] To a DMF (1 ml) solution of Tetrahydro-2H-pyran-4-carboxylic
acid (125 mg, 0.958 mmol) and triethylamine (194 mg, 1.92 mmol) was
added dropwise ethyl chloroformate (94 mg, 0.862 mmol) at room
temperature. After the reaction solution was stirred at the same
temperature for 5 minutes, compound 98-a (50 mg, 0.0958 mmol) was
added, and the mixture was stirred for 5 hours. The reaction
solution was diluted by ethyl acetate (10 ml), and water was added.
The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate once. The extract was washed with
water three times, and dried with sodium sulfate, and the solvent
was distilled off. the resulting solid was washed with ethyl
acetate-diisopropyl ether to obtain 30 mg of compound of Example
98.
[3681] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=7.5 Hz),
1.98-2.13 (4H, m), 2.95-3.03 (1H, m), 3.40-3.57 (2H, m), 3.95-4.14
(2H, m), 4.31 (1H, d, J=14.1 Hz), 4.45 (1H, d, J=13.2 Hz), 4.92
(1H, d, J=13.5 Hz), 5.16 (1H, s), 5.45-5.57 (1H, m), 5.60 (1H, d,
J=14.1 Hz), 5.95 (1H, d, J=7.8 Hz), 6.91 (2H, brs), 7.09-7.26 (5H,
m), 7.53 (1H, d, J=8.1 hz).
Example 99
##STR01099##
[3683] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (3H, d, J=7.2 Hz),
1.98-2.14 (4H, m), 2.95-3.05 (1H, m), 3.49-3.57 (3H, m), 4.03-4.09
(2H, m), 4.44 (1H, d, J=13.2 Hz), 4.91 (1H, d, J=12.9 Hz), 5.13
(1H, s), 5.44-5.54 (1H, m), 5.66 (1H, d, J=13.5 Hz), 5.94 (1H, d,
J=8.1 Hz), 6.91-6.99 (3H, m), 7.07-7.22 (5H, m).
Example 100
##STR01100##
[3685] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (3H, d, J=7.2 Hz),
2.01-2.13 (4H, m), 2.95-3.04 (1H, m), 3.49-3.57 (2H, m), 3.96-4.08
(3H, m), 4.41 (1H, d, J=13.5 Hz), 4.94 (1H, d, J=13.5 Hz), 5.26
(1H, s), 5.45-5.55 (1H, m), 5.86 (1H, d, J=14.7 Hz), 5.95 (1H, d,
J=7.5 Hz), 6.91-6.93 (2H, m), 7.07-7.19 (3H, m), 7.38-7.39 (2H, m),
7.79-7.82 (1H, m).
Example 101
##STR01101##
[3687] .sup.1H-NMR (CDCl.sub.3) .delta.:1.15 (3H, d, J=7.2 Hz),
1.98-2.12 (4H, m), 2.94-3.04 (1H, m), 3.48-3.56 (2H, m), 4.04-4.07
(2H, m), 4.21 (1H, d, J=13.8 Hz), 4.45 (1H, d, J=13.2 Hz), 4.92
(1H, d, J=13.2 Hz), 5.20 (1H, s), 5.37 (1H, d, J=13.5 Hz),
5.43-5.54 (1H, m), 5.93 (1H, d, J=7.8 Hz), 6.77 (1H, brs),
6.82-6.86 (1H, m), 6.97-6.99 (1H, m), 7.04 (2H, d, J=7.5 Hz),
7.17-7.25 (3H, m).
Example 102
##STR01102##
[3689] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, d, J=7.2 Hz),
2.50 (6H, s), 3.55-3.68 (2H, m), 4.31 (1H, d, J=13.8 Hz), 4.44 (1H,
d, J=13.2 Hz), 4.92 (1H, d, J=13.2 Hz), 5.45-5.58 (1H, m), 5.61
(1H, d, J=13.8 Hz), 5.95 (1H, d, J=7.8 Hz), 6.90 (2H, brs),
7.07-7.11 (3H, m), 7.16-7.25 (2H, m), 7.52 (2H, d, J=6.9 Hz).
Example 103
##STR01103##
[3691] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=7.2 Hz),
2.17 (2H, s), 3.32 (3H, s), 3.63-3.66 (2H, m), 3.87-3.90 (2H, m),
4.31 (1H, d, J=13.8 Hz), 4.45 (1H, d, J=13.5 Hz), 6.60 (2H, d,
J=2.1 Hz), 4.92 (1H, d, J=12.6 Hz), 5.15 (1H, s), 5.44-5.54 (1H,
m), 5.60 (1H, d, J=13.8 Hz), 5.95 (1H, d, J=7.8 Hz), 6.89-6.90 (2H,
m), 7.07-7.14 (3H, m), 7.16-7.25 (2H, m), 7.52 (1H, d, J=6.9
Hz).
Example 104
##STR01104##
[3693] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, d, J=7.2 Hz),
2.09 (4H, m), 3.03 (1H, dm), 3.55 (2H, m), 4.10 (2H, m), 4.26 (1H,
d, J=13.6 Hz), 4.48 (1H, d, J=13.1 Hz), 4.96 (1H, d, J=12.8 Hz),
5.28 (1H, s), 5.46 (1H, d, J=13.4 Hz), 5.54 (1H, d, J=8.1 Hz), 6.03
(1H, d, J=7.9 Hz), 6.94-7.34 (7H, m).
[3694] MS: m/z=652 [M+H].sup.+.
Example 105
##STR01105##
[3696] According to the method shown in Bioorganic & Medicinal
Chemistry Letters; English; 14; 12; 2004; 3231-3234, ethyl
chloroformate (93 mg, 0.862 mmol) was added to a DMF (1 ml)
solution of 2-(tert-butyldimethylsilyloxy)acetic acid (82 mg, 0.958
mmol) and triethylamine (194 mg, 1.92 mmol) at room temperature,
and the mixture was stirred at the same temperature for 3 minutes.
Compound 98-a (50 mg, 0.0958 mmol) was added to the reaction
solution, and the mixture was further stirred for 1 hour. The
reaction solution was diluted with ethyl acetate (10 ml), and water
was added. The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate once. The extract was washed with
water three times, and dried with sodium sulfate, and the solvent
was distilled off. The resulting crude product was dissolved in THF
(2 ml), a 1M THF solution (0.287 ml, 0.287 mmol) of TBAF was added
at room temperature, and the mixture was stirred at the same
temperature for 30 minutes. Water was added to the reaction
solution, followed by extraction with ethyl acetate two times. The
extract was dried with sodium sulfate, and the solvent was
distilled off, then the resulting solid was washed with ethyl
acetate-diisopropyl ether to obtain 30 mg of compound of Example
105.
[3697] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (3H, d, J=7.2 Hz),
4.36 (1H, d, J=14.1 Hz), 4.52 (1H, d, J=13.2 Hz), 4.62 (1H, d,
J=16.5 Hz), 4.90-4.97 (2H, m), 5.14 (1H, s), 5.51-5.62 (2H, m),
6.12 (1H, d, J=7.8 Hz), 6.68 (1H, d, J=7.2 Hz), 6.84-6.90 (1H, m),
7.10-7.18 (3H, m), 7.20-7.24 (1H, m), 7.37 (1H, d, J=7.8 Hz), 7.55
(1H, d, J=6.9 Hz).
Example 106
##STR01106##
[3699] (S)-2-(tert-butoxycarbonylamino)propanoic acid (301 mg, 1.59
mmol) was dissolved in THF (2 ml), N-methylmorpholine (0.175 ml,
1.59 mmol) and isobutyl chloroformate (0.209 ml, 1.59 mmol) were
added at 0.degree. C., and the mixture was stirred for 15 minutes.
A dichloromethane solution (1 ml) of 106-a (69.0 mg, 0.159 mmol)
synthesized according to Example was added at 0.degree. C., and the
mixture was stirred at room temperature for 4 hours. To the
reaction solution was added water, the mixture was extracted with
ethyl acetate, and the organic layer was dried with sodium sulfate.
The solvent was distilled off under reduced pressure, and the
resulting crude product was purified by silica gel column
chromatography, and eluted with chloroform-methanol (97:3, v/v).
The resulting product was solidified by adding
dichloromethane-diisopropyl ether-diethyl ether to obtain 40 mg of
compound of Example 106 as a white solid.
Example 107
##STR01107##
[3700] First Step
[3701] To a methanol (80 mL) solution of (R)-methyl
2,2-dimethyl-1,3-dioxolane-4-carboxylate (107-a, 11.22 g, 70.1
mmol) was added sodium hydroxide monohydrate (2.94 g, 70.1 mmol) at
room temperature, and the mixture was stirred for 3 hours. The
solvent was distilled off under reduced pressure, to the resulting
residue was added 2N hydrochloric acid (35 mL) under ice-cooling,
and the mixture was extracted with chloromethane (100 mL.times.2).
The organic layer was washed with water (50 mL), and dried with
magnesium sulfate. The solvent was distilled off under reduced
pressure, and the resulting crude product of compound 107-b was
used in a next reaction without purification.
Second Step
[3702] To a dichloromethane (2 mL) solution of compound 98-a (41.7
mg, 0.285 mmol), triethylamine (0.106 mL, 0.765 mmol) and
4-dimethylaminopyridine (5.7 mg, 0.047 mmol) was added
2-methyl-6-nitrobenzoic anhydride (100 mg, 0.290 mmol) at room
temperature, and the mixture was stirred for 10 minutes. Compound
5C (51.7 mg, 0.099 mmol) was added to the reaction solution, and
the mixture was stirred for 1.5 hours. To the reaction solution was
added water (2 mL), then the mixture was extracted with
dichloromethane, and the organic layer was dried with sodium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (ethyl acetate/n-hexane=60%-100%) to obtain compound
of Example 107 (40.4 mg, 63%) as a white solid.
[3703] MS: m/z=650.35 [M+H].sup.+.
Example 108
##STR01108##
[3704] First Step
[3705] To a dichloromethane (1 mL) solution of compound 98-a (50.0
mg, 0.096 mmol), triethylamine (0.0660 mL, 0.476 mmol) and
N-methylimidazole (0.0038 mL, 0.048 mmol) was added
3-methoxypropionyl chloride (33.0 mg, 0.269 mmol) at room
temperature, and the mixture was stirred for 16 hours. To the
reaction solution were added water (1 mL) and hydrochloric acid
(2M, 1 mL), the mixture was extracted with dichloromethane, and the
organic layer was dried with sodium sulfate. The solvent was
distilled off under reduced pressure, the resulting residue was
purified by silica gel column chromatography (ethyl
acetate/n-hexane=60%.fwdarw.100%), and the resulting product was
converted into a powder with ethyl acetate-isopropyl ether to
obtain compound of Example 108 (47.0 mg, 81%) as a white solid.
[3706] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=7.2 Hz),
3.03 (2H, t, J=6.9 Hz), 3.43 (3H, s), 3.85 (2H, m), 4.31 (1H, d,
J=13.7 Hz), 4.45 (1H, d, J=13.2 Hz), 4.92 (1H, d, J=13.2 Hz), 5.16
(1H, s), 5.52 (1H, m), 5.60 (1H, d, J=13.7 Hz), 5.96 (1H, d, J=8.1
Hz), 6.90 (2H, m), 7.10-7.23 (5H, m), 7.53 (1H, d, J=8.1 Hz).
[3707] MS: m/z=608.20 [M].sup.+.
Example 109
##STR01109##
[3709] According to Example 108, compound of Example 109 was
synthesized by the same procedure.
[3710] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=7.5 Hz),
2.83 (2H, t, J=7.4 Hz), 3.10 (2H, t, J=7.4 Hz), 3.74 (3H, s), 4.31
(1H, d, J=13.8 Hz), 4.45 (1H, d, J=13.2 Hz), 4.92 (1H, d, J=13.2
Hz), 5.15 (1H, s), 5.50 (1H, m), 5.60 (1H, d, J=13.8 Hz), 5.96 (1H,
d, J=8.1 Hz), 6.91 (2H, m), 7.10-7.23 (5H, m), 7.53 (1H, d, J=8.1
Hz).
[3711] MS: m/z=636.15 [M].sup.+.
Example 110
##STR01110##
[3713] According to Example 108, compound of Example 110 was
synthesized by the same procedure.
[3714] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=7.2 Hz),
2.22 (3H, s), 4.31 (1H, d, J=13.8 Hz), 4.46 (1H, d, J=13.4 Hz),
4.92 (1H, d, J=13.4 Hz), 5.05 (1H, d, J=16.5 Hz), 5.15 (1H, d,
J=16.5 Hz), 5.15 (1H, s), 5.54 (1H, m), 5.60 (1H, d, J=13.8 Hz),
5.97 (1H, d, J=8.1 Hz), 6.82-6.94 (2H, m), 7.09-7.23 (5H, m), 7.54
(1H, d, J=8.1 Hz).
[3715] MS: m/z=622.15 [M].sup.+.
Example 111
##STR01111##
[3717] A dichloromethane (1.0 mL) solution of compound 98-a (50 mg,
0.10 mmol) was ice-cooled, triethylamine (0.040 ml, 0.29 mmol) and
2-methoxyacetyl chloride (11 mg, 0.11 mmol) were added, and the
mixture was stirred for 1 hour under ice-cooling, then stirred at
room temperature for 2 hours. Thereafter, to the reaction solution
was added ethyl acetate, the mixture was washed with water, and
sodium sulfide was added to dry it. The solvent was distilled off,
and a solid of the resulting oil was precipitated by using ethyl
acetate to obtain 31 mg of compound of Example 111 as a white
solid.
[3718] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, d, 7.1 Hz), 3.59
(3H, s), 4.31 (1H, d, J=13.9 Hz), 4.41-4.54 (3H, m), 4.93 (1H, d,
J=13.3 Hz), 5.16 (1H, s), 5.46-5.63 (2H, m), 5.97 (1H, d, J=7.9
Hz), 6.90 (2H, brs), 7.09-7.24 (5H, m), 7.53 (1H, d, J=7.4 Hz).
[3719] MS: m/z=594 [M+H].sup.+.
Example 112
##STR01112##
[3720] First Step
[3721] An acetonitrile (2 ml) solution of compound 106-a (100 mg,
0.231 mmol), chloromethyl pivalate (482 mg, 3.20 mmol) and sodium
iodide (480 mg, 3.20 mmol) was stirred at 80.degree. C. for 6
hours. After cooled to room temperature, water was added, and the
mixture was extracted with ethyl acetate three times. The combined
extracts were dried with sodium sulfate, and the solvent was
distilled off. The resulting oil was purified by silica gel column
chromatography. The materials were eluted firstly with ethyl
acetate and, then, with ethyl acetate-methanol (7:3, v/v).
Concentration of an objective fraction afforded 35 mg of compound
of Example 112 as a solid.
[3722] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.06 (3H, d, J=16.2 Hz),
10.9 (3H, d, J=9.3 Hz), 1.26 (9H, s), 3.58 (1H, d, J=13.2 Hz), 4.29
(1H, d, J=13.2 Hz), 4.73-4.82 (1H, m), 4.77 (1H, d, J=12.9 Hz),
5.10 (1H, s), 5.68 (2H, d, J=13.2 Hz), 5.88-5.93 (3H, m), 6.86-6.88
(2H, m), 7.04-7.10 (2H, m), 7.15-7.27 (3H, m), 7.32-7.42 (2H,
m).
Example 113
##STR01113##
[3724] To an aqueous (0.5 mL) suspension of compound 113-a (50 mg,
0.10 mmol) and potassium carbonate (40 mg, 0.29 mmol) were added
tetrabutylammonium hydrogen sulfate (33 mg, 0.10 mmol) and
dichloromethane (1.0 ml), and the mixture was stirred at room
temperature for 10 minutes. To the reaction solution was added a
dichloromethane (1.0 ml) solution of iodomethyl acetate (56 mg,
0.19 mmol), and the mixture was further stirred for 2 hours.
Thereafter, to the reaction solution was added water, the
dichloromethane layer was separated, and the aqueous layer was
extracted with dichloromethane once. The combined extracts were
washed with an aqueous saturated sodium chloride solution and
brine, and then sodium sulfide was added to dry them. The solvent
was distilled off, and the resulting oil was purified by silica gel
column chromatography. The materials were eluted firstly with
chloroform and, then, with chloroform-methanol (94:6, v/v). An
objective fraction was concentrated, and solidified by adding
diisopropyl ether to obtain 41 mg of compound of Example 113 as a
white solid.
[3725] .sup.1H-NMR (DMSO-d6) .delta.: 0.98 (3H, d, J=7.2 Hz), 2.02
(3H, s), 3.98 (1H, d, J=7.2 Hz), 4.48 (1H, d, J=7.2 Hz), 5.05 (1H,
d, J=7.2 Hz), 5.42-5.49 (1H, m), 5.61 (1H, d, J=7.2 Hz), 5.66-5.77
(3H, m), 5.87 (1H, d, J=7.2 Hz), 6.86-6.95 (2H, m), 7.16-7.20 (3H,
m), 7.45-7.52 (3H, m).
[3726] MS: m/z=594 [M+H].sup.+.
[3727] According to Example 113, the following compounds were
synthesized by the same procedure.
Example 114
##STR01114##
[3729] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.07 (3H, d, J=6.6 Hz),
1.09 (3H, d, J=6.6 Hz), 2.15 (3H, s), 7.58 (1H, d, J=13.5 Hz), 4.30
(1H, d, J=12.9 Hz), 4.75-4.83 (1H, m), 4.77 (1H, d, J=12.9 Hz),
5.12 (1H, s), 5.69 (d, J=13.5 Hz), 5.82-5.92 (3H, m), 6.84-6.91
(2H, m), 7.04-7.08 (2H, m), 7.20-7.28 (3H, m), 7.32-7.42 (2H,
m).
Example 115
##STR01115##
[3731] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.17 (3H, d, J=7.3 Hz),
2.12 (3H, s), 3.90 (1H, d, J=14.7 Hz), 4.38 (1H, d, J=13.3 Hz),
4.91 (1H, d, J=13.3 Hz), 5.23 (1H, s), 5.57 (1H, m), 5.86 (1H, d,
J=6.4 Hz), 5.86 (1H, d, J=14.7 Hz), 5.94 (1H, d, J=7.8 Hz), 6.84
(1H, dd, J=1.2, 7.9 Hz), 6.91 (1H, dt, J=1.7, 6.8 Hz), 7.09 (1H,
dd, J=1.4, 7.6 Hz), 7.12 (1H, dd, J=1.4, 6.6 Hz), 7.16 (1H, d,
J=7.8 Hz), 7.6-7.42 (2H, m), 7.81 (1H, dd, J=2.1, 6.8 Hz).
[3732] MS: m/z=628 [M+H].sup.+.
Example 116
##STR01116##
[3734] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, d, J=7.2 Hz),
2.15 (3H, s), 4.26 (1H, d, J=13.9 Hz), 4.45 (1H, d, J=12.9 Hz),
4.92 (1H, d, J=13.3 Hz), 5.24 (1H, s), 5.45 (1H, dd, J=13.8, 1.9
Hz), 5.53-5.63 (1H, m), 5.89 (1H, d, J=6.4 Hz), 5.95 (1H, d, J=6.4
Hz), 6.01 (1H, d, J=7.7 Hz), 6.84-7.34 (7H, m).
[3735] MS: m/z=612 [M+H].sup.+.
Example 117
##STR01117##
[3737] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.17 (3H, d, J=7.2 Hz),
2.10 (3H, s), 4.11 (1H, d, J=13.6 Hz), 4.42 (1H, d, J=13.1 Hz),
4.89 (1H, d, J=13.0 Hz), 5.13 (1H, s), 5.33 (1H, dd, J=13.6, 2.2
Hz), 5.55 (1H, m), 5.84-5.94 (3H, m), 6.81-7.25 (8H, m).
Example 118
##STR01118##
[3739] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=7.3 Hz),
2.11 (3H, s), 3.56 (1H, d, J=13.6 Hz), 4.42 (1H, d, J=13.0 Hz),
4.88 (1H, d, J=13.4 Hz), 5.10 (1H, s), 5.55 (1H, m), 5.67 (1H, d,
J=13.4 Hz), 5.85-5.94 (3H, m), 6.81-7.26 (8H, m).
[3740] MS: m/z=578 [M+H].sup.+.
Example 119
##STR01119##
[3742] MS: m/z=592 [M+H].sup.+.
Example 120
##STR01120##
[3744] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (3H, d, 6.1 Hz), 2.10
(3H, s), 3.60 (1H, d, 13.4 Hz), 4.42 (1H, d, J=13.0 Hz), 4.87 (1H,
d, J=13.1 Hz), 5.07 (1H, s), 5.48-5.64 (2H, m), 5.85-5.97 (3H, m),
6.80-6.89 (2H, m), 7.05-7.44 (7H, m).
[3745] MS: m/z=560 [M+H].sup.+.
Example 121
##STR01121##
[3747] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, 7.3 Hz), 2.10
(3H, s), 4.31 (1H, d, 13.9 Hz), 4.42 (1H, d, J=13.3 Hz), 4.88 (1H,
d, J=12.8 Hz), 5.12 (1H, s), 5.50-5.62 (2H, m), 5.84-5.94 (3H, m),
6.80-6.91 (2H, m), 7.07-7.22 (5H, m), 7.52 (1H, d, J=7.6 Hz).
[3748] MS: m/z=594 [M+H].sup.+.
Example 122
##STR01122##
[3750] To an aqueous (1.0 mL) suspension of compound 122-a (50 mg,
0.10 mmol) and potassium carbonate (138 mg, 0.22 mmol) were added
tetrabutylammonium hydrogen sulfate (34 mg, 0.10 mmol) and
dichloromethane (0.5 ml), and the mixture was stirred at room
temperature for 10 minutes. To the reaction solution was added a
dichloromethane (0.5 ml) solution of iodomethyl 2-methoxyethyl
carbonate (57 mg, 0.22 mmol), and the mixture was further stirred
for 2 hours. Thereafter, to the reaction solution was added water,
the dichloromethane layer was separated, and the aqueous layer was
extracted with dichloromethane once. The combined extracts were
washed with an aqueous saturated sodium chloride solution and
brine, and then sodium sulfide was added to dry them. The solvent
was distilled off, and the resulting oil was purified by silica gel
column chromatography. The materials were eluted firstly with
chloroform and, then, with chloroform-methanol (94:6, v/v). An
objective fraction was concentrated, and washed using
hexane-diethyl ether to obtain 39 mg of compound of Example 122 as
a white solid.
[3751] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, d, J=7.2 Hz),
3.38 (3H, s), 3.58-3.69 (3H, m), 4.28-4.44 (3H, m), 4.87 (1H, d,
J=13.0 Hz), 5.09 (1H, s), 5.51-5.66 (2H, m), 5.90-5.96 (3H, m),
6.84-7.44 (9H, m).
[3752] MS: m/z=620 [M+H].sup.+.
Example 123
##STR01123##
[3754] According to Example 122, compound of Example 123 was
synthesized by the same procedure.
[3755] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.32 (3H, d, J=7.3 Hz),
3.39 (3H, s), 3.59 (1H, d, J=13.3 Hz), 3.68-3.71 (2H, m), 4.39 (2H,
dt, J=7.22, 2.14 Hz), 4.53 (1H, d, J=12.7 Hz), 4.92 (1H, d, J=12.7
Hz), 5.23-5.36 (2H, m), 5.67 (1H, d, J=13.2 Hz), 5.84 (1H, d, J=6.4
Hz), 5.92 (1H, d, J=6.5 Hz), 5.95 (1H, d, J=7.8 Hz), 6.83-7.41 (9H,
m).
[3756] MS: m/z=620 [M+H].sup.+.
Example 124
##STR01124##
[3758] According to Example 122, compound of Example 124 was
synthesized by the same procedure.
[3759] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (3H, d, J=7.3 Hz),
3.60 (1H, d, J=13.4 Hz), 3.75 (2H, t, J=4.4 Hz), 4.33-4.42 (3H, m),
4.57 (2H, s), 4.85 (1H, d, J=13.6 Hz), 5.07 (1H, s), 5.46-5.64 (2H,
m), 5.90-5.96 (3H, m), 6.82-6.88 (2H, m), 7.06-7.43 (12H, m).
[3760] MS: m/z=696 [M+H].sup.+.
Example 125
##STR01125##
[3762] According to Example 122, compound of Example 125 was
synthesized by the same procedure.
[3763] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14 (3H, d, J=7.2 Hz),
3.61 (1H, d, J=13.4 Hz), 3.83 (3H, s), 4.42 (1H, d, J=13.2 Hz),
4.87 (1H, d, J=13.0 Hz), 5.08 (1H, s), 5.48-5.65 (2H, m), 5.87 (1H,
d, J=6.5 Hz), 5.94 (1H, d, J=6.2 Hz), 5.96 (1H, d, J=4.8 Hz),
6.79-6.85 (2H, m), 7.05-7.44 (7H, m).
[3764] MS: m/z=576 [M+H].sup.+.
Example 126
##STR01126##
[3766] According to Example 122, compound of Example 126 was
synthesized by the same procedure.
[3767] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (3H, d, 6.0 Hz), 3.36
(3H, s), 3.52-3.79 (7H, m), 4.31-4.44 (3H, m), 4.87 (1H, d, J=13.0
Hz), 5.09 (1H, s), 5.50-5.73 (2H, m), 5.89-5.98 (3H, m), 6.81-6.88
(2H, m), 7.05-7.45 (7H, m).
[3768] MS: m/z=664 [M+H].sup.+.
Example 127
##STR01127##
[3770] According to Example 122, compound of Example 127 was
synthesized by the same procedure.
[3771] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, d, 7.2 Hz), 3.37
(1H, s), 3.62-3.69 (2H, m), 4.29-4.43 (4H, m), 4.88 (1H, d, J=13.6
Hz), 5.14 (1H, s), 5.50-5.63 (2H, m), 5.90-5.96 (3H, m), 6.82-6.89
(2H, m), 7.05-7.24 (5H, m), 7.52 (1H, d, J=7.9 Hz).
[3772] MS: m/z=654 [M+H].sup.+.
Example 128
##STR01128##
[3774] According to Example 122, compound of Example 128 was
synthesized by the same procedure.
[3775] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, d, 7.2 Hz), 3.83
(3H, s), 4.31 (1H, d, J=13.9 Hz), 4.42 (1H, d, J=13.1 Hz), 4.89
(1H, d, J=13.4 Hz), 5.12 (1H, s), 5.49-5.61 (2H, m), 5.87 (1H, d,
J=6.5 Hz), 5.93-5.97 (2H, m), 6.77-6.89 (2H, m), 7.09-7.24 (5H, m),
7.52 (1H, d, J=8.2 Hz).
[3776] MS: m/z=610 [M+H].sup.+.
Example 129
##STR01129##
[3778] According to Example 122, compound of Example 129 was
synthesized by the same procedure.
[3779] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (3H, d, 7.3 Hz), 3.77
(3H, s), 4.31 (1H, d, J=14.0 Hz), 4.43 (1H, d, J=13.3 Hz),
4.60-4.70 (2H, m), 4.85-4.93 (2H, m), 5.31 (1H, s), 5.56-5.66 (2H,
m), 5.93-6.01 (3H, m), 6.86-6.92 (2H, m), 7.08-7.51 (5H, m), 7.52
(1H, d, J=7.8 Hz).
[3780] MS: m/z=668 [M+H].sup.+.
Example 130
##STR01130##
[3782] According to Example 122, compound of Example 130 was
synthesized by the same procedure.
[3783] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16-1.37 (3H, m),
2.77-2.87 (1H, m), 3.04-3.15 (1H, m), 3.41-3.53 (1H, m), 3.83-3.89
(3H, m), 4.24-4.42 (2H, m), 4.70-4.82 (1H, m), 5.02-5.45 (2H, m),
5.82-5.99 (3H, m), 6.72-7.35 (9H, m).
[3784] MS: m/z=558 [M+H].sup.+.
Example 131
##STR01131##
[3786] According to Example 122, compound of Example 131 was
synthesized by the same procedure.
[3787] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.17 (3H, d, 7.2 Hz), 3.65
(1H, d, J=13.4 Hz), 3.83 (3H, s), 4.41 (1H, d, 13.3 Hz), 4.88 (1H,
d, J=13.4 Hz), 5.17 (1H, s), 5.47-5.57 (1H, m), 5.68 (1H, d, J=13.4
Hz), 5.87 (1H, d, J=6.6 Hz), 5.95-6.00 (2H, m), 6.65 (1H, d, J=7.3
Hz), 6.83-6.99 (3H, m), 7.01-7.20 (3H, m).
[3788] MS: m/z=612 [M+H].sup.+.
Example 132
##STR01132##
[3790] According to Example 122, compound of Example 132 was
synthesized by the same procedure.
[3791] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (3H, d, 7.2 Hz), 3.62
(1H, d, J=13.3 Hz), 3.83 (3H, s), 4.40 (1H, d, 12.9 Hz), 4.86 (1H,
d, J=12.7 Hz), 5.06 (1H, s), 5.48-5.62 (2H, m), 5.88 (1H, d, J=6.5
Hz), 5.97 (1H, d, J=6.6 Hz), 6.02 (1H, d, J=7.8 Hz), 6.75-6.85 (2H,
m), 7.08-7.43 (6H, m).
[3792] MS: m/z=610 [M+H].sup.+.
Example 133
##STR01133##
[3794] According to Example 122, compound of Example 133 was
synthesized by the same procedure.
[3795] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (3H, d, 7.1 Hz), 3.68
(1H, d, J=13.4 Hz), 3.84 (3H, s), 4.43 (1H, d, 13.5 Hz), 4.88 (1H,
d, J=12.8 Hz), 5.16 (1H, s), 5.47-5.64 (2H, m), 5.90 (1H, d, J=6.4
Hz), 5.95-5.99 (2H, m), 7.00 (1H, d, J=7.7 Hz), 7.11-7.49 (8H,
m).
[3796] MS: m/z=644 [M+H].sup.+.
Example 134
##STR01134##
[3798] According to Example 122, compound of Example 134 was
synthesized by the same procedure.
[3799] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19-1.35 (3H, m),
2.77-2.89 (1H, m), 3.04-3.14 (1H, m), 3.37-3.51 (1H, m), 3.83-3.89
(3H, m), 4.27-4.41 (2H, m), 4.71-4.82 (1H, m), 5.03-5.52 (2H, m),
5.89-6.00 (3H, m), 6.68-7.19 (7H, m).
[3800] MS: m/z=594 [M+H].sup.+.
Example 135
##STR01135##
[3802] According to Example 122, compound of Example 135 was
synthesized by the same procedure.
[3803] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, 7.4 Hz), 3.83
(3H, s), 4.37-4.43 (2H, m), 4.89 (1H, d, J=12.9 Hz), 5.19 (1H, s),
5.49-5.64 (2H, m), 5.87 (1H, d, J=6.5 Hz), 5.95-6.00 (2H, m), 6.65
(1H, d, J=7.3 Hz), 7.07-7.25 (4H, m), 7.54 (1H, d, J=7.0 Hz).
[3804] MS: m/z=628 [M+H].sup.+.
Example 136
##STR01136##
[3806] According to Example 122, compound of Example 136 was
synthesized by the same procedure.
[3807] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (3H, d, 7.0 Hz), 3.61
(1H, d, J=13.7 Hz), 3.83 (3H, s), 4.40 (1H, d, J=13.0 Hz), 4.86
(1H, d, J=13.5 Hz), 5.08 (1H, s), 5.49-5.65 (2H, m), 5.88 (1H, d,
J=6.5 Hz), 5.95-6.02 (2H, m), 6.53-6.60 (1H, m), 6.79-6.84 (2H, m),
7.14-7.43 (5H, m).
[3808] MS: m/z=594 [M+H].sup.+.
Example 137
##STR01137##
[3810] According to Example 122, compound of Example 137 was
synthesized by the same procedure.
[3811] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08 (3H, d, 7.2 Hz), 3.38
(3H, s), 3.60-3.68 (3H, m), 4.28-4.39 (3H, m), 4.85 (1H, d, J=13.0
Hz), 5.48-5.57 (1H, m), 5.65 (1H, d, J=13.6 Hz), 5.87-5.98 (4H, m),
6.87-6.96 (2H, m), 7.07-7.17 (3H, m), 7.25-7.34 (3H, m).
[3812] MS: m/z=654 [M+H].sup.+.
Example 138
##STR01138##
[3814] According to Example 122, compound of Example 138 was
synthesized by the same procedure.
[3815] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, 7.4 Hz), 1.81
(2H, brs), 2.02 (2H, brs), 3.54-3.62 (2H, m), 3.91-3.99 (3H, m),
4.31 (1H, d, J=13.7 Hz), 4.42 (1H, d, J=12.9 Hz), 4.86-4.92 (2H,
m), 5.11 (1H, s), 5.45-5.61 (2H, m), 5.90-5.95 (3H, m), 6.71-6.87
(2H, m), 7.03-7.25 (5H, m), 7.52 (1H, d, J=6.9 Hz).
[3816] MS: m/z=680 [M+H].sup.+.
Example 139
##STR01139##
[3818] According to Example 122, compound of Example 139 was
synthesized by the same procedure.
[3819] MS: m/z=720 [M+H].sup.+.
Example 140
##STR01140##
[3821] Compound of Example 140 was obtained as a by-product of
Example 139.
[3822] MS: m/z=606 [M+H].sup.+.
Example 141
##STR01141##
[3824] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=7.2 Hz),
3.84 (3H, s), 3.99 (1H, d, J=14.7 Hz), 4.39 (1H, d, J=13.2 Hz),
4.92 (1H, d, J=13.2 Hz), 5.23 (1H, s), 5.55 (1H, m), 5.8-6.0 (4H,
m), 6.7-7.0 (2H, m), 7.0-7.3 (3H, m), 7.3-7.5 (2H, m), 7.81 (1H,
dd, J=6.3 Hz, J=2.7 Hz)
[3825] MS: m/z=644 [M+H].sup.+.
Example 142
##STR01142##
[3827] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=7.5 Hz),
3.85 (3H, s), 4.24 (1H, d, J=13.8 Hz), 4.43 (1H, d, J=13.2 Hz),
4.91 (1H, d, J=13.2 Hz), 5.23 (1H, s), 5.43 (1H, d, J=13.8 Hz),
5.54 (1H, m), 5.8-6.1 (3H, m), 6.7-7.1 (3H, m), 7.1-7.4 (4H, m)
[3828] MS: m/z=628 [M+H].sup.+.
Example 143
##STR01143##
[3830] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.17 (3H, d, J=7.5 Hz),
2.25 (3H, s), 3.83 (3H, s), 4.21 (1H, d, J=13.8 Hz), 4.43 (1H, d,
J=13.5 Hz), 4.90 (1H, d, J=13.5 Hz), 5.17 (1H, s), 5.37 (1H, d,
J=15.6 Hz), 5.53 (1H, m), 5.8-6.0 (3H, m), 6.6-6.8 (2H, m), 6.9-7.1
(2H, m), 7.1-7.3 (3H, m)
[3831] MS: m/z=608 [M+H].sup.+.
Example 144
##STR01144##
[3833] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=6.9 Hz),
3.84 (3H, s), 4.12 (1H, d, J=13.8 Hz), 4.42 (1H, d, J=13.2 Hz),
4.90 (1H, d, J=13.2 Hz), 5.14 (1H, s), 5.34 (1H, d, J=13.8 Hz),
5.54 (1H, m), 5.8-6.0 (3H, m), 6.7-6.9 (2H, m), 6.9-7.1 (3H, m),
7.1-7.3 (3H, m)
[3834] MS: m/z=594 [M+H].sup.+.
Example 145
##STR01145##
[3836] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=7.5 Hz),
3.56 (1H, d, J=13.5 Hz), 3.84 (3H, s), 4.42 (1H, d, J=13.2 Hz),
4.89 (1H, d, J=13.2 Hz), 5.10 (1H, s), 5.53 (1H, m), 5.66 (1H, d,
J=13.5 Hz), 5.8-6.0 (3H, m), 6.7-7.0 (3H, m), 7.0-7.3 (5H, m)
[3837] MS: m/z=594 [M+H].sup.+.
Example 146
##STR01146##
[3839] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08 (3H, d, J=7.2 Hz),
3.63 (1H, d, J=12.6 Hz), 3.83 (3H, s), 4.39 (1H, d, J=13.2 Hz),
4.86 (1H, d, J=13.2 Hz), 5.23 (1H, m), 5.65 (1H, d, J=13.5 Hz),
5.8-6.0 (4H, m), 6.8-7.0 (2H, m), 7.0-7.2 (3H, m), 7.2-7.4 (3H,
m)
[3840] MS: m/z=610 [M+H].sup.+.
Example 147
##STR01147##
[3842] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (3H, d, J=6.0 Hz),
1.34 (3H, t, J=7.1 Hz), 3.65 (1H, m), 4.29 (3H, m), 4.42 (1H, d,
J=13.5 Hz), 4.90 (1H, d, J=13.5 Hz), 5.13 (1H, s), 5.58 (2H, m),
5.92 (3H, m), 6.82 (2H, m), 7.00-7.26 (5H, m), 7.53 (1H, d, J=8.4
Hz).
[3843] MS: m/z=624.15 [M].sup.+.
Example 148
##STR01148##
[3845] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=7.2 Hz),
1.34 (3H, t, J=6.3 Hz), 1.35 (3H, t, J=6.3 Hz), 4.32 (1H, d, J=13.7
Hz), 4.42 (1H, d, J=13.1 Hz), 4.89 (1H, d, J=13.1 Hz), 4.96 (1H,
m), 5.13 (1H, s), 5.54 (1H, m), 5.60 (1H, d, J=13.7 Hz), 5.87 (1H,
d, J=6.8 Hz), 5.95 (2H, d, J=6.9 Hz), 6.85 (2H, m), 7.06-7.26 (5H,
m), 7.53 (1H, d, J=6.8 Hz).
[3846] MS: m/z=638.15 [M].sup.+.
Example 149
##STR01149##
[3848] MS: m/z=628.35 [M].sup.+.
Example 150
##STR01150##
[3850] MS: m/z=594.15 [M].sup.+.
Example 151
##STR01151##
[3852] According to Example 122, compound 151-a was synthesized by
the same procedure.
[3853] To an ethyl acetate (2.0 mL) solution of compound 151-a (67
mg, 0.093 mmol) was added a 4N HCl ethyl acetate solution (2.0 ml),
and the mixture was stirred at room temperature overnight.
Thereafter, to the reaction solution were added ethyl acetate and
water, the ethyl acetate layer was separated, and the aqueous layer
was extracted with ethyl acetate two times. To the combined
extracts was added sodium sulfide, and the mixture was dried, then
the solvent was distilled off. To the resulting oil was added
diisopropyl ether, and the precipitated solid was filtered to
obtain 12 mg of compound of Example 151 as a white solid.
[3854] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.24 (3H, d, 6.8 Hz), 2.80
(2H, brs), 4.31 (1H, d, J=13.7 Hz), 4.40-4.51 (3H, m), 4.86 (2H,
m), 4.86 (1H, d, 13.1 Hz), 5.21 (1H, s), 5.53-5.62 (2H, m),
5.83-5.93 (3H, m), 6.75-6.86 (2H, m), 7.09-7.25 (5H, m), 7.48 (1H,
d, J=9.0 Hz).
[3855] MS: m/z=668 [M+H].sup.+.
Example 152
##STR01152##
[3857] Compound 98-a (43 mg, 0.29 mmol) and silver(I) oxide (44 mg,
0.10 mmol) were added to an acetonitrile (1.5 mL) solution of
1-chloroethyl methyl carbonate (166 mg, 0.96 mmol), and the mixture
was stirred at 50.degree. C. for 4 hours, and then allowed to stand
at room temperature overnight. Thereafter, the reaction solution
was filtered with celite, the solvent was distilled off, and the
resulting oil was purified by silica gel column chromatography. The
materials were eluted firstly with chloroform and, then, with
chloroform-methanol (95:5, v/v). An objective fraction was
concentrated, and washed using hexane-diisopropyl ether to obtain
54 mg of compound of Example 152 as a white solid.
[3858] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14-1.16 (3H, m),
1.82-1.85 (3H, m), 3.66-3.83 (3H, m), 4.27-4.43 (2H, m), 4.82-4.91
(1H, m), 5.10-5.12 (1H, m), 5.54-5.62 (2H, m), 5.89-5.93 (1H, m),
6.52-6.56 (1H, m), 6.75-6.98 (2H, m), 7.07-7.21 (5H, m), 7.52 (1H,
d, J=8.1 Hz).
[3859] MS: m/z=624 [M+H].sup.+.
Example 153
##STR01153##
[3861] According to Example 152, compound of Example 153 was
synthesized by the same procedure.
[3862] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14-1.16 (3H, m),
1.21-1.41 (3H, m), 1.84 (3H, d, J=5.1 Hz), 4.02-4.43 (4H, m),
4.83-4.89 (1H, m), 5.09-5.11 (1H, m), 5.54-5.61 (2H, m), 5.88-5.92
(1H, m), 6.48-6.55 (1H, m), 6.75-7.21 (7H, m), 7.51 (1H, d, J=8.2
Hz).
[3863] MS: m/z=638 [M+H].sup.+.
Example 154
##STR01154##
[3865] According to Example 152, compound of Example 154 was
synthesized by the same procedure.
[3866] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10-1.43 (9H, m), 1.83
(3H, d, J=5.3 Hz), 4.27-4.43 (2H, m), 4.67-4.90 (2H, m), 5.08-5.12
(1H, m), 5.54-5.60 (2H, m), 5.86-5.91 (1H, m), 6.43-6.57 (1H, m),
6.71-7.20 (7H, m), 7.51 (1H, d, J=8.1 Hz).
[3867] MS: m/z=652 [M+H].sup.+.
Example 155
##STR01155##
[3869] According to Example 152, compound of Example 155 was
synthesized by the same procedure.
[3870] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12-1.15 (3H, m),
1.82-1.85 (3H, m), 3.66-3.84 (3H, m), 4.08-4.14 (1H, m), 4.37-4.44
(1H, m), 4.82-4.92 (1H, m), 5.12-5.14 (1H, m), 5.28-5.32 (1H, m),
5.52-5.60 (1H, m), 5.89-5.93 (1H, m), 6.51-6.55 (1H, m), 6.77-7.24
(8H, m).
[3871] MS: m/z=608 [M+H].sup.+.
Example 156
##STR01156##
[3873] According to Example 152, compound of Example 156 was
synthesized by the same procedure.
[3874] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10-1.14 (3H, m),
1.82-1.84 (3H, m), 3.65-3.83 (3H, m), 4.17-4.23 (1H, m), 4.36-4.42
(1H, m), 4.82-4.90 (1H, m), 5.17-5.19 (1H, m), 5.35-5.58 (2H, m),
5.92-5.96 (1H, m), 6.49-6.53 (1H, m), 6.71-7.14 (4H, m), 7.21-7.29
(3H, m).
[3875] MS: m/z=642 [M+H].sup.+.
Example 157
##STR01157##
[3877] According to Example 152, compound of Example 157 was
synthesized by the same procedure.
[3878] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12-1.15 (3H, m),
1.82-1.85 (3H, m), 3.51-3.55 (1H, m), 3.66-3.83 (3H, m), 4.37-4.43
(1H, m), 4.81-4.89 (1H, m), 5.07-5.09 (1H, m), 5.53-5.68 (2H, m),
5.88-5.91 (1H, m), 6.51-6.56 (1H, m), 6.76-7.00 (3H, m), 7.06-7.18
(5H, m).
[3879] MS: m/z=608 [M+H].sup.+.
Example 158
##STR01158##
[3881] According to Example 152, compound of Example 158 was
synthesized by the same procedure.
[3882] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10-1.14 (3H, m),
1.81-1.84 (3H, m), 2.24-2.25 (3H, m), 3.65-3.83 (3H, m), 4.17-4.23
(1H, m), 4.38-4.43 (1H, m), 4.82-4.90 (1H, m), 5.14-5.16 (1H, m),
5.31-5.38 (1H, m), 5.51-5.60 (1H, m), 5.86-5.90 (1H, m), 6.51-6.56
(1H, m), 6.65-7.23 (7H, m).
[3883] MS: m/z=622 [M+H].sup.+.
Example 159
##STR01159##
[3885] According to Example 152, compound of Example 159 was
synthesized by the same procedure.
[3886] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10-1.16 (3H, m),
1.63-2.02 (7H, m), 3.44-4.04 (4H, m), 4.27-4.44 (2H, m), 4.62-4.90
(2H, m), 5.05-5.13 (1H, m), 5.49-5.61 (2H, m), 5.87-5.91 (1H, m),
6.44-6.58 (1H, m), 6.78-7.26 (7H, m), 7.53 (1H, d, J=7.8 Hz).
[3887] MS: m/z=694 [M+H].sup.+.
Example 160
##STR01160##
[3889] According to Example 152, compound of Example 160 was
synthesized by the same procedure.
[3890] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12-1.15 (3H, m),
1.82-1.85 (3H, m), 3.66-3.84 (3H, m), 3.94-4.00 (1H, m), 4.33-4.39
(1H, m), 4.84-4.92 (1H, m), 5.20-5.21 (1H, m), 5.52-5.62 (1H, m),
5.80-5.93 (2H, m), 6.51-6.56 (1H, m), 6.71-7.14 (5H, m), 7.36-7.38
(2H, m), 7.78-7.81 (1H, m).
[3891] MS: m/z=658 [M+H].sup.+.
Example 161
##STR01161##
[3893] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.05 (6H, m), 1.19-1.27
(3H, m), 1.34-1.45 (3H, m), 1.82-1.87 (3H, m), 2.80 (1H, ddd, J=4.2
Hz, 4.2 Hz, 13.8 Hz), 4.02-3.14 (1H, m), 3.43-3.52 (1H, m),
4.15-4.21 (1H, m), 4.25-4.38 (1H, m), 4.59-4.77 (2H, m), 5.05 (1H,
d, J=11.7 Hz), 5.76-5.81 (1H, m), 6.45-6.51 (1H, m), 6.64-6.67 (1H,
m), 6.79 (0.5H, d, J=7.5 Hz), 6.90-7.35 (6.5H, m).
Example 162
##STR01162##
[3895] According to Example 152, compound of Example 162 was
synthesized by the same procedure.
[3896] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (3H, d, 7.3 Hz), 1.84
(3H, d, 5.2 Hz), 3.60 (1H, d, 13.5 Hz), 3.65 (3H, s), 4.41 (1H, d,
J=13.0 Hz), 4.87 (1H, d, J=12.7 Hz), 5.06 (1H, s), 5.52-5.62 (2H,
m), 5.91 (1H, d, J=7.8 Hz), 6.53 (1H, q, J=5.3), 6.76-6.84 (2H, m),
7.06-7.43 (7H, m).
[3897] MS: m/z=590 [M+H].sup.+.
Example 163
##STR01163##
[3899] According to Example 122, compound 163-a was synthesized by
the same procedure.
[3900] To an acetonitrile (1.0 mL) solution of compound 163-a (70
mg, 0.10 mmol) and potassium carbonate (138 mg, 0.22 mmol) were
added 2-morpholinoethanamine (31 mg, 0.24 mmol), DMAP (13 mg, 0.10
mmol) and triethylamine (0.042 ml, 0.30 mmol), and the mixture was
stirred at room temperature overnight. Thereafter, to the reaction
solution was added water, the dichloromethane layer was separated,
and the aqueous layer was extracted with dichloromethane once. The
combined extracts were washed with an aqueous saturated sodium
chloride solution and brine, and then sodium sulfide was added to
dry them. The solvent was distilled off, and the resulting oil was
purified by silica gel column chromatography. The materials were
eluted firstly with chloroform and, then, with chloroform-methanol
(94:6, v/v). An objective fraction was concentrated, and washed
using diisopropyl ether to obtain 26 mg of compound of Example 163
as a yellowish-white solid.
[3901] MS: m/z=674 [M+H].sup.+.
Example 164
##STR01164##
[3903] According to Example 163, compound of Example 164 was
synthesized by the same procedure.
[3904] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (3H, d, 7.0 Hz),
1.33-1.36 (6H, m), 3.61 (1H, d, J=13.4 Hz), 4.42 (1H, d, J=13.3
Hz), 4.85-4.99 (2H, m), 5.08 (1H, s), 5.49-5.64 (2H, m), 5.86 (1H,
d, J=6.4 Hz), 5.93-5.97 (2H, m), 6.82-6.88 (2H, m), 7.05-7.44 (7H,
m).
[3905] MS: m/z=604 [M+H].sup.+.
Example 165
##STR01165##
[3907] According to Example 163, compound of Example 165 was
synthesized by the same procedure.
[3908] MS: m/z=675 [M+H].sup.+.
Example 166
##STR01166##
[3910] According to Example 163, compound of Example 166 was
synthesized by the same procedure.
[3911] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (3H, d, 7.3 Hz), 2.78
(3H, d, J=5.0), 3.60 (1H, d, J=13.1 Hz), 4.42 (1H, d, J=13.3 Hz),
4.78 (1H, brs), 4.87 (1H, d, J=12.9 Hz), 5.09 (1H, s), 5.54-5.64
(2H, m), 5.84-5.94 (3H, m), 6.83-6.89 (2H, m), 7.07-7.44 (7H,
m).
[3912] MS: m/z=575 [M+H].sup.+.
Example 167
##STR01167##
[3914] According to Example 163, compound of Example 167 was
synthesized by the same procedure.
[3915] MS: m/z=675 [M+H].sup.+.
Example 168
##STR01168##
[3917] According to Example 163, compound of Example 168 was
synthesized by the same procedure.
[3918] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (3H, d, 7.4 Hz),
3.35-3.38 (5H, m), 3.46 (2H, t, J=5.1 Hz), 3.60 (1H, d, J=13.4 Hz),
4.42 (1H, d, J=13.1), 4.87 (1H, d, J=12.4 Hz), 5.09-5.16 (2H, m),
5.87-5.94 (3H, m), 6.81-6.89 (2H, m), 7.05-7.45 (7H, m).
[3919] MS: m/z=619 [M+H].sup.+.
Example 169
##STR01169##
[3921] According to Example 163, compound of Example 169 was
synthesized by the same procedure.
[3922] MS: m/z=673 [M+H].sup.+.
Example 170
##STR01170##
[3924] According to Example 163, compound of Example 170 was
synthesized by the same procedure.
[3925] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12 (3H, d, 7.3 Hz),
3.48-3.77 (9H, m), 4.42 (1H, d, J=13.4 Hz), 4.87 (1H, d, J=13.4),
5.07 (1H, s), 5.49-5.63 (2H, m), 5.91-5.94 (3H, m), 6.84-6.86 (2H,
m), 7.06-7.45 (7H, m).
[3926] MS: m/z=631 [M+H].sup.+.
Example 171
##STR01171##
[3928] According to Example 163, compound of Example 171 was
synthesized by the same procedure.
[3929] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.17 (3H, d, 7.3 Hz), 4.31
(1H, d, J=13.9 Hz), 4.42 (1H, d, J=13.2 Hz), 4.72 (2H, brs), 4.89
(1H, d, J=12.8 Hz), 5.14 (1H, s), 5.55-5.62 (2H, m), 5.87 (2H, s),
5.94 (1H, d, J=7.8 Hz), 6.81-6.89 (2H, m), 7.07-7.21 (5H, m), 7.52
(1H, d, J=7.1 Hz).
[3930] MS: m/z=595 [M+H].sup.+.
Example 172
##STR01172##
[3932] According to Example 163, compound of Example 172 was
synthesized by the same procedure.
[3933] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (3H, d, 7.8 Hz), 2.89
(3H, s), 2.95 (3H, s), 4.31 (1H, d, J=14.0 Hz), 4.41 (1H, d, J=13.5
Hz), 4.89 (1H, d, J=13.3 Hz), 5.13 (1H, s), 5.52-5.61 (2H, m),
5.85-5.96 (3H, m), 6.83-6.88 (2H, m), 7.07-7.22 (5H, m), 7.52 (1H,
d, J=7.0 Hz).
[3934] MS: m/z=623 [M+H].sup.+.
Example 173
##STR01173##
[3936] According to Example 163, compound of Example 173 was
synthesized by the same procedure.
[3937] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33 (3H, d, 7.4 Hz),
3.37-3.62 (8H, m), 4.52 (1H, d, J=12.4 Hz), 4.92 (1H, d, J=12.4
Hz), 5.23-5.30 (3H, m), 5.65 (1H, d, 13.0 Hz), 5.80-5.95 (3H, m),
6.84-6.91 (2H, m), 7.03-7.09 (2H, m), 7.18-7.41 (5H, m).
[3938] MS: m/z=619 [M+H].sup.+.
Example 174
##STR01174##
[3940] According to Example 163, compound of Example 174 was
synthesized by the same procedure.
[3941] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38 (3H, d, 7.2 Hz), 2.92
(1H, d, 4.5 Hz), 3.10 (1H, d, 4.5 Hz), 3.45 (2H, brs), 4.34 (1H, d,
J=14.3 Hz), 4.52-4.57 (2H, m), 4.90 (1H, d, J=13.8 Hz), 5.10 (1H,
brs), 5.52-5.60 (3H, m), 5.75 (1H, d, J=6.9 Hz), 6.02 (1H, d, J=6.8
Hz), 6.85-6.96 (3H, m), 7.07-7.28 (3H, m), 7.50-7.57 (2H, m), 7.73
(1H, d, J=7.4 Hz).
[3942] MS: m/z=667 [M+H].sup.+.
Example 175
##STR01175##
[3944] According to Example 163, compound of Example 175 was
synthesized by the same procedure.
[3945] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (3H, d, 7.3 Hz), 2.01
(3H, s), 3.19-3.45 (4H, m), 4.32 (1H, d, 14.0 Hz), 4.46 (1H, d,
J=13.2 Hz), 4.90 (1H, d, J=13.1 Hz), 5.17-5.19 (2H, m), 5.53-5.68
(3H, m), 5.89-5.97 (2H, m), 6.87-6.95 (2H, m), 7.08-7.26 (5H, m),
7.54 (1H, d, J=7.8 Hz).
[3946] MS: m/z=680 [M+H].sup.+.
Example 176
##STR01176##
[3948] According to Example 163, compound of Example 176 was
synthesized by the same procedure.
[3949] MS: m/z=666 [M+H].sup.+.
Example 177
##STR01177##
[3951] According to Example 163, compound 177-a was synthesized by
the same procedure.
[3952] To an ethyl acetate solution (2.0 mL) solution of compound
177-a (129 mg, 0.17 mmol) was added a 4N HCl ethyl acetate solution
(2.0 ml), and the mixture was stirred at room temperature for 30
minutes. Thereafter, to the reaction solution was added water, the
ethyl acetate layer was separated, and the aqueous layer was
extracted with ethyl acetate two times. The combined extracts were
washed with an aqueous saturated sodium chloride solution and
brine, and then sodium sulfide was added to dry them. The solvent
was distilled off, and the resulting oil was purified by silica gel
column chromatography. The materials were eluted firstly with
chloroform and, then, with chloroform-methanol (94:6, v/v). An
objective fraction was concentrated, and washed using diisopropyl
ether to obtain 10 mg of compound of Example 177 as a pale pink
solid.
[3953] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, d, 7.2 Hz), 3.61
(1H, d, 13.4 Hz), 3.92 (2H, brs), 4.30-4.51 (3H, m), 4.86 (1H, d,
J=12.8), 5.09 (1H, s), 5.44-5.62 (2H, m), 5.86 (1H, d, J=6.6 Hz),
5.94-5.97 (2H, m), 6.88-6.90 (2H, m), 7.08-7.44 (7H, m).
[3954] MS: m/z=606 [M+H].sup.+.
Example 178
##STR01178##
[3956] According to Example 163, compound 178-a was synthesized by
the same procedure.
[3957] To an ethyl acetate solution (1.0 mL) solution of compound
178-a (81 mg, 0.11 mmol) was added a 4N HCl ethyl acetate solution
(1.0 ml), and the mixture was stirred at room temperature for 1
hour and 30 minutes. A solid precipitated from the reaction
solution was filtered, and washed with diisopropyl ether to obtain
54 mg of compound of Example 178 as a white solid.
[3958] MS: m/z=638 [M+H].sup.+.
Example 179
##STR01179##
[3960] A DMF (1 ml) solution of compound 179-a (50 mg, 0.120 mmol)
and triethylamine (61 mg, 0.60 mmol) was cooled to 1 to 3.degree.
C., and ethyl chloroformate (26 mg, 0.24 mmol) was added dropwise
while the same temperature was retained. After the reaction
solution was stirred at room temperature for 30 minutes, water was
added, and the mixture was extracted with ethyl acetate three
times. The extract was washed with water three times, and dried
with sodium sulfate, then the solvent was distilled off. The
resulting solid was washed with ethyl-diisopropyl ether to obtain
24 mg of compound of Example 179.
[3961] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.11 (3H, d, J=6.9 Hz),
1.12 (3H, d, J=6.9 Hz), 1.44 (3H, t, J=6.9 Hz), 2.82 (1H, ddd,
J=4.5 Hz, 4.5 Hz, 14.1 Hz), 3.09 (1H, ddd, J=3.9H, 13.5 Hz, 13.5
Hz), 3.49 (1H, ddd, J=4.2 Hz, 4.2 Hz, 17.4 Hz), 4.24 (1H, d, 13.2
Hz), 4.29-4.43 (2H, m), 4.40 (1H, d, J=7.2 Hz), 4.66-4.77 (1H, m),
4.69 (1H, d, J=12.9 Hz), 5.10 (1H, s), 5.87 (1H, d, J=8.1 Hz), 6.77
(1H, d, J=7.8 Hz), 6.79-6.82 (1H, m), 6.98 (1H, t, J=7.2 Hz),
7.07-7.37 (6H, m).
[3962] According to Example 179, the following compounds of
Examples were synthesized by the same procedure.
Example 180
##STR01180##
[3964] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (3H, d, J=7.2 Hz),
3.98 (3H, s), 4.31 (1H, d, J=13.8 Hz), 4.46 (1H, d, J=13.2 Hz),
4.93 (1H, d, J=13.2 Hz), 5.16 (1H, s), 5.48-5.57 (1H, m), 5.60 (1H,
d, J=14.1 Hz), 5.99 (1H, d, J=7.8 Hz), 6.23-6.93 (2H, m), 7.07-7.25
(6H, m), 7.51-7.54 (1H, m).
Example 181
##STR01181##
[3966] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (3H, d, J=7.2 Hz),
3.45 (3H, s), 3.74 (2H, t, J=5.1 Hz), 4.31 (1H, d, J=13.8 Hz),
4.43-4.48 (3H, m), 4.93 (1H, d, J=13.2 Hz), 5.16 (1H, s), 5.48-5.57
(1H, m), 5.60 (1H, d, J=14.1 Hz), 5.98 (1H, d, J=7.8 Hz), 6.82-6.92
(2H, m), 7.06-7.12 (3H, m), 7.14-7.25 (2H, m), 7.52 (1H, d, J=8.1
Hz).
Example 182
##STR01182##
[3968] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22 (3H, d, J=7.2 Hz),
4.31 (1H, d, J=13.8 Hz), 4.48 (1H, d, J=13.2 Hz), 4.95 (1H, d,
J=13.2 Hz), 5.17 (1H, s), 5.53-5.63 (2H, m), 6.02 (1H, d, J=7.8
Hz), 6.83-6.88 (2H, m), 7.06-7.13 (3H, m), 7.17-7.39 (3H, m),
7.41-7.51 (4H, m), 7.51-7.55 (1H, m).
Example 183
##STR01183##
[3970] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.04 (6H, d, J=6.6 Hz),
1.19 (3H, d, J=7.2 Hz), 2.08-2.17 (1H, m), 4.11 (2H, d, J=6.6 Hz),
4.31 (1H, d, J=13.8 Hz), 4.46 (1H, d, J=13.5 Hz), 4.93 (1H, d,
J=12.9 Hz), 5.16 (1H, s), 5.48-5.62 (2H, m), 5.98 (1H, d, J=8.1
Hz), 6.82-6.92 (2H, m), 7.07-7.26 (5H, m), 7.51-7.55 (1H, m).
Example 184
##STR01184##
[3972] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, d, J=7.2 Hz),
1.60 (9H, s), 4.31 (1H, d, J=13.8 Hz), 4.45 (1H, d, J=13.2 Hz),
4.92 (1H, d, J=13.2 Hz), 5.17 (1H, s), 5.48-5.63 (2H, m), 5.97 (1H,
d, J=7.5 Hz), 6.81-6.92 (2H, m), 7.07-7.14 (3H, m), 7.17-7.22 (2H,
m), 7.12-7.54 (1H, m).
Example 185
##STR01185##
[3974] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.01 (6H, t, J=7.17 Hz),
1.31 (3H, t, J=7.09 Hz), 3.88 (1H, d, J=13.27 Hz), 4.20-4.30 (3H,
m), 4.61 (1H, t, J=6.71 Hz), 5.00 (1H, d, J=13.42 Hz), 5.32 (1H,
s), 5.65 (1H, d, J=13.27 Hz), 5.87 (1H, d, J=7.78 Hz), 6.82-6.93
(2H, m), 7.06-7.15 (2H, m), 7.22-7.50 (5H, m).
[3975] MS: m/z=505.95 [M+H].sup.+.
Example 186
##STR01186##
[3977] According to the method shown in Journal of Medicinal
Chemistry; English; 39; 2; 1996; 480-486, to a DMF (1 ml) solution
of compound 98-a (50 mg, 0.0958 mmol) and triethylamine (48 mg,
0.48 mmol) were added (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl
4-nitrophenyl carbonate (85 mg, 0.29 mmol) and DMAP (1.2 mg, 0.096
mmol) at room temperature, and the mixture was stirred at the same
temperature for 6 hours. The reaction solution was diluted with
ethyl acetate (10 ml), and water was added. The organic layer was
separated, and the aqueous layer was extracted with ethyl acetate
once. The extract was washed with water three times, and dried with
sodium sulfate, and the solvent was distilled off. The resulting
crude product was purified by silica gel column chromatography. The
materials were eluted firstly with ethyl acetate and, then, with
ethyl acetate-methanol (4:1, v/v). Concentration of an objective
fraction afforded 31 mg of compound of Example 186 as a solid.
[3978] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (3H, d, J=7.2 Hz),
2.27 (3H, s), 4.33 (1H, d, J=14.1 Hz), 4.47 (1H, d, J=13.5 Hz),
4.91 (2H, d, J=13.2 Hz), 5.18 (1H, d, J=17.7 Hz), 5.21 (1H, s),
5.38-5.49 (1H, m), 5.58 (1H, d, J=13.8 Hz), 6.01 (1H, d, J=7.8 Hz),
6.83-6.89 (2H, m), 7.08-7.15 (2H, m), 7.18-7.27 (3H, m), 7.51-7.54
(1H, m).
[3979] According to Example 186, the following compounds were
synthesized by the same procedure.
Example 187
##STR01187##
[3981] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (3H, d, J=7.2 Hz),
1.87-2.01 (2H, m), 2.06-2.17 (2H, m), 3.57-3.64 (2H, m), 3.98-4.04
(2H, m), 4.32 (1H, d, J=14.1 Hz), 4.46 (1H, d, J=13.2 Hz),
4.92-5.02 (2H, m), 5.16 (1H, s), 5.46-5.58 (1H, m), 6.60 (1H, d,
J=14.1 Hz), 5.99 (1H, d, J=8.1 Hz), 6.81-6.93 (2H, m), 7.08-7.28
(4H, m), 7.54 (1H, d, J=6.6 Hz).
Example 188
##STR01188##
[3983] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.12-1.27 (12H, m),
3.55-3.66 (5H, m), 3.73-3.79 (4H, m), 4.31 (1H, d, J=13.8 Hz), 4.45
(1H, d, J=13.2 Hz), 4.93 (1H, d, J=13.2 Hz), 5.03-5.06 (1H, m),
5.16 (1H, s), 5.46-5.62 (2H, m), 5.95-6.00 (1H, m), 6.85-6.92 (2H,
m), 7.07-7.26 (5H, m), 7.53 (1H, d, J=7.8 Hz).
Example 189
##STR01189##
[3985] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, d, J=7.2 Hz),
2.94 (3H, s), 4.32 (1H, d, J=13.8 Hz), 4.46 (1H, d, J=13.2 Hz),
4.93 (1H, d, J=13.8 Hz), 5.16 (1H, s), 5.51-5.62 (2H, m), 5.98 (1H,
d, J=7.8 Hz), 6.82-6.84 (1H, m), 6.88-6.93 (1H, m), 7.07-7.12 (3H,
m), 7.14-7.26 (3H, m), 7.51-7.54 (1H, m).
Example 190
##STR01190##
[3987] Compound 106-a (80.0 mg, 0.185 mmol) was dissolved in
dichloromethane (1 ml), triethylamine (0.051 ml, 0.37 mmol),
dimethylcarbamic chloride (39.7 mg, 0.369 mmol), and DMAP (cat.)
were added, and the mixture was stirred at 50.degree. C. for 3
hours. To the reaction solution was added water, the mixture was
extracted with ethyl acetate, and the organic layer was washed with
water, and dried with sodium sulfate. The solvent was distilled off
under reduced pressure, and the resulting crude product was
purified by silica gel column chromatography, and eluted with
chloroform-methanol (97:3, v/v). Dichloromethane-ethyl
acetate-diethyl ether were added, and the mixture was solidified to
obtain 47 mg of compound of Example 190 as a white solid.
[3988] MS: m/z=505 [M+H].sup.+.
Example 191
##STR01191##
[3990] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.17 (3H, d, J=7.2 Hz),
2.96 (3H, d, J=5.1 Hz), 4.30 (1H, d, J=13.8 Hz), 4.45 (1H, d,
J=13.2 Hz), 4.92 (1H, d, J=12.9 Hz), 5.20 (1H s), 5.29-5.30 (1H,
m), 5.48-5.58 (1H, m), 5.60 (1H, d, J=13.8 Hz), 5.96 (1H, d, J=13.8
Hz), 6.91-6.92 (2H, m), 7.06-7.21 (5H, m), 7.50-7.53 (1H, m).
Example 192
##STR01192##
[3991] First Step
[3992] According to the method described in Chem. Pharm. Bull. 55,
328-333 (2007), compound 192-b was synthesized.
Second Step
[3993] To a pyridine (1 mL) solution of compound 192-b (78.0 mg,
0.273 mmol) was added compound 98-a (51.0 mg, 0.098 mmol), and the
mixture was stirred at room temperature for 1.5 hours, at
50.degree. C. for 3 hours, and 70.degree. C. for 7 hours. The
reaction solution was diluted with ethyl acetate (10 mL), the
mixture was washed with water (5 mL) and hydrochloric acid (2M, 5
mL), and the organic layer was dried with sodium sulfate. The
solvent was distilled off under reduced pressure, and the resulting
crude product of compound 192-c was used in a next reaction without
purification.
Third Step
[3994] To an ethanol (0.5 mL) solution of the crude product of
compound 192-c obtained in the second step was added concentrated
hydrochloric acid (0.050 ml) at room temperature, and the mixture
was stirred for 2 hours. To the reaction solution was added water
(20 mL), and the mixture was extracted with chloroform, then the
organic layer was dried with sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (ethyl
acetate/n-hexane=80%-100%), and the resulting product was converted
into a powder with ethyl acetate-ethyl ether to obtain compound of
Example 192 (39.7 mg, 65%) as a white solid.
[3995] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.17 (3H, d, J=6.9 Hz),
3.02-3.70 (5H, m), 3.80-4.25 (4H, m), 4.32 (1H, m), 4.47 (1H, d,
J=13.2 Hz), 4.94 (1H, m), 5.18 (1H, m), 5.30 (1H, m), 5.60 (1H, d,
J=13.8 Hz), 5.97 (1H, m), 6.75-7.25 (5H, m), 7.52 (1H, d, J=7.8
Hz).
[3996] MS: m/z=623.15 [M].sup.+.
Example 193
##STR01193##
[3998] According to Example 192, compound of Example 193 was
synthesized by the same procedure.
[3999] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.17 (3H, d, J=8.1 Hz),
1.80-2.20 (4H, m), 3.50-4.20 (6H, m), 4.20-4.80 (3H, m), 4.92 (1H,
m), 5.19 (1H, m), 5.56 (1H, m), 5.61 (1H, d, J=14.1 Hz), 5.97 (1H,
d, J=8.4 Hz), 6.60-7.26 (5H, m), 7.53 (1H, d, J=8.4 Hz).
[4000] MS: m/z=649.20 [M].sup.+.
Example 194
##STR01194##
[4002] To a pyridine (1.0 mL) solution of compound 98-a (50 mg,
0.10 mmol) was added morpholine-4-carbonyl chloride (43 mg, 0.29
mmol), and the mixture was stirred at 50.degree. C. for 10 hours.
Thereafter, to the reaction solution were added an aqueous 2N HCl
solution and ethyl acetate, the ethyl acetate layer was separated,
and the aqueous layer was extracted with ethyl acetate. To the
combined extracts was added sodium sulfide to dry them, then the
solvent was distilled off, and the resulting oil was purified by
silica gel column chromatography. The materials were eluted firstly
with chloroform and, then, with chloroform-methanol (97:3, v/v). An
objective fraction was concentrated, and washed using diisopropyl
ether to obtain 49 mg of compound of Example 194 as a white
solid.
[4003] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, d, 7.1 Hz),
3.60-3.81 (8H, m), 4.30 (1H, d, J=14.3 Hz), 4.44 (1H, d, J=13.3
Hz), 4.89 (1H, d, J=14.8 Hz), 5.19 (1H, s), 5.48-5.62 (2H, m), 5.93
(1H, d, J=7.4 Hz), 6.95-7.24 (7H, m), 7.52 (1H, d, J=7.5 Hz).
[4004] MS: m/z=635 [M+H].sup.+.
Example 195
##STR01195##
[4006] According to Example 194, compound of Example 195 was
synthesized by the same procedure.
[4007] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.15 (3H, d, 6.5 Hz),
2.97-3.18 (6H, m), 4.29 (1H, d, J=13.73 Hz), 4.44 (1H, d, J=13.3
Hz), 4.89 (1H, d, J=13.5 Hz), 5.21 (1H, brs), 5.47-5.62 (2H, m),
5.94 (1H, brs), 6.97-7.24 (7H, m), 7.51 (1H, d, J=7.9 Hz).
[4008] MS: m/z=593 [M+H].sup.+.
Example 196, Example 196-b
##STR01196##
[4009] First Step
[4010] Compound 106-a (140 mg, 0.323 mmol) was dissolved in DMF (2
mL), and a DMF (1.0 ml) solution of potassium carbonate (89 mg,
0.646 mmol) and dibenzyl chloromethyl phosphate (158 mg, 0.484
mmol) were added at 0.degree. C. under nitrogen stream. The
reaction mixed solution was stirred at room temperature for 1 week,
and water was added. The mixture was extracted with ethyl acetate
(2.times.20 mL), and the combined organic layers were washed with
water and an aqueous saturated sodium chloride solution, and dried
with sodium sulfate, then filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (chloroform-methanol=50:1) to obtain compound of
Example 196-b.
[4011] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.01 (6H, dd, J=8.90, 6.88
Hz), 3.58 (1H, d, J=13.09 Hz), 4.21 (1H, d, J=13.09 Hz), 4.61-4.73
(2H, m), 5.01-5.10 (5H, m), 5.63 (1H, d, J=13.26 Hz), 5.77 (1H, dd,
J=13.26, 5.37 Hz), 5.87-5.95 (2H, m), 6.81-6.85 (2H, m), 7.02-7.08
(2H, m), 7.13-7.42 (15H, m).
Second Step
[4012] Compound 196-b (60 mg, 0.083 mmol) was dissolved in a mixed
solvent of THF (2 mL) and methanol (2 mL), and 10%-palladium-carbon
(10 mg) was added. Under hydrogen stream, the mixture was stirred
at room temperature for 2 hours, and filtered with celite. The
filtrate was purified by preparative HPLC to obtain objective
compound of Example 196. (18 mg, 40%)
[4013] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.01 (6H, dd, J=14.64,
6.86 Hz), 3.90 (1H, d, J=13.27 Hz), 4.32 (1H, d, J=13.57 Hz),
4.59-4.71 (1H, m), 5.01 (1H, d, J=13.42 Hz), 5.43-5.62 (4H, m),
6.17 (1H, d, J=7.63 Hz), 6.80-6.89 (1H, m), 6.91-6.99 (1H, m),
7.07-7.14 (2H, m), 7.27 (1H, t, J=6.63 Hz), 7.38-7.52 (4H, m).
Example 197, Example 197-b
##STR01197##
[4014] First Step
[4015] To an acetone (3 ml) solution of (S)-chloromethyl
2-(tert-butoxycarbonylamino)-3-d cesium carbonate (138 mg, 0.519
mmol) was added sodium iodide (390 mg, 2.6 mmol) at room
temperature under nitrogen stream, and the mixture was stirred for
20 hours. After filtration, the filtrate was concentrated under
reduced pressure, a 10%-aqueous sodium thiosulfate solution was
added to the residue, and the mixture was extracted with ethyl
acetate (30 mL). The organic layer was washed with water, dried
with sodium sulfate, and filtered, then concentrated under reduced
pressure. The residue was dissolved in acetone (0.5 mL), compound
106-a (100 mg, 0.231 mmol) and cesium carbonate (169 mg, 0.52 mmol)
were added to the mixture stirred for 30 minutes in acetone (2.5
ml) under nitrogen stream under ice-cooling. This reaction mixture
was stirred at room temperature for 4 hours, and concentrated under
reduced pressure, and then water was added. The mixture was
extracted with ethyl acetate (2.times.30 mL), and the combined
organic layers were washed with water and an aqueous saturated
sodium chloride solution, and dried with sodium sulfate, then
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography
(chloroform-methanol=50:1) to obtain compound of Example 197-b.
(130 mg, 85%)
[4016] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.90-1.11 (12H, m), 1.44
(9H, d, J=9.00 Hz), 2.20-2.41 (1H, m), 3.59 (1H, d, J=13.27 Hz),
4.27-4.43 (2H, m), 4.76-4.86 (2H, m), 5.10-5.29 (2H, m), 5.68 (1H,
dd, J=13.27, 2.44 Hz), 5.81-6.17 (3H, m), 6.80-6.94 (2H, m),
7.03-7.15 (2H, m), 7.20-7.44 (5H, m).
[4017] MS: m/z=668.05 [M+H].sup.+.
Second Step
[4018] Compound 197-b (130 mg, 0.196 mmol) was dissolved in ethyl
acetate (4 ml), a 4N hydrochloric acid ethyl acetate solution (4
ml, 16.00 mmol) was added at room temperature, and the mixture was
stirred for 3 hours. After concentration under reduced pressure,
the residue was diluted with ether, and the solid was filtered to
obtain hydrochloride of compound of Example 197. (85 mg, 72.3%)
[4019] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.96-1.05 (11H, m),
2.22-2.28 (1H, m), 3.90 (2H, d, J=12.36 Hz), 4.28 (1H, d, J=13.73
Hz), 4.55-4.65 (1H, m), 4.90-4.99 (1H, m), 5.30 (1H, d, J=7.42 Hz),
5.63 (1H, d, J=13.46 Hz), 5.86-5.89 (4H, m), 6.87-6.96 (2H, m),
7.07-7.16 (2H, m), 7.27-7.32 (2H, m), 7.44-7.49 (3H, m), 8.42 (3H,
s).
[4020] MS: m/z=563.25 [M+H].sup.+.
Example 198
##STR01198##
[4022] According to Example 197, compound of Example 198 was
synthesized by the same procedure.
[4023] MS: m/z=651 [M+H].sup.+.
Example 199
##STR01199##
[4025] A DMF (1 ml) solution of compound 106-a (33 mg, 0.076 mmol)
and triethylamine (24 mg, 0.235 mmol) was cooled to 1 to 3.degree.
C., and chloromethyl methyl ether (12.6 mg, 0.157 mmol) was added
dropwise while the same temperature was retained. After the
reaction solution was stirred at the same temperature for 30
minutes, water was added, and the mixture was extracted with ethyl
acetate three times. The extract was washed with water three times,
and dried with sodium sulfate, then the solvent was distilled off.
The resulting solid was washed with ethyl-diisopropyl ether to
obtain 22 mg of compound of Example 199.
[4026] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.08 (3H, d, J=7.2 Hz),
1.11 (3H, d, J=7.2 Hz), 3.59 (1H, d, J=13.2 Hz), 3.64 (3H, s), 4.32
(1H, d, J=12.9 Hz), 4.77-4.85 (2H, m), 5.14 (1H, s), 5.32 (1H, d,
J=6.0 Hz), 5.50 (1H, d, J=6.0 Hz), 5.70 (1H, d, J=13.2 Hz), 5.90
(1H, d, J=6.9 Hz), 6.77-6.84 (2H, m), 7.05-7.07 (2H, m), 7.18-7.28
(3H, m), 7.33-7.43 (2H, m).
Example 200
##STR01200##
[4028] A DMF (1 ml) solution of 4-(hydroxymethyl)phenyl acetate (53
mg, 0.287 mmol) and sodium iodide (72 mg, 0.48 mmol) was stirred at
room temperature for 30 minutes. To the reaction solution were
added potassium carbonate (66 mg, 0.48 mmol) and compound 98-a (50
mg, 0.0958 mmol), and the mixture was further stirred at the same
temperature for 5 hours. The reaction solution was diluted with
ethyl acetate (10 ml), and water was added. The organic layer was
separated, and the aqueous layer was extracted with ethyl acetate
once. The extract was washed with water three times, and dried with
sodium sulfate, and the solvent was distilled off. The resulting
crude product was purified by silica gel column chromatography. The
materials were eluted firstly with ethyl acetate and, then, with
ethyl acetate-methanol (7:3, v/v). Concentration of an objective
fraction afforded 34 mg of compound of Example 200 as a solid.
[4029] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (3H, d, J=7.2 Hz),
2.28 (3H, s), 4.29 (1H, d, J=13.8 Hz), 4.38 (1H, d, J=13.2 Hz),
4.81 (1H, d, J=12.9 Hz), 5.08 (1H, s), 5.45 (1H, d, J=10.8 Hz),
5.52-5.61 (2H, m), 5.87 (1H, d, J=7.5 Hz), 6.57 (1H, d, J=7.5 Hz),
6.73-6.79 (1H, m), 7.04-7.20 (7H, m), 7.51 (1H, d, J=7.2 Hz), 7.57
(2H, d, J=8.4 Hz).
Example 201
##STR01201##
[4030] First Step
[4031] Compound 106-a (80.0 mg, 0.185 mmol) synthesized according
to Example and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (41.1 mg,
0.277 mmol) were dissolved in DMF (1 ml), potassium carbonate (93.0
mg, 0.673 mmol) was added, and the mixture was stirred at
50.degree. C. for 2 hours. To the reaction solution was added
water, the mixture was extracted with ethyl acetate, and the
organic layer was washed with water, and dried with sodium sulfate.
The solvent was distilled off under reduced pressure, and the
resulting crude product was purified by silica gel column
chromatography, and eluted with chloroform-methanol (95:5, v/v).
Dichloromethane-diethyl ether were added, and the mixture was
solidified to obtain 60 mg of compound of Example 201 as a white
solid.
[4032] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.00 (6H, s), 2.10 (3H,
s), 3.89 (1H, d, J=13.1 Hz), 4.25 (1H, d, J=12.7 Hz), 4.59 (1H, m),
4.90-5.04 (3H, m), 5.27 (1H, s), 5.62 (1H, d, J=13.3 Hz), 5.83 (1H,
d, J=4.9 Hz), 6.91-7.44 (9H, m).
[4033] MS: m/z=546 [M+H].sup.+.
Example 202
##STR01202##
[4035] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18 (3H, d, J=7.2 Hz),
2.18 (3H, s), 4.33 (1H, d, J=13.8 Hz), 4.43 (1H, d, J=13.2 Hz),
4.86 (1H, d, J=13.5 Hz), 5.15 (1H, d, J=13.5 Hz), 5.17 (1H, s),
5.35 (1H, d, J=13.8 Hz), 5.48-5.59 (2H, m), 5.94 (1H, d, J=13.8
Hz), 6.77 (1H, d, J=7.5 Hz), 6.86-6.91 (1H, m), 7.07-7.26 (5H, m),
7.50-7.53 (1H, m).
Example 203
##STR01203##
[4037] A DMF (1.0 mL) solution of compound 98-a (50 mg, 0.10 mmol)
was ice-cooled, and triethylamine (0.040 ml, 0.29 mmol) and
1-(chloromethoxy)-2-methoxyethane (24 mg, 0.19 mmol) were added,
and the mixture was stirred for 1 hour under ice-cooling, then
stirred at room temperature overnight. Thereafter, to the reaction
solution were added water and ethyl acetate, the ethyl acetate
layer was separated, and the aqueous layer was extracted with ethyl
acetate. The combined extracts were washed with water and brine,
and then sodium sulfide was added to dry them. The solvent was
distilled off, and the resulting oil was purified by silica gel
column chromatography. The materials were eluted firstly with
chloroform and, then, with chloroform-methanol (97:3, v/v). An
objective fraction was concentrated, and washed using diisopropyl
ether to obtain 18 mg of compound of Example 203 as a white
solid.
[4038] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, d, 7.6 Hz), 3.36
(3H, s), 3.51-3.55 (2H, m), 3.93-4.00 (2H, m), 4.32 (1H, d, 14.2
Hz), 4.43 (1H, d, J=13.3 Hz), 4.88 (1H, d, J=12.8 Hz), 5.14 (1H,
s), 5.55-5.66 (3H, m), 5.90 (1H, d, J=7.8 Hz), 6.73-6.85 (2H, m),
7.09-7.22 (5H, m), 7.53 (1H, d, J=8.9 Hz).
[4039] MS: m/z=610 [M+H].sup.+.
Example 204
##STR01204##
[4041] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.06 (3H, d, J=7.1 Hz),
1.09 (3H, d, J=7.1 Hz), 2.43 (3H, s), 3.59 (1H, d, J=13.5 Hz), 4.34
(1H, d, J=13.2 Hz), 4.70-4.86 (2H, m), 5.14 (1H, s), 5.70 (1H, d,
J=13.5 Hz), 5.94 (1H, d, J=7.7 Hz), 6.81-6.92 (2H, m), 7.03-7.08
(2H, m), 7.15-7.26 (3H, m), 7.32-7.44 (2H, m).
[4042] MS: m/z=476 [M+H].sup.+.
Example 205
##STR01205##
[4044] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.02-1.15 (9H, m), 1.39
(3H, d, J=6.9 Hz), 1.58-1.72 (1H, m), 1.90-2.05 (1H, m), 2.71-2.84
(1H, m), 3.59 (1H, d, J=13.2 Hz), 4.34 (1H, d, J=12.9 Hz),
4.69-4.90 (2H, m), 5.15 (1H, s), 5.70 (1H, d, J=12.9 Hz), 5.86-5.98
(1H, m), 6.76-6.99 (2H, m), 7.04-7.10 (2H, m), 7.15-7.29 (3H, m),
7.32-7.44 (2H, m).
[4045] MS: m/z=518 [M+H].sup.+.
Example 206
##STR01206##
[4047] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.41 (3H, s), 3.58 (1H, d,
J=13.5 Hz), 4.41-4.87 (6H, m), 5.07 (1H, d, J=13.2 Hz), 5.26 (1H,
s), 5.65 (1H, d, J=13.5 Hz), 5.97 (1H, d, J=7.7 Hz), 6.80-6.92 (2H,
m), 7.04-7.10 (2H, m), 7.25-7.45 (5H, m).
[4048] MS: m/z=512 [M+H].sup.+.
Example 207
##STR01207##
[4050] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20 (3H, d, J=7.3 Hz),
2.44 (3H, s), 4.32 (1H, d, J=13.9 Hz), 4.46 (1H, d, J=13.3 Hz),
4.93 (1H, d, J=13.3 Hz), 5.16 (1H, s), 5.45-5.58 (1H, m), 5.61 (1H,
d, J=13.9 Hz), 5.97 (1H, d, J=7.9 Hz), 6.80-6.94 (2H, m), 7.05-7.13
(3H, m), 7.15-7.24 (2H, m), 7.53 (1H, d, J=7.8 Hz).
[4051] MS: m/z=564 [M+H].sup.+.
Example 208
##STR01208##
[4053] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.13 (3H, d, J=7.3 Hz),
3.63 (1H, d, J=13.4 Hz), 4.48 (1H, d, J=13.1 Hz), 4.95 (1H, d,
J=13.0 Hz), 5.17 (1H, s), 5.44-5.58 (1H, m), 5.65 (1H, d, J=13.0
Hz), 6.02 (1H, d, J=7.9 Hz), 6.90-7.61 (12H, m).
[4054] MS: m/z=628 [M+H].sup.+.
Example 209
##STR01209##
[4056] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.16 (3H, d, J=7.4 Hz),
1.99-2.15 (4H, m), 2.93-3.06 (1H, m), 3.47-3.58 (2H, m), 4.01-4.16
(3H, m), 4.45 (1H, d, J=13.2 Hz), 4.93 (1H, d, J=13.5 Hz), 5.18
(1H, s), 5.35 (1H, d, J=14.0 Hz), 5.43-5.56 (1H, m), 5.95 (1H, d,
J=7.7 Hz), 6.82-7.02 (3H, m), 7.06-7.15 (2H, m), 7.19-7.26 (3H,
m).
[4057] MS: m/z=618 [M+H].sup.+.
Example 210
##STR01210##
[4058] Step
[4059] To compound 210-a (101 mg, 0.193 mmol) were added
dimethylformamide (1 mL), HATU (50 mg, 0.148 mmol) and
N-methylmorpholine (0.041 mL, 0.370 mmol), and the mixture was
stirred at room temperature for 6 hours. The reaction solution was
purified by preparative LCMS (method 14) to obtain compound of
Example 210 (50 mg, yield 51%).
[4060] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 7.53 (s, 1H), 7.47 (s,
3H), 7.20 (s, 2H), 6.99 (s, 1H), 6.87 (s, 1H), 6.17 (s, 1H), 5.83
(s, 1H), 5.61 (d, J=13.0 Hz, 1H), 5.50 (s, 1H), 5.24 (d, J=13.0 Hz,
1H), 4.67 (d, J=13.0 Hz, 1H), 4.04 (d, J=11.0 Hz, 1H), 3.10 (s,
6H), 3.05 (s, 6H), 1.09 (s, 3H).
[4061] MS: m/z=620 [M+H].sup.+. RT=1.73 min.
Example 211
##STR01211##
[4063] MS: m/z=645 [M+H].sup.+. RT=2.53 min.
Example 212
##STR01212##
[4065] MS: m/z=662 [M+H].sup.+. RT=2.35 min.
Example 213
##STR01213##
[4067] MS: m/z=590 [M+H].sup.+. RT=2.17 min.
Example 214
##STR01214##
[4069] MS: m/z=712 [M+H].sup.+. RT=2.52 min.
Example 215
##STR01215##
[4071] MS: m/z=618 [M+H].sup.+. RT=2.56 min.
Example 216
##STR01216##
[4073] MS: m/z=654 [M+H].sup.+. RT=2.71 min.
Example 217
##STR01217##
[4075] MS: m/z=645 [M+H].sup.+. RT=2.35 min.
Example 218
##STR01218##
[4077] MS: m/z=590 [M+H].sup.+. RT=2.19 min.
Example 219
##STR01219##
[4079] MS: m/z=608 [M+H].sup.+. RT=2.17 min.
Example 220
##STR01220##
[4081] MS: m/z=578 [M+H].sup.+. RT=2.23 min.
Example 221
##STR01221##
[4083] MS: m/z=648 [M+H].sup.+. RT=2.24 min.
Example 222
##STR01222##
[4085] MS: m/z=592 [M+H].sup.+. RT=2.38 min.
Example 223
##STR01223##
[4087] MS: m/z=606 [M+H].sup.+. RT=2.10 min.
Example 224
##STR01224##
[4089] MS: m/z=592 [M+H].sup.+. RT=2.38 min.
Example 225
##STR01225##
[4091] MS: m/z=526 [M+H].sup.+. RT=2.27 min.
Example 226
##STR01226##
[4093] MS: m/z=626 [M+H].sup.+. RT=2.38 min.
Example 227
##STR01227##
[4095] MS: m/z=632 [M+H].sup.+. RT=2.69 min.
Example 228
##STR01228##
[4097] MS: m/z=576.11 [M+H].sup.+.
Example 229
##STR01229##
[4099] MS: m/z=643.88 [M+H].sup.+.
Example 230
##STR01230##
[4101] MS: m/z=636.88 [M+H].sup.+.
Example 231
##STR01231##
[4103] MS: m/z=681.26 [M+H].sup.+.
Example 232
##STR01232##
[4105] MS: m/z=735.19 [M+H].sup.+.
Example 233
##STR01233##
[4106] Example 234
##STR01234##
[4108] MS: m/z=731.19 [M+H].sup.+.
Example 235
##STR01235##
[4110] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09 (d, J=7.2 Hz, 3H),
3.65 (d, J=13.8 Hz, 1H), 3.82 (s, 3H), 4.39 (d, J=13.2 Hz, 1H),
4.87 (d, J=13.2 Hz, 1H), 5.52 (m, 1H), 5.63 (d, J=13.8 Hz, 1H),
5.88 (d, J=6.6 Hz, 1H), 5.94 (s, 1H), 6.00 (d, J=6.6 Hz, 1H),
6.88-6.98 (m, 2H), 7.14-7.19 (m, 2H), 7.27-7.38 (m, 3H), 7.52 (s,
1H).
[4111] MS: m/z=644.2 [M+H].sup.+.
Example 236
##STR01236##
[4113] MS: m/z=654 [M+H].sup.+.
Example 237
##STR01237##
[4115] MS: m/z=654 [M+H].sup.+.
Example 238
##STR01238##
[4117] MS: m/z=564.15 [M+H].sup.+.
Example 239
##STR01239##
[4119] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.09 (d, J=7.1 Hz, 3H),
3.55 (s, 3H), 3.63 (d, J=13.5 Hz, 1H), 4.40 (d, J=13.2 Hz, 1H),
4.87 (d, J=13.2 Hz, 1H), 5.26 (d, J=6.0 Hz, 1H), 5.51-5.70 (m, 3H),
5.89-5.95 (m, 2H), 6.84-6.89 (m, 2H), 7.07-7.20 (m, 3H), 7.26-7.37
(m, 3H).
Example 240
##STR01240##
[4121] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.10 (d, J=7.1 Hz, 3H),
2.48 (s, 3H), 3.63 (d, J=13.5 Hz, 1H), 3.83 (s, 3H), 4.41 (d,
J=13.2 Hz, 1H), 4.87 (d, J=13.2 Hz, 1H), 5.47-5.58 (m, 1H), 5.68
(d, J=13.5 Hz, 1H), 5.87 (d, J=6.6 Hz, 1H), 5.93 (s, 1H), 6.01 (d,
J=6.6 Hz, 1H), 6.84-6.91 (m, 1H), 6.95 (d, J=7.4 Hz, 1H), 7.05-7.15
(m, 2H), 7.25-7.38 (m, 3H), 7.93 (s, 1H).
Example 241
##STR01241##
[4123] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.21 (d, J=7.1 Hz, 3H),
3.83 (s, 3H), 4.11 (d, J=13.7 Hz, 1H), 4.42 (d, J=13.2 Hz, 1H),
4.91 (d, J=13.2 Hz, 1H), 5.13 (s, 1H), 5.40 (dd, J=13.7, 2.6 Hz,
1H), 5.49-5.59 (m, 1H), 5.87 (d, J=6.6 Hz, 1H), 5.93-5.96 (m, 2H),
6.79 (d, J=7.4 Hz, 1H), 6.84-6.91 (m, 1H), 6.97 (dd, J=8.7, 4.3 Hz,
1H), 7.04-7.15 (m, 3H), 7.26 (d, J=4.7 Hz, 1H).
[4124] LCMS measurement conditions of compounds of Reference
examples and Examples are described below.
1) Conditions for the Case where not Specifically Stated;
Column: ACQUITY UPLC(R)BEH C18 (1.7 .mu.m i.d. 2.1.times.50 mm)
(Waters)
[4125] Flow rate: 0.8 mL/min. UV detection wavelength: 254 nm
Mobile phase: an aqueous solution containing 0.1% formic acid for
[A], an acetonitrile solution containing 0.1% formic acid for [B]
Gradient: a linear gradient of 10% to 100% solvent [B] was
performed over 3.5 minutes, and 100% solvent [B] was retained for
0.5 minutes.
2) Method 6;
Column: Gemini-NX (5 .mu.m, i.d. 4.6.times.50 mm) (Phenomenex)
[4126] Flow rate: 3 mL/min. UV detection wavelength: 254 nm Mobile
phase: an aqueous solution containing 0.1% formic acid for [A], an
acetonitrile solution containing 0.1% formic acid for [B] Gradient:
a linear gradient of 5% to 100% solvent [B] was performed over 3.5
minutes, and 100% solvent [B] was retained for 0.5 minutes.
3) Method 14;
[4127] Column: Gemini-NX (C18, 5 .mu.m, AXIA Packed, i.d.
21.2.times.50 mm) (Phenomenex) Flow rate: 25 mL/min. UV detection
wavelength: 254 nm Mobile phase: an aqueous solution containing
0.1% formic acid for [A], an acetonitrile solution containing 0.1%
formic acid for [B]
Gradient:
[4128] Narrow Gradient (6 min): a linear gradient of X % to Y %
solvent [B] was performed over 4 minutes, and 100% solvent [B] was
retained for 1 minute.
[4129] Intermediate compound i-7: X=35, Y=55
[4130] Intermediate compound i-10: X=30, Y=50
[4131] Intermediate compound i-14: X=30, Y=50
[4132] Example 210: X=20, Y=40
Standard Gradient (7 min): a linear gradient of 10% to 100% solvent
[B] was performed over 5 minutes, and 100% solvent [B] was retained
for 1 minute.
[4133] Further, the following combinations of substituents can be
also synthesized by the method described in the above Reference
examples and Examples, and are a preferable embodiment of the
present invention.
[4134] Compounds in which, in the following formula (I):
##STR01242##
combinations of R.sup.3a and R.sup.7a of the following formulae
(I-A) and (I-B):
##STR01243##
[4135] (wherein P.sup.R is same as that of item 1)
[4136] are selected from the following Tables 15 to 20,
respectively.
Combinations of (R.sup.3a, R.sup.7a) (R3-1, R7-1), (R3-1, R7-2),
(R3-1, R7-3), (R3-1, R7-4), (R3-1, R7-5), (R3-1, R7-6), (R3-1,
R7-7), (R3-1, R7-8), (R3-1, R7-9), (R3-1, R7-10), (R3-1, R7-11),
(R3-1, R7-12), (R3-1, R7-13), (R3-1, R7-14), (R3-1, R7-15), (R3-1,
R7-16), (R3-1, R7-17), (R3-1, R7-18), (R3-1, R7-19), (R3-1, R7-20),
(R3-1, R7-21), (R3-1, R7-22), (R3-1, R7-23), (R3-1, R7-24), (R3-1,
R7-25), (R3-1, R7-26), (R3-1, R7-27), (R3-1, R7-28), (R3-1, R7-29),
(R3-1, R7-30), (R3-1, R7-31), (R3-1, R7-32), (R3-1, R7-33), (R3-1,
R7-34), (R3-1, R7-35), (R3-1, R7-36), (R3-1, R7-37), (R3-1, R7-38),
(R3-1, R7-39), (R3-1, R7-40), (R3-1, R7-41), (R3-1, R7-42), (R3-1,
R7-43), (R3-1, R7-44), (R3-1, R7-45), (R3-1, R7-46), (R3-1, R7-47),
(R3-1, R7-48), (R3-1, R7-49), (R3-1, R7-50), (R3-1, R7-51), (R3-1,
R7-52), (R3-1, R7-53), (R3-1, R7-54), (R3-1, R7-55), (R3-1, R7-56),
(R3-1, R7-57), (R3-1, R7-58), (R3-1, R7-59), (R3-1, R7-60), (R3-1,
R7-61), (R3-1, R7-62), (R3-1, R7-63), (R3-1, R7-64), (R3-1, R7-65),
(R3-1, R7-66), (R3-1, R7-67), (R3-1, R7-68), (R3-1, R7-69), (R3-1,
R7-70), (R3-1, R7-71), (R3-1, R7-72), (R3-1, R7-73), (R3-1, R7-74),
(R3-1, R7-75), (R3-1, R7-76), (R3-1, R7-77), (R3-2, R7-1), (R3-2,
R7-2), (R3-2, R7-3), (R3-2, R7-4), (R3-2, R7-5), (R3-2, R7-6),
(R3-2, R7-7), (R3-2, R7-8), (R3-2, R7-9), (R3-2, R7-10), (R3-2,
R7-11), (R3-2, R7-12), (R3-2, R7-13), (R3-2, R7-14), (R3-2, R7-15),
(R3-2, R7-16), (R3-2, R7-17), (R3-2, R7-18), (R3-2, R7-19), (R3-2,
R7-20), (R3-2, R7-21), (R3-2, R7-22), (R3-2, R7-23), (R3-2, R7-24),
(R3-2, R7-25), (R3-2, R7-26), (R3-2, R7-27), (R3-2, R7-28), (R3-2,
R7-29), (R3-2, R7-30), (R3-2, R7-31), (R3-2, R7-32), (R3-2, R7-33),
(R3-2, R7-34), (R3-2, R7-35), (R3-2, R7-36), (R3-2, R7-37), (R3-2,
R7-38), (R3-2, R7-39), (R3-2, R7-40), (R3-2, R7-41), (R3-2, R7-42),
(R3-2, R7-43), (R3-2, R7-44), (R3-2, R7-45), (R3-2, R7-46), (R3-2,
R7-47), (R3-2, R7-48), (R3-2, R7-49), (R3-2, R7-50), (R3-2, R7-51),
(R3-2, R7-52), (R3-2, R7-53), (R3-2, R7-54), (R3-2, R7-55), (R3-2,
R7-56), (R3-2, R7-57), (R3-2, R7-58), (R3-2, R7-59), (R3-2, R7-60),
(R3-2, R7-61), (R3-2, R7-62), (R3-2, R7-63), (R3-2, R7-64), (R3-2,
R7-65), (R3-2, R7-66), (R3-2, R7-67), (R3-2, R7-68), (R3-2, R7-69),
(R3-2, R7-70), (R3-2, R7-71), (R3-2, R7-72), (R3-2, R7-73), (R3-2,
R7-74), (R3-2, R7-75), (R3-2, R7-76), (R3-2, R7-77), (R3-3, R7-1),
(R3-3, R7-2), (R3-3, R7-3), (R3-3, R7-4), (R3-3, R7-5), (R3-3,
R7-6), (R3-3, R7-7), (R3-3, R7-8), (R3-3, R7-9), (R3-3, R7-10),
(R3-3, R7-11), (R3-3, R7-12), (R3-3, R7-13), (R3-3, R7-14), (R3-3,
R7-15), (R3-3, R7-16), (R3-3, R7-17), (R3-3, R7-18), (R3-3, R7-19),
(R3-3, R7-20), (R3-3, R7-21), (R3-3, R7-22), (R3-3, R7-23), (R3-3,
R7-24), (R3-3, R7-25), (R3-3, R7-26), (R3-3, R7-27), (R3-3, R7-28),
(R3-3, R7-29), (R3-3, R7-30), (R3-3, R7-31), (R3-3, R7-32), (R3-3,
R7-33), (R3-3, R7-34), (R3-3, R7-35), (R3-3, R7-36), (R3-3, R7-37),
(R3-3, R7-38), (R3-3, R7-39), (R3-3, R7-40), (R3-3, R7-41), (R3-3,
R7-42), (R3-3, R7-43), (R3-3, R7-44), (R3-3, R7-45), (R3-3, R7-46),
(R3-3, R7-47), (R3-3, R7-48), (R3-3, R7-49), (R3-3, R7-50), (R3-3,
R7-51), (R3-3, R7-52), (R3-3, R7-53), (R3-3, R7-54), (R3-3, R7-55),
(R3-3, R7-56), (R3-3, R7-57), (R3-3, R7-58), (R3-3, R7-59), (R3-3,
R7-60), (R3-3, R7-61), (R3-3, R7-62), (R3-3, R7-63), (R3-3, R7-64),
(R3-3, R7-65), (R3-3, R7-66), (R3-3, R7-67), (R3-3, R7-68), (R3-3,
R7-69), (R3-3, R7-70), (R3-3, R7-71), (R3-3, R7-72), (R3-3, R7-73),
(R3-3, R7-74), (R3-3, R7-75), (R3-3, R7-76), (R3-3, R7-77).
TABLE-US-00015 TABLE 15 R.sup.3a R3-1 ##STR01244## R3-2
##STR01245## R3-3 ##STR01246##
TABLE-US-00016 TABLE 16 R.sup.7a R7-1 ##STR01247## R7-2
##STR01248## R7-3 ##STR01249## R7-4 ##STR01250## R7-5 ##STR01251##
R7-6 ##STR01252## R7-7 ##STR01253## R7-8 ##STR01254## R7-9
##STR01255## R7-10 ##STR01256## R7-11 ##STR01257## R7-12
##STR01258## R7-13 ##STR01259## R7-14 ##STR01260## R7-15
##STR01261## R7-16 ##STR01262## R7-17 ##STR01263## R7-18
##STR01264##
TABLE-US-00017 TABLE 17 R.sup.7a R7-19 ##STR01265## R7-20
##STR01266## R7-21 ##STR01267## R7-22 ##STR01268## R7-23
##STR01269## R7-24 ##STR01270## R7-25 ##STR01271## R7-26
##STR01272## R7-27 ##STR01273## R7-28 ##STR01274## R7-29
##STR01275## R7-30 ##STR01276## R7-31 ##STR01277## R7-32
##STR01278## R7-33 ##STR01279## R7-34 ##STR01280## R7-35
##STR01281## R7-36 ##STR01282##
TABLE-US-00018 TABLE 18 R.sup.7a R7-37 ##STR01283## R7-38
##STR01284## R7-39 ##STR01285## R7-40 ##STR01286## R7-41
##STR01287## R7-42 ##STR01288## R7-43 ##STR01289## R7-44
##STR01290## R7-45 ##STR01291## R7-46 ##STR01292## R7-47
##STR01293## R7-48 ##STR01294## R7-49 ##STR01295## R7-50
##STR01296## R7-51 ##STR01297## R7-52 ##STR01298## R7-53
##STR01299## R7-54 ##STR01300##
TABLE-US-00019 TABLE 19 R.sup.7a R7-55 ##STR01301## R7-56
##STR01302## R7-57 ##STR01303## R7-58 ##STR01304## R7-59
##STR01305## R7-60 ##STR01306## R7-61 ##STR01307## R7-62
##STR01308## R7-63 ##STR01309## R7-64 ##STR01310## R7-65
##STR01311## R7-66 ##STR01312## R7-67 ##STR01313## R7-68
##STR01314## R7-69 ##STR01315## R7-70 ##STR01316## R7-71
##STR01317## R7-72 ##STR01318##
TABLE-US-00020 TABLE 20 R.sup.7a R7-73 ##STR01319## R7-74
##STR01320## R7-75 ##STR01321## R7-76 ##STR01322## R7-77
##STR01323##
[4137] In addition, the following combinations of substituents can
be also synthesized by the method described in the above Reference
examples and Examples, and are a preferable embodiment of the
present invention.
Compounds in which,
[4138] combinations of P.sup.R and R.sup.7a of the following
formula (I-C):
##STR01324##
[4139] are selected from the following Table 21 and the above
Tables 15 to 20, respectively.
Combinations of (P.sup.R, R.sup.7a) (PR-1, R7-1), (PR-1, R7-2),
(PR-1, R7-3), (PR-1, R7-4), (PR-1, R7-5), (PR-1, R7-6), (PR-1,
R7-7), (PR-1, R7-8), (PR-1, R7-9), (PR-1, R7-10), (PR-1, R7-11),
(PR-1, R7-12), (PR-1, R7-13), (PR-1, R7-14), (PR-1, R7-15), (PR-1,
R7-16), (PR-1, R7-17), (PR-1, R7-18), (PR-1, R7-19), (PR-1, R7-20),
(PR-1, R7-21), (PR-1, R7-22), (PR-1, R7-23), (PR-1, R7-24), (PR-1,
R7-25), (PR-1, R7-26), (PR-1, R7-27), (PR-1, R7-28), (PR-1, R7-29),
(PR-1, R7-30), (PR-1, R7-31), (PR-1, R7-32), (PR-1, R7-33), (PR-1,
R7-34), (PR-1, R7-35), (PR-1, R7-36), (PR-1, R7-37), (PR-1, R7-38),
(PR-1, R7-39), (PR-1, R7-40), (PR-1, R7-41), (PR-1, R7-42), (PR-1,
R7-43), (PR-1, R7-44), (PR-1, R7-45), (PR-1, R7-46), (PR-1, R7-47),
(PR-1, R7-48), (PR-1, R7-49), (PR-1, R7-50), (PR-1, R7-51), (PR-1,
R7-52), (PR-1, R7-53), (PR-1, R7-54), (PR-1, R7-55), (PR-1, R7-56),
(PR-1, R7-57), (PR-1, R7-58), (PR-1, R7-59), (PR-1, R7-60), (PR-1,
R7-61), (PR-1, R7-62), (PR-1, R7-63), (PR-1, R7-64), (PR-1, R7-65),
(PR-1, R7-66), (PR-1, R7-67), (PR-1, R7-68), (PR-1, R7-69), (PR-1,
R7-70), (PR-1, R7-71), (PR-1, R7-72), (PR-1, R7-73), (PR-1, R7-74),
(PR-1, R7-75), (PR-1, R7-76), (PR-1, R7-77), (PR-2, R7-1), (PR-2,
R7-2), (PR-2, R7-3), (PR-2, R7-4), (PR-2, R7-5), (PR-2, R7-6),
(PR-2, R7-7), (PR-2, R7-8), (PR-2, R7-9), (PR-2, R7-10), (PR-2,
R7-11), (PR-2, R7-12), (PR-2, R7-13), (PR-2, R7-14), (PR-2, R7-15),
(PR-2, R7-16), (PR-2, R7-17), (PR-2, R7-18), (PR-2, R7-19), (PR-2,
R7-20), (PR-2, R7-21), (PR-2, R7-22), (PR-2, R7-23), (PR-2, R7-24),
(PR-2, R7-25), (PR-2, R7-26), (PR-2, R7-27), (PR-2, R7-28), (PR-2,
R7-29), (PR-2, R7-30), (PR-2, R7-31), (PR-2, R7-32), (PR-2, R7-33),
(PR-2, R7-34), (PR-2, R7-35), (PR-2, R7-36), (PR-2, R7-37), (PR-2,
R7-38), (PR-2, R7-39), (PR-2, R7-40), (PR-2, R7-41), (PR-2, R7-42),
(PR-2, R7-43), (PR-2, R7-44), (PR-2, R7-45), (PR-2, R7-46), (PR-2,
R7-47), (PR-2, R7-48), (PR-2, R7-49), (PR-2, R7-50), (PR-2, R7-51),
(PR-2, R7-52), (PR-2, R7-53), (PR-2, R7-54), (PR-2, R7-55), (PR-2,
R7-56), (PR-2, R7-57), (PR-2, R7-58), (PR-2, R7-59), (PR-2, R7-60),
(PR-2, R7-61), (PR-2, R7-62), (PR-2, R7-63), (PR-2, R7-64), (PR-2,
R7-65), (PR-2, R7-66), (PR-2, R7-67), (PR-2, R7-68), (PR-2, R7-69),
(PR-2, R7-70), (PR-2, R7-71), (PR-2, R7-72), (PR-2, R7-73), (PR-2,
R7-74), (PR-2, R7-75), (PR-2, R7-76), (PR-2, R7-77), (PR-3, R7-1),
(PR-3, R7-2), (PR-3, R7-3), (PR-3, R7-4), (PR-3, R7-5), (PR-3,
R7-6), (PR-3, R7-7), (PR-3, R7-8), (PR-3, R7-9), (PR-3, R7-10),
(PR-3, R7-11), (PR-3, R7-12), (PR-3, R7-13), (PR-3, R7-14), (PR-3,
R7-15), (PR-3, R7-16), (PR-3, R7-17), (PR-3, R7-18), (PR-3, R7-19),
(PR-3, R7-20), (PR-3, R7-21), (PR-3, R7-22), (PR-3, R7-23), (PR-3,
R7-24), (PR-3, R7-25), (PR-3, R7-26), (PR-3, R7-27), (PR-3, R7-28),
(PR-3, R7-29), (PR-3, R7-30), (PR-3, R7-31), (PR-3, R7-32), (PR-3,
R7-33), (PR-3, R7-34), (PR-3, R7-35), (PR-3, R7-36), (PR-3, R7-37),
(PR-3, R7-38), (PR-3, R7-39), (PR-3, R7-40), (PR-3, R7-41), (PR-3,
R7-42), (PR-3, R7-43), (PR-3, R7-44), (PR-3, R7-45), (PR-3, R7-46),
(PR-3, R7-47), (PR-3, R7-48), (PR-3, R7-49), (PR-3, R7-50), (PR-3,
R7-51), (PR-3, R7-52), (PR-3, R7-53), (PR-3, R7-54), (PR-3, R7-55),
(PR-3, R7-56), (PR-3, R7-57), (PR-3, R7-58), (PR-3, R7-59), (PR-3,
R7-60), (PR-3, R7-61), (PR-3, R7-62), (PR-3, R7-63), (PR-3, R7-64),
(PR-3, R7-65), (PR-3, R7-66), (PR-3, R7-67), (PR-3, R7-68), (PR-3,
R7-69), (PR-3, R7-70), (PR-3, R7-71), (PR-3, R7-72), (PR-3, R7-73),
(PR-3, R7-74), (PR-3, R7-75), (PR-3, R7-76), (PR-3, R7-77), (PR-4,
R7-1), (PR-4, R7-2), (PR-4, R7-3), (PR-4, R7-4), (PR-4, R7-5),
(PR-4, R7-6), (PR-4, R7-7), (PR-4, R7-8), (PR-4, R7-9), (PR-4,
R7-10), (PR-4, R7-11), (PR-4, R7-12), (PR-4, R7-13), (PR-4, R7-14),
(PR-4, R7-15), (PR-4, R7-16), (PR-4, R7-17), (PR-4, R7-18), (PR-4,
R7-19), (PR-4, R7-20), (PR-4, R7-21), (PR-4, R7-22), (PR-4, R7-23),
(PR-4, R7-24), (PR-4, R7-25), (PR-4, R7-26), (PR-4, R7-27), (PR-4,
R7-28), (PR-4, R7-29), (PR-4, R7-30), (PR-4, R7-31), (PR-4, R7-32),
(PR-4, R7-33), (PR-4, R7-34), (PR-4, R7-35), (PR-4, R7-36), (PR-4,
R7-37), (PR-4, R7-38), (PR-4, R7-39), (PR-4, R7-40), (PR-4, R7-41),
(PR-4, R7-42), (PR-4, R7-43), (PR-4, R7-44), (PR-4, R7-45), (PR-4,
R7-46), (PR-4, R7-47), (PR-4, R7-48), (PR-4, R7-49), (PR-4, R7-50),
(PR-4, R7-51), (PR-4, R7-52), (PR-4, R7-53), (PR-4, R7-54), (PR-4,
R7-55), (PR-4, R7-56), (PR-4, R7-57), (PR-4, R7-58), (PR-4, R7-59),
(PR-4, R7-60), (PR-4, R7-61), (PR-4, R7-62), (PR-4, R7-63), (PR-4,
R7-64), (PR-4, R7-65), (PR-4, R7-66), (PR-4, R7-67), (PR-4, R7-68),
(PR-4, R7-69), (PR-4, R7-70), (PR-4, R7-71), (PR-4, R7-72), (PR-4,
R7-73), (PR-4, R7-74), (PR-4, R7-75), (PR-4, R7-76), (PR-4, R7-77),
(PR-5, R7-1), (PR-5, R7-2), (PR-5, R7-3), (PR-5, R7-4), (PR-5,
R7-5), (PR-5, R7-6), (PR-5, R7-7), (PR-5, R7-8), (PR-5, R7-9),
(PR-5, R7-10), (PR-5, R7-11), (PR-5, R7-12), (PR-5, R7-13), (PR-5,
R7-14), (PR-5, R7-15), (PR-5, R7-16), (PR-5, R7-17), (PR-5, R7-18),
(PR-5, R7-19), (PR-5, R7-20), (PR-5, R7-21), (PR-5, R7-22), (PR-5,
R7-23), (PR-5, R7-24), (PR-5, R7-25), (PR-5, R7-26), (PR-5, R7-27),
(PR-5, R7-28), (PR-5, R7-29), (PR-5, R7-30), (PR-5, R7-31), (PR-5,
R7-32), (PR-5, R7-33), (PR-5, R7-34), (PR-5, R7-35), (PR-5, R7-36),
(PR-5, R7-37), (PR-5, R7-38), (PR-5, R7-39), (PR-5, R7-40), (PR-5,
R7-41), (PR-5, R7-42), (PR-5, R7-43), (PR-5, R7-44), (PR-5, R7-45),
(PR-5, R7-46), (PR-5, R7-47), (PR-5, R7-48), (PR-5, R7-49), (PR-5,
R7-50), (PR-5, R7-51), (PR-5, R7-52), (PR-5, R7-53), (PR-5, R7-54),
(PR-5, R7-55), (PR-5, R7-56), (PR-5, R7-57), (PR-5, R7-58), (PR-5,
R7-59), (PR-5, R7-60), (PR-5, R7-61), (PR-5, R7-62), (PR-5, R7-63),
(PR-5, R7-64), (PR-5, R7-65), (PR-5, R7-66), (PR-5, R7-67), (PR-5,
R7-68), (PR-5, R7-69), (PR-5, R7-70), (PR-5, R7-71), (PR-5, R7-72),
(PR-5, R7-73), (PR-5, R7-74), (PR-5, R7-75), (PR-5, R7-76), (PR-5,
R7-77).
TABLE-US-00021 TABLE 21 ##STR01325## PR-1 ##STR01326## PR-2
##STR01327## PR-3 ##STR01328## PR-4 ##STR01329## PR-5
##STR01330##
[4140] Further, in the above compounds of Reference examples 1 to
775, the following combinations in which a part corresponding to
--OH group of the following formula (II):
##STR01331##
[4141] (wherein each substituent is same meaning as that of item
1)
[4142] are converted into a prodrug by PR-1 to PR-5 in the above
Table 21 are also a preferable embodiment of the present invention.
These compounds can be also synthesized by a general method known
to a person skilled in the art or the method described in Examples,
using the above compound of Reference example as a raw
material.
Combinations of (Number of Compound of Reference Example,
P.sup.R)
[4143] (Reference example 1, PR-1), (Reference example 1, PR-2),
(Reference example 1, PR-3), (Reference example 1, PR-4),
(Reference example 1, PR-5), (Reference example 2, PR-1),
(Reference example 2, PR-2), (Reference example 2, PR-3),
(Reference example 2, PR-4), (Reference example 2, PR-5),
(Reference example 3, PR-1), (Reference example 3, PR-2),
(Reference example 3, PR-3), (Reference example 3, PR-4),
(Reference example 3, PR-5), (Reference example 4, PR-1),
(Reference example 4, PR-2), (Reference example 4, PR-3),
(Reference example 4, PR-4), (Reference example 4, PR-5),
(Reference example 5, PR-1), (Reference example 5, PR-2),
(Reference example 5, PR-3), (Reference example 5, PR-4),
(Reference example 5, PR-5), (Reference example 6, PR-1),
(Reference example 6, PR-2), (Reference example 6, PR-3),
(Reference example 6, PR-4), (Reference example 6, PR-5),
(Reference example 7, PR-1), (Reference example 7, PR-2),
(Reference example 7, PR-3), (Reference example 7, PR-4),
(Reference example 7, PR-5), (Reference example 8, PR-1),
(Reference example 8, PR-2), (Reference example 8, PR-3),
(Reference example 8, PR-4), (Reference example 8, PR-5),
(Reference example 9, PR-1), (Reference example 9, PR-2),
(Reference example 9, PR-3), (Reference example 9, PR-4),
(Reference example 9, PR-5), (Reference example 10, PR-1),
(Reference example 10, PR-2), (Reference example 10, PR-3),
(Reference example 10, PR-4), (Reference example 10, PR-5),
(Reference example 11, PR-1), (Reference example 11, PR-2),
(Reference example 11, PR-3), (Reference example 11, PR-4),
(Reference example 11, PR-5), (Reference example 12, PR-1),
(Reference example 12, PR-2), (Reference example 12, PR-3),
(Reference example 12, PR-4), (Reference example 12, PR-5),
(Reference example 13, PR-1), (Reference example 13, PR-2),
(Reference example 13, PR-3), (Reference example 13, PR-4),
(Reference example 13, PR-5), (Reference example 14, PR-1),
(Reference example 14, PR-2), (Reference example 14, PR-3),
(Reference example 14, PR-4), (Reference example 14, PR-5),
(Reference example 15, PR-1), (Reference example 15, PR-2),
(Reference example 15, PR-3), (Reference example 15, PR-4),
(Reference example 15, PR-5), (Reference example 16, PR-1),
(Reference example 16, PR-2), (Reference example 16, PR-3),
(Reference example 16, PR-4), (Reference example 16, PR-5),
(Reference example 17, PR-1), (Reference example 17, PR-2),
(Reference example 17, PR-3), (Reference example 17, PR-4),
(Reference example 17, PR-5), (Reference example 18, PR-1),
(Reference example 18, PR-2), (Reference example 18, PR-3),
(Reference example 18, PR-4), (Reference example 18, PR-5),
(Reference example 19, PR-1), (Reference example 19, PR-2),
(Reference example 19, PR-3), (Reference example 19, PR-4),
(Reference example 19, PR-5), (Reference example 20, PR-1),
(Reference example 20, PR-2), (Reference example 20, PR-3),
(Reference example 20, PR-4), (Reference example 20, PR-5),
(Reference example 21, PR-1), (Reference example 21, PR-2),
(Reference example 21, PR-3), (Reference example 21, PR-4),
(Reference example 21, PR-5), (Reference example 22, PR-1),
(Reference example 22, PR-2), (Reference example 22, PR-3),
(Reference example 22, PR-4), (Reference example 22, PR-5),
(Reference example 23, PR-1), (Reference example 23, PR-2),
(Reference example 23, PR-3), (Reference example 23, PR-4),
(Reference example 23, PR-5), (Reference example 24, PR-1),
(Reference example 24, PR-2), (Reference example 24, PR-3),
(Reference example 24, PR-4), (Reference example 24, PR-5),
(Reference example 25, PR-1), (Reference example 25, PR-2),
(Reference example 25, PR-3), (Reference example 25, PR-4),
(Reference example 25, PR-5), (Reference example 26, PR-1),
(Reference example 26, PR-2), (Reference example 26, PR-3),
(Reference example 26, PR-4), (Reference example 26, PR-5),
(Reference example 27, PR-1), (Reference example 27, PR-2),
(Reference example 27, PR-3), (Reference example 27, PR-4),
(Reference example 27, PR-5), (Reference example 28, PR-1),
(Reference example 28, PR-2), (Reference example 28, PR-3),
(Reference example 28, PR-4), (Reference example 28, PR-5),
(Reference example 29, PR-1), (Reference example 29, PR-2),
(Reference example 29, PR-3), (Reference example 29, PR-4),
(Reference example 29, PR-5), (Reference example 30, PR-1),
(Reference example 30, PR-2), (Reference example 30, PR-3),
(Reference example 30, PR-4), (Reference example 30, PR-5),
(Reference example 31, PR-1), (Reference example 31, PR-2),
(Reference example 31, PR-3), (Reference example 31, PR-4),
(Reference example 31, PR-5), (Reference example 32, PR-1),
(Reference example 32, PR-2), (Reference example 32, PR-3),
(Reference example 32, PR-4), (Reference example 32, PR-5),
(Reference example 33, PR-1), (Reference example 33, PR-2),
(Reference example 33, PR-3), (Reference example 33, PR-4),
(Reference example 33, PR-5), (Reference example 34, PR-1),
(Reference example 34, PR-2), (Reference example 34, PR-3),
(Reference example 34, PR-4), (Reference example 34, PR-5),
(Reference example 35, PR-1), (Reference example 35, PR-2),
(Reference example 35, PR-3), (Reference example 35, PR-4),
(Reference example 35, PR-5), (Reference example 36, PR-1),
(Reference example 36, PR-2), (Reference example 36, PR-3),
(Reference example 36, PR-4), (Reference example 36, PR-5),
(Reference example 37, PR-1), (Reference example 37, PR-2),
(Reference example 37, PR-3), (Reference example 37, PR-4),
(Reference example 37, PR-5), (Reference example 38, PR-1),
(Reference example 38, PR-2), (Reference example 38, PR-3),
(Reference example 38, PR-4), (Reference example 38, PR-5),
(Reference example 39, PR-1), (Reference example 39, PR-2),
(Reference example 39, PR-3), (Reference example 39, PR-4),
(Reference example 39, PR-5), (Reference example 40, PR-1),
(Reference example 40, PR-2), (Reference example 40, PR-3),
(Reference example 40, PR-4), (Reference example 40, PR-5),
(Reference example 41, PR-1), (Reference example 41, PR-2),
(Reference example 41, PR-3), (Reference example 41, PR-4),
(Reference example 41, PR-5), (Reference example 42, PR-1),
(Reference example 42, PR-2), (Reference example 42, PR-3),
(Reference example 42, PR-4), (Reference example 42, PR-5),
(Reference example 43, PR-1), (Reference example 43, PR-2),
(Reference example 43, PR-3), (Reference example 43, PR-4),
(Reference example 43, PR-5), (Reference example 44, PR-1),
(Reference example 44, PR-2), (Reference example 44, PR-3),
(Reference example 44, PR-4), (Reference example 44, PR-5),
(Reference example 45, PR-1), (Reference example 45, PR-2),
(Reference example 45, PR-3), (Reference example 45, PR-4),
(Reference example 45, PR-5), (Reference example 46, PR-1),
(Reference example 46, PR-2), (Reference example 46, PR-3),
(Reference example 46, PR-4), (Reference example 46, PR-5),
(Reference example 47, PR-1), (Reference example 47, PR-2),
(Reference example 47, PR-3), (Reference example 47, PR-4),
(Reference example 47, PR-5), (Reference example 48, PR-1),
(Reference example 48, PR-2), (Reference example 48, PR-3),
(Reference example 48, PR-4), (Reference example 48, PR-5),
(Reference example 49, PR-1), (Reference example 49, PR-2),
(Reference example 49, PR-3), (Reference example 49, PR-4),
(Reference example 49, PR-5), (Reference example 50, PR-1),
(Reference example 50, PR-2), (Reference example 50, PR-3),
(Reference example 50, PR-4), (Reference example 50, PR-5),
(Reference example 51, PR-1), (Reference example 51, PR-2),
(Reference example 51, PR-3), (Reference example 51, PR-4),
(Reference example 51, PR-5), (Reference example 52, PR-1),
(Reference example 52, PR-2), (Reference example 52, PR-3),
(Reference example 52, PR-4), (Reference example 52, PR-5),
(Reference example 53, PR-1), (Reference example 53, PR-2),
(Reference example 53, PR-3), (Reference example 53, PR-4),
(Reference example 53, PR-5), (Reference example 54, PR-1),
(Reference example 54, PR-2), (Reference example 54, PR-3),
(Reference example 54, PR-4), (Reference example 54, PR-5),
(Reference example 55, PR-1), (Reference example 55, PR-2),
(Reference example 55, PR-3), (Reference example 55, PR-4),
(Reference example 55, PR-5), (Reference example 56, PR-1),
(Reference example 56, PR-2), (Reference example 56, PR-3),
(Reference example 56, PR-4), (Reference example 56, PR-5),
(Reference example 57, PR-1), (Reference example 57, PR-2),
(Reference example 57, PR-3), (Reference example 57, PR-4),
(Reference example 57, PR-5), (Reference example 58, PR-1),
(Reference example 58, PR-2), (Reference example 58, PR-3),
(Reference example 58, PR-4), (Reference example 58, PR-5),
(Reference example 59, PR-1), (Reference example 59, PR-2),
(Reference example 59, PR-3), (Reference example 59, PR-4),
(Reference example 59, PR-5), (Reference example 60, PR-1),
(Reference example 60, PR-2), (Reference example 60, PR-3),
(Reference example 60, PR-4), (Reference example 60, PR-5),
(Reference example 61, PR-1), (Reference example 61, PR-2),
(Reference example 61, PR-3), (Reference example 61, PR-4),
(Reference example 61, PR-5), (Reference example 62, PR-1),
(Reference example 62, PR-2), (Reference example 62, PR-3),
(Reference example 62, PR-4), (Reference example 62, PR-5),
(Reference example 63, PR-1), (Reference example 63, PR-2),
(Reference example 63, PR-3), (Reference example 63, PR-4),
(Reference example 63, PR-5), (Reference example 64, PR-1),
(Reference example 64, PR-2), (Reference example 64, PR-3),
(Reference example 64, PR-4), (Reference example 64, PR-5),
(Reference example 65, PR-1), (Reference example 65, PR-2),
(Reference example 65, PR-3), (Reference example 65, PR-4),
(Reference example 65, PR-5), (Reference example 66, PR-1),
(Reference example 66, PR-2), (Reference example 66, PR-3),
(Reference example 66, PR-4), (Reference example 66, PR-5),
(Reference example 67, PR-1), (Reference example 67, PR-2),
(Reference example 67, PR-3), (Reference example 67, PR-4),
(Reference example 67, PR-5), (Reference example 68, PR-1),
(Reference example 68, PR-2), (Reference example 68, PR-3),
(Reference example 68, PR-4), (Reference example 68, PR-5),
(Reference example 69, PR-1), (Reference example 69, PR-2),
(Reference example 69, PR-3), (Reference example 69, PR-4),
(Reference example 69, PR-5), (Reference example 70, PR-1),
(Reference example 70, PR-2), (Reference example 70, PR-3),
(Reference example 70, PR-4), (Reference example 70, PR-5),
(Reference example 71, PR-1), (Reference example 71, PR-2),
(Reference example 71, PR-3), (Reference example 71, PR-4),
(Reference example 71, PR-5), (Reference example 72, PR-1),
(Reference example 72, PR-2), (Reference example 72, PR-3),
(Reference example 72, PR-4), (Reference example 72, PR-5),
(Reference example 73, PR-1), (Reference example 73, PR-2),
(Reference example 73, PR-3), (Reference example 73, PR-4),
(Reference example 73, PR-5), (Reference example 74, PR-1),
(Reference example 74, PR-2), (Reference example 74, PR-3),
(Reference example 74, PR-4), (Reference example 74, PR-5),
(Reference example 75, PR-1), (Reference example 75, PR-2),
(Reference example 75, PR-3), (Reference example 75, PR-4),
(Reference example 75, PR-5), (Reference example 76, PR-1),
(Reference example 76, PR-2), (Reference example 76, PR-3),
(Reference example 76, PR-4), (Reference example 76, PR-5),
(Reference example 77, PR-1), (Reference example 77, PR-2),
(Reference example 77, PR-3), (Reference example 77, PR-4),
(Reference example 77, PR-5), (Reference example 78, PR-1),
(Reference example 78, PR-2), (Reference example 78, PR-3),
(Reference example 78, PR-4), (Reference example 78, PR-5),
(Reference example 79, PR-1), (Reference example 79, PR-2),
(Reference example 79, PR-3), (Reference example 79, PR-4),
(Reference example 79, PR-5), (Reference example 80, PR-1),
(Reference example 80, PR-2), (Reference example 80, PR-3),
(Reference example 80, PR-4), (Reference example 80, PR-5),
(Reference example 81, PR-1), (Reference example 81, PR-2),
(Reference example 81, PR-3), (Reference example 81, PR-4),
(Reference example 81, PR-5), (Reference example 82, PR-1),
(Reference example 82, PR-2), (Reference example 82, PR-3),
(Reference example 82, PR-4), (Reference example 82, PR-5),
(Reference example 83, PR-1), (Reference example 83, PR-2),
(Reference example 83, PR-3), (Reference example 83, PR-4),
(Reference example 83, PR-5), (Reference example 84, PR-1),
(Reference example 84, PR-2), (Reference example 84, PR-3),
(Reference example 84, PR-4), (Reference example 84, PR-5),
(Reference example 85, PR-1), (Reference example 85, PR-2),
(Reference example 85, PR-3), (Reference example 85, PR-4),
(Reference example 85, PR-5), (Reference example 86, PR-1),
(Reference example 86, PR-2), (Reference example 86, PR-3),
(Reference example 86, PR-4), (Reference example 86, PR-5),
(Reference example 87, PR-1), (Reference example 87, PR-2),
(Reference example 87, PR-3), (Reference example 87, PR-4),
(Reference example 87, PR-5), (Reference example 88, PR-1),
(Reference example 88, PR-2), (Reference example 88, PR-3),
(Reference example 88, PR-4), (Reference example 88, PR-5),
(Reference example 89, PR-1), (Reference example 89, PR-2),
(Reference example 89, PR-3), (Reference example 89, PR-4),
(Reference example 89, PR-5), (Reference example 90, PR-1),
(Reference example 90, PR-2), (Reference example 90, PR-3),
(Reference example 90, PR-4), (Reference example 90, PR-5),
(Reference example 91, PR-1), (Reference example 91, PR-2),
(Reference example 91, PR-3), (Reference example 91, PR-4),
(Reference example 91, PR-5), (Reference example 92, PR-1),
(Reference example 92, PR-2), (Reference example 92, PR-3),
(Reference example 92, PR-4), (Reference example 92, PR-5),
(Reference example 93, PR-1), (Reference example 93, PR-2),
(Reference example 93, PR-3), (Reference example 93, PR-4),
(Reference example 93, PR-5), (Reference example 94, PR-1),
(Reference example 94, PR-2), (Reference example 94, PR-3),
(Reference example 94, PR-4), (Reference example 94, PR-5),
(Reference example 95, PR-1), (Reference example 95, PR-2),
(Reference example 95, PR-3), (Reference example 95, PR-4),
(Reference example 95, PR-5), (Reference example 96, PR-1),
(Reference example 96, PR-2), (Reference example 96, PR-3),
(Reference example 96, PR-4), (Reference example 96, PR-5),
(Reference example 97, PR-1), (Reference example 97, PR-2),
(Reference example 97, PR-3), (Reference example 97, PR-4),
(Reference example 97, PR-5), (Reference example 98, PR-1),
(Reference example 98, PR-2), (Reference example 98, PR-3),
(Reference example 98, PR-4), (Reference example 98, PR-5),
(Reference example 99, PR-1), (Reference example 99, PR-2),
(Reference example 99, PR-3), (Reference example 99, PR-4),
(Reference example 99, PR-5), (Reference example 100, PR-1),
(Reference example 100, PR-2), (Reference example 100, PR-3),
(Reference example 100, PR-4), (Reference example 100, PR-5),
(Reference example 101, PR-1), (Reference example 101, PR-2),
(Reference example 101, PR-3), (Reference example 101, PR-4),
(Reference example 101, PR-5), (Reference example 102, PR-1),
(Reference example 102, PR-2), (Reference example 102, PR-3),
(Reference example 102, PR-4), (Reference example 102, PR-5),
(Reference example 103, PR-1), (Reference example 103, PR-2),
(Reference example 103, PR-3), (Reference example 103, PR-4),
(Reference example 103, PR-5), (Reference example 104, PR-1),
(Reference example 104, PR-2), (Reference example 104, PR-3),
(Reference example 104, PR-4), (Reference example 104, PR-5),
(Reference example 105, PR-1), (Reference example 105, PR-2),
(Reference example 105, PR-3), (Reference example 105, PR-4),
(Reference example 105, PR-5), (Reference example 106, PR-1),
(Reference example 106, PR-2), (Reference example 106, PR-3),
(Reference example 106, PR-4), (Reference example 106, PR-5),
(Reference example 107, PR-1), (Reference example 107, PR-2),
(Reference example 107, PR-3), (Reference example 107, PR-4),
(Reference example 107, PR-5), (Reference example 108, PR-1),
(Reference example 108, PR-2), (Reference example 108, PR-3),
(Reference example 108, PR-4), (Reference example 108, PR-5),
(Reference example 109, PR-1), (Reference example 109, PR-2),
(Reference example 109, PR-3), (Reference example 109, PR-4),
(Reference example 109, PR-5), (Reference example 110, PR-1),
(Reference example 110, PR-2), (Reference example 110, PR-3),
(Reference example 110, PR-4), (Reference example 110, PR-5),
(Reference example 111, PR-1), (Reference example 111, PR-2),
(Reference example 111, PR-3), (Reference example 111, PR-4),
(Reference example 111, PR-5), (Reference example 112, PR-1),
(Reference example 112, PR-2), (Reference example 112, PR-3),
(Reference example 112, PR-4), (Reference example 112, PR-5),
(Reference example 113, PR-1), (Reference example 113, PR-2),
(Reference example 113, PR-3), (Reference example 113, PR-4),
(Reference example 113, PR-5), (Reference example 114, PR-1),
(Reference example 114, PR-2), (Reference example 114, PR-3),
(Reference example 114, PR-4), (Reference example 114, PR-5),
(Reference example 115, PR-1), (Reference example 115, PR-2),
(Reference example 115, PR-3), (Reference example 115, PR-4),
(Reference example 115, PR-5), (Reference example 116, PR-1),
(Reference example 116, PR-2), (Reference example 116, PR-3),
(Reference example 116, PR-4), (Reference example 116, PR-5),
(Reference example 117, PR-1), (Reference example 117, PR-2),
(Reference example 117, PR-3), (Reference example 117, PR-4),
(Reference example 117, PR-5), (Reference example 118, PR-1),
(Reference example 118, PR-2), (Reference example 118, PR-3),
(Reference example 118, PR-4), (Reference example 118, PR-5),
(Reference example 119, PR-1), (Reference example 119, PR-2),
(Reference example 119, PR-3), (Reference example 119, PR-4),
(Reference example 119, PR-5), (Reference example 120, PR-1),
(Reference example 120, PR-2), (Reference example 120, PR-3),
(Reference example 120, PR-4), (Reference example 120, PR-5),
(Reference example 121, PR-1), (Reference example 121, PR-2),
(Reference example 121, PR-3), (Reference example 121, PR-4),
(Reference example 121, PR-5), (Reference example 122, PR-1),
(Reference example 122, PR-2), (Reference example 122, PR-3),
(Reference example 122, PR-4), (Reference example 122, PR-5),
(Reference example 123, PR-1), (Reference example 123, PR-2),
(Reference example 123, PR-3), (Reference example 123, PR-4),
(Reference example 123, PR-5), (Reference example 124, PR-1),
(Reference example 124, PR-2), (Reference example 124, PR-3),
(Reference example 124, PR-4), (Reference example 124, PR-5),
(Reference example 125, PR-1), (Reference example 125, PR-2),
(Reference example 125, PR-3), (Reference example 125, PR-4),
(Reference example 125, PR-5), (Reference example 126, PR-1),
(Reference example 126, PR-2), (Reference example 126, PR-3),
(Reference example 126, PR-4), (Reference example 126, PR-5),
(Reference example 127, PR-1), (Reference example 127, PR-2),
(Reference example 127, PR-3), (Reference example 127, PR-4),
(Reference example 127, PR-5), (Reference example 128, PR-1),
(Reference example 128, PR-2), (Reference example 128, PR-3),
(Reference example 128, PR-4), (Reference example 128, PR-5),
(Reference example 129, PR-1), (Reference example 129, PR-2),
(Reference example 129, PR-3), (Reference example 129, PR-4),
(Reference example 129, PR-5), (Reference example 130, PR-1),
(Reference example 130, PR-2), (Reference example 130, PR-3),
(Reference example 130, PR-4), (Reference example 130, PR-5),
(Reference example 131, PR-1), (Reference example 131, PR-2),
(Reference example 131, PR-3), (Reference example 131, PR-4),
(Reference example 131, PR-5), (Reference example 132, PR-1),
(Reference example 132, PR-2), (Reference example 132, PR-3),
(Reference example 132, PR-4), (Reference example 132, PR-5),
(Reference example 133, PR-1), (Reference example 133, PR-2),
(Reference example 133, PR-3), (Reference example 133, PR-4),
(Reference example 133, PR-5), (Reference example 134, PR-1),
(Reference example 134, PR-2), (Reference example 134, PR-3),
(Reference example 134, PR-4), (Reference example 134, PR-5),
(Reference example 135, PR-1), (Reference example 135, PR-2),
(Reference example 135, PR-3), (Reference example 135, PR-4),
(Reference example 135, PR-5), (Reference example 136, PR-1),
(Reference example 136, PR-2), (Reference example 136, PR-3),
(Reference example 136, PR-4), (Reference example 136, PR-5),
(Reference example 137, PR-1), (Reference example 137, PR-2),
(Reference example 137, PR-3), (Reference example 137, PR-4),
(Reference example 137, PR-5), (Reference example 138, PR-1),
(Reference example 138, PR-2), (Reference example 138, PR-3),
(Reference example 138, PR-4), (Reference example 138, PR-5),
(Reference example 139, PR-1), (Reference example 139, PR-2),
(Reference example 139, PR-3), (Reference example 139, PR-4),
(Reference example 139, PR-5), (Reference example 140, PR-1),
(Reference example 140, PR-2), (Reference example 140, PR-3),
(Reference example 140, PR-4), (Reference example 140, PR-5),
(Reference example 141, PR-1), (Reference example 141, PR-2),
(Reference example 141, PR-3), (Reference example 141, PR-4),
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PR-5), (Reference example 627, PR-1), (Reference example 627,
PR-2), (Reference example 627, PR-3), (Reference example 627,
PR-4), (Reference example 627, PR-5), (Reference example 628,
PR-1), (Reference example 628, PR-2), (Reference example 628,
PR-3), (Reference example 628, PR-4), (Reference example 628,
PR-5), (Reference example 629, PR-1), (Reference example 629,
PR-2), (Reference example 629, PR-3), (Reference example 629,
PR-4), (Reference example 629, PR-5), (Reference example 630,
PR-1), (Reference example 630, PR-2), (Reference example 630,
PR-3), (Reference example 630, PR-4), (Reference example 630,
PR-5), (Reference example 631, PR-1), (Reference example 631,
PR-2), (Reference example 631, PR-3), (Reference example 631,
PR-4), (Reference example 631, PR-5), (Reference example 632,
PR-1), (Reference example 632, PR-2), (Reference example 632,
PR-3), (Reference example 632, PR-4), (Reference example 632,
PR-5), (Reference example 633, PR-1), (Reference example 633,
PR-2), (Reference example 633, PR-3), (Reference example 633,
PR-4), (Reference example 633, PR-5), (Reference example 634,
PR-1), (Reference example 634, PR-2), (Reference example 634,
PR-3), (Reference example 634, PR-4), (Reference example 634,
PR-5), (Reference example 635, PR-1), (Reference example 635,
PR-2), (Reference example 635, PR-3), (Reference example 635,
PR-4), (Reference example 635, PR-5), (Reference example 636,
PR-1), (Reference example 636, PR-2), (Reference example 636,
PR-3), (Reference example 636, PR-4), (Reference example 636,
PR-5), (Reference example 637, PR-1), (Reference example 637,
PR-2), (Reference example 637, PR-3), (Reference example 637,
PR-4), (Reference example 637, PR-5), (Reference example 638,
PR-1), (Reference example 638, PR-2), (Reference example 638,
PR-3), (Reference example 638, PR-4), (Reference example 638,
PR-5), (Reference example 639, PR-1), (Reference example 639,
PR-2), (Reference example 639, PR-3), (Reference example 639,
PR-4), (Reference example 639, PR-5), (Reference example 640,
PR-1), (Reference example 640, PR-2), (Reference example 640,
PR-3), (Reference example 640, PR-4), (Reference example 640,
PR-5), (Reference example 641, PR-1), (Reference example 641,
PR-2), (Reference example 641, PR-3), (Reference example 641,
PR-4), (Reference example 641, PR-5), (Reference example 642,
PR-1), (Reference example 642, PR-2), (Reference example 642,
PR-3), (Reference example 642, PR-4), (Reference example 642,
PR-5), (Reference example 643, PR-1), (Reference example 643,
PR-2), (Reference example 643, PR-3), (Reference example 643,
PR-4), (Reference example 643, PR-5), (Reference example 644,
PR-1), (Reference example 644, PR-2), (Reference example 644,
PR-3), (Reference example 644, PR-4), (Reference example 644,
PR-5), (Reference example 645, PR-1), (Reference example 645,
PR-2), (Reference example 645, PR-3), (Reference example 645,
PR-4), (Reference example 645, PR-5), (Reference example 646,
PR-1), (Reference example 646, PR-2), (Reference example 646,
PR-3), (Reference example 646, PR-4), (Reference example 646,
PR-5), (Reference example 647, PR-1), (Reference example 647,
PR-2), (Reference example 647, PR-3), (Reference example 647,
PR-4), (Reference example 647, PR-5), (Reference example 648,
PR-1), (Reference example 648, PR-2), (Reference example 648,
PR-3), (Reference example 648, PR-4), (Reference example 648,
PR-5), (Reference example 649, PR-1), (Reference example 649,
PR-2), (Reference example 649, PR-3), (Reference example 649,
PR-4), (Reference example 649, PR-5), (Reference example 650,
PR-1), (Reference example 650, PR-2), (Reference example 650,
PR-3), (Reference example 650, PR-4), (Reference example 650,
PR-5), (Reference example 651, PR-1), (Reference example 651,
PR-2), (Reference example 651, PR-3), (Reference example 651,
PR-4), (Reference example 651, PR-5), (Reference example 652,
PR-1), (Reference example 652, PR-2), (Reference example 652,
PR-3), (Reference example 652, PR-4), (Reference example 652,
PR-5), (Reference example 653, PR-1), (Reference example 653,
PR-2), (Reference example 653, PR-3), (Reference example 653,
PR-4), (Reference example 653, PR-5), (Reference example 654,
PR-1), (Reference example 654, PR-2), (Reference example 654,
PR-3), (Reference example 654, PR-4), (Reference example 654,
PR-5), (Reference example 655, PR-1), (Reference example 655,
PR-2), (Reference example 655, PR-3), (Reference example 655,
PR-4), (Reference example 655, PR-5), (Reference example 656,
PR-1), (Reference example 656, PR-2), (Reference example 656,
PR-3), (Reference example 656, PR-4), (Reference example 656,
PR-5), (Reference example 657, PR-1), (Reference example 657,
PR-2), (Reference example 657, PR-3), (Reference example 657,
PR-4), (Reference example 657, PR-5), (Reference example 658,
PR-1), (Reference example 658, PR-2), (Reference example 658,
PR-3), (Reference example 658, PR-4), (Reference example 658,
PR-5), (Reference example 659, PR-1), (Reference example 659,
PR-2), (Reference example 659, PR-3), (Reference example 659,
PR-4), (Reference example 659, PR-5), (Reference example 660,
PR-1), (Reference example 660, PR-2), (Reference example 660,
PR-3), (Reference example 660, PR-4), (Reference example 660,
PR-5), (Reference example 661, PR-1), (Reference example 661,
PR-2), (Reference example 661, PR-3), (Reference example 661,
PR-4), (Reference example 661, PR-5), (Reference example 662,
PR-1), (Reference example 662, PR-2), (Reference example 662,
PR-3), (Reference example 662, PR-4), (Reference example 662,
PR-5), (Reference example 663, PR-1), (Reference example 663,
PR-2), (Reference example 663, PR-3), (Reference example 663,
PR-4), (Reference example 663, PR-5), (Reference example 664,
PR-1), (Reference example 664, PR-2), (Reference example 664,
PR-3), (Reference example 664, PR-4), (Reference example 664,
PR-5), (Reference example 665, PR-1), (Reference example 665,
PR-2), (Reference example 665, PR-3), (Reference example 665,
PR-4), (Reference example 665, PR-5).
[4150] For example, the above (Reference example 1, PR-1) means a
compound shown by the following structural formula:
##STR01332##
[4151] As intermediate synthesis examples, methods for synthesizing
intermediates useful for carrying out the present application are
shown below.
Intermediate Synthesis Example 1
##STR01333##
[4152] First Step
[4153] A solution of benzyl alcohol (1.00 g, 9.25 mmol) in THF (3
ml) was added to a suspension of sodium tert-pentoxide (2.55 g,
23.2 mmol) in THF (4 ml) at room temperature under nitrogen
atmosphere, and the mixture was stirred at 40.degree. C. for 2
hours. This reaction solution was cooled in an ice bath, and a THF
(3 ml) solution of compound 1a (1.53 g, 10.2 mmol) was added
dropwise at 0 to 10.degree. C. After the reaction solution was
stirred at room temperature for 2 hours, 2N hydrochloric acid (15
ml) was added, followed by extraction with ethyl acetate two times.
The combined extracts were washed sequentially with water,
saturated sodium bicarbonate water, water and aqueous saturated
sodium chloride solution, and then dried with anhydrous sodium
sulfate. The solvent was distilled off, and the resulting oil was
purified by silica gel column chromatography (n-hexane-ethyl
acetate 4:1, v/v) to obtain 1.89 g (yield 92%) of compound 1b as an
oil product.
[4154] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.56 (2H, s), 3.71 (3H,
s), 4.14 (2H, s), 4.59 (2H, s), 7.27-7.42 (5H, m).
Second Step
[4155] Compound 1b (1.80 g, 8.1 mmol) was dissolved in 1,4-dioxane
(18 mL), N,N-dimethylformamide dimethyl acetal (1.45 g, 12.2 mmol)
was added, and the mixture was stirred at room temperature for 6
hours. The reaction solution was concentrated under reduced
pressure, and the residue was purified by silica gel column
chromatography (n-hexane-ethyl acetate 1:4, v/v) to obtain 1.77 g
(yield 79%) of compound 1c as an oil product.
[4156] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.90 (3H, br), 3.25 (3H,
br), 3.69 (3H, s), 4.45 (2H, s), 4.59 (2H, s), 7.24-7.40 (5H, m),
7.73 (s, 1H).
Third Step
[4157] Sodium tert-butoxide (2.55 g, 23.2 mmol), dimethyl oxalate
(639 mg, 5.41 mmol) and DMI (3 ml) were added to a three-neck flask
under nitrogen atmosphere, and a DMI (2 ml) solution of compound 1c
(0.50 g, 1.80 mmol) was added dropwise thereto at 25 to 30.degree.
C. After stirring at room temperature for 7 hours, 2N hydrochloric
acid (10 ml) was added, and the mixture was stirred at room
temperature for 15 hours. The reaction solution was extracted with
ethyl acetate two times, and the combined extracts were washed
sequentially with water, saturated sodium bicarbonate water, water
and aqueous saturated sodium chloride solution, and then dried with
anhydrous sodium sulfate. The solvent was distilled off, and the
resulting residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate 2:1 to 1:1, v/v) to obtain 488 mg (yield
85%) of compound 1d as a white solid.
[4158] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.89 (3H, s), 3.93 (3H,
s), 5.34 (2H, s), 7.32-7.40 (3H, m), 7.45-7.49 (2H, m), 8.50 (1H,
s).
Intermediate Synthesis Example 2
##STR01334##
[4159] First Step
[4160] A DMI (3 ml) solution of benzyl alcohol (0.66 g, 6.1 mmol)
was added to a DMI (4 ml) suspension of sodium tert-pentoxide (1.67
g, 15.2 mmol) at room temperature under nitrogen atmosphere, and
the mixture was stirred at 40.degree. C. for 2 hours. This reaction
solution was cooled in an ice bath, and a DMI (3 ml) solution of
compound 2a (1.10 g, 6.68 mmol) was added dropwise at 0 to
10.degree. C. The reaction solution was stirred at 0 to 5.degree.
C. for 2 hours, and at room temperature for 3 hours, and 2N
hydrochloric acid (15 ml) was added, followed by extraction with
ethyl acetate two times. The combined extracts were washed
sequentially with water, saturated sodium bicarbonate water, water
and aqueous saturated sodium chloride solution, and then dried with
anhydrous sodium sulfate. The solvent was distilled off, and the
resulting oil product was purified by silica gel column
chromatography (n-hexane-ethyl acetate 4:1, v/v) to obtain 1.29 g
(yield 90%) of compound 2b as an oil product.
[4161] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (3H, t, J=7.2 Hz),
3.54 (2H, s), 4.14 (2H, s), 4.17 (2H, q, J=7.2 Hz), 4.59 (2H, s),
7.28-7.40 (5H, m).
Second Step
[4162] Compound 2b (9.73 g, 41.2 mmol) was dissolved in toluene (45
ml), N,N-dimethylformamide dimethyl acetal (7.36 g, 61.8 mmol) was
added, and the mixture was stirred at room temperature for 5 hours.
Water was added to the reaction solution, followed by extraction
with ethyl acetate two times. The combined extracts were washed
sequentially with water, and aqueous saturated sodium chloride
solution, and then dried with anhydrous magnesium sulfate. The
solvent was distilled off, and the resulting oil product was
purified by silica gel column chromatography (n-hexane-ethyl
acetate 1:1 to 3:7, v/v) to obtain 7.90 g (yield 66%) of compound
2c as an oil product.
[4163] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.25 (3H, t, J=7.2 Hz),
2.95 (3H, br), 3.22 (3H, br), 4.15 (2H, q, J=7.2 Hz), 4.45 (2H, s),
4.59 (2H, s), 7.22-7.40 (5H, m), 7.73 (1H, s).
Third Step
[4164] Sodium tert-butoxide (495 mg, 5.15 mmol) and DMI (2 ml) were
added to a three-neck flask under nitrogen atmosphere, and dimethyl
oxalate (608 mg, 5.15 mmol) and a DMI (3 ml) solution of compound
2c (0.50 g, 1.72 mmol) were added dropwise thereto at 25 to
30.degree. C. After stirring at room temperature for 4 hours, 2N
hydrochloric acid (10 ml) was added, and the mixture was stirred at
room temperature for 15 hours. The reaction solution was extracted
with toluene two times, and the combined extracts were washed
sequentially with water, saturated sodium bicarbonate water, water
and aqueous saturated sodium chloride solution, and then dried with
anhydrous sodium sulfate. The solvent was distilled off, and the
resulting residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate 2:1, v/v) to obtain 420 mg (yield 74%) of
compound 2d as a white solid.
[4165] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.39 (3H, t, J=7.2 Hz),
3.88 (3H, s), 4.39 (2H, q, J=7.2 Hz), 5.34 (2H, s), 7.30-7.41 (3H,
m), 7.45-7.50 (2H, m), 8.48 (1H, s).
Intermediate Synthesis Example 3
##STR01335##
[4166] First Step
[4167] N,N-dimethylformamide dimethyl acetal (4.9 ml, 36.5 mmol)
was added dropwise to compound 3a (5.0 g, 30.4 mmol) at 0.degree.
C. under cooling. After stirring at 0.degree. C. for 1 hour, 100 ml
of ethyl acetate was added to the reaction solution, followed by
washing with 0.5N hydrochloric acid (50 ml). The aqueous layer was
separated, and extracted with ethyl acetate (50 ml). The organic
layers were combined, washed sequentially with saturated sodium
bicarbonate water and aqueous saturated sodium chloride solution,
and then dried with anhydrous sodium sulfate. The solvent was
distilled off, and the resulting residue was purified by silica gel
column chromatography (n-hexane-ethyl acetate 1:1
(v/v).fwdarw.ethyl acetate) to obtain 4.49 g (yield 67%) of
compound 3b as an oil product.
[4168] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.32 (3H, t, J=7.1 Hz),
2.90 (3H, brs), 3.29 (3H, brs), 4.23 (2H, q, J=7.1 Hz), 4.54 (2H,
s), 7.81 (1H, s).
Second Step
[4169] Lithium hexamethyldisilazide (1.0 M toluene solution, 49 ml,
49.0 mmol) was diluted with THF (44 ml), a THF (10 ml) solution of
compound 3b (4.49 g, 20.4 mmol) was added dropwise thereto at
-78.degree. C. under cooling, and a THF (10 ml) solution of ethyl
oxalyl chloride (3.35 g, 24.5 mmol) was added dropwise. After
stirring at -78.degree. C. for 2 hours, temperature was raised to
0.degree. C. After 2N hydrochloric acid was added to the reaction
solution, and the mixture was stirred for 20 minutes, the solution
was extracted with ethyl acetate (200 ml.times.2), and the organic
layer was washed with saturated sodium bicarbonate water and
aqueous saturated sodium chloride solution and then dried with
anhydrous sodium sulfate. The solvent was distilled off, and the
resulting residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate 7:3.fwdarw.5:5.fwdarw.0:10 (v/v)) to obtain
1.77 g (yield 31%) of compound 3c as a white solid.
[4170] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.36-1.46 (6H, m),
4.35-4.52 (8H, m), 8.53 (1H, s).
Third Step
[4171] Aminoacetaldehyde dimethyl acetal (0.13 ml, 1.20 mmol) was
added to an ethanol (6 ml) solution of compound 3c (300 mg, 1.09
mmol) at 0.degree. C., and the mixture was stirred at 0.degree. C.
for 1 hour and 30 minutes, at room temperature for 18 hours and,
then, at 60.degree. C. for 4 hours. After the solvent was distilled
off from the reaction solvent under reduced pressure, the resulting
residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate 5:5.fwdarw.0:10 (v/v)) to obtain 252 mg
(yield 64%) of compound 3d as an oil product.
[4172] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.36-1.47 (6H, m), 3.42
(6H, s), 3.90 (2H, d, J=5.2 Hz), 4.37 (3H, q, J=7.2 Hz), 4.50 (2H,
q, J=7.2 Hz), 8.16 (1H, s).
[4173] Intermediate Synthesis Example 4
##STR01336##
First Step
[4174] N,N-dimethylformamide dimethyl acetal (12.2 ml, 92.2 mmol)
was added dropwise to compound 4a (10.0 g, 76.8 mmol) at 0.degree.
C. under cooling. After stirring at 0.degree. C. for 1 hour and 30
minutes and, then, at room temperature for 2 hours and 30 minutes,
100 ml of ethyl acetate was added to the reaction solution, and the
solvent was distilled off. The resulting residue was purified by
silica gel column chromatography (n-hexane-ethyl acetate
5:5.fwdarw.0:10 (v/v)) to obtain 12.45 g (yield 88%) of compound 4b
as an oil product.
[4175] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.32 (3H, t, J=7.1 Hz),
2.33 (3H, s), 3.04 (6H, brs), 4.23 (2H, q, J=7.2 Hz), 7.68 (1H,
s).
Second Step
[4176] Lithium hexamethyldisilazide (1.0M toluene solution, 24 ml,
24.0 mmol) was diluted with THF (20 ml), a THF (5 ml) solution of
compound 4b (1.85 g, 10.0 mmol) was added dropwise thereto at
-78.degree. C. under cooling, and a THF (5 ml) solution of ethyl
oxalyl chloride (1.34 ml, 12.0 mmol) was added dropwise. After
stirring at -78.degree. C. for 2 hours, 2N-hydrochloric acid was
added to the reaction solution, and the mixture was stirred at room
temperature for 20 minutes. The solution was extracted with ethyl
acetate, and the organic layer was washed sequentially with
saturated sodium bicarbonate water and aqueous saturated sodium
chloride solution, and then dried with anhydrous sodium sulfate.
The solvent was distilled off, and the resulting residue was
purified by silica gel column chromatography (n-hexane-ethyl
acetate 75:25.fwdarw.455:5 (v/v)) to obtain 1.03 g (yield 43%) of
compound 4c as a brown oil product.
[4177] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38 (3H, t, J=7.1 Hz),
1.42 (3H, t, J=7.4 Hz), 4.33-4.47 (4H, m), 7.19 (1H, s), 8.54 (1H,
s).
Third Step
[4178] Aminoacetaldehyde dimethyl acetal (0.34 ml, 3.11 mmol) was
added to an ethanol (6.8 ml) solution of compound 4c (680 mg, 2.83
mmol) at 0.degree. C., and the mixture was allowed to stand at room
temperature for 16 hours. After the solvent was distilled off from
the reaction solution under reduced pressure, the resulting residue
was purified by silica gel column chromatography (n-hexane-ethyl
acetate 90:10 (v/v)) to obtain 875 mg (yield 94%) of compound 4d as
an oil product.
[4179] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38 (3H, t, J=7.1 Hz),
1.39 (3H, t, J=7.1 Hz), 3.40 (6H, s), 4.33 (2H, d, J=4.7 Hz), 4.37
(4H, q, J=7.1 Hz), 4.49 (1H, t, J=4.7 Hz), 7.06 (1H, s), 8.17 (1H,
s).
Fourth Step
[4180] N-bromosuccinimide (1.46 g, 8.18 mmol) was added to a DMF
(10 ml) solution of compound 4d (2.68 g, 8.18 mmol), and the
mixture was stirred at room temperature for 48 hours. After
saturated sodium bicarbonate water was added to the reaction
solution, the solution was extracted with ethyl acetate, and the
organic layer was washed sequentially with water and aqueous
saturated sodium chloride solution, and then dried with anhydrous
sodium sulfate. The solvent was distilled off, and the resulting
residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate 90:10 (v/v)) to obtain 2.83 g (yield 85%)
of compound 4e as an oil product.
[4181] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.38 (3H, t, J=7.1 Hz),
1.46 (3H, t, J=7.1 Hz), 3.42 (6H, s), 3.88 (3H, d, J=5.0 Hz), 4.37
(3H, q, J=7.1 Hz), 4.51 (2H, q, J=7.1 Hz), 4.54 (2H, t, J=5.2 Hz),
8.17 (1H, s).
Intermediate Synthesis Example 5
##STR01337##
[4182] First Step
[4183] Compound 5a (598 mg, 4.09 mmol) and N,N-dimethylformamide
dimethyl acetal (488 mg, 4.09 mmol) were dissolved in toluene (1
ml), and the solution was stirred at room temperature for 11 hours.
The solvent was distilled off from the reaction solution under
reduced pressure, and the resulting residue (containing compound
5b) was used in Second step without purification.
Second Step
[4184] Sodium tert-butoxide (400 mg, 4.16 mmol) was suspended in
DMI (5 ml), a DMI (5 ml) solution of the crude product obtained in
First step was added thereto, then, a THF (10 ml) solution of
dimethyl oxalate (983 mg, 8.32 mmol) was added dropwise, and the
mixture was stirred at room temperature for 45 minutes. The
reaction solution was poured into 2N hydrochloric acid-methanol (20
ml), and the mixture was stirred at 0.degree. C. for 20 minutes.
Water was added, the solution was extracted with ethyl acetate, and
the organic layer was washed sequentially with water, saturated
sodium bicarbonate water, and aqueous saturated sodium chloride
solution, and dried with anhydrous sodium sulfate. After the
solvent was distilled off, the resulting residue was purified by
silica gel column chromatography to obtain 222 mg (yield: 22% from
5a) of compound 3C.
[4185] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.91 (3H, s), 3.97 (3H,
s), 4.05 (3H, s), 8.50 (1H, s).
Intermediate Synthesis Example 6
##STR01338##
[4186] First Step
[4187] Lithium hexamethyldisilazide (1.0M toluene solution, 12 ml,
12.0 mmol) was diluted with THF (11 ml), a THF (2 ml) solution of
compound 6a (1.46 g, 5.0 mmol) was added dropwise thereto at
-78.degree. C. under cooling, and a THF (2 ml) solution of ethyl
oxalyl chloride (0.67 ml, 6.0 mmol) was added dropwise. After
stirring at -78.degree. C. for 2 hours, ammonium acetate (500 mg)
and acetic acid (10 ml) were added to the reaction solution, and
the mixture was stirred at 65.degree. C. for 1 hour and 30 minutes.
Water was added to the reaction solution, the solvent was extracted
with ethyl acetate, and the organic layer was washed sequentially
with water, and saturated sodium bicarbonate water, and dried with
anhydrous sodium sulfate. The solvent was distilled off, and the
resulting residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate 55:45.fwdarw.45:55 (v/v)) to obtain 505.1
mg of compound 6b as a yellow solid. It was washed with isopropyl
ether-hexane (1:2), and dried under reduced pressure to obtain
416.8 mg (yield 24%) of compound 6b as a yellow crystal.
[4188] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.35 (3H, t, J=7.1 Hz),
1.46 (3H, t, J=7.1 Hz), 4.40 (2H, q, J=7.2 Hz), 4.50 (2H, q, J=7.1
Hz), 5.20 (2H, s), 7.33-7.41 (3H, m), 7.49-7.52 (2H, m), 8.76 (1H,
s), 11.61 (1H, brs).
Second Step
[4189] Cesium carbonate (73.3 mg, 0.23 mmol) and bromoacetaldehyde
dimethyl acetal (38.0 mg, 0.23 mmol) were added to a DMF (1 ml)
solution of compound 6b (51.8 mg, 0.15 mmol), and the mixture was
stirred at room temperature overnight. Cesium carbonate (73.3 mg,
0.23 mmol) and bromoacetaldehyde dimethyl acetal (38.0 mg, 0.23
mmol) were further added, and the mixture was further stirred at
100.degree. C. for 20 minutes. After water was added to the
reaction solution, the solution was extracted with ethyl acetate,
and the organic layer was washed sequentially with water and
aqueous saturated sodium chloride solution, and dried with
anhydrous sodium sulfate. The solvent was distilled off, and the
resulting residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate 50:50.fwdarw.30:70 (v/v)) to obtain 35.3 mg
(yield 54%) of compound 6c as a colorless oil product.
[4190] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.26 (3H, t, J=7.1 Hz),
1.40 (3H, t, J=7.1 Hz), 3.39 (6H, s), 3.91 (2H, d, J=5.0 Hz), 4.29
(2H, q, J=7.1 Hz), 4.40 (2H, q, J=7.2 Hz), 4.50 (1H, t, J=5.0 Hz),
5.30 (2H, s), 7.31-7.37 (3H, m), 7.43-7.46 (2H, m), 8.12 (1H,
s).
[4191] Intermediate Synthesis Example 7
##STR01339##
First Step
[4192] Aminoacetaldehyde dimethyl acetal (7.80 mmol) was added to
an ethanol (5 ml) solution of compound 7a (900 mg, 2.60 mmol), and
the mixture was stirred at room temperature for 22 hours. Ethyl
acetate (5 ml) and water (5 ml) were added to the reaction
solution, followed by extraction with ethyl acetate (5 ml). After
the organic layer was washed with water (10 ml), the solvent was
distilled off, and the resulting residue was purified by silica gel
column chromatography (n-hexane-ethyl acetate 2:1) to obtain 0.37 g
(yield 33%) of compound 7b as a colorless oil product.
[4193] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.90 (1H, s), 7.45-7.43
(5H, m), 5.30 (2H, s), 4.51 (1H, t, J=5.1 Hz), 4.40 (2H, q, J=7.1
Hz), 4.30 (2H, q, J=7.1 Hz), 3.91 (2H, d, J=5.1 Hz), 3.46 (6H, s),
1.40 (3H, t, J=7.1 Hz), 1.26 (3H, t, J=7.1 Hz).
[4194] The compounds in connection with the present invention
and/or the parent compounds of the compounds in connection with the
present invention are useful for symptoms and/or diseases which are
induced by influenza virus. For example, they are useful for
treating and/or preventing, or improving symptoms of, cold-like
symptoms accompanying fever, algor, headache, muscular pain,
general malaise etc., airway inflammation symptoms such as
pharyngalgia, nasal secretion, nasal congestion, cough, sputum
etc., gastrointestinal symptoms such as abdominal pain, vomitus,
diarrhea etc. and, further, complications accompanying secondary
infection such as acute encephalopathy and pneumonia.
[4195] Since the compounds in connection with the present invention
are a prodrug and thus have advantages that oral absorbability is
high, good bioavailability is exhibited, good clearance is
exhibited, and pulmonary transitivity is high, they can be
excellent medicaments.
[4196] Since the parent compounds of the compounds in connection
with the present invention have the effects such as high inhibitory
activity on cap structure-dependent endonuclease, and high
selectivity due to a virus-specific enzyme, they can be medicaments
having reduced side effects.
[4197] Further, since the compounds in connection with the present
invention and/or the parent compounds of the compounds in
connection with the present invention also have advantages that
metabolism stability is high, solubility is high, oral
absorbability is high, good bioavailability is exhibited, good
clearance is exhibited, pulmonary transitivity is high, a half life
is long, a non-protein binding rate is high, hERG channel
inhibition is low, CYP inhibition is low, CPE (CytoPathic Effect)
inhibiting effect is recognized, and/or negativity is exhibited in
a phototoxicity test, an Ames test and a gene toxicity test, or
toxicity such as liver damage is not caused. Therefore, the
compounds in connection with the present invention can be excellent
medicaments.
[4198] The compounds in connection with the present invention
and/or the parent compounds of the compounds in connection with the
present invention can be administered orally or parenterally. In
the case of oral administration, the present compounds can be also
used as a normal preparation, for example, as any dosage form of
solid preparations such as tablets, powders, granules, capsules
etc.; solutions; oleaginous suspensions; or liquid preparations
such as syrups or elixirs etc. In the case of parenteral
administration, the compounds in connection with the present
invention can be used as aqueous or oleaginous suspension
injectables, or nose drops. Upon preparation of them, conventional
excipients, binders, lubricants, aqueous solvents, oleaginous
solvents, emulsifiers, suspending agents, preservatives,
stabilizers etc. can be arbitrarily used. The pharmaceutical
composition of the present invention can be produced by combining
(for example, mixing) a therapeutically effective amount of the
present compound with pharmaceutically acceptable carriers or
diluents.
[4199] A dose of the compounds in connection with the present
invention is different depending on an administration method, an
age, a weight and the state of a patient, and a kind of a disease
and, usually, in the case of oral administration, about 0.05 mg to
3000 mg, preferably about 0.1 mg to 1000 mg for adult per day may
be administered, if necessary, by division. In addition, in the
case of parenteral administration, about 0.01 mg to 1000 mg,
preferably about 0.05 mg to 500 mg for adult per day is
administered.
Test Example 1: Measurement of Cap-Dependant Endonuclease (CEN)
Inhibitory Activity
1) Preparation of Substrate
[4200] 30merRNA(5'-pp-[m2'-O] GAA UAU(-Cy3) GCA UCA CUA GUA AGC UUU
GCU CUA-BHQ2-3': manufactured by Japan Bio Services Co., LTD.) in
which G at a 5' end is diphosphate-modified, a hydroxy group at 2'
position is methoxylation-modified, U sixth from a 5' end is
labelled with Cy3, and a 3' end is labelled with BHQ2 was
purchased, and a cap structure was added using ScriptCap system
manufactured by EPICENTRE (a product was m7G [5']-ppp-[5']
[m2'-O]GAA UAU(-Cy3) GCA UCA CUA GUA AGC UUU GCU CUA(-BHQ2)-3').
This was separated and purified by denatured polyacrylamide gel
electrophoresis, and used as a substrate.
2) Preparation of Enzyme
[4201] RNP was prepared from a virus particle using standard method
(Reference Document: VIROLOGY (1976) 73, p 327-338 OLGA M.
ROCHOVANSKY). Specifically, A/WSN/33 virus (1.times.10.sup.3
PFU/mL, 200 .mu.L) was inoculated in a 10 days old embryonated
chicken egg. After incubation at 37.degree. C. for 2 days, the
allantoic fluid of the chicken egg was recovered. A virus particle
was purified by ultracentrifugation using 20% sucrose, solubilized
using TritonX-100 and lysolecithin, and an RNP fraction (50-70%
glycerol fraction) was collected by ultracentrifugation using a
30-70% glycerol density gradient, and was used as an enzyme
solution (containing approximately 1 nM PB1-PB2-PA complex).
3) Enzymatic Reaction
[4202] An enzymatic reaction solution (2.5 .mu.L) (composition: 53
mM Tris-hydrochloride (pH 7.8), 1 mM MgCl.sub.2, 1.25 mM
dithiothreitol, 80 mM NaCl, 12.5% glycerol, enzyme solution 0.15
.mu.L) was dispensed into a 384-well plate made of polypropylene.
Then, 0.5 .mu.L of a test compound solution which had been serially
diluted with dimethyl sulfoxide (DMSO) was added to the plate. As a
positive control (PC) or a negative control (NC), 0.5 .mu.L of DMSO
was added to the plate respectively. Each plate was mixed well.
Then, 2 .mu.L of a substrate solution (1.4 nM substrate RNA, 0.05%
Tween20) was added to initiate a reaction. After room temperature
incubation for 60 minutes, 1 .mu.L of the reaction solution was
collected and added to 10 .mu.L of a Hi-Di formamide solution
(containing GeneScan 120 Liz Size Standard as a sizing marker:
manufactured by Applied Biosystems (ABI)) in order to stop the
reaction. For NC, the reaction was stopped in advance by adding
EDTA (4.5 mM) before initiation of the reaction (all concentrations
described above are final concentrations).
3) Measurement of Inhibition Ratio (IC.sub.50 Value)
[4203] The solution for which the reaction was stopped was heated
at 85.degree. C. for 5 minutes, rapidly cooled on ice for 2
minutes, and analyzed with an ABI PRIZM 3730 genetic analyzer. A
peak of the cap-dependent endonuclease product was quantitated by
analysis software ABI Genemapper, a CEN reaction inhibition ratio
(%) of a test compound was obtained by setting fluorescent
intensities of PC and NC to be 0% inhibition and 100% inhibition,
respectively, an IC.sub.50 value was obtained using curve fitting
software (XLfit2.0: Model 205 (manufactured by IDBS) etc.). The
IC.sub.50 values of test substances being a parent compound, are
shown in Tables 22 to 34.
Test Example 2: CYP Inhibition Test
[4204] Using commercially available pooled human liver microsomes,
and employing, as markers, 7-ethoxyresorufin O-deethylation
(CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin
4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation
(CYP2D6), and terfenadine hydroxylation (CYP3A4) as typical
substrate metabolism reactions of human main five CYP enzyme forms
(CYP1A2, 2C9, 2C19, 2D6, 3A4), an inhibitory degree of each
metabolite production amount by a test compound was assessed.
[4205] The reaction conditions were as follows: substrate, 0.5
.mu.mol/L ethoxyresorufin (CYP1A2), 100 .mu.mol/L tolbutamide
(CYP2C9), 50 .mu.mol/L S-mephenytoin (CYP2C19), 5 .mu.mol/L
dextromethorphan (CYP2D6), 1 .mu.mol/L terfenadine (CYP3A4);
reaction time, 15 minutes; reaction temperature, 37.degree. C.;
enzyme, pooled human liver microsomes 0.2 mg protein/mL; test drug
concentration, 1, 5, 10, 20 .mu.mol/L (four points).
[4206] Each five kinds of substrates, human liver microsomes, or a
test drug in 50 mM Hepes buffer as a reaction solution was added to
a 96-well plate at the composition as described above, NADPH, as a
cofactor was added to initiate metabolism reactions as markers and,
after the reaction at 37.degree. C. for 15 minutes, a
methanol/acetonitrile=1/1 (v/v) solution was added to stop the
reaction. After the centrifugation at 3000 rpm for 15 minutes,
resorufin (CYP1A2 metabolite) in the centrifugal supernatant was
quantified by a fluorescent multilabel counter and tolubtamide
hydroxide (CYP2C9 metabolite), mephenytoin 4' hydroxide (CYP2C19
metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine
alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.
[4207] Addition of only DMSO being a solvent dissolving a drug to a
reaction system was adopted as a control (100%), remaining activity
(%) was calculated at each concentration of a test drug added as
the solution and IC.sub.50 was calculated by reverse presumption by
a logistic model using a concentration and an inhibition rate.
Test Example 3: Solubility Test
[4208] The solubility of each compound was determined under 1% DMSO
addition conditions. A 10 mM solution of the compound was prepared
with DMSO, and 6 .mu.L of the compound solution was added to 594
.mu.L of an artificial intestinal juice (water and 118 mL of 0.2
mol/L NaOH reagent were added to 250 mL of 0.2 mol/L potassium
dihydrogen phosphate reagent to reach 1000 mL) with pH of 6.8. The
mixture was left standing for 16 hours at 25.degree. C., and the
mixture was vacuum-filtered. The filtrate was two-fold diluted with
methanol/water=1/1, and the compound concentration in the filtrate
was measured with HPLC or LC/MS/MS by the absolute calibration
method.
Test Example 4: Metabolism Stability Test
[4209] A reaction was performed (oxidative reaction) at 37.degree.
C. for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in
0.2 mL of a buffer (50 mmol/L tris-HCl pH 7.4, 150 mmol/L potassium
chloride, 10 mmol/L magnesium chloride) containing 0.5 mg
protein/mL of human liver microsomes. After the reaction, 50 .mu.L
of the reaction solution was added to 100 .mu.L of a
methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at 3000 rpm
for 15 minutes. The test compound in the supernatant was quantified
by LC/MS/MS, and a remaining amount of the test compound after the
reaction was calculated, letting a compound amount at 0 minute
reaction time to be 100%. Hydrolysis reaction was performed in the
absence of NADPH and glucuronidation reaction was performed in the
presence of 5 mM UDP-glucuronic acid in place of NADPH, followed by
similar operations.
Test Example 5: hERG Test
[4210] For the purpose of assessing risk of an electrocardiogram QT
interval prolongation, effects on delayed rectifier K.sup.+ current
(I.sub.Kr), which plays an important role in the ventricular
repolarization process, was studied using HEK293 cells expressing
human ether-a-go-go related gene (hERG) channel.
[4211] After a cell was retained at a membrane potential of -80 mV
by whole cell patch clamp method using an automated patch clamp
system (PatchXpress 7000A, Axon Instruments Inc.), I.sub.Kr induced
by depolarization pulse stimulation at +50 mV for 2 seconds and,
further, repolarization pulse stimulation at -50 mV for 2 seconds
was recorded. After the generated current was stabilized,
extracellular solution (NaCl: 137 mmol/L, KCl: 4 mmol/L,
CaCl.sub.2.2H.sub.2O: 1.8 mmol/L, MgCl.sub.2.6H.sub.2O: 1 mmol/L,
glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-piperazine
ethanesulfonic acid): 10 mmol/L, pH=7.4) in which the test
substance had been dissolved at an objective concentration was
applied to the cell under the room temperature condition for 10
minutes. From the resulting I.sub.Kr, an absolute value of the tail
peak current was measured based on the current value at the resting
membrane potential using an analysis software (DataXpress ver. 1,
Molecular Devices Corporation). Further, the inhibition rate
relative to the tail peak current before application of the test
substance was calculated, and compared with the vehicle-applied
group (0.1% dimethyl sulfoxide solution) to assess influence of the
test substance on I.sub.Kr.
Test Example 6: CPE Inhibitory Effect Confirming Assay
<Material>
[4212] 2% FCS E-MEM (prepared by adding kanamycin and FCS to MEM
(Minimum Essential Medium) (Invitrogen))
[4213] 0.5% BSA E-MEM (prepared by adding kanamycin and BSA to MEM
(Minimum Essential Medium) (Invitrogen))
[4214] HBSS (Hanks' Balanced Salt Solution)
[4215] MDBK Cell
Cells were adjusted to the appropriate cell number
(3.times.10.sup.5/mL) with 2% FCS E-MEM.
[4216] MDCK Cell
[4217] After washing with HBSS two times, cells were adjusted to
the appropriate cell number (5.times.10.sup.5/mL) with 0.5% BSA
E-MEM.
[4218] Trypsin Solution
Trypsin from porcine pancreas (SIGMA) was dissolved in PBS(-), and
filtrated with a 0.45 .mu.m filter.
[4219] EnVision (PerkinElmer)
[4220] WST-8 Kit (Kishida Chemical Co., Ltd.)
[4221] 10% SDS solution
<Operation Procedure>
[4222] Dilution and Dispensation of Test Sample
[4223] As a culture medium, 2% FCS E-MEM was used at the use of
MDBK cells, and 0.5% BSA E-MEM was used at the use of MDCK cells.
Hereinafter, for diluting virus, cells and a test sample, the same
culture medium was used.
[4224] A test sample was diluted with a culture medium to an
appropriate concentration in advance, and then 2 to 5-fold serial
dilution on a 96 well plate (50 .mu.L/well) was prepared. Two
plates, one for measuring anti-Flu activity and the another for
measuring cytotoxity, were prepared. Each assay was performed
triplicate for each drug.
[4225] At the use of MDCK cells, Trypsin was added to the cells to
be a final concentration of 3 pg/mL only for measuring anti-Flu
activity.
[4226] Dilution and Dispensation of Influenza Virus
[4227] An influenza virus was diluted with a culture medium to an
appropriate concentration in advance, and each 50 .mu.L/well was
dispensed on a 96-well plate containing a test substance. Each 50
.mu.L/well of a culture medium was dispensed on a plate containing
a test substance for measuring cytotoxity.
[4228] Dilution and Dispensation of Cell
[4229] Each 100 .mu.L/well of cells which had been adjusted to the
appropriate cell number was dispensed on a 96 well plate containing
a test sample.
[4230] This was mixed with a plate mixer, and incubated in a CO2
incubator for 3 days for measuring anti-Flu activity and measuring
cytotoxity.
[4231] Dispensation of WST-8
[4232] The cells in the 96-well plate which had been incubated for
3 days was observed visually under a microscope, and appearance of
the cells, the presence or absence of a crystal of test substance
were checked. The supernatant was removed so that the cells were
not absorbed from the plate.
[4233] WST-8 Kit was diluted 10-fold with a culture medium, and
each 100 .mu.L was dispensed into each well. After mixing with a
plate mixer, cells were incubated in a CO2 incubator for 1 to 3
hours.
[4234] After incubation, regarding the plate for measuring anti-Flu
activity, each 10 .mu.L/well of a 10% SDS solution was dispensed in
order to inactivate a virus.
[4235] Measurement of Absorbance
[4236] After the 96-well plate was mixed, absorbance was measured
with EnVision at two wavelengths of 450 nm/620 nm.
<Calculation of Each Measurement Item Value>
[4237] The value was calculated using Microsoft Excel or a program
having the equivalent calculation and processing ability, based on
the following calculation equation.
[4238] Calculation of Effective Inhibition Concentration to Achieve
50% Influenza Infected Cell Death (EC50)
EC50=10{circumflex over ( )}Z
Z=(50%-High %)/(High %-Low %).times.{log(High conc.)-log(Low
conc.)}+log(High conc.)
[4239] For test substances (compounds of Reference examples) being
a parent compound, measurement results of Test Example 1 and Test
Example 6 are shown in Tables 22 to 34.
TABLE-US-00022 TABLE 22 Reference CEN IC.sub.50 CPE EC.sub.50
example No. (.mu.M) (.mu.M) 2 0.048 0.293 14 0.043 0.313 16 0.065
0.632 26 0.108 0.547 37 0.101 0.318 43 0.078 1.410 48 0.087 10.90
56 0.358 3.860 62 0.110 1.680 63 0.170 2.000 94 0.096 1.470 99
0.341 2.000 108 0.037 0.019 128 0.063 0.416 138 0.166 0.100 139
0.189 0.741 143 0.224 0.333 150 0.193 0.553 175 0.132 0.102 178
0.061 0.075
TABLE-US-00023 TABLE 23 Reference CEN IC.sub.50 CPE EC.sub.50
example No. (.mu.M) (.mu.M) 181 0.049 0.349 182 0.099 0.562 183
0.074 2.370 184 0.055 0.403 185 0.132 1.920 186 0.085 0.159 187
0.085 0.282 190 0.143 2.640 191 0.238 2.820 199 0.236 2.720 204
0.299 2.360 224 0.276 0.119 225 0.283 0.663 228 0.243 0.141 230
0.282 0.525 233 0.228 2.240 238 0.101 0.440 240 0.037 0.048 241
0.197 0.063 242 0.114 0.059 243 0.076 0.020 244 0.249 0.108 246
0.082 0.026 247 0.282 2.260 248 0.103 0.489 249 0.151 1.890 250
0.113 0.476 251 0.058 0.157 252 0.107 0.454 253 0.235 0.280 254
0.135 0.564 255 0.052 0.319 256 0.038 0.400
TABLE-US-00024 TABLE 24 Reference CEN IC.sub.50 CPE EC.sub.50
example No. (.mu.M) (.mu.M) 257 0.041 0.055 258 0.042 0.028 259
0.066 0.026 260 0.091 0.065 261 0.058 0.047 262 0.032 0.038 263
0.085 0.075 264 0.064 0.128 265 0.172 0.036 266 0.043 0.085 267
0.029 0.063 268 0.018 0.074 269 0.073 0.417 270 0.058 0.129 271
0.073 0.102 272 0.082 0.030 273 0.016 0.084 274 0.038 0.016 274
0.157 0.056 276 0.053 0.089 277 0.039 0.071 278 0.205 0.074 279
0.056 0.119 280 0.068 0.145 281 0.026 0.018 282 0.036 0.029 283
0.028 0.021 284 0.042 0.019 285 0.044 0.017 286 0.161 0.121 287
0.154 0.268 288 0.299 0.085 289 0.031 0.419
TABLE-US-00025 TABLE 25 Reference CEN IC.sub.50 CPE EC.sub.50
example No. (.mu.M) (.mu.M) 290 0.067 0.492 292 0.155 2.230 293
0.290 0.437 294 0.035 0.018 295 0.052 0.334 296 0.130 0.397 297
0.045 0.033 298 0.044 0.012 299 0.050 0.015 300 0.058 0.021 301
0.062 0.017 302 0.035 0.014 304 0.018 0.015 305 0.059 0.103 306
0.076 0.021 307 0.052 0.095 308 0.072 0.019 309 0.040 0.013 310
0.108 0.522 311 0.040 0.026 312 0.019 0.029 313 0.189 0.050 314
0.149 0.026 315 0.057 0.115 316 0.069 0.083 317 0.048 0.017 318
0.130 0.015 320 0.045 0.011 321 0.019 0.019 322 0.113 0.028 323
0.077 0.019 324 0.107 0.035 325 0.032 0.025
TABLE-US-00026 TABLE 26 Reference CEN IC.sub.50 CPE EC.sub.50
example No. (.mu.M) (.mu.M) 326 0.043 0.005 327 0.092 0.024 328
0.029 0.168 329 0.058 0.023 330 0.026 0.019 331 0.045 0.335 332
0.048 0.020 333 0.021 0.425 334 0.075 0.032 335 0.019 0.016 336
0.051 0.070 337 0.058 0.028 338 0.074 0.085 339 0.183 0.040 340
0.101 0.027 341 0.016 0.027 342 0.099 0.026 343 0.122 0.018 344
0.050 0.009 345 0.097 0.008 346 0.028 0.018 347 0.014 0.017 348
0.054 0.080 349 0.053 0.075 351 0.091 0.019 352 0.067 0.020 354
0.025 0.083 355 0.040 0.075 356 0.066 0.020 357 0.138 0.386 358
0.051 0.069 359 0.037 0.080 360 0.042 0.087
TABLE-US-00027 TABLE 27 Reference CEN IC.sub.50 CPE EC.sub.50
example No. (.mu.M) (.mu.M) 361 0.039 0.145 362 0.084 0.067 363
0.058 0.067 364 0.112 0.515 365 0.041 2.250 366 0.090 0.838 368
0.140 0.470 369 0.294 0.434 370 0.113 0.061 371 0.161 0.074 372
0.164 0.146 373 0.065 0.050 374 0.137 0.154 375 0.037 0.073 376
0.063 0.092 377 0.024 0.022 378 0.047 0.022 380 0.123 0.018 381
0.200 0.034 382 0.032 0.094 384 0.153 0.293 386 0.075 0.096 387
0.300 1.150 388 0.133 0.063 390 0.095 0.029 391 0.264 0.071 392
0.153 0.025 394 0.087 0.064 395 0.043 0.089 396 0.056 0.060 397
0.055 0.077 398 0.034 0.118 399 0.105 0.061
TABLE-US-00028 TABLE 28 Reference CEN IC.sub.50 CPE EC.sub.50
example No. (.mu.M) (.mu.M) 400 0.067 0.079 401 0.089 0.133 402
0.085 0.081 403 0.090 0.070 404 0.084 0.063 405 0.074 0.051 406
0.119 0.022 407 0.035 0.017 408 0.135 0.061 409 0.093 0.029 410
0.265 0.014 411 0.046 0.014 412 0.292 0.203 413 0.050 0.005 414
1.890 0.131 415 0.285 0.022 416 0.112 0.019 417 0.030 0.003 418
0.121 0.072 419 0.124 0.019 420 0.058 0.021 423 0.280 0.019 425
0.183 0.047 429 0.016 0.004 430 0.168 0.029 431 0.097 0.011 432
0.155 0.062 433 0.014 0.017 441 0.044 0.005 443 0.166 0.004 444
0.066 0.003 445 0.013 0.004 446 0.007 0.011
TABLE-US-00029 TABLE 29 Reference CEN IC.sub.50 CPE EC.sub.50
example No. (.mu.M) (.mu.M) 447 0.096 0.018 448 0.039 0.008 449
0.062 0.021 450 0.023 0.014 452 0.177 0.016 453 0.186 0.049 454
0.012 0.004 455 0.025 0.071 456 0.032 0.004 457 0.242 0.014 458
0.048 0.014 459 0.287 0.048 460 0.085 0.009 461 0.255 0.074 462
0.069 0.011 463 0.012 0.005 464 0.024 0.014 469 0.016 0.004 470
0.008 0.003 475 0.164 0.441 476 0.031 0.014 478 0.088 0.129 479
0.117 0.064 480 0.151 0.084 481 0.114 0.086 482 0.103 0.031 483
0.101 0.027 485 0.221 0.424 486 0.140 0.072 487 0.091 0.026 488
0.151 0.027 489 0.133 0.014 490 0.212 0.468
TABLE-US-00030 TABLE 30 Reference CEN IC.sub.50 CPE EC.sub.50
example No. (.mu.M) (.mu.M) 491 0.069 0.099 492 0.121 0.160 493
0.112 0.101 495 0.277 0.310 496 0.170 0.177 497 0.215 0.511 498
0.161 0.351 502 0.042 0.142 506 0.247 1.620 507 0.063 0.197 508
0.036 0.056 509 0.015 0.014 511 0.175 0.015 514 0.049 0.018 515
0.197 0.019 516 0.039 0.017 518 0.049 0.024 520 0.212 0.017 521
0.191 0.015 522 0.039 0.014 523 0.035 0.014 524 0.057 0.026 525
0.141 0.090 526 0.044 0.019 527 0.127 0.088 532 0.098 0.075 533
0.065 0.391 534 0.165 1.200 536 0.071 0.027 537 0.152 0.022 538
0.196 0.030 544 0.168 0.051 546 0.202 0.124
TABLE-US-00031 TABLE 31 Reference CEN IC.sub.50 CPE EC.sub.50
example No. (.mu.M) (.mu.M) 547 0.032 0.027 548 0.086 0.038 549
0.076 2.100 550 0.042 0.042 551 0.041 0.107 552 0.230 0.085 553
0.028 0.030 554 0.065 0.465 555 0.023 0.012 556 0.023 0.412 557
0.281 2.470 558 0.114 0.541 560 0.027 0.173 561 0.073 0.008 562
0.022 0.062 563 0.049 0.464 564 0.088 0.136 565 0.154 0.726 568
0.264 2.810 569 0.138 1.010 570 0.081 2.050 571 0.065 0.320 573
0.055 0.158 574 0.165 0.442 575 0.058 0.087 576 0.063 0.027 577
0.233 0.337 581 0.083 0.480
TABLE-US-00032 TABLE 32 Reference CEN IC.sub.50 CPE EC.sub.50
example No. (.mu.M) (.mu.M) 592 0,029 0.012 594 0.011 0.004 597
0.339 0.049 598 0.016 0.005 599 0.025 0.008 600 0.059 0.036 601
0.025 0.008 602 0.005 0.004 603 0.037 0.015 609 0.053 0.025 611
0.055 0.043 612 0.055 0.013 613 0.173 0.018 617 0.053 0.017 618
0.029 0.018 619 0.005 0.006 621 0.006 0.002 622 0.089 0.012 623
0.021 0.003 624 0.065 0.057 628 0.043 0.013 629 0.089 0.064 631
0.075 0.041 632 0.132 0.038
TABLE-US-00033 TABLE 33 Reference CEN IC.sub.50 CPE EC.sub.50
example No. (.mu.M) (.mu.M) 633 0.053 0.022 634 0.103 0.017 636
0,074 0.015 638 0.130 0.021 639 0.055 0.017 640 0.057 0.006 641
0.046 0.023 642 0.256 0.094 643 0.163 0.132 644 0.238 0.060 645
0.105 0.016 648 0.132 0.059 649 0.182 0.051 650 0.219 0.103 651
0.056 0.013 652 0.330 0.079 654 0.008 0.001 656 0.070 0.019 658
0.053 0.019 660 0.036 0.011 661 0.135 0.014 662 0.316 0.022 663
0.031 0.018 665 0.018 0.005
TABLE-US-00034 TABLE 34 Reference CEN IC.sub.50 CPE EC.sub.50
example No. (.mu.M) (.mu.M) 666 0.00336 0.00391 668 0.0126 0.00384
682 0.0197 0.0035 686 0.0151 0.00786 691 0.00367 0.00405 692 0.0369
0.00964 704 0.0111 0.0035 706 0.0186 0.00719 707 0.0402 0.00305 708
0.0465 0.00849 709 0.0343 0.00709 710 0.0206 0.00981 711 0.00557
0.00428 712 0.0164 0.00645 716 0.00554 0.0056 719 0.0026 0.00836
720 0.0191 0.00624 721 0.00696 0.00395 722 0.0192 0.00378 724
0.00507 0.00633 726 0.00374 0.00393 728 0.0747 0.00432 730 0.00252
0.000799 731 0.00576 0.00208 741 0.021 0.00351 748 0.0242 0.00914
752 0.0142 0.00312 753 0.109 0.0185 762 0.0315 0.0059 768 0.0153
0.00364 771 0.00589 0.00405 772 0.00522 0.00368
[4240] Based on the above results, the parent compounds exhibit
high cap-dependent endonuclease (CEN) inhibitory activity and/or
high CPE inhibitory effect and thus can be a useful agent for
treatment and/or prevention of symptom and/or disease induced by
infection with influenza virus.
Test Example 7: Influenza Virus-Infected Mouse Lethality Inhibitory
Test
<Mouse>
[4241] BALB/cAnNCrlCrlj (female, 5-week-old; CHARLES RIVER
LABORATORIES JAPAN, INC.) was purchased, and 6- to 7-week-old mice
were used in the test.
<Preparation of Virus Solution>
[4242] A/WS/33, A/Victoria/3/75 or B/Maryland/1/59 (ATCC) was
passaged in mouse lung to make a mouse-acclimatized virus. A
freezing-stored mouse-acclimatized virus solution was rapidly
thawed, and diluted with DPBS to an infectivity titer to be used
(in the case of A/WS/33: 800-4000TCID.sub.50/mouse, in the case of
A/Victoria/3/75: 750 TCID.sub.50/mouse, in the case of
B/Maryland/1/59: 100 TCID.sub.50/mouse).
<Infection>
[4243] Under anesthesia with ketamine.xylazine mixture, 100 ul of
the prepared virus solution was nasally inoculated to directly
infect mouse lung.
<Preparation of Test Sample>
[4244] A test sample was suspended in a 0.5% methylcellulose
solution to a suitable concentration.
<Administration of Test Sample to Infected Mouse>
[4245] A suitably diluted test sample was orally administered at
200 ul to a mouse immediately after virus infection or after the
elapse of a certain period of time.
<Drug Efficacy Assessment>
[4246] The mouse was reared for 14 days after virus infection, and
a necessary dose per day for 50% lethality inhibition, ED.sub.50
(mg/kg/day), a lethality inhibition rate at a maximum dose (%
survival), or days during which the mouse survives 50% as compared
with a control at a maximum dose (50% life extension days) was
calculated. Alternatively, the amount of virus in the lung for
several days after virus infection was measured, and compared with
the amount of virus of control to evaluate virus inhibitory
effect.
<Euthanasia>
[4247] The mouse after completion of the test was euthanized by
carbon dioxide or halothane excessive administration.
<Result>
[4248] The ED.sub.50 values of single dose are shown.
[4249] Number of compound of Reference example 413: 12.3
[4250] Number of compound of Example 20: 4.4
[4251] Based on the above results, it was revealed that compound of
Example 20 obtained by converting compound of Reference example 413
being a parent compound into a prodrug exhibits lethality
inhibitory effect at lower concentration.
Test Example 8: BA Test
Experimental Material and Method for Studying Oral
Absorbability
[4252] (1) Animal to be used: A mouse or rat was used.
[4253] (2) Rearing conditions: Mouse and rat ingested a solid feed
and sterilized tap water ad-libitum.
[4254] (3) Dose and setting of grouping: A predetermined dose was
administered orally or intravenously. A group was set as follows.
(a dose varied for every compound)
[4255] Oral administration 1 to 30 mg/kg (n=2 to 3)
[4256] Intravenous administration 0.5 to 10 mg/kg (n=2 to 3)
[4257] (4) Preparation of administration solution: For oral
administration, a solution or suspension was administered. For
intravenous administration, a compound which was solubilized was
administered.
[4258] (5) Administration method: For oral administration, the
administration solution was forcibly administered to the stomach by
oral sonde. For intravenous administration, the administration
solution was administered with a syringe equipped with an injection
needle through a tail vein.
[4259] (6) Assessment item: Blood was collected with time, and a
plasma drug concentration was measured using LC/MS/MS.
[4260] (7) Statistical analysis: Regarding plasma concentration
transition, an area under a plasma concentration-time curve (AUC)
was calculated using a non-linear minimum square method program
WinNonlin (registered trademark), and bioavailability (BA) was
calculated from AUC of an oral-administered group and an
intervenous-administered group.
<Result>
[4261] The measurement results measured using a rat are shown in
the following Table 35.
TABLE-US-00035 TABLE 35 Reference example No Parent compound
Example No. Prodrug (Parent compound) BA (%) (Prodrug) BA (%) 301
2.3 114 6.8 301 2.3 204 13.0 413 4.3 20 13.2 429 13.3 137 19.8 429
13.3 146 30.5 445 12.1 117 23.3 445 12.1 155 26.9 445 12.1 209 18.6
592 4.2 100 10.7 592 4.2 141 17.9 592 4.2 160 15.8 594 5.0 104 14.8
594 5.0 116 21.3 594 5.0 142 10.3 594 5.0 156 17.8
[4262] Based on the above results, the prodrug had improved
bioavailability other than the parent compound.
[4263] Therefore, the compound of the present invention has
excellent oral absorbability and can be a useful agent for
treatment and/or prevention of symptom and/or disease induced by
infection with influenza virus.
[4264] FIGS. 1 to 4 show a result of determining changes in the
plasma concentration of Reference example 301, for compounds of
Examples 114 and 204 prepared by converting compound of Reference
example 301 being a parent compound into a prodrug, after oral
administration to rat under non-fasting conditions.
[4265] BA after oral administrating Examples 114 and 204 was 6.8%
and 13.0%, respectively. Improvement of bioavailability was found
when compared to the case of orally administrating compound of
Reference example 301 being a parent compound (BA=2.3%). The Tmax
values of both compounds were 1 hr or less, and it was shown that
oral absorbability was high. In addition, in compounds of Examples
114 and 204, the concentration in all plasma samples was a
determination limit or less.
[4266] Based on the above test results, it was revealed that the
compound of Example converted into a prodrug was absorbed into the
body after oral administration, and rapidly converted into a parent
compound in the blood. Therefore, the compound of the present
invention can be a useful agent for treatment and/or prevention of
symptom and/or disease induced by infection with influenza
virus.
Formulation Example 1
[4267] A granule containing the following ingredients is
manufactured.
TABLE-US-00036 Ingredients A compound represented by formula (I) 10
mg Lactose 700 mg Cornstarch 274 mg HPC-L 16 mg 1000 mg
[4268] A compound represented by formula (I) and lactose are passed
through a 60 mesh sieve. Cornstarch is passed through a 120 mesh
sieve. These are mixed with a V-type blender. To the mixed powder
is added an aqueous HPC-L (low viscosity hydroxypropylcellulose)
solution, and the mixture is kneaded together, granulated
(extrusion granulation, pore diameter 0.5-1 mm), and dried. The
obtained dried granule is passed through a vibrating sieve (12/60
mesh) to obtain a granule.
Formulation Example 2
[4269] A granule for encapsulation containing the following
ingredients is manufactured.
TABLE-US-00037 Ingredients A compound represented by formula (I) 15
mg Lactose 90 mg Cornstarch 42 mg HPC-L 3 mg 150 mg
[4270] A compound represented by formula (I) and lactose are passed
through a 60 mesh sieve. Cornstarch is passed through a 120 mesh
sieve. These are mixed, a HPC-L solution is added to the mixed
powder, then the mixture is kneaded together, granulated, and
dried. The obtained dried granule is trimmed, and then 150 mg
thereof is filled into a No. 4 hard gelatin capsule.
Formulation Example 3
[4271] A tablet containing the following ingredients is
manufactured.
TABLE-US-00038 Ingredients A compound represented by formula (I) 10
mg Lactose 90 mg microcrystalline cellulose 30 mg CMC-Na 15 mg
Magnesium stearate 5 mg 150 mg
[4272] A compound represented by formula (I), lactose,
microcrystalline cellulose, and CMC-Na (carboxymethylcellulose
sodium salt) are passed through a 60 mesh sieve and mixed.
Magnesium stearate is added to the mixed powder to obtain a mixed
powder for tablet. The mixed powder is compressed directly to
obtain a 150 mg tablet.
Formulation Example 4
[4273] The following ingredients were mixed under heat, and then
sterilized to obtain an injectable solution.
TABLE-US-00039 Ingredients A compound shown by formula (I) 3 mg
Nonionic surfactant 15 mg Purified water for injection 1 ml
INDUSTRIAL APPLICABILITY
[4274] The compound of the present invention has cap-dependent
endonuclease (CEN) inhibitory activity after absorption into the
body. The compound of the present invention can be a useful agent
for treatment and/or prevention of symptom and/or disease induced
by infection with influenza virus.
* * * * *