U.S. patent application number 12/081773 was filed with the patent office on 2009-05-28 for novel quinoxalinone derivatives.
Invention is credited to Hiroshi Hirai, Masaaki Hirose, Kaori Kamijyo, Nobuhiko Kawanishi, Kouta Masutani, Jun Shibata, Tetsuya Sugimoto.
Application Number | 20090137597 12/081773 |
Document ID | / |
Family ID | 32211587 |
Filed Date | 2009-05-28 |
United States Patent
Application |
20090137597 |
Kind Code |
A1 |
Hirai; Hiroshi ; et
al. |
May 28, 2009 |
Novel quinoxalinone derivatives
Abstract
A quinoxalinone derivative of the formula (I): ##STR00001## or a
pharmaceutically acceptable salt or ester thereof, wherein; X is
NH, S or the like; Y is O or the like; the partial structure
##STR00002## is, for example, the formula: ##STR00003## B.sub.1,
B.sub.2, . . . , B.sub.n-1 and B.sub.n, (in which n is 4, 5 or 6)
are each independently CH, N or the like; B'.sub.1, B'.sub.2, . . .
, B'.sub.n-1 and B'.sub.n (in which n is 4, 5 or 6) are each
independently hydrogen or the like; and R is hydrogen, lower alkyl
or the like.
Inventors: |
Hirai; Hiroshi; (Tsukuba,
JP) ; Kawanishi; Nobuhiko; (Tsukuba, JP) ;
Hirose; Masaaki; (Tsukuba, JP) ; Sugimoto;
Tetsuya; (Tsukuba, JP) ; Kamijyo; Kaori;
(Tsukuba, JP) ; Shibata; Jun; (Tsukuba, JP)
; Masutani; Kouta; (Tsukuba, JP) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W., SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
32211587 |
Appl. No.: |
12/081773 |
Filed: |
April 21, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10532677 |
Jun 15, 2005 |
7388010 |
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PCT/JP03/13707 |
Oct 27, 2003 |
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12081773 |
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Current U.S.
Class: |
514/250 ;
540/456 |
Current CPC
Class: |
A61K 31/517 20130101;
C07D 498/18 20130101; A61K 31/5377 20130101; A61K 31/55 20130101;
C07D 487/18 20130101; C07D 498/22 20130101; A61P 35/00 20180101;
C07D 515/22 20130101; A61P 43/00 20180101; A61K 31/506 20130101;
A61K 31/4995 20130101; C07D 515/18 20130101 |
Class at
Publication: |
514/250 ;
540/456 |
International
Class: |
A61K 31/4985 20060101
A61K031/4985; C07D 513/22 20060101 C07D513/22; A61P 35/00 20060101
A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 29, 2002 |
JP |
2002-313588 |
Claims
1-16. (canceled)
17. A quinoxalinone derivative of the formula (I): ##STR00453## or
a pharmaceutically acceptable salt thereof, wherein; X is S; Y is O
or NR', wherein R' is hydrogen or lower alkyl; the partial
structure ##STR00454## is the following formula: ##STR00455##
wherein B.sub.1, B.sub.2, B.sub.3, B.sub.4 and B.sub.5 are each
independently CH, CR.sub.0, N or O, wherein when B.sub.1, B.sub.2,
B.sub.3, B.sub.4 and B.sub.5 are each independently O, then
B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and B'.sub.5 are each taken
together with B.sub.1, B.sub.2, B.sub.3, B.sub.4 and B.sub.5,
respectively, to form O, with the proviso that two or more members
of B.sub.1, B.sub.2, B.sub.3, B.sub.4 and B.sub.5, at the same
time, are not taken together with B'.sub.1, B'.sub.2, B'.sub.3,
B'.sub.4 and B'.sub.5, respectively, to form O; and R.sub.0 is
lower alkyl, and B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and
B'.sub.5 are each independently hydrogen, halogen, hydroxy, oxo,
lower alkoxy, amino, lower alkylamino, di-lower alkylamino, lower
alkyl or lower alkenyl, wherein said lower alkyl and said lower
alkenyl may be substituted with one or more, same or different
substituents selected from the group consisting of hydroxy, lower
alkoxy, amino and lower alkylamino, and among B'.sub.1, B'.sub.2,
B'.sub.3, B'.sub.4 and B'.sub.5, B'.sub.1 and B'.sub.3 taken
together with B.sub.1, B.sub.2 and B.sub.3, B'.sub.2 and B'.sub.4
taken together with B.sub.2, B.sub.3 and B.sub.4, B'.sub.3 and
B'.sub.5 taken together with B.sub.3, B.sub.4 and B.sub.5, B'.sub.1
and B'.sub.4 taken together with B.sub.1, B.sub.2, B.sub.3 and
B.sub.4, or B'.sub.2 and B'.sub.5 taken together with B.sub.2,
B.sub.3, B.sub.4 and B.sub.5 may form a C.sub.5-C.sub.6 cycloalkyl
or an aliphatic heterocyclic group selected from the substituent
group .beta..sub.1 mentioned below, and said cycloalkyl and said
aliphatic heterocyclic group may be substituted with one or more,
same or different substituents selected from lower alkyl and the
substituent group .alpha.mentioned below; R is hydrogen, lower
alkyl, lower alkenyl, amino in which the nitrogen atom is
di-substituted with R.sub.a and R.sub.b, amino-lower alkyl in which
the nitrogen atom is di-substituted with R.sub.a and R.sub.b, or L,
wherein R.sub.a and R.sub.b are each independently hydrogen, lower
alkyl, lower alkoxyalkyl or halogenated lower alkyl, and L is
L.sub.1-L.sub.2-L.sub.3, wherein L.sub.1 is a single bond,
--(CH.sub.2).sub.k1--, --(CH.sub.2).sub.k1--O--, or
--(CH.sub.2).sub.k1--NH--, in which k1 is an integer of 1 to 3;
L.sub.2 is a single bond or --(CH.sub.2).sub.k2-- in which k2 is an
integer of 1 to 3; and L.sub.3 is lower alkyl, lower alkoxy,
C.sub.3-C.sub.6 cycloalkyl, phenyl, pyridyl, pyrrolidinyl or
piperidinyl, said lower alkyl, lower alkoxy, C.sub.3-C.sub.6
cycloalkyl, phenyl, pyridyl, pyrrolidinyl or piperidinyl being
optionally substituted with one or more fluorine atoms; or
alternatively R is a substituent selected from the substituent
group .alpha. mentioned below, which may be substituted with one or
more, same or different substituents selected from the substituent
group .gamma. mentioned below, or R is lower alkyl substituted with
said substituent; or alternatively R is a cyclic group selected
from the substituent group .beta..sub.2 mentioned below, which may
be substituted with one or more, same or different substituents
selected from a lower alkyl, the substituent group .alpha.
mentioned below and the substituent group .gamma. mentioned below
and also which may be substituted with J, wherein J is
J.sub.1-J.sub.2-J.sub.3; J.sub.1 is a single bond, --C(.dbd.O)--,
--O--, --NH--, --NHCO--, --(CH.sub.2).sub.k3-- or
--(CH.sub.2).sub.k3--O--, in which k3 is an integer of 1 to 3);
J.sub.2 is a single bond or --(CH.sub.2).sub.k4--, in which k4 is
an integer of 1 to 3; and J.sub.3 is lower alkyl, lower alkoxy,
--CONR.sub.aR.sub.b, wherein R.sub.a and R.sub.b each have the same
meaning as defined above, phenyl, pyridyl, pyrrolidinyl or
piperidinyl, said lower alkyl, lower alkoxy, phenyl, pyridyl,
pyrrolidinyl or piperidinyl being optionally substituted with one
or more fluorine atoms, or R is lower alkyl substituted with said
cyclic group, and in the above, the substituent group .alpha., the
substituent group .alpha..sub.1, the substituent group .beta..sub.2
and the substituent group .gamma. each have the meanings shown
below: the substituent group .alpha. is a member selected from the
group consisting of hydroxy, hydroxy-lower alkyl, cyano, halogen,
carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkoxy, lower
alkoxyalkyl, amino, lower alkylamino, lower alkylsulfonyl,
halogenated lower alkyl, halogenated lower alkoxy, halogenated
lower alkylamino, nitro and lower alkanoylamino, the substituent
group .beta..sub.1 is a member selected from the group consisting
of ##STR00456## the substituent group .beta..sub.2 is a member
selected from the group consisting of ##STR00457## the substituent
group .gamma. is a member selected from the group consisting of
C.sub.3-C.sub.6 cycloalkyl, lower alkyl substituted with
C.sub.3-C.sub.6 cycloalkyl, phenyl, lower alkyl substituted with
phenyl, pyridyl, pyrrolidinyl and piperidinyl, said C.sub.3-C.sub.6
cycloalkyl, phenyl, pyridyl, pyrrolidinyl and piperidinyl being
optionally substituted with one or more fluorine atoms.
18. The compound according to claim 17 or a pharmaceutically
acceptable salt thereof, wherein; Y is O.
19. The compound according to claim 18 or a pharmaceutically
acceptable salt thereof, wherein; B.sub.1, B.sub.2, B.sub.3,
B.sub.4 and B.sub.5 are each independently CH; or B.sub.1, B.sub.2,
B.sub.4 and B.sub.5 are each independently CH, and B.sub.3 is N or
O.
20. The compound according to claim 19 or a pharmaceutically
acceptable salt thereof, wherein; the substituent group .alpha. is
selected from hydroxy, hydroxy-lower alkyl, halogen, lower
alkoxycarbonyl, lower alkoxy, lower alkoxyalkyl, lower alkylamino,
methyl substituted with one to three fluorine atoms, methoxy
substituted with one to three fluorine atoms and lower alkylamino
substituted with one to three fluorine atoms; and the substituent
group .beta..sub.1 is ##STR00458##
21. The compound according to claim 20 or a pharmaceutically
acceptable salt thereof, wherein; B.sub.1, B.sub.2, B.sub.4 and
B.sub.5 are each independently CH, B.sub.3 is N, and all of
B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and B'.sub.5 are hydrogen;
or one of B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and B'.sub.5 is
lower alkyl or lower alkenyl, and all the others are hydrogen; or
at least two of B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and B'.sub.5
are each independently lower alkyl or lower alkenyl, and all the
others are hydrogen; or among B'.sub.1, B'.sub.2, B'.sub.3,
B'.sub.4 and B'.sub.5, B'.sub.1 and B'.sub.3 taken together with
B.sub.1, B.sub.2 and B.sub.3, B'.sub.2 and B'.sub.4 taken together
with B.sub.2, B.sub.3 and B.sub.4, or B'.sub.3 and B'.sub.5 taken
together with B.sub.3, B.sub.4 and B.sub.5, form an aliphatic
heterocycle group selected from the substituent group .beta..sub.1,
wherein said aliphatic heterocycle may be substituted with one or
more, same or different substituents selected from lower alkyl and
the substituent group .alpha., and the others are hydrogen, lower
alkyl or lower alkenyl.
22. The compound according to any one of claim 21 or a
pharmaceutically acceptable salt thereof, wherein; the R binds to
quinoxalinone as described in the following formula:
##STR00459##
23. The compound according to claim 22 or a pharmaceutically
acceptable salt thereof, wherein; R is hydrogen, amino-lower alkyl
in which the nitrogen atom is di-substituted with R.sub.a and
R.sub.b, or L, wherein R.sub.a and R.sub.b are each independently
lower alkyl, and L is L.sub.1-L.sub.2-L.sub.3, wherein L.sub.1 is a
single bond, --(CH.sub.2).sub.k1--, --(CH.sub.2).sub.k1--O-- or
--(CH.sub.2).sub.k1--NH--, in which k1 is an integer of 1 or 2;
L.sub.2 is a single bond or --(CH.sub.2).sub.k2--, in which k2 is
an integer of 1 or 2; and L.sub.3 is lower alkoxy or
C.sub.3-C.sub.6 cycloalkyl; or R is a cyclic group selected from
the substituent group .beta..sub.2, which may be substituted with
one or more, same or different substituents selected from lower
alkyl and the substituent group .alpha., or R is lower alkyl
substituted with said cyclic group, wherein the substituent group
.beta..sub.2 is selected from ##STR00460## and the substituent
group .alpha. is selected from halogen, lower alkoxy, lower
alkoxyalkyl, methyl substituted with one to three fluorine atoms,
and methoxy substituted with one to three fluorine atoms; or lower
alkyl substituted with a substituent selected from the group
consisting of lower alkylamino and lower alkylamino substituted
with one to three fluorine atoms.
24. The compound according to claim 18 or a pharmaceutically
acceptable salt thereof, wherein; the partial structure
##STR00461## is selected from the group consisting of ##STR00462##
wherein R'' is hydrogen or methyl; and R is selected from the group
consisting of ##STR00463##
25. The compound according to claim 17 or a pharmaceutically
acceptable salt thereof, wherein; the quinoxalinone derivative is
##STR00464##
26. A pharmaceutical composition comprising a quinoxalinone
derivative according to claim 17 as an active ingredient, together
with a pharmaceutically acceptable carrier or diluent.
27. A pharmaceutical composition comprising a quinoxalinone
derivative according to claim 18 as an active ingredient, together
with a pharmaceutically acceptable carrier or diluent.
28. A pharmaceutical composition comprising a quinoxalinone
derivative according to claim 19 as an active ingredient, together
with a pharmaceutically acceptable carrier or diluent.
29. A pharmaceutical composition comprising a quinoxalinone
derivative according to claim 20 as an active ingredient, together
with a pharmaceutically acceptable carrier or diluent.
30. A pharmaceutical composition comprising a quinoxalinone
derivative according to claim 21 as an active ingredient, together
with a pharmaceutically acceptable carrier or diluent.
31. A pharmaceutical composition comprising a quinoxalinone
derivative according to claim 22 as an active ingredient, together
with a pharmaceutically acceptable carrier or diluent.
32. A pharmaceutical composition comprising a quinoxalinone
derivative according to claim 23 as an active ingredient, together
with a pharmaceutically acceptable carrier or diluent.
33. A pharmaceutical composition comprising a quinoxalinone
derivative according to claim 24 as an active ingredient, together
with a pharmaceutically acceptable carrier or diluent.
34. A pharmaceutical composition comprising a quinoxalinone
derivative according to claim 25 as an active ingredient, together
with a pharmaceutically acceptable carrier or diluent.
35. A method of inhibiting Cdk4, which comprises administering to a
patient in need thereof a therapeutically effective amount of a
quinoxalinone derivative according to claim 17 as an active
ingredient, together with a pharmaceutically acceptable carrier or
diluent.
36. A method of inhibiting Cdk4, which comprises administering to a
patient in need thereof a therapeutically effective amount of a
quinoxalinone derivative according to claim 18 as an active
ingredient, together with a pharmaceutically acceptable carrier or
diluent.
37. A method of inhibiting Cdk4, which comprises administering to a
patient in need thereof a therapeutically effective amount of a
quinoxalinone derivative according to claim 19 as an active
ingredient, together with a pharmaceutically acceptable carrier or
diluent.
38. A method of inhibiting Cdk4, which comprises administering to a
patient in need thereof a therapeutically effective amount of a
quinoxalinone derivative according to claim 20 as an active
ingredient, together with a pharmaceutically acceptable carrier or
diluent.
39. A method of inhibiting Cdk4, which comprises administering to a
patient in need thereof a therapeutically effective amount of a
quinoxalinone derivative according to claim 21 as an active
ingredient, together with a pharmaceutically acceptable carrier or
diluent.
40. A method of inhibiting Cdk4, which comprises administering to a
patient in need thereof a therapeutically effective amount of a
quinoxalinone derivative according to claim 22 as an active
ingredient, together with a pharmaceutically acceptable carrier or
diluent.
41. A method of inhibiting Cdk4, which comprises administering to a
patient in need thereof a therapeutically effective amount of a
quinoxalinone derivative according to claim 23 as an active
ingredient, together with a pharmaceutically acceptable carrier or
diluent.
42. A method of inhibiting Cdk4, which comprises administering to a
patient in need thereof a therapeutically effective amount of a
quinoxalinone derivative according to claim 24 as an active
ingredient, together with a pharmaceutically acceptable carrier or
diluent.
43. A method of inhibiting Cdk4, which comprises administering to a
patient in need thereof a therapeutically effective amount of a
quinoxalinone derivative according to claim 25 as an active
ingredient, together with a pharmaceutically acceptable carrier or
diluent.
44. A method for treatment of cancer selected from the group
consisting of glioma (blastoma), breast, lung, gastrointestinal,
endometrial, leukemia, head and neck, liver, ovary or testicular,
and mesothelima, which comprises administering to a patient in need
thereof a quinoxalinone derivative according to claim 17 as an
active ingredient, together with a pharmaceutically acceptable
carrier or diluent.
45. A method for treatment of cancer selected from the group
consisting of glioma (blastoma), breast, lung, gastrointestinal,
endometrial, leukemia, head and neck, liver, ovary or testicular,
and mesothelima, which comprises administering to a patient in need
thereof a quinoxalinone derivative according to claim 18 as an
active ingredient, together with a pharmaceutically acceptable
carrier or diluent.
46. A method for treatment of cancer selected from the group
consisting of glioma (blastoma), breast, lung, gastrointestinal,
endometrial, leukemia, head and neck, liver, ovary or testicular,
and mesothelima, which comprises administering to a patient in need
thereof a quinoxalinone derivative according to claim 19 as an
active ingredient, together with a pharmaceutically acceptable
carrier or diluent.
47. A method for treatment of cancer selected from the group
consisting of glioma (blastoma), breast, lung, gastrointestinal,
endometrial, leukemia, head and neck, liver, ovary or testicular,
and mesothelima, which comprises administering to a patient in need
thereof a quinoxalinone derivative according to claim 20 as an
active ingredient, together with a pharmaceutically acceptable
carrier or diluent.
48. A method for treatment of cancer selected from the group
consisting of glioma (blastoma), breast, lung, gastrointestinal,
endometrial, leukemia, head and neck, liver, ovary or testicular,
and mesothelima, which comprises administering to a patient in need
thereof a quinoxalinone derivative according to claim 21 as an
active ingredient, together with a pharmaceutically acceptable
carrier or diluent.
49. A method for treatment of cancer selected from the group
consisting of glioma (blastoma), breast, lung, gastrointestinal,
endometrial, leukemia, head and neck, liver, ovary or testicular,
and mesothelima, which comprises administering to a patient in need
thereof a quinoxalinone derivative according to claim 22 as an
active ingredient, together with a pharmaceutically acceptable
carrier or diluent.
50. A method for treatment of cancer selected from the group
consisting of glioma (blastoma), breast, lung, gastrointestinal,
endometrial, leukemia, head and neck, liver, ovary or testicular,
and mesothelima, which comprises administering to a patient in need
thereof a quinoxalinone derivative according to claim 23 as an
active ingredient, together with a pharmaceutically acceptable
carrier or diluent.
51. A method for treatment of cancer selected from the group
consisting of glioma (blastoma), breast, lung, gastrointestinal,
endometrial, leukemia, head and neck, liver, ovary or testicular,
and mesothelima, which comprises administering to a patient in need
thereof a quinoxalinone derivative according to claim 24 as an
active ingredient, together with a pharmaceutically acceptable
carrier or diluent.
52. A method for treatment of cancer selected from the group
consisting of glioma (blastoma), breast, lung, gastrointestinal,
endometrial, leukemia, head and neck, liver, ovary or testicular,
and mesothelima, which comprises administering to a patient in need
thereof a quinoxalinone derivative according to claim 25 as an
active ingredient, together with a pharmaceutically acceptable
carrier or diluent.
Description
TECHNICAL FIELD
[0001] The present invention relates to a novel quinoxalinone
derivative which is useful as pharmaceuticals, a process for
preparing the same and a composition containing the same as an
active ingredient.
BACKGROUND ART
[0002] In the process of normal cell proliferation, cell division
and its pause occur orderly in accordance with cell cycle, while
cancer cell proliferation is characterized by disorder. For this
reason, abnormality in the cell cycle control mechanism is supposed
to have a direct relation with oncogenesis or malignant alteration
of cancer. The cell cycle of a mammalian cell is regulated by a
serine/threonine kinase called cyclin-dependent kinase (hereinafter
abbreviated as Cdk) family, and Cdk needs to form a complex with
the regulatory subunit called cyclin in order to exhibit its
enzymatic activity. A cyclin itself also have a family, and each
Cdk molecule is considered to regulate the progression of a certain
cell cycle by forming a complex with a cyclin molecule which is
expressed specifically at the corresponding stage of the cell
cycle. For example, D type cyclin, in combination with Cdk4 or
Cdk6, regulates the progression of G1 phase, cyclin E-Cdk2
regulates G1/S boundary, cyclin A-Cdk2 regulates the progression of
S phase, and cyclin B-cdc2 regulates the progression of G2/M,
respectively. In addition, three sub-types D1, D2 and D3 are known
as a D type cyclin, and moreover the activity of Cdk is considered
to be regulated not only by its association with cyclins but also
by phosphorylation/dephosphorylation of Cdk molecules, degradation
of cyclin molecules and binding with Cdk inhibitor proteins
(Advanced Cancer Research, Vol. 66, pp 181-212 (1995); Current
Opinion in Cell Biology, Vol. 7, pp 773-780 (1995): Nature, Vol.
374, pp 131-134 (1995)).
[0003] Cdk inhibitor proteins in a mammalian cell are classified
roughly into two kinds due to the differences in structure and
property; Cip/Kip family and INK4 family. The former inhibits
cyclin-Cdk complex widely, while the latter binds with Cdk4 or
Cdk6, thereby specifically inhibiting cyclin-Cdk complex (Nature,
vol. 366, pp 704-707 (1993); Molecular and Cellular Biology, vol.
15, pp 2627-2681 (1995): Genes and Development, vol. 9, pp
1149-1163 (1995)).
[0004] For example, P21 (Sdi1/Cip1/Waf1) is nominated for a
representative example of the former, of which RNA transcription is
induced by a cancer repressor gene product, p53.
[0005] On the other hand, for example, p16 (INK4a/MTS1/CDK4I/CDKN2)
is one of the Cdk inhibitor proteins belonging to the latter. The
P16 gene is located on the human chromosome 9p21 which are found to
be abnormal with a high frequency in human cancer cells. Actually,
many cases of deletion of the p16 gene have been reported in
clinical patients. Also, high-frequency of tumorigenesis in a p16
knockout-mouse has been reported (Nature Genetics, vol. 8, pp 27-32
(1994); Trends in Genetics, vol. 11, pp 136-140 (1995); Cell, vol.
85, pp 27-37 (1996)).
[0006] Each Cdk regulates the progression of cell cycle by
phosphorylation of a certain target protein in a specific phase of
cell cycle, and above all, the retinoblastoma (RB) protein is
considered to be one of the most important target proteins. The RB
protein plays an important role in progression from G1 phase to S
phase and is rapidly phosphorylated during the term from late G1
phase to initial S phase. It is considered that this
phosphorylation is carried out by cyclin D-Cdk4/Cdk6 complex
followed by cyclin E-Cdk2 complex, following progression of cell
cycle. The complex composed of hypophosphorylated RB and
transcription factor E2F in early G1 phase dissociates when the RB
protein becomes hyperphosphorylated. As a result, E2F becomes a
transcriptional activator, and at the same time, the suppression of
the promoter activity by RB-E2F complex is removed, thus leading to
the activation of E2F dependent transcription. At present, the
Cdk-RB pathway consisting of E2F, its suppressor RB protein,
Cdk4/Cdk6 which repressively regulates the function of RB protein,
Cdk inhibitory protein which controls the kinase activity of
Cdk4/Cdk6, and D-type cyclin is thought to be an important
mechanism to regulate the progression from G1 phase to S phase
(Cell, vol. 58, pp 1097-1105 (1989); Cell, vol. 65, pp 1053-1061
(1991); Oncogene, vol. 7, pp 1067-1074 (1992); Current Opinion in
Cell Biology, Vol. 8, pp 805-814 (1996); Molecular and Cellular
Biology, vol. 18, pp 753-761 (1998)). In fact, E2F-binding DNA
sequence is located, for example, upstream of the sequence of many
cell growth-related genes which are important in S phase, and it is
reported that in several genes among them the transcription is
activated in an E2F-dependent manner during the term from late G1
phase to initial S phase (The EMBO Journal, vol. 9, pp 2179-2184,
(1990); Molecular and Cellular Biology, vol. 13, pp 1610-1618
(1993)).
[0007] Abnormalities of any factors which relates to in the Cdk-RB
pathway such as, for example, deletion of functional p16, high
expression of cyclin D1, high expression of Cdk4 and deletion of
functional RB protein are frequently found in human cancer cells
(Science, vol. 254, pp 1138-1146 (1991); Cancer Research, Vol. 53,
pp 5535-5541 (1993); Current Opinion in Cell Biology, Vol. 8, pp
805-814 (1996). These are abnormal to such an extent that they tend
to promote the progression from G1 phase to S phase, and thus it is
obvious that this pathway plays an important role in malignant
alteration or abnormal growth of cancer cells.
[0008] Previously, as known compounds having an inhibitory activity
on Cdk family, a series of chromone derivatives represented, for
example, by flavopiridol are known (WO 97/16447, 98/13344);
however, the inhibitory activity of those chromone derivatives is
not sufficient.
DISCLOSURE OF THE INVENTION
[0009] The present inventors previously prepared a novel pyrazinone
derivative having inhibitory activity against Cdk, and filed a PCT
international application (PCT/JP01/05545; WO 02/02550).
[0010] Although the above pyrazinone derivative showed Cdk
inhibitory activity, its cell growth-inhibitory activity was not
sufficient.
[0011] Therefore, a compound with a novel basic structure having an
excellent cell growth-inhibitory activity as well as inhibitory
activity against CdK is now desired.
[0012] The present inventors conducted intensive studies in order
to provide a novel compound having an excellent cell
growth-inhibitory activity as well as CdK inhibitory activity. As a
result, we found that a novel quinoxalinone derivative has both an
inhibitory activity against Cdk and cell growth-inhibitory
activity, and thus completed the present invention. It is obvious
that the quinoxalinone derivative of the present invention has
completely structural originality as compared to the above
pyrazinone derivative in light of its cyclic structure containing a
quinoxalinone core structure.
[0013] Thus, the present invention relates to a quinoxalinone
derivative of the formula (I):
##STR00004##
or a pharmaceutically acceptable salt or ester thereof,
wherein;
[0014] X is NH, S, O or CH.sub.2;
[0015] Y is O or NR', wherein R' is hydrogen or lower alkyl;
[0016] the partial structure
##STR00005##
[0017] is selected from the following formula:
##STR00006##
[0018] wherein B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n, and
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n (in which n is
4, 5 or 6) are each defined as follows:
[0019] B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n are each
independently C, CH, CR.sub.0, N or O (wherein
[0020] when B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n are
each independently C, then B'.sub.1, B'.sub.2, . . . , B'.sub.n-1
and B'.sub.n are oxo, respectively;
[0021] when B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n are
each independently O, then B'.sub.1, B'.sub.2, . . . , B'.sub.n-1
and B'.sub.n are each taken together with B.sub.1, B.sub.2, . . . ,
B.sub.n-1 and B.sub.n, respectively, to form O, with the proviso
that two or more members of B.sub.1, B.sub.2, . . . , B.sub.n-1 and
B.sub.n, at the same time, are not taken together with B'.sub.1,
B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n, respectively, to form O;
and
[0022] R.sub.0 is lower alkyl), and
[0023] B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n are each
independently hydrogen, halogen, hydroxy, oxo, lower alkoxy, amino,
lower alkylamino, di-lower alkylamino, lower alkyl or lower alkenyl
(wherein
[0024] said lower alkyl and said lower alkenyl may be substituted
with one or more, same or different substituents selected from the
group consisting of hydroxy, lower alkoxy, amino and lower
alkylamino, and
[0025] among B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n,
B'.sub.i and B'.sub.i+2 (in which is 1, 2 or 3) taken together with
B.sub.i, B.sub.i+1 and B.sub.i+2, or B'.sub.i and B'.sub.i+3 (in
which i is 1 or 2) taken together with B.sub.i, B.sub.i+1,
B.sub.i+2 and B.sub.i+3, may form a cycloalkyl having five to six
carbon atoms or an aliphatic heterocyclic group selected from
<substituent group .beta..sub.1>, and said cycloalkyl and
said aliphatic heterocyclic group may be substituted with one or
more, same or different substituents selected from lower alkyl and
<substituent group .alpha.>);
[0026] R is hydrogen, lower alkyl, lower alkenyl, amino of which
nitrogen is di-substituted with R.sub.a and R.sub.b, amino-lower
alkyl of which nitrogen is di-substituted with R.sub.a and R.sub.b,
or L, wherein R.sub.a and R.sub.b are each independently hydrogen,
lower alkyl, lower alkoxyalkyl or halogenated lower alkyl, and L is
L.sub.1-L.sub.2-L.sub.3 (wherein L.sub.1 is a single bond,
--(CH.sub.2).sub.k1--, --(CH.sub.2).sub.k1--O-- or
--(CH.sub.2).sub.k1--NH-- (in which k1 is an integer of 1 to 3);
L.sub.2 is a single bond or --(CH.sub.2).sub.k2-- (in which k2 is
an integer of 1 to 3); and L.sub.3 is lower alkyl, lower alkoxy,
cycloalkyl having three to six carbon atoms, phenyl, pyridyl,
pyrrolidinyl or piperidinyl, said lower alkyl, lower alkoxy,
cycloalkyl having three to six carbon atoms, phenyl, pyridyl,
pyrrolidinyl or piperidinyl being optionally substituted with one
or more fluorine atoms); or
[0027] a substituent selected from <substituent group
.alpha.>, which may be substituted with one or more, same or
different substituents selected from <substituent group
.gamma.>, or lower alkyl substituted with said substituent;
or
[0028] a cyclic group selected from <substituent group
.beta..sub.2>, which may be substituted with one or more, same
or different substituents selected from a lower alkyl,
<substituent group .alpha.> and <substituent group
.gamma.>, and also may be substituted with J (wherein J is
J.sub.1-J.sub.2-J.sub.3; J.sub.1 is a single bond, --C(.dbd.O)--,
--O--, --NH--, --NHCO--, --(CH.sub.2).sub.k3-- or
--(CH.sub.2).sub.k3--O-- (in which k3 is an integer of 1 to 3);
J.sub.2 is a single bond or --(CH.sub.2).sub.k4-- (in which k4 is
an integer of 1 to 3); and J.sub.3 is lower alkyl, lower alkoxy,
--CONR.sub.aR.sub.b (wherein R.sub.a and R.sub.b each have the same
meaning as defined above), phenyl, pyridyl, pyrrolidinyl or
piperidinyl, said lower alkyl, lower alkoxy, phenyl, pyridyl,
pyrrolidinyl or piperidinyl being optionally substituted with one
or more fluorine atoms), or lower alkyl substituted with said
cyclic group, and
[0029] in the above, <substituent group .alpha.>,
<substituent group .beta..sub.1>, <substituent group
.beta..sub.2> and <substituent group .gamma.> each have
the meaning shown below:
[0030] <substituent group .alpha.>
hydroxy, hydroxy-lower alkyl, cyano, halogen, carboxyl, lower
alkanoyl, lower alkoxycarbonyl, lower alkoxy, lower alkoxyalkyl,
amino, lower alkylamino, lower alkylsulfonyl, halogenated lower
alkyl, halogenated lower alkoxy, halogenated lower alkylamino,
nitro and lower alkanoylamino,
[0031] <Substituent Group .beta..sub.1>
##STR00007##
[0032] <Substituent Group .beta..sub.2>
##STR00008##
[0033] <Substituent Group .gamma.>
cycloalkyl having three to six carbon atoms, lower alkyl
substituted with cycloalkyl having three to six carbon atoms,
phenyl, lower alkyl substituted with phenyl, pyridyl, pyrrolidinyl
and piperidinyl, wherein said cycloalkyl having three to six carbon
atoms, phenyl, pyridyl, pyrrolidinyl and piperidinyl may be
substituted with one or more fluorine atoms.
[0034] The symbols and terms described in the present specification
are hereinafter explained.
[0035] The term "lower alkyl" in the above formula (I) refers to a
straight- or branched-chain alkyl group having one to six carbon
atoms; for example, methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl or the like;
preferably methyl, ethyl, propyl, isopropyl, tert-butyl or pentyl;
particularly preferably methyl.
[0036] The term "lower alkenyl" in the above formula (I) refers to
a straight- or branched-chain alkenyl group having two to six
carbon atoms; for example, vinyl, 1-propenyl, allyl, isopropenyl,
1-butenyl, 3-butenyl, 1,3-butanedienyl, 2-pentenyl, 4-pentenyl,
1-hexenyl, 3-hexenyl, 5-hexenyl or the like; preferably
1-propenyl.
[0037] The term "halogen" in the above formula (I) refers to, for
example, fluorine atom, chlorine atom, bromine atom, iodine atom or
the like; preferably fluorine atom, chlorine atom or bromine atom;
more preferably fluorine atom.
[0038] The term "lower alkoxy" in the above formula (I) refers to a
group in which oxygen atom is substituted with "lower alkyl";
concretely for example, methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,
neopentyloxy, hexyloxy, isohexyloxy or the like; preferably
methoxy, ethoxy, isopropyloxy or tert-butoxy; more preferably
methoxy or ethoxy, particularly preferably methoxy.
[0039] The term "lower alkoxyalkyl" in the above formula (I) refers
to the above "lower alkyl" substituted with the above "lower
alkoxy"; for example, methoxymethyl, ethoxymethyl,
isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl,
tert-butoxymethyl, pentyloxymethyl, neopentyloxymethyl,
hexyloxymethyl, isohexyloxymethyl, 1-methoxyethyl, 1-ethoxyethyl,
1-isopropoxyethyl, 1-butoxyethyl, 1-isobutoxyethyl,
1-sec-butoxyethyl, 1-tert-butoxyethyl, 1-pentyloxyethyl,
1-neopentyloxyethyl, 1-hexyloxyethyl, 1-isohexyloxyethyl,
2-methoxyethyl, 2-ethoxyethyl, 2-isopropoxyethyl, 2-butoxyethyl,
2-isobutoxyethyl, 2-sec-butoxyethyl, 2-tert-butoxyethyl,
2-pentyloxyethyl, 2-neopentyloxyethyl, 2-hexyloxyethyl,
2-isohexyloxyethyl, 1-methoxy-1-methylethyl,
1-ethoxy-1-methylethyl, 1-isopropoxy-1-methylethyl,
1-butoxy-1-methylethyl, 1-isobutoxy-1-methylethyl,
1-sec-butoxy-1-methylethyl, 1-tert-butoxy-1-methylethyl,
1-pentyloxy-1-methylethyl, 1-neopentyloxy-1-methylethyl,
1-hexyloxy-1-methylethyl, 1-isohexyloxy-1-methylethyl or the like;
preferably, for example, methoxymethyl, ethoxymethyl or
isopropoxymethyl; particularly preferably methoxymethyl.
[0040] The term "halogenated lower alkyl" in the above formula (I)
refers to "lower alkyl" substituted with "halogen"; preferably
"lower alkyl" substituted with one to three fluorine atoms; more
preferably "lower alkyl" substituted with three fluorine atoms.
Concrete examples thereof include trifluoromethyl, difluoromethyl,
2,2,2-trifluoroethyl, pentafluoroethyl and the like; preferably
trifluoromethyl.
[0041] The term "halogenated lower alkoxy" in the above formula (I)
refers to "lower alkoxy" substituted with "halogen"; preferably
"lower alkoxy" substituted with one to three fluorine atoms; more
preferably "lower alkoxy" substituted with three fluorine atoms.
Concrete examples thereof include trifluoromethoxy,
difluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and the
like; preferably trifluoromethoxy.
[0042] The term "lower alkoxycarbonyl" in the above formula (I)
refers to a carbonyl group substituted with the above "lower
alkoxy"; concretely for example, methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,
pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl,
isohexyloxycarbonyl or the like, preferably methoxycarbonyl,
ethoxycarbonyl, isopropoxycarbonyl or tert-butoxycarbonyl; more
preferably methoxycarbonyl or ethoxycarbonyl; particularly
preferably methoxycarbonyl.
[0043] The term "lower alkanoyl" in the above formula (I) refers to
a carbonyl group substituted with the above "lower alkyl"; for
example, acetyl, propionyl, butyryl, isobutyryl, pivaloyl or the
like; preferably acetyl.
[0044] The term "lower alkylamino" in the above formula (I) refers
to an amino group which is N-substituted with the above "lower
alkyl"; for example, N-methylamino, N-ethylamino, N-propylamino,
N-isopropylamino, N-butylamino, N-isobutylamino, N-tert-butylamino,
N-pentylamino, N-hexylamino or the like; preferably, for example,
N-methylamino, N-ethylamino, N-butylamino or N-tert-butylamino,
particularly preferably N-tert-butylamino.
[0045] The term "halogenated lower alkylamino" in the above formula
(I) refers to "lower alkylamino" substituted with "halogen";
preferably "lower alkylamino" substituted with one to three
fluorine atoms; more preferably "lower alkylamino" substituted with
three fluorine atoms. Concrete examples thereof include
2,2,2-trichloroethyl, 2,2,2-trifluoroethyl and the like;
particularly preferably 2,2,2-trifluoroethyl.
[0046] The term "di-lower alkylamino" in the above formula (I)
refers to an amino group which is N,N-disubstituted with the above
"lower alkyl"; for example, N,N-dimethylamino, N,N-diethylamino,
N,N-dipropylamino, N,N-diisopropylamino, N,N-dibutylamino,
N,N-diisobutylamino, N,N-di-tert-butylamino, N,N-dipentylamino,
N,N-dihexylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino or
the like; preferably, for example, N,N-dimethylamino,
N,N-diethylamino, N,N-dibutylamino, N-ethyl-N-methylamino or
N-methyl-N-propylamino.
[0047] The term "lower alkylsulfonyl" in the above formula (I)
refers to a sulfonyl group substituted with the above "lower
alkyl"; for example, methylsulfonyl, ethylsulfonyl, butylsulfonyl
or the like; preferably, for example, methylsulfonyl or
ethylsulfonyl; particularly preferably methylsulfonyl.
[0048] The term "cycloalkyl having three to six carbon atoms" in
the above formula (I) refers to cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclopentyl.
The term "cycloalkyl having five to six carbon atoms" in the above
formula (I) refers to cyclopentyl or cyclohexyl, preferably
cyclopentyl.
[0049] The term "hydroxy-lower alkyl" in the above formula (I)
refers to the above "lower alkyl" substituted with a hydroxy group;
preferably "lower alkyl" substituted with one to three hydroxy
groups; particularly preferably "lower alkyl" substituted with one
hydroxy group. Concrete examples thereof include hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl,
3-hydroxypropyl, 1-hydroxy-2-methylethyl, 1-hydroxybutyl,
1-hydroxy-2-methylpropyl, 1-hydroxy-2,2-dimethylethyl,
1-hydroxypentyl, 1-hydroxy-2-methylbutyl, 1-hydroxyhexyl,
1-hydroxy-2-methylpentyl and the like; preferably hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl and 1-hydroxy-2-methylethyl.
[0050] The term "amino-lower alkyl" in the above formula (I) refers
to the above "lower alkyl" substituted with an amino group;
concretely for example, aminomethyl, 1-amino, 2-aminoethyl,
1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 1-amino-2-methylethyl,
1-aminobutyl, 1-amino-2-methylpropyl, 1-amino-2,2-dimethylethyl,
1-aminopentyl, 1-amino-2-methylbutyl, 1-aminohexyl,
1-amino-2-methylpentyl or the like, preferably aminomethyl,
1-aminoethyl, 2-aminoethyl, or 1-amino-2-methylethyl.
[0051] The term "lower alkanoyl" in the above formula (I) refers to
a carbonyl group substituted with the above "lower alkyl";
preferably a carbonyl group substituted with an alkyl group having
one to five carbon atoms. Concrete examples thereof include acetyl,
propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,
pentanoyl and the like; preferably acetyl, propionyl and pivaloyl;
particularly preferably acetyl.
[0052] The term "lower alkanoylamino" in the above formula (I)
refers to an amino group substituted with the above "lower
alkanoyl"; for example, N-acetylamino, N-propionylamino,
N-butyrylamino or the like; preferably, for example, N-acetylamino
or N-propionylamino.
[0053] "Cdk" refers to a cyclin-dependent kinase including Cdk2,
Cdc2 (=Cdk1), Cdk4, Cdk6, Cdk7 and the like. Here, Cdk2 is
cyclin-dependent kinase 2, Cdc2 is a cell division cycle 2, Cdk1 is
a cyclin-dependent kinase 1, Cdk4 is a cyclin-dependent kinase 4,
Cdk6 is a cyclin-dependent kinase 6, and Cdk7 is a cyclin-dependent
kinase 7. The term "Cdk inhibitor" means an inhibitor against a
cyclin-dependent kinase including Cdk2, Cdc2, Cdk4, Cdk6, Cdk7 and
the like.
[0054] The aforementioned term "pharmaceutically acceptable salt or
ester thereof" is explained later.
BEST MODE FOR CARRYING OUT THE INVENTION
[0055] The embodiments of the compound of the formula (I) will be
described in more detail below.
[0056] X is NH, S, O or CH.sub.2; preferably NH or S; particularly
preferably NH.
[0057] Y is O or NR' (wherein R' is hydrogen or lower alkyl),
preferably O.
[0058] The partial structure
##STR00009##
is selected from the following formula:
##STR00010##
preferably the following formula:
##STR00011##
more preferably the following formula:
##STR00012##
[0059] The above B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n,
and B'.sub.1, B'.sub.2, . . . , B.sub.n-1 and B'.sub.n (in which n
is 4, 5 or 6) are explained below. In the above formula (I),
B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n, and B'.sub.1,
B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n (in which n is 4, 5 or 6)
mean B.sub.1, B.sub.2, B.sub.3 and B.sub.4, and B'.sub.1, B'.sub.2,
B'.sub.3 and B'.sub.4 when n=4; B.sub.1, B.sub.2, B.sub.3, B.sub.4
and B.sub.5, and B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and
B'.sub.5 when n=5; B.sub.1, B.sub.2, B.sub.3, B.sub.4, B.sub.5 and
B.sub.6, and B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4, B'.sub.5 and
B'.sub.6 when n=6, respectively.
[0060] B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n are each
independently C, CH, CR.sub.0, N or O, wherein R.sub.0 is lower
alkyl, and
[0061] when the partial structure
##STR00013##
is the formula:
##STR00014##
then preferably B.sub.1, B.sub.2, B.sub.3, B.sub.4 and B.sub.5 are
each independently CH; or B.sub.1, B.sub.2, B.sub.4 and B.sub.5 are
each independently CH and B.sub.3 is N or O; particularly
preferably, B.sub.1, B.sub.2, B.sub.4 and B.sub.5 are each
independently CH and B.sub.3 is N, and
[0062] when the partial structure
##STR00015##
is the formula:
##STR00016##
then preferably B.sub.1, B.sub.2, B.sub.3, B.sub.5 and B.sub.6 are
each independently CH and B.sub.4 is N.
[0063] Also, when at least one carbon atom of B.sub.1, B.sub.2,
B.sub.3, B.sub.4 and B.sub.5 is an asymmetric carbon, a compound of
the above formula (I) includes any optical isomer thereof as well
as a racemate thereof.
[0064] In the above B.sub.1, B.sub.2, . . . , B.sub.n-1 and
B.sub.n,
[0065] when B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n are
each independently C, then B'.sub.1, B'.sub.2, . . . , B'.sub.n-1
and B'.sub.n are oxo, respectively;
[0066] when B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n are
each independently O, then B'.sub.1, B'.sub.2, . . . , B'.sub.n-1
and B'.sub.n are each taken together with B.sub.1, B.sub.2,
B.sub.n-1 and B.sub.n, respectively, to form O, with the proviso
that two or more members of B.sub.1, B.sub.2, . . . , B.sub.n-1 and
B.sub.n, at the same time, are not taken together with B'.sub.1,
B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n, respectively, to form
O.
[0067] B'.sub.1, B'.sub.2, B'.sub.n-1 and B'.sub.n are each
independently hydrogen, halogen, hydroxy, oxo, lower alkoxy, amino,
lower-alkyl amino, di-lower-alkylamino, lower alkyl or lower
alkenyl, wherein B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and
B'.sub.n, are each independently taken together with B.sub.1,
B.sub.2, . . . , B.sub.n-1 and B.sub.n, respectively, to form O,
with the proviso that two or more members of B'.sub.1, B'.sub.2, .
. . , B'.sub.n-1 and B'.sub.n, at the same time, are not taken
together with B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n,
respectively, to form O.
[0068] In the above B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and
B'.sub.n, said lower alkyl and said lower alkenyl may be
substituted with one or more, same or different substituents
selected from the group consisting of hydroxy, lower alkoxy, amino
and lower alkylamino.
[0069] Also, among the above B'.sub.1, B'.sub.2, . . . , B'.sub.n-1
and B'.sub.n, B'.sub.1 and B'.sub.i+2 (in which i is 1, 2 or 3)
taken together with B.sub.i, B.sub.i+1 and B.sub.i+2, or B'.sub.i
and B'.sub.i+3 (in which i is 1 or 2) taken together with B.sub.i,
B.sub.i+1, B.sub.i+2 and B.sub.i+3, may form a cycloalkyl having
five to six carbon atoms or an aliphatic heterocyclic group
selected from the group consisting of
##STR00017##
(hereinafter referred to as <substituent group
.beta..sub.1>), and said cycloalkyl and said aliphatic
heterocycle may be substituted with one or more, same or different
substituents selected from the group consisting of hydroxy,
hydroxy-lower alkyl, cyano, halogen, carboxyl, lower alkanoyl,
lower alkoxycarbonyl, lower alkoxy, lower alkoxyalkyl, amino, lower
alkylamino, lower alkylsulfonyl, halogenated lower alkyl,
halogenated lower alkoxy, halogenated lower alkylamino, nitro and
lower alkanoylamino (hereinafter referred to as <substituent
group .alpha.>) and lower alkyl.
[0070] Moreover, in the above B'.sub.1, B'.sub.2, . . . ,
B'.sub.n-1 and B'.sub.n, when the partial structure
##STR00018##
is the formula:
##STR00019##
then preferably
[0071] all of B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and B'.sub.5
are hydrogen; or
[0072] one of B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and B'.sub.5
is lower alkyl or lower alkenyl, and all the others are hydrogen;
or
[0073] at least two of B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and
B'.sub.5 are each independently lower alkyl or lower alkenyl, and
all the others are hydrogen; or
[0074] among B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and B'.sub.5,
B'.sub.i and B'.sub.i+2 (in which is 1, 2 or 3) taken together with
B.sub.i, B.sub.i+1 and B.sub.i+2, form an aliphatic heterocycle
selected from the group of
##STR00020##
(hereinafter referred to as <substituent group
.alpha..sub.1a>), wherein said aliphatic heterocycle may be
substituted with one or more, same or different substituents
selected from the group consisting of hydroxy, hydroxy-lower alkyl,
halogen, lower alkoxycarbonyl, lower alkoxy, lower alkoxyalkyl,
lower alkylamino, methyl substituted with one to three fluorine
atoms, methoxy substituted with one to three fluorine atoms and
lower alkylamino substituted with one to three fluorine atoms
(hereinafter referred to as <substituent group
.alpha..sub.a>) and lower alkyl, and the others are hydrogen,
lower alkyl or lower alkenyl; more preferably,
[0075] B.sub.1, B.sub.2, B.sub.4 and B.sub.5 are each independently
CH, B.sub.3 is N, and all of B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4
and B'.sub.5 are hydrogen; or
[0076] one of B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and B'.sub.5
is lower alkyl or lower alkenyl, and all the others are hydrogen;
or
[0077] at least two of B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and
B'.sub.5 are each independently lower alkyl or lower alkenyl, and
all the others are hydrogen; or
[0078] among B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and B'.sub.5,
B'.sub.i and B'.sub.i+2 (in which is 1, 2 or 3) taken together with
B.sub.i, B.sub.i+1 and B.sub.i+2, form an aliphatic heterocycle
selected from <substituent group .beta..sub.1a>, wherein said
aliphatic heterocycle may be substituted with one or more, same or
different substituents selected from lower alkyl and
<substituent group .alpha..sub.a>, and the others are
hydrogen, lower alkyl or lower alkenyl;
particularly preferably,
[0079] X is NH;
[0080] B.sub.1, B.sub.2, B.sub.4 and B.sub.5 are each independently
CH and B.sub.3 is N;
[0081] among B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and B'.sub.5,
B'.sub.1 and B'.sub.i+2 (in which is 1) taken together with
B.sub.i, B.sub.i+1 and B.sub.i+2 form an aliphatic heterocycle
selected from <substituent group .beta..sub.1a>, wherein said
aliphatic heterocycle may be substituted with lower alkyl, and the
others are hydrogen.
[0082] Furthermore, in the above B'.sub.1, B'.sub.2, . . . ,
B'.sub.n-1 and B'.sub.n, when the partial structure
##STR00021##
is the formula:
##STR00022##
then preferably B'.sub.i and B'.sub.i+3 (in which i is 1 or 2)
among B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4, B'.sub.5 and
B'.sub.6, taken together with B.sub.i, B.sub.i+1, B.sub.i+2 and
B.sub.i+3, form
##STR00023##
and all the others are hydrogen; more preferably B'.sub.1,
B'.sub.2, B'.sub.3, B'.sub.5 and B'.sub.6 are each independently
CH, B.sub.4 is N, and B'.sub.i and B'.sub.i+3 (in which i is 1 or
2) among B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4, B'.sub.5 and
B'.sub.6, taken together with B.sub.i, B.sub.i+1, B.sub.i+2 and
B.sub.i+3, form
##STR00024##
and all the others are hydrogen.
[0083] The partial structure
##STR00025##
includes, for example,
##STR00026## ##STR00027##
wherein R'' is hydrogen or methyl, more preferably
##STR00028##
particularly preferably
##STR00029##
[0084] As mentioned above, in terms of improvement in solubility of
compounds of the formula (I), it is preferable that any one of
B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n is a nitrogen
atom.
[0085] R is hydrogen, lower alkyl, lower alkenyl, amino of which
nitrogen is di-substituted with R.sub.a and R.sub.b, amino-lower
alkyl of which nitrogen is di-substituted with R.sub.a and R.sub.b,
or L, wherein R.sub.a and R.sub.b are each independently hydrogen,
lower alkyl, lower alkoxyalkyl or halogenated lower alkyl; and L is
L.sub.1-L.sub.2-L.sub.3 (wherein L.sub.1 is a single bond,
--(CH.sub.2).sub.k1--, --(CH.sub.2).sub.k1--O-- or
--(CH.sub.2).sub.k1--NH-- (in which k1 is an integer of 1 to 3);
L.sub.2 is a single bond or --(CH.sub.2).sub.k2-- (in which k2 is
an integer of 1 to 3); and L.sub.3 is lower alkyl, lower alkoxy,
cycloalkyl having three to six carbon atoms, phenyl, pyridyl,
pyrrolidinyl or piperidinyl, said L.sub.3 is lower alkyl, lower
alkoxy, cycloalkyl having three to six carbon atoms, phenyl,
pyridyl, pyrrolidinyl or piperidinyl being optionally substituted
with one or more fluorine atoms); or
[0086] a substituent selected from <substituent group
.alpha.> which may be substituted with one or more, same or
different substituents selected from the group consisting of
cycloalkyl having three to six carbon atoms, lower alkyl
substituted with cycloalkyl having three to six carbon atoms,
phenyl, lower alkyl substituted with phenyl, pyridyl, pyrrolidinyl
and piperidinyl, said cycloalkyl having three to six carbon atoms,
phenyl, pyridyl, pyrrolidinyl and piperidinyl being optionally
substituted with one or more fluorine atoms (hereinafter referred
to as <substituent group .gamma.>, or lower alkyl substituted
with said substituent; or
[0087] a cyclic group selected from the group consisting of
##STR00030##
(hereinafter referred to as <substituent group
.beta..sub.2>), wherein said cyclic group may be substituted
with one or more, same or different substituents selected from
lower alkyl, <substituent group .alpha.> and <substituent
group .gamma.>, and also may be substituted with J. Here, J is
J.sub.1-J.sub.2-J.sub.3, wherein J.sub.1 is a single bond,
--C(.dbd.O)--, --O--, --NH--, --NHCO--, --(CH.sub.2).sub.k3-- or
--(CH.sub.2).sub.k3--O-- (in which k3 is an integer of 1 to 3);
J.sub.2 is a single bond or --(CH.sub.2).sub.k4-- (in which k4 is
an integer of 1 to 3); and J.sub.3 is lower alkyl, lower alkoxy,
--CONR.sub.aR.sub.b (wherein R.sub.a, and R.sub.b each has the same
meaning as defined above), phenyl, pyridyl, pyrrolidinyl or
piperidinyl, said lower alkyl, lower alkoxy, phenyl, pyridyl,
pyrrolidinyl or piperidinyl being optionally substituted with one
or more fluorine atoms, or lower alkyl substituted with said cyclic
group.
[0088] In addition, R is preferably hydrogen, amino-lower alkyl of
which nitrogen is di-substituted with R.sub.a and R.sub.b, or L,
wherein R.sub.a and R.sub.b are each independently lower alkyl, and
L is L.sub.1-L.sub.2-L.sub.3 (wherein L is a single bond,
--(CH.sub.2).sub.k1--, --(CH.sub.2).sub.k1--O-- or
--(CH.sub.2).sub.k1--NH--(in which k1 is 1 or 2); L.sub.2 is a
single bond or --(CH.sub.2).sub.n-- (in which k2 is 1 or 2); and
L.sub.3 is lower alkoxy or cycloalkyl having three to six carbon
atoms); or
[0089] a cyclic group selected from <substituent group
.beta..sub.2> which may be substituted with one or more, same or
different substituents selected from lower alkyl and
<substituent group .alpha.>, or lower alkyl substituted with
said cyclic group, wherein <substituent group .beta..sub.2>
is selected from
##STR00031##
and <substituent group .alpha.> is selected from halogen,
lower alkoxy, lower alkoxyalkyl, methyl substituted with one to
three fluorine atoms and methoxy substituted with one to three
fluorine atoms; or
[0090] lower alkyl substituted with a substituent selected from the
group consisting of lower alkylamino and lower alkylamino
substituted with one to three fluorine atoms.
[0091] The above R binds to the quinoxalinone structure preferably
as described in the following formula:
##STR00032##
[0092] The above R includes, for example,
##STR00033## ##STR00034##
and the like; preferably includes
##STR00035##
[0093] more preferably includes
##STR00036##
[0094] The present invention relating to a compound of the formula
(I), including a pharmaceutically acceptable salt or ester thereof,
may also be described as follows.
[0095] (i) A quinoxalinone derivative of the formula (I):
##STR00037##
or a pharmaceutically acceptable salt or ester thereof,
wherein;
[0096] X is NH, S, O or CH.sub.2;
[0097] Y is O or NR', wherein R' is hydrogen or lower alkyl; the
partial structure
##STR00038##
is selected from the following formula:
##STR00039##
wherein B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n, and
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n (in which n is
4, 5 or 6) are each defined as follows:
[0098] B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n are each
independently C, CH, CR.sub.0, N or O (wherein
[0099] when B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n are
each independently C, then B'.sub.1, B'.sub.2, . . . , B'.sub.n-1
and B'.sub.n are oxo, respectively;
[0100] when B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n are
each independently O, then B'.sub.1, B'.sub.2, . . . , B'.sub.n-1
and B'.sub.n are each taken together with B.sub.1, B.sub.2,
B.sub.n-1 and B.sub.n, respectively, to form O, with the proviso
that two or more members of B.sub.1, B.sub.2, . . . , B.sub.n-1 and
B.sub.n, at the same time, are not taken together with B'.sub.1,
B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n, respectively, to form O;
and
[0101] R.sub.0 is lower alkyl), and
[0102] B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n are each
independently hydrogen, halogen, hydroxy, oxo, lower alkoxy, amino,
lower alkylamino, di-lower alkylamino, lower alkyl or lower alkenyl
(wherein said lower alkyl and said lower alkenyl may be substituted
with one or more, same or different substituents selected from the
group consisting of hydroxy, lower alkoxy, amino and lower
alkylamino, and
[0103] among B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n,
B'.sub.i and B'.sub.i+2 (in which is 1, 2 or 3) taken together with
B.sub.i, B.sub.i+1 and B.sub.i+2, or B'.sub.i and B'.sub.i+3 (in
which i is 1 or 2) taken together with B.sub.i, B.sub.i+1,
B.sub.i+2 and B.sub.i+3, may form a cycloalkyl having five to six
carbon atoms or an aliphatic heterocyclic group selected from
<substituent group .beta..sub.1>, and said cycloalkyl and
said aliphatic heterocyclic group may be substituted with one or
more, same or different substituents selected from lower alkyl and
<substituent group .alpha.>);
[0104] R is hydrogen, lower alkyl, lower alkenyl, amino in which
the nitrogen atom is di-substituted with R.sub.a, and R.sub.b,
amino-lower alkyl in which the nitrogen atom is di-substituted with
R.sub.a and R.sub.b, or L, wherein R.sub.a and R.sub.b are each
independently hydrogen, lower alkyl, lower alkoxyalkyl or
halogenated lower alkyl, and L is L.sub.1-L.sub.2-L.sub.3 (wherein
L.sub.1 is a single bond, --(CH.sub.2).sub.k1--,
--(CH.sub.2).sub.k1--O-- or --(CH.sub.2).sub.k1--NH-- (in which k1
is an integer of 1 to 3); L.sub.2 is a single bond or
--(CH.sub.2).sub.k2-- (in which k2 is an integer of 1 to 3); and
L.sub.3 is lower alkyl, lower alkoxy, cycloalkyl having three to
six carbon atoms, phenyl, pyridyl, pyrrolidinyl or piperidinyl,
said lower alkyl, lower alkoxy, cycloalkyl having three to six
carbon atoms, phenyl, pyridyl, pyrrolidinyl or piperidinyl being
optionally substituted with one or more fluorine atoms); or
[0105] a substituent selected from <substituent group
.alpha.>, which may be substituted with one or more, same or
different substituents selected from <substituent group
.gamma.>, or lower alkyl substituted with said substituent;
or
[0106] a cyclic group selected from <substituent group
.beta..sub.2>, which may be substituted with one or more, same
or different substituents selected from a lower alkyl,
<substituent group .alpha.> and <substituent group
.gamma.>, and also may be substituted with J (wherein J is
J.sub.1-J.sub.2-J.sub.3; J.sub.1 is a single bond, --C(.dbd.O)--,
--O--, --NH--, --NHCO--, --(CH.sub.2).sub.k3-- or
--(CH.sub.2).sub.k3--O-- (in which k3 is an integer of 1 to 3);
J.sub.2 is a single bond or --(CH.sub.2).sub.k4-- (in which k4 is
an integer of 1 to 3); and J.sub.3 is lower alkyl, lower alkoxy,
--CONR.sub.aR.sub.b (wherein R.sub.a and R.sub.b each have the same
meaning as defined above), phenyl, pyridyl, pyrrolidinyl or
piperidinyl, said lower alkyl, lower alkoxy, phenyl, pyridyl,
pyrrolidinyl or piperidinyl being optionally substituted with one
or more fluorine atoms), or lower alkyl substituted with said
cyclic group, and in the above, <substituent group .alpha.>,
<substituent group .beta..sub.1>, <substituent group
.beta.2> and <substituent group .gamma.> each have the
meaning shown below:
[0107] <Substituent Group .alpha.>
hydroxy, hydroxy-lower alkyl, cyano, halogen, carboxyl, lower
alkanoyl, lower alkoxycarbonyl, lower alkoxy, lower alkoxyalkyl,
amino, lower alkylamino, lower alkylsulfonyl, halogenated lower
alkyl, halogenated lower alkoxy, halogenated lower alkylamino,
nitro and lower alkanoylamino,
[0108] <Substituent Group .beta..sub.1>
##STR00040##
[0109] <Substituent Group .beta..sub.2>
##STR00041##
[0110] <Substituent Group .gamma.>
cycloalkyl having three to six carbon atoms, lower alkyl
substituted with cycloalkyl having three to six carbon atoms,
phenyl, lower alkyl substituted with phenyl, pyridyl, pyrrolidinyl
and piperidinyl, wherein said cycloalkyl having three to six carbon
atoms, phenyl, pyridyl, pyrrolidinyl and piperidinyl may be
substituted with one or more fluorine atoms; or
[0111] (ii) The compound according to the above (i) or a
pharmaceutically acceptable salt or ester thereof, wherein:
[0112] X is NH or S; and
[0113] Y is O; or
[0114] (iii) The compound according to the above (ii) or a
pharmaceutically acceptable salt or ester thereof, wherein;
[0115] the partial structure
##STR00042##
is the formula:
##STR00043##
[0116] (iv) The compound according to the above (iii) or a
pharmaceutically acceptable salt or ester thereof, wherein;
[0117] B.sub.1, B.sub.2, B.sub.3, B.sub.4 and B.sub.5 are each
independently CH; or
[0118] B.sub.1, B.sub.2, B.sub.4 and B.sub.5 are each independently
CH, and B.sub.3 is N or O; or
[0119] (v) The compound according to the above (iv) or a
pharmaceutically acceptable salt or ester thereof, wherein;
[0120] the <substituent group .alpha.> is selected from
hydroxy, hydroxy-lower alkyl, halogen, lower alkoxycarbonyl, lower
alkoxy, lower alkoxyalkyl, lower alkylamino, methyl substituted
with one to three fluorine atoms, methoxy substituted with one to
three fluorine atoms and lower alkylamino substituted with one to
three fluorine atoms, and the <substituent group
.beta..sub.1> is
##STR00044##
or
[0121] (vi) The compound according to the above (v) or a
pharmaceutically acceptable salt or ester thereof, wherein;
[0122] B.sub.1, B.sub.2, B.sub.4 and B.sub.5 are each independently
CH, B.sub.3 is N, and all of B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4
and B'.sub.5 are hydrogen; or
[0123] one of B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and B'.sub.5
is lower alkyl or lower alkenyl, and all the others are hydrogen;
or
[0124] at least two of B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and
B'.sub.5 are each independently lower alkyl or lower alkenyl, and
all the others are hydrogen; or
[0125] among B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and B'.sub.5,
B'.sub.i and B'.sub.i+2 (in which is 1, 2 or 3) taken together with
B.sub.i, B.sub.i+1 and B.sub.i+2 form an aliphatic heterocycle
selected from <substituent group .beta..sub.1> (wherein said
aliphatic heterocycle may be substituted with one or more, same or
different substituents selected from lower alkyl and
<substituent group .alpha.>), and the others are hydrogen,
lower alkyl or lower alkenyl; or
[0126] (vii) The compound according to the above (vi) or a
pharmaceutically acceptable salt or ester thereof, wherein;
[0127] X is NH;
[0128] B.sub.1, B.sub.2, B.sub.4 and B.sub.5 are each independently
CH, and B.sub.3 is N;
[0129] among B'.sub.1, B'.sub.2, B'.sub.3, B'.sub.4 and B'.sub.5,
B'.sub.i and B'.sub.i+2 (in which i is 1) taken together with
B.sub.i, B.sub.i+1 and B.sub.i+2 form an aliphatic heterocycle
selected from <substituent group .beta..sub.1> (wherein said
aliphatic heterocycle may be substituted with lower alkyl), and the
others are hydrogen; or
[0130] (viii) The compound according to the above (ii) or a
pharmaceutically acceptable salt or ester thereof, wherein;
[0131] the partial structure
##STR00045##
is the formula:
##STR00046##
wherein B.sub.1, B.sub.2, B.sub.3, B.sub.5 and B.sub.6 are each
independently CH, and B.sub.4 is N; among B'.sub.1, B'.sub.2,
B'.sub.3, B'.sub.4, B'.sub.5 and B'.sub.6, B'.sub.i and B'.sub.i+3
(in which i is 1 or 2) taken together with B.sub.i, B.sub.i+1,
B.sub.i+2 and B.sub.i+3 form
##STR00047##
and all the others are hydrogen; or
[0132] (ix) The compound according to any one of the above (vi) to
(viii) or a pharmaceutically acceptable salt or ester thereof,
wherein the R binds to quinoxalinone as described in the following
formula:
##STR00048##
[0133] (x) The compound according to the above (ix) or a
pharmaceutically acceptable salt or ester thereof, wherein;
[0134] R is hydrogen, amino-lower alkyl in which the nitrogen atom
is di-substituted with R.sub.a and R.sub.b, or L, wherein R.sub.a
and R.sub.b are each independently lower alkyl, and L is
L.sub.1-L.sub.2-L.sub.3 (wherein L.sub.1 is a single bond,
--(CH.sub.2).sub.k1--, --(CH.sub.2).sub.k1--O-- or
--(CH.sub.2).sub.k1--NH-- (in which k1 is an integer of 1 or 2;
L.sub.2 is a single bond or --(CH.sub.2).sub.k2-- (in which k2 is
an integer of 1 or 2); and L.sub.3 is lower alkoxy or cycloalkyl
having three to six carbon atoms); or
[0135] a cyclic group selected from <substituent group
.beta..sub.2>, which may be substituted with one or more, same
or different substituents selected from lower alkyl and
<substituent group .alpha.>, or lower alkyl substituted with
said cyclic group, wherein the <substituent group
.beta..sub.2> is selected from
##STR00049##
and the <substituent group .alpha.> is selected from halogen,
lower alkoxy, lower alkoxyalkyl, methyl substituted with one to
three fluorine atoms, and methoxy substituted with one to three
fluorine atoms; or lower alkyl substituted with a substituent
selected from the group consisting of lower alkylamino and lower
alkylamino substituted with one to three fluorine atoms; or
[0136] (xi) The compound according to the above (ii) or a
pharmaceutically acceptable salt or ester thereof, wherein;
[0137] the partial structure
##STR00050##
is selected from the group consisting of
##STR00051##
wherein R'' is hydrogen or methyl; and
[0138] R is selected from the group consisting of
##STR00052##
[0139] (xii) The compound according to the above (xi) or a
pharmaceutically acceptable salt or ester thereof, wherein;
[0140] X is NH; and
[0141] the partial structure
##STR00053##
is the formula:
##STR00054##
wherein R'' is methyl; or
[0142] (xiii) The compound according to the above (i) or a
pharmaceutically acceptable salt or ester thereof, wherein;
[0143] the quinoxalinone derivative is
##STR00055## ##STR00056##
[0144] (xiv) A pharmaceutical composition comprising one or more
kinds of the quinoxalinone derivative according to the above (i) as
an active ingredient, together with a pharmaceutically acceptable
carrier or diluent; or
[0145] (xv) A Cdk inhibitor comprising one or more kinds of the
quinoxalinone derivative according to the above (i) as an active
ingredient, together with a pharmaceutically acceptable carrier or
diluent; or
[0146] (xvi) An anti-cancer agent comprising one or more kinds of
the quinoxalinone derivative according to the above (i) as an
active ingredient, together with a pharmaceutically acceptable
carrier or diluent.
[0147] As mentioned above, in the compound of the formula (I):
##STR00057##
wherein X, Y, n; the partial structure
##STR00058##
B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n; B'.sub.1,
B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n; R, <substituent group
.alpha.>, <substituent group .beta..sub.1>,
<substituent group .beta..sub.2> and <substituent group
.gamma.> each have the same meaning as defined above, the
partial structure
##STR00059##
is selected from the following formula:
##STR00060##
[0148] Therefore, the compound of the formula (I) may also be
defined as the compound of the formula (I):
##STR00061##
wherein X, Y, n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n; R,
<substituent group .alpha.>, <substituent group 1>,
<substituent group .beta..sub.2> and <substituent group
.gamma.> each have the same meaning as defined above.
[0149] On the basis of the above newly defined formula (I), a
preparation method of the compound of the formula (I) is
hereinafter described.
[0150] The compound of the formula (I):
##STR00062##
wherein X, Y, n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n; R,
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2> and
<substituent group .gamma.> each have the same meaning as
defined above, can be prepared by removing a protecting group from
the compound of the below-mentioned formula (II) or (III):
##STR00063##
wherein X, Y, n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n; R,
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2> and
<substituent group .gamma.> each have the same meaning as
defined above, and PG is 4-methoxybenzyl, 2,4-dimethoxybenzyl,
benzyl, t-butyl, methyl, ethyl, methoxymethyl,
2-(trimethylsilylethoxy)methyl or the like, preferably, methyl or
2-(trimethylsilylethoxy)methyl, methoxymethyl. Removal of the
protecting group can be carried out according to the method
described in Protective Groups in Organic Synthesis (T. W. Greene,
John Wiley & Sons, Inc, 1981) or its analogous methods, such as
solvolysis using an acid, though it depends on the kind of
protecting groups and the stability of compounds used.
[0151] The preparation methods of the compounds of the formula (II)
or (III):
##STR00064##
are hereinafter described.
Preparation Method A:
[0152] The compound of the above formula (II) or (III) wherein Y is
an oxygen atom can be prepared by subjecting the compound of the
below formula (IV) or (V):
##STR00065##
wherein X, Y, n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n; R,
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.> and PG each have the same meaning
as defined above, to the Mitsunobu reaction for intramolecular
cyclization (Synthesis, 1981, 1). For example, the compound of the
above formula (II) or (III) can be prepared by reacting the
compound of the above formula (IV) or (V) with triphenylphosphine
and diethyl azodicarboxylate in a solvent such as tetrahydrofuran,
1,4-dioxan, methylene chloride, chloroform, toluene or the like. In
this reaction, the reaction temperature is usually 0.degree. C. to
room temperature, although it may be appropriately chosen depending
on the starting material or the reaction solvent to be used.
Further, the reaction is usually completed within 1 to 24 hours,
but the reaction time may be appropriately adjusted to make it
longer or shorter.
[0153] The compound of the above formula (IV) can be prepared by
removing the protecting group represented by PG.sub.2 or PG.sub.3
from the compound of the formula (VI):
##STR00066##
wherein n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n; R,
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2> and
<substituent group .gamma.> each have the same meaning as
defined above; PG.sub.1, PG.sub.2 and PG.sub.3 are each a
protecting group; PG.sub.1 and PG.sub.2 are the same or different
and are each 4-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, t-butyl,
methyl, ethyl, methoxymethyl, 2-(trimethylsilylethoxy)methyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, acetyl, benzoyl, or the
like, preferably methyl, 2-(trimethylsilylethoxy)methyl or
methoxymethyl; and PG.sub.3 is hydrogen, 4-methoxybenzyl,
2,4-dimethoxybenzyl, benzyl, methoxymethyl,
2-(trimethylsilylethoxy)methyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, acetyl, benzoyl or the like, preferably
t-butyldimethylsilyl, t-butyldiphenylsilyl, acetyl or benzoyl.
[0154] Removal of the protecting group can be carried out according
to the method described in Protective Groups in Organic Synthesis
(T. W. Greene, John Wiley & Sons, Inc, 1981) or its analogous
methods such as solvolysis using an acid or a base, chemical
reduction using a metal complex hydride, and catalytic reduction
using a palladium carbon catalyst or Raney nickel catalyst, though
it depends on the kind of protecting groups and the stability of
compounds used.
[0155] The compounds of the above formula, (VI) wherein X is S can
be prepared by reacting the compound of the formula (VII) or
(VIII):
##STR00067##
wherein n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n; R,
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2> and
<substituent group .gamma.>, PG.sub.1, PG.sub.2 and PG.sub.3
each have the same meaning as defined above; and W is a leaving
group such as methanesulfonyloxy, with a base such as sodium
hydroxide, lithium hydroxide or the like in a solvent such as
1,4-dioxan or the like. In this reaction, the reaction temperature
is usually room temperature to the boiling point of the solvent
used, preferably 100.degree. C., though it may be appropriately
chosen depending on the starting material or the reaction solvent
used. Further, the reaction is usually completed within 1 to 24
hours, but the reaction time may be appropriately adjusted to make
it longer or shorter.
[0156] The compound of the above formula (VII) can be prepared by
reacting the compound of the formula (IX):
##STR00068##
wherein R, <substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.>, PG.sub.1 and PG.sub.2 each have
the same meaning as defined above, with a base such as lithium
hexamethyldisilazide or the like in a solvent such as
tetrahydrofuran or the like. In this reaction, the reaction
temperature is usually 0.degree. C. to the boiling point of the
solvent used, preferably room temperature, though it may be
appropriately chosen depending on the starting material or the
reaction solvent to be used. Further, the reaction is usually
completed within 1 to 24 hours, preferably for 1 hour, but the
reaction time may be appropriately adjusted to make it longer or
shorter.
[0157] The compound of the above formula (IX) can be prepared from
the compound of the formula (X):
##STR00069##
wherein R.sub.1 is lower alkyl such as methyl, ethyl or the like;
R, <substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.> and PG.sub.2 each have the same
meaning as defined above, and 2-cyanoethylamine, according to a
method similar to the Preparation Method B-1 described in WO
02/02550.
[0158] The compound of the above formula (X) can be prepared from
the compound of the formula (XI):
##STR00070##
wherein R.sub.1 and R.sub.2 are the same or different and are each
lower alkyl such as methyl, ethyl or the like, according to a
method similar to the Preparation Method A described in WO
02/02550.
[0159] The compound of the above formula (XI) can be prepared by
reacting a corresponding (2-fluoro-3-iodophenyl)oxoacetic acid
ester with carbon monoxide in a mixed solvent of a solvent such as
N,N-dimethylacetamide, N-methylpyrrolidone, N,N-dimethylformamide
or the like, and an alcohol such as methanol, ethanol or the like,
in the presence of a ligand such as
1,1'-bis(diphenylphosphino)ferrocene or the like, a palladium
catalyst such as palladium(II) acetate or the like, and a base such
as triethylamine or the like. In this reaction, the reaction
temperature is usually 50.degree. C. to the boiling point of the
solvent to be used, though it may be appropriately chosen depending
on the starting material or the reaction solvent to be used.
Further, the reaction is usually completed within 1 to 24 hours,
but the reaction time may be appropriately adjusted to make it
longer or shorter.
[0160] In addition to the aforementioned method, the compound of
the above formula (VI) wherein X is S can be prepared from the
compound of the above formula (X) and the compound of the below
formula (XII):
##STR00071##
wherein n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n;
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.> and PG.sub.3 each have the same
meaning as defined above, according to a method similar to the
Preparation Method B-1 described in WO 02/02550.
[0161] The compound of the above formula (VI) wherein. X is NH can
be prepared from the compound of the above formula (X) and the
compound of the below formula (XIII):
##STR00072##
wherein n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-3 and B'.sub.n;
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.> and PG.sub.3 each have the same
meaning as defined above; and PG.sub.4 is t-butoxycarbonyl,
benzyloxycarbonyl, allyloxycarbonyl, formyl, acetyl,
trifluoroacetyl or the like, preferably t-butoxycarbonyl,
allyloxycarbonyl or the like, according to a method similar to the
Preparation Method B-2b described in WO 02/02550.
[0162] The compound of the above formula (VI) wherein X is O can be
prepared from the compound of the above formula (X) and the
compound of the below formula (XIV):
##STR00073##
wherein n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n;
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.> and PG.sub.3 each have the same
meaning as defined above, according to a method similar to the
Preparation Method B-3 described in WO 02/02550.
[0163] The compound of the above formula (V) wherein X is S can be
prepared from the compound of the below formula (XV):
##STR00074##
wherein n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n; R,
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.>, PG.sub.1, PG.sub.2 and PG.sub.3
each have the same meaning as defined above, according to a method
similar to the Preparation Method B-1 described in WO 02/02550.
[0164] The compound of the above formula (XV) can be prepared from
the compound of the below formula (XVI):
##STR00075##
wherein n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1, and B.sub.n; R,
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.>, PG.sub.1, PG.sub.2 and PG.sub.3
each have the same meaning as defined above, according to the
Preparation Method B-1 described in WO 02/02550. Alternatively, the
compound of the above formula (XV) can be prepared by an improved
version of the Preparation Method B-1 described in WO 02/02550.
That is, the compound of the above formula (XV) can also be
prepared by reacting the compound of the above formula (XVI) with
sulfuryl chloride in a solvent such as methylene chloride or the
like in the presence of an organic base such as
N-methylpyrrolidine, triethylamine or the like. In this reaction,
the reaction temperature is usually -78.degree. C. to -50.degree.
C., though it may be appropriately chosen depending on the starting
material or the reaction solvent to be used. The reaction is,
usually completed within 10 to 60 minutes, but the reaction time
may be appropriately adjusted to make it longer or shorter.
[0165] The compound of the above formula (XVI) can be prepared from
the compound of the below formula (XVII):
##STR00076##
wherein R, <substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.>, R.sub.1, PG.sub.1 and PG.sub.2
each have the same meaning as defined above, according to a method
similar to the Preparation Method B-1 described in WO 02/02550.
[0166] The compound of the above formula (XVII) can be prepared by
reacting the compound of the below formula (XVIII):
##STR00077##
wherein R, <substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.>, R.sub.1 and PG.sub.2 each have
the same meaning as defined above, with an alkali metal alkoxide
such as sodium methoxide or the like in a solvent such as
tetrahydrofuran, methanol or the like. In this reaction, the
reaction temperature is usually room temperature to 50.degree. C.,
preferably room temperature, though it may be appropriately chosen
depending on the starting material or the reaction solvent to be
used. Further, the reaction is usually completed within 1 to 24
hours, but the reaction time may be appropriately adjusted to make
it longer or shorter.
[0167] The compound of the above formula (XVIII) can be prepared by
reacting the compound of the above formula (X) with thionyl
chloride and N,N-dimethylformamide. In this reaction, the reaction
temperature is usually room temperature to the boiling point of the
solvent to be used, preferably the boiling point, although it may
be appropriately chosen depending on the starting material to be
used. Further, the reaction is usually completed within 10 to 60
minutes, but the reaction time may be appropriately adjusted to
make it longer or shorter.
[0168] The compound of the above formula (V) wherein X is NH can be
prepared from the compound of the below formula (XIX):
##STR00078##
wherein n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n; R,
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.>, PG.sub.1, PG.sub.2 and PG.sub.3
each have the same meaning as defined above, according to a method
similar to the Preparation Method B-2b described in WO
02/02550.
[0169] The compound of the above formula (XIX) can be prepared from
the compound of the above formula (XVII) and the compound of the
above formula (XIII) according to a method similar to the
Preparation Method B-2b described in WO 02/02550. Alternatively,
the compound of the above formula (XIX) can also be prepared from
the compound of the below formula (XX):
##STR00079##
wherein n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n; R,
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.>, PG.sub.1, PG.sub.2 and PG.sub.3
each have the same meaning as defined above, with a nucleophile
such as diethylamine, formic acid or the like in a solvent such as
tetrahydrofuran or the like in the presence of a palladium catalyst
such as tetrakis(triphenylphosphine)palladium(0) or the like. In
this reaction, the reaction temperature is usually 0.degree. C. to
room temperature, although it may be appropriately chosen depending
on the starting materials and the reaction solvent to be used.
Further, the reaction is usually completed within 1 to 24 hours,
but the reaction time may be appropriately adjusted to make it
longer or shorter.
[0170] The compound of the above formula (XX) can be prepared from
the compound of the above formula (XVII) and the compound of the
above formula (XIII) wherein PG.sub.4 is allyloxycarbonyl,
according to a method similar to the Preparation Method B-2b
described in WO 02/02550.
Preparation Method B:
[0171] The compound of the above formula (II) or (III) wherein Y is
an oxygen atom can be prepared by reacting the compound of the
below formula (XXI) or (XXII):
##STR00080##
wherein X, n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n; R,
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.> and PG each have the same meaning
as defined above; and W is a leaving group such as a iodine atom, a
bromine atom, a methanesulfonyloxy group or the like, with a base
such as potassium carbonate or the like in an aprotic polar solvent
such as N,N-dimethylformamide or the like. In this reaction, the
reaction temperature is usually room temperature to 100.degree. C.,
preferably 60.degree. C. to 80.degree. C., although it may be
appropriately chosen depending on the starting material and the
reaction solvent to be used. Further, the reaction is usually
completed within 1 to 24 hours, but the reaction time may be
appropriately adjusted to make it longer or shorter.
[0172] The compound of the above formula (XXI) or (XXII) can be
prepared according to a method similar to the Preparation Method A
as mentioned above.
Preparation Method C:
[0173] The compound of the above formula (II) or (III) wherein X is
NH and Y is a nitrogen atom can be prepared by reacting the
compound of the below formula (XXIII) or (XXIV) with the compound
of the below formula (XXV):
##STR00081##
wherein X, n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B.sub.2, . . . , B'.sub.n-1 and B'.sub.n; R,
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.> and PG each have the same meaning
as defined above; and W.sub.1 and W.sub.2 are each independently a
leaving group such as a iodine atom, a bromine atom, a
methanesulfonyloxy group or the like, in an aprotic polar solvent
such as N,N-dimethylformamide or the like. In this reaction, the
reaction temperature is usually room temperature to the boiling
point of the solvent used, preferably 60.degree. C. to 80.degree.
C., although it may be appropriately chosen depending on the
starting materials and the reaction solvent to be used. Further,
the reaction is usually completed within 10 to 60 minutes, but the
reaction time may be appropriately adjusted to make it longer or
shorter.
[0174] The compound of the above formula (XXIII) or (XXIV) can be
prepared according to a method similar to the above Preparation
Method A and the methods described in WO 02/02550.
[0175] The introduction or conversion of R may be carried out at
any one of steps in the preparation of the above synthetic
intermediates. Hereinafter, such introduction or conversion of R in
the compound of the above formula (II) or (III) is described.
[0176] The compound of the above formula (II) or (III) wherein R is
methyl can be prepared from the corresponding compound of the above
formula (II) or (III) wherein R is hydroxymethyl. That is, the
compound of the above formula (II) or (III) wherein R is methyl can
be prepared by converting said hydroxymethyl group into
methanesulfonyloxymethyl group, chloromethyl group or the like,
followed by catalytic hydrogenation using a transition metal
catalyst. Also, the compound of the above formula (II) or (III)
wherein R is methanesulfonyloxymethyl is reacted in a solvent such
as tetrahydrofuran, methanol, 1,4-dioxane or the like, or a mixed
solvent thereof in the presence of a transition metal catalyst such
as 10% palladium-carbon catalyst or the like under a hydrogen
atmosphere, thereby to produce the compound of the above formula
(II) or (III) wherein R is methyl. In this reaction, the reaction
temperature is usually 0.degree. C. to the boiling point of the
solvent used, although it may be appropriately chosen depending on
the starting material and the solvent to be used in the reaction.
Further, the reaction is usually completed within 1 to 24 hours,
but the reaction time may be appropriately adjusted to make it
longer or shorter.
[0177] Also, the compound of the above formula (II) or (III)
wherein R is vinyl can be prepared from the corresponding compound
of the above formula (II) or (III) wherein R is a bromine atom. For
example, the compound of the above formula (II) or (III) wherein R
is a bromine atom is reacted with tributylvinyltin in a solvent
such as toluene, 1,4-dioxane, N,N-dimethylformamide or the like,
preferably toluene, in the presence of a palladium catalyst such as
tetrakis(triphenylphosphine)palladium(0) or the like, thereby to
produce the compound of the above formula (II) or (III) wherein R
is vinyl. In this reaction, the reaction temperature is usually
room temperature to the boiling point of the solvent used,
preferably 80.degree. C. to 100.degree. C., although it may be
appropriately chosen depending on the starting material and the
reaction solvent to be used. Further, the reaction is usually
completed within 1 to 24 hours, but the reaction time may be
appropriately adjusted to make it longer or shorter.
[0178] The compound of the above formula (II) or (III) wherein R is
N-alkyl-lower alkanoylamino can be prepared from the corresponding
compound of the above formula (II) or (III) wherein R is a bromine
atom. For example, the compound of the above formula (II) or (III)
wherein R is a bromine atom is reacted with an amide such as
2-pyrrolidinone or the like, in a solvent such as toluene,
1,4-dioxane, N,N-dimethylformamide or the like, preferably
1,4-dioxane, in the presence of a phosphine such as
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like, a
palladium catalyst such as
tris(benzylideneacetone)dipalladium(0)-chloroform adduct or the
like, and a base such as cesium carbonate or the like, thereby to
produce the compound of the above formula (II) or (III) wherein R
is N-alkyl-lower alkanoylamino. In this reaction, the reaction
temperature is usually room temperature to the boiling point of the
solvent used, preferably 60.degree. C. to 120.degree. C., though it
may be appropriately chosen depending on the starting material and
the reaction solvent to be used. Further, the reaction is usually
completed within 1 to 24 hours, but the reaction time may be
appropriately adjusted to make it longer or shorter.
[0179] The compound of the above formula (II) or (III) wherein R is
(dialkyl)aminomethyl or (monoalkyl)aminomethyl can be prepared from
the compound of the above formula (II) or (III) wherein R is
hydroxymethyl. That is, the hydroxymethyl of the compound of the
above formula (II) or (III) wherein R is (dialkyl)aminomethyl or
(monoalkyl)aminomethyl is converted into the
methanesulfonyloxymethyl thereof, the chloromethyl thereof or the
like, followed by alkylation of the resulting product with
dialkylamine or (monoalkyl)amine, or alkylation of the resulting
product with dialkylamine in the presence of an acid catalyst.
[0180] According to the former method, the compound of the above
formula (II) or (III) wherein R is methanesulfonyloxymethyl can be
prepared by reacting the compound of the above formula (II) or
(III) wherein R is hydroxymethyl, with methanesulfonyl chloride in
a solvent such as chloroform, methylene chloride, tetrahydrofuran,
N,N-dimethylformamide, diethyl ether, ethyl acetate or the like, in
the presence of an organic base such as triethylamine,
diisopropylethylamine or the like. In this reaction, the reaction
temperature is usually 0.degree. C. to room temperature, although
it may be appropriately chosen depending on the starting material
to be used, and the reaction is usually completed within 1 to 2
hours, but the reaction time may be appropriately adjusted to make
it longer or shorter. Further, the compound of the above formula
(II) or (III) wherein R is methanesulfonyloxymethyl is reacted with
a dialkylamine such as piperidine, morpholine, N-methylpiperazine,
diethylamine or the like, or (monoalkyl)amine such as
cyclopentylamine, t-butylamine or the like in a solvent such as
chloroform, methylene chloride, tetrahydrofuran,
N,N-dimethylformamide or the like in the presence of an inorganic
base such as potassium carbonate or the like, thereby to produce
the compound of the above formula (II) or (III) wherein R is
(dialkyl)aminomethyl or (monoalkyl)aminomethyl. In this reaction,
the reaction temperature is usually 0.degree. C. to the boiling
point of the reaction solvent used, although it may be
appropriately chosen depending on the starting material and the
reaction solvent to be used, and the reaction is usually completed
within 1 to 24 hours, but the reaction time may be appropriately
adjusted to make it longer or shorter. According to the latter
method, the compound of the above formula (II) or (III) wherein R
is hydroxymethyl is reacted with a dialkylamine such as piperidine,
morpholine, N-methylpiperazine, diethylamine or the like in a
solvent such as chloroform, methylene chloride, tetrahydrofuran,
N,N-dimethylformamide, diethyl ether, ethyl acetate, toluene or the
like in the presence of an acid catalyst such as acetic acid,
hydrochloric acid, sulfuric acid, 4-toluenesulfonic acid or the
like, thereby to produce the compound of the above formula (II) or
(III) wherein R is (dialkyl)aminomethyl. In this reaction, the
reaction temperature is usually room temperature to the boiling
point of the solvent used for the reaction, although it may be
appropriately chosen depending on the starting material and the
reaction solvent to be used, and the reaction is usually completed
within 1 to 3 days, but the reaction time may be appropriately
adjusted to make it longer or shorter.
[0181] Further, the compound of the above formula (II) or (III)
wherein R is 2-[(dialkyl)amino]ethyl can be prepared by addition
reaction of the dialkylamino to the corresponding compound of the
above formula (II) or (III) wherein R is vinyl, and the production
is mentioned above. For example, the compound of the above formula
(II) or (III) wherein R is vinyl is reacted in a sealed tube using
a dialkylamine such as pyrrolidine or the like as a solvent usually
at 100.degree. C. to 150.degree. C., preferably 120.degree. C.,
although the reaction temperature may be appropriately chosen
depending on the starting material and the reaction solvent to be
used, thereby to produce the compound of the above formula (II) or
(III) wherein R is 2-[(dialkyl)amino]ethyl. The reaction is
completed within 1 to 24 hours, but the reaction time may be
appropriately adjusted to make it longer or shorter.
[0182] Also, the compound of the above formula (II) or (III)
wherein R is alkoxycarbonyl can be prepared from the corresponding
compound of the above formula (II) or (III) wherein R is a bromine
atom. For example, the compound of the above formula (II) or (III)
wherein R is a bromine atom is reacted with carbon monoxide in a
solvent including a mixture of a solvent such as
N,N-dimethylacetamide, N-methylpyrrolidone, N,N-dimethylacetamide
or the like, and an alcohol such as methanol, ethanol or the like,
in the presence of a ligand such as
1,1'-bis(diphenylphosphino)ferrocene or the like, a palladium
catalyst such as palladium(II) acetate or the like, and a base such
as sodium hydrogencarbonate or the like, thereby to produce the
compound of the above formula (II) or (III) wherein R is an
alkoxycarbonyl group. In this reaction, the reaction temperature is
usually 50.degree. C. to the boiling point of the solvent used in
the reaction, though it may be appropriately chosen depending on
the starting material and the reaction solvent to be used, and the
reaction is usually completed within 1 to 24 hours, but the
reaction time may be appropriately adjusted to make it longer or
shorter.
[0183] The compound of the above formula (II) or (III) wherein R is
amino can be prepared from the compound of the above formula (II)
or (III) wherein R is a bromine atom. For example, the compound of
the above formula (II) or (III) wherein R is a bromine atom is
reacted with a dialkylamine such as N-methylpiperazine, piperidine,
morpholine or the like in a solvent such as toluene, 1,4-dioxane,
N,N-dimethylformamide or the like, preferably toluene, in the
presence of a palladium catalyst such as tris(benzylideneacetone)
dipalladium-chloroform adduct or the like, a phosphine such as
(R)-(+)-2,2'-bis(di-4-tolylphosphino)-1,1'-binaphthyl or the like
and a base such as sodium t-butoxide or the like, thereby to
produce the compound of the above formula (II) or (III) wherein R
is a dialkylamino group. In this reaction, the reaction temperature
is usually room temperature to the boiling point of the solvent
used in the reaction, preferably 60.degree. C. to 120.degree. C.,
though it may be appropriately chosen depending on the starting
material and the reaction solvent to be used, and the reaction is
usually completed within 1 to 24 hours, but the reaction time may
be appropriately adjusted to make it longer or shorter.
[0184] The compound of the above formula (II) or (III) wherein R is
hydroxycarbonyl can be prepared by reacting the corresponding
compound of the above formula (II) or (III) wherein R is
alkoxycarbonyl, with an aqueous solution of sodium hydroxide,
potassium hydroxide, lithium hydroxide or the like in a solvent
such as tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the
like. In this reaction, the reaction temperature is usually
0.degree. C. to the boiling point of the solvent used in the
reaction, preferably room temperature, though it may be
appropriately chosen depending on the starting material and the
reaction solvent to be used, and the reaction is usually completed
within 1 to 24 hours, but the reaction time may be appropriately
adjusted to make it longer or shorter.
[0185] Further, the compound of the above formula (II) or (III)
wherein R is hydroxymethyl can be prepared by reducing the
corresponding compound of the above formula (II) or (III) wherein R
is hydroxycarbonyl. For example, the compound of the above formula
(II) or (III) wherein R is hydroxycarbonyl is reacted with a
condensing agent such as
benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate
or the like in a solvent such as tetrahydrofuran or the like in the
presence of an organic base such as N,N-diisopropylethylamine or
the like at 0.degree. C. to room temperature for 5 minutes to 1
hour, followed by reaction with a reducing agent such as lithium
tetrahydroborate or the like, thereby to produce the compound of
the above formula (II) or (III) wherein R is hydroxymethyl. In this
reaction, the reaction temperature is usually 0.degree. C. to room
temperature, though it may be appropriately chosen depending on the
starting material and the reaction solvent to be used, and the
reaction is usually completed within 10 minutes to 24 hours, but
the reaction time may be appropriately adjusted to make it longer
or shorter.
[0186] In addition, the compound of the above formula (II) or (III)
wherein R is alkoxymethyl can be prepared by alkylation of the
corresponding compound of the above formula (II) or (III) wherein R
is hydroxymethyl. For example, the compound of the above formula
(II) or (III) wherein R is hydroxymethyl is reacted with an
alkylating agent such as methyl iodide, dimethyl sulfate or the
like in a solvent such as N,N-dimethylformamide, 1,4-dioxane,
tetrahydrofuran or the like in the presence of an inorganic base
such as sodium hydride, potassium, t-butoxide or the like, thereby
to produce the compound of the above formula (II) or (III) wherein
R is alkoxymethyl. In this reaction, the reaction temperature is
usually 0.degree. C. to the boiling point of the solvent used in
the reaction, preferably room temperature, though it may be
appropriately chosen depending on the starting material and the
reaction solvent to be used, and the reaction is usually completed
within 1 to 24 hours, but the reaction time may be appropriately
adjusted to make it longer or shorter.
[0187] The compound of the above formula (II) or (III) wherein R is
an aromatic cyclic group or an aromatic heterocyclic group attached
via the carbon atom to the quinoxalinone core structure can be
prepared from the corresponding compound of the above formula (II)
or (III) wherein R is a bromine atom. For example, the compound of
the above formula (II) or (III) wherein R is a bromine atom is
reacted with a boronic acid such as pyrimidine-5-boronic acid or
the like in a solvent such as 1,2-dimethoxyethane-water,
toluene-water, 1,4-dioxane-water, N,N-dimethylamide or the like in
the presence of a palladium catalyst such as
tetrakis(triphenylphosphine)palladium or the like, and a base such
as potassium carbonate or the like, thereby to produce the compound
of the above formula (II) or (III) wherein R is an aromatic cyclic
group or an aromatic heterocyclic groups attached via the carbon
atom to the quinoxalinone core structure. In this reaction, the
reaction temperature is usually room temperature to the boiling
point of the solvent used in the reaction, preferably 60.degree. C.
to 120.degree. C., though it may be appropriately chosen depending
on the starting material and the reaction solvent to be used, and
the reaction is usually completed within 1 to 24 hours, but the
reaction time may be appropriately adjusted to make it longer or
shorter.
[0188] The compound of the above formula (II) or (III) wherein R is
an aromatic heterocyclic group attached via the nitrogen atom to
the quinoxalinone core structure can be prepared from the
corresponding compound of the above formula (II) or (III) wherein R
is a bromine atom. For example, the compound of the above formula
(II) or (III) wherein R is a bromine atom is reacted with an
aromatic heterocyclic compound such as indole or the like in a
solvent such as toluene, 1,4-dioxane, N,N-dimethylformamide or the
like, preferably 1,4-dioxane, in the presence of a phosphine such
as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like, a
palladium catalyst such as
tris(benzylideneacetone)dipalladium(0)-chloroform adduct or the
like and a base such as cesium carbonate or the like, thereby to
produce the compound of the above formula (II) or (III) wherein R
is an aromatic heterocyclic group attached via the nitrogen atom to
the quinoxalinone core structure. In this reaction, the reaction
temperature is usually room temperature to the boiling point of the
solvent used in the reaction, preferably 60.degree. C. to
120.degree. C., though it may be appropriately chosen depending on
the starting material and the reaction solvent to be used, and the
reaction is usually completed within 1 to 24 hours, but the
reaction time may be appropriately adjusted to make it longer or
shorter.
[0189] Further, the compounds having other groups represented by R,
such as lower alkyl such as ethyl or the like; lower alkyl
substituted by aliphatic heterocyclic group; and aliphatic
heterocyclic group bonded via the nitrogen atom to the quinoxaline
core structure, may be prepared according to the aforementioned
methods.
[0190] The starting materials, reagents,
(2-fluoro-3-iodophenyl)oxoacetic acid ester, and the compounds of
the above formulae (VIII), (XII), (XIII), (XIV) and (XXV) used in
the preparation of the compounds of the formula (I) are all known,
or they can be prepared by the per se known method utilizing the
known compounds.
[0191] Hereinafter, (2-fluoro-3-iodophenyl)oxoacetic acid ester,
and the compounds of the above formulae (VIII), (XII), (XIII),
(XIV) and (XXV) are described.
[0192] The (2-fluoro-3-iodophenyl)oxoacetic acid ester can be
prepared by reacting a commercially available
2-fluoro-1-iodobenzene with a strong base such as lithium
diisopropylamide, or the like in an ether solvent such as
tetrahydrofuran or the like at a low temperature and then reacting
the resultant lithio compound with a chlorooxoacetate derivative or
an oxalic acid diester.
[0193] The compound of the above formula (VIII) can be prepared
from the diol compound of the following formula (XXVI):
##STR00082##
wherein n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n;
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2> and
<substituent group .gamma.> each have the same meaning as
defined above, and the diol compound is commercially available or
can be prepared from the known compounds such as corresponding
diesters, dicarboxylic acids or the like by the known method such
as reduction with lithium aluminum hydride. That is, the compound
of the above formula (VIII) can be prepared by introducing a
protecting group into one of the hydroxy groups in the diol
compound of the above formula (XXVI) to convert into the compound
of the formula (XXVII):
##STR00083##
wherein n; B.sub.1, B.sub.2, . . . , B.sub.n-1 and B.sub.n;
B'.sub.1, B'.sub.2, . . . , B'.sub.n-1 and B'.sub.n;
<substituent group .alpha.>, <substituent group
.beta..sub.1>, <substituent group .beta..sub.2>,
<substituent group .gamma.> and PG.sub.3 each have the same
meaning as defined above, and then reacting the other hydroxy group
with methanesulfonyl chloride or the like in the presence of a base
such as triethylamine or the like.
[0194] The aminoalcohol derivative of the above formula (XII) is
commercially available, or can be prepared by introducing a
protecting group into the hydroxy group of the commercially
available aminoalcohol. Alternatively, the aminoalcohol derivative
of the above formula (XII) can be prepared by substituting the
leaving group W of the compound of the above formula (VIII) with an
azido group using sodium azide or the like in a polar solvent such
as dimethylformamide or the like and then subjecting the resulting
product to catalytic hydrogenation using a palladium catalyst,
thereby to reduce the azide group into the amino group.
[0195] The hydrazine derivative of the above formula (XIII) can be
prepared by oxidizing a commercially available aldehyde or ketone
or the hydroxy group of the compound of the above formula (XXVII)
with a sulfur trioxide-pyridine complex and then obtaining the
objective compound from the resultant aldehyde or ketone. That is,
the carbonyl group of these compounds is converted into the
hydrazide group, and then the resultant compound is reacted with a
reducing agent such as sodium tetrahydroborate, sodium
cyanotrihydroborate, sodium triacetoxyhydroborate or the like in
the presence of an acid such as acetic acid, trifluoroacetic acid,
hydrochloric acid, 4-toluenesulfonic acid, zinc chloride or the
like, thereby to give the compound of the above formula (XIII).
[0196] The hydroxylamine derivatives of the above formula (XIV) can
be prepared by introducing a protecting group into the two hydroxy
groups of a hydroxylamine obtained by the reduction of a
commercially available oxime according to a method similar to the
aforementioned method.
[0197] The dihalogenated alkyl derivative or disulfonic acid ester
derivative of the above formula (XXV) is commercially available, or
can be prepared by converting the two hydroxy groups of the
compound of the above formula (XXVI) into the disulfonic acid ester
with methanesulfonyl chloride or the like. Further, the disulfonic
acid ester is reacted with sodium iodide in a polar solvent such as
dimethylformamide or the like to produce the corresponding
dihalogenated alkyl derivative.
[0198] With respect to the novel quinoxalinone compounds prepared
by the above methods, Cdk inhibitory activity (cyclin D2-Cdk4
inhibitory activity and cyclin D2-Cdk6 inhibitory activity are
described as examples) and inhibitory activity of
5-bromo-2'-deoxyuridine:BrdU) uptake are shown below.
Cdk4 Inhibitory Activities
(1) Purification of Cyclin D2-Cdk4
[0199] cDNAs of Cdk4 and its activating factor cyclin D2 were each
introduced into a baculovirus expression vector to obtain a
recombinant baculovirus; it was then co-infected to an insect cell
Sf9 to highly express active cyclin D2/Cdk4 complexes. The cells
were recovered, solubilized and the enzymes were purified by HPLC
column chromatography (The Embo Journal, vol. 15, 7060-7069
(1996)).
(2) Determination of Cyclin D2-Cdk4 Activity
[0200] In the determination of cyclin D2-Cdk4 activity, a synthetic
peptide Arg-Pro-Pro-Thr-Leu-Ser-Pro-Ile-Pro-His-Ile-Pro-Arg
corresponding to the amino acid number 775-787 of RB protein was
used as a substrate [The EMBO Journal, vol. 15, 7060-7069
(1996)].
[0201] The reaction was carried out according to a method partially
modifying Kitagawa et al. (Oncogene, vol. 7, 1067-1074 (1992)).
Purified cyclin D2-Cdk4, 100 .mu.M substrate peptide, 50 .mu.M
non-labeled adenosine triphosphate (ATP) and 1 .mu.Ci
[.gamma.-33P]-labeled ATP (2000-4000 Ci/mmole) were added to a
reaction buffer (referred to as R buffer) consisting of 20 mM
Tris-HCl buffer (pH 7.4), 10 mM magnesium chloride, 4.5 mM
2-mercaptoethanol and 1 mM ethylene glycol bis(.beta.-aminoethyl
ether)-N,N,N',N'-tetraacetic acid (EGTA) to make a total volume of
21.1 .mu.l. The mixture was incubated at 30.degree. C. for 45
minutes. After that, 350 mM phosphate buffer (10 .mu.l) was added
to the reaction solution to stop the reaction. The peptide
substrate was adsorbed on a P81 paper filter in a 96-well plate,
and the plate was washed several times with 75 mM phosphate buffer,
and then its radioactivity was measured by a liquid scintillation
counter. The [.gamma.-33P]-labeled ATP was purchased from Daiichi
Pure Chemicals.
[0202] Addition of test compounds to the reaction system was
carried out in such a manner that the compounds were dissolved in
dimethyl sulfoxide to prepare a series of diluted solutions, and
then each aliquot (1.1 .mu.l) was added to the reaction system. A
control group was prepared by addition of only dimethyl sulfoxide
(1.1 .mu.l) to the reaction system.
[0203] The compounds in the following Working Examples were chosen
as typical compounds of the present invention, and IC.sub.50 values
against cyclin D2-Cdk4 activity of those compounds were determined.
The results are shown in the table below.
TABLE-US-00001 TABLE 1 Compound of Working Example (shown by the
number only) IC.sub.50(nM) [1] 3.6 [4] 2.5 [5] 4.3 [6] 2.9 [7] 3.5
[8] 6.1 [9] 11 [10] 6.3 [11] 12 [12] 11 [14] 2.2 [20] 1.6 [23] 2.1
[25] 8.2 [28] 16 [31] 6.4 [32] 9 [34] 12 [35] 12 [36] 34 [37] 17
[38] 12 [39] 6.9 [45] 14 [46] 3.1 [48] 3.6 [51] 6.1 [54] 8.5 [55]
7.9 [56] 9.2 [65] 6.9 [71] 13 [80] 1.7 [83] 2 [84] 6.2 [85] 6.7
[86] 2.7 [87] 2.6 [89] 2.7 [90] 3.7 [91] 3.2 [92] 2.8 [94] 3.6 [95]
4.1 [99] 5.2 [100] 2.4 [102] 1.4 [104] 1.6 [107] 7.7 [111] 5.5
[118] 14 [122] 2.5 [123] 9.6 [124] 8.2 [125] 15 [126] 9.4 [127] 11
[128] 3.5 [129] 4.9 [130] 6.5 [131] 8.2 [134] 6.4 [135] 2.5 [136]
3.2 [137] 3.4 [138] 4.2 [139] 3 [140] 3 [141] 26 [142] 15 [143] 2.2
[144] 2.9 [145] 2.7 [146] 5.2
[0204] These results clearly show that the compounds of the present
invention exhibit strong inhibitory activities against cyclin
D2-Cdk4.
Cdk6 Inhibitory Activities
[0205] (1) Purification of cyclin D2-Cdk6
[0206] In the same manner as with cyclin D2-Cdk4, cDNAs of Cdk6 and
its activating factor cyclin D2 were each introduced into a
baculovirus expression vector to obtain a recombinant vaculovirus;
it was then co-infected to an insect cell Sf9 to highly express
active cyclin D2/Cdk6 complexes. The cells were recovered,
solubilized and the enzymes were purified by a HPLC column
chromatography.
(2) Determination of cyclin D2-Cdk6 activity In the determination
of cyclin D2-Cdk6 activity, a synthetic peptide
Arg-Pro-Pro-Thr-Leu-Ser-Pro-Ile-Pro-His-Ile-Pro-Arg was used.
[0207] The reaction was carried out according to a method partially
modifying Kitagawa et al. (Oncogene, vol. 7, 1067-1074 (1992)).
Purified cyclin D2-Cdk6, 100 .mu.M substrate peptide, 50 .mu.M
non-labeled ATP and 1.5 .mu.Ci [.gamma.-33P]-labeled ATP (2000-4000
Ci/mmole) were added to R buffer to make a total volume of 21.1
.mu.l. The mixture was reacted at 30.degree. C. for 40 minutes, and
then 350 mM phosphate buffer (10 .mu.l) was added to the reaction
solution to stop the reaction. The peptide substrate was adsorbed
on a P81 paper in a 96-well plate, and the plate was washed with 75
mM phosphate buffer, and then its radioactivity was measured by a
liquid scintillation counter.
[0208] Addition of test compounds to the reaction system was
carried out in such a manner that the compounds were dissolved in
DMSO to prepare a series of diluted solutions, and then each
aliquot (1.1 .mu.l) was added to the reaction system. A control
group was prepared by addition of only dimethylsulfoxide (1.1
.mu.l) to the reaction system.
[0209] The compounds of [11], [51] and [134] were chosen as typical
compounds of the present invention, and IC.sub.50 values against
cyclin D2-Cdk6 activity of those compounds were determined. The
results are shown in the table below.
TABLE-US-00002 TABLE 2 Compound of Working Example (shown by the
number only) IC.sub.50(nM) [11] 24 [51] 25 [134] 12
[0210] These results clearly show that the compounds of the present
invention exhibit strong inhibitory activities against cyclin
D2-Cdk6.
[0211] As mentioned above, since the compounds of the present
invention have strong Cdk inhibitory activities, they are useful as
a Cdk inhibitory agent. Further, the Cdk inhibitory agent may
contain a pharmaceutically acceptable carrier or diluent.
Inhibitory Activities of 5-Bromo-2'-Deoxyuridinee (BrdU) Uptake
[0212] Growing cells perform DNA duplication in the S phase of the
cell cycle, and divide into daughter cells in the M phase via the
G2 phase. As an index for the cell growth, there is a method to
determine the amount of BrdU taken into newly synthesized DNAs in
the DNA duplicating cells ((J. Immunol. Methods, vol. 82, p.
169-179 (1985); J. Immunolog. Methods, vol. 106, p. 95-100 (1988);
Cytometry, vol. 14, p. 640-648 (1993)). Inhibitory activities of
BrdU uptake was determined in order to investigate the effect of
the compounds of the present invention against cancer cells.
(1) Method for Cell Culture
[0213] HCT116 cells derived from human colon cancer were cultured
in Dulbecco's modified Eagle's medium containing 10% fetal bovine
serum at 37.degree. C. in the presence of 5% carbon dioxide under
an atmosphere of saturated steam.
(2) Determination of inhibitory activities of BrdU uptake Cell
culture medium (100 .mu.l each) containing 2.5.times.10.sup.3 of
HCT116 cells was dispensed into each well of a 96-well cell culture
dish, and then the cells were pre-cultured overnight. On the next
day, a series of diluted solutions was prepared with DMSO from a
DMSO solution containing the compounds of the present invention.
Then, a series of diluted solutions, or DMSO only as a control
without addition of the compound, was added in an amount of 1% to
the cell culture medium. Finally, 100 .mu.l of culture medium
containing the above diluted solution containing the compounds or
DMSO only were each added to the cells which had been pre-cultured
in the 96-well dish, and then the cells were cultured for 12
hours.
[0214] Quantitative determination of BrdU uptake was performed
using the Cell Proliferation ELISA, BrdU (chemiluminescence) (Roche
Diagnostics). Each 20 .mu.L of 10.times. concentrated BrdU labeling
reagent was added to the cells which had been cultured together
with the compound for 12 hours, which were subjected to pulse
labeling at 37.degree. C. for 1 hour, and then the culture solution
was removed. Then, after addition of a FixDenat solution to the
cells, the cells were incubated at room temperature for 30 minutes
for fixation of cells and denaturation of DNA. After removal of the
FixDenat solution, anti-BrdU antibody labeled with peroxidase was
added to the cells, and then the cells were incubated at room
temperature for 90 minutes. The cells were washed four times with a
washing solution, and a substrate was added thereto. The cells were
incubated at room temperature for 10 minutes and chemical
luminescence was determined with a luminometer.
[0215] As typical compounds of the present invention, the compounds
[11], [12], [39], [51], [71], [83], [85], [134] and [141] were
chosen, and IC50 values of these compounds on BrdU uptake were
determined. The results are shown in table 3.
TABLE-US-00003 TABLE 3 Compounds of Working Examples (hereinafter
shown by the number only) IC.sub.50(nM) [11] 16 [12] 9.7 [39] 9.4
[51] 23 [71] 75 [83] 30 [85] 20 [134] 7.8 [141] 20
[0216] The compounds of the present invention are useful as
anti-cancer agents (cancer remedies) for treatment of cancers,
because they strongly inhibit BrdU uptake and thus apparently have
cell growth-inhibitory activity. That is, a pharmaceutical
composition containing a novel quinoxalinone derivative or a
pharmaceutically acceptable salt or ester thereof according to the
present invention, or an anti-cancer agent containing a novel
quinoxalinone derivative or a pharmaceutically acceptable salt or
ester thereof according to the present invention are effective for
the treatment of cancer patients. Also, said pharmaceutical
composition and anti-cancer agent may contain a pharmaceutically
acceptable carrier or diluent. In the above description,
"pharmaceutically acceptable carrier or diluent" means excipients
(e.g. fat, bees wax, semi-solid or liquid polyol, natural or
hydrogenated (hardened) oil); water (e.g. distilled water,
especially distilled water for injection); physiological saline,
alcohols (e.g. ethanol), glycerol, polyol, aqueous glucose,
mannitol, vegetable oil or the like; and additives (e.g. fillers,
disintegrating agents, binders, lubricants, wetting agents,
stabilizers, emulsifiers, dispersing agents, preservatives,
sweeteners, pigments, condiments or perfumes, thickening agents,
diluting agents, buffers, solvents or solubilizers, agents for
attaining storage effect, salts for adjusting osmotic pressure,
coating agents or anti-oxidants).
[0217] Suitable tumors against which the compounds of the present
invention are expected to exhibit a therapeutic effect are, for
example, human solid cancers. Examples of the human solid cancers
are brain cancer, head and neck cancer, esophagus cancer, thyroid
cancer, small cell cancer, non-small cell cancer, breast cancer,
stomach cancer, gallbladder/bile duct cancer, hepatic cancer,
pancreatic cancer, colon cancer, rectal cancer, ovarian cancer,
chorioepithelioma, uterine cancer, cervical cancer, renal
pelvic/ureteral cancer, bladder cancer, prostate cancer, penile
cancer, testicular cancer, embryonal cancer, Wilms cancer, skin
cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's
sarcoma and soft tissue sarcoma.
[0218] The aforementioned "a pharmaceutically acceptable salt or
ester" is described below.
[0219] When the compounds of the present invention are used as an
anti-cancer agent, they may be used as a pharmaceutically
acceptable salt thereof. Typical examples of such pharmaceutically
acceptable salt are a salt with an alkali metal such as sodium,
potassium or the like, hydrochloride, and trifluoroacetate.
[0220] A pharmaceutically, if desired, acceptable salt of the
present invention may be prepared by combination of conventional
methods employed in the field of synthetic organic chemistry. A
specific example includes neutralization of a free-form solution of
the compounds of the present invention with an alkali solution or
an acidic solution.
[0221] The esters of the compounds of the present invention
include, for example, methyl ester and ethyl ester. These esters
can be prepared by esterification of a free carboxyl group of the
compounds according to a conventional method.
[0222] The dosage form of the compounds of the present invention
can be chosen from a variety of forms, and include, for example,
oral formulations such as tablets, capsules, powders, granules,
solution or the like, and sterilized liquid parenteral formulations
such as solutions, suspensions or the like.
[0223] Here, the solid pharmaceutical preparations may be
manufactured as tablets, capsules, granules or powders, with or
without a suitable additive according to a conventional method.
Such additive includes, for example, sugars such as lactose and
glucose; starches such as corn starch, wheat, and rice; fatty acids
such as stearic acid; inorganic salts such as sodium metasilicate,
magnesium aluminate, and anhydrous calcium phosphate; synthetic
polymers such as polyvinylpyrrolidone, and polyalkylene glycol;
fatty acid salts such as calcium stearate, and magnesium stearate;
alcohols such as stearyl alcohol, and benzyl alcohol; synthetic
cellulose derivatives such as methylcellose, carboxymethyl
cellulose, ethyl cellulose, and hydroxypropylmethyl cellulose; and
other additives commonly used such as water, gelatin, talc,
vegetable oil, gum arabic or the like.
[0224] These solid preparations such as tablets, capsules, granules
or powders may generally contain 0.1 to 100%, preferably 5 to 100%,
more preferably 5 to 85%, particularly preferably 5 to 30%, by
weight, of an active ingredient.
[0225] The liquid preparations such as suspensions, syrups or
injections can be prepared by using a suitable additive (e.g.
water, alcohols, or plant-derived oils such as soy bean oil, peanut
oil or sesame oil) commonly used for the preparation of liquid
preparations.
[0226] Especially, examples of suitable solutions or diluents for
parenteral administration such as intramuscular, intravenous, or
subcutaneous injection are distilled water for injection, aqueous
solution of lidocaine hydrochloride (for intramuscular injection),
physiological saline, aqueous glucose solution, ethanol,
intravenous injection solutions (e.g. aqueous solutions of citric
acid or sodium citrate), electrolytic solutions (e.g. intravenous
drip infusion, intravenous injection) and a mixed solution
thereof.
[0227] Further, these injection preparations can be in a
previously-dissolved form as well as a powder itself with or
without additives which are to be dissolved when used. These
injection solutions usually may contain 0.1 to 10%, preferably 1 to
5%, by weight, of an active ingredient.
[0228] The preferred practical dosage of the compounds of the
present invention may be properly determined depending on the kind
of compounds to be used, the kind of compositions to be combined,
administration frequency, a specific part of human body to be
treated, and the conditions of patients. For example, a daily dose
per adult is: in the case of oral administration, 10 to 500 mg,
preferably 10 to 200 mg; in the case of parenteral administration,
preferably intravenous injection, 1.0 to 100 mg, preferably 10 to
30 mg. Although administration frequency varies depending on the
administration route and the diseases of patients, it can be
administered in single or two to five divisions, preferably two to
three divisions.
EXAMPLES
[0229] The present invention will be described in more detail in
conjunction with Working Examples hereinafter, but it is to be
construed that the present invention is not limited thereto.
[0230] For example, when a racemate is described in Working
Examples, chiral compounds thereof should be included in the
present invention. Also, preparation methods of the compounds
represented by the formulae [A-1] to [A-34] are described in
Reference Examples 1 to 34.
[0231] Thin-layer chromatography in Working Examples and Reference
Examples was carried out using silica gel .sub.60F.sub.254 (Merck)
as a plate and a UV detector as a detection method.
Wakogel.TM.C-300 or C-200 (Wako Pure Chemical Industries, Ltd.) or
NH (Fuji Silysia Chemical) was used as silica gel for the column
chromatography. Mass spectrum was measured by use of JMS-SX102A
(JEOL Ltd.) or QUATTROII (Micromass Ltd.). Determination of NMR
spectrum by use of deutero dimethyl sulfoxide was carried out with
Gemini-200 spectrometer (200 MHz; Varian Inc.), Gemini-300
spectrometer (300 MHz; Varian Inc.) or VXR-300 spectrometer (300
MHz; Varian Inc.), respectively using dimethyl sulfoxide as an
internal standard. All 6 values were expressed in terms of ppm.
[0232] The Abbreviations Used in the Determination of NMR Spectrum
are as Follows:
[0233] s: singlet
[0234] d: doublet
[0235] dd: double doublet
[0236] t: triplet
[0237] dt: double triplet
[0238] q: quartet
[0239] m: multiplet
[0240] br: broad
[0241] J: coupling constant
[0242] Hz: hertz
[0243] DMSO-d.sub.6: deutero dimethyl sulfoxide
[0244] The Abbreviations Used in Working Examples and Reference
Examples are as Follows:
[0245] TBS: t-butyldimethylsilyl
[0246] Ms: methanesulfonyl
[0247] Bz: benzoyl
[0248] TBDPS: t-butyldiphenylsilyl
[0249] Alloc: allyloxycarbonyl
[0250] Ac: acetyl
[0251] DMTrt: 4,4'-dimethoxytrityl
[0252] Boc: t-butoxycarbonyl
[0253] SEM: 2-(trimethylsilyl)ethoxymethyl
[0254] Bn: benzyl
[0255] MOM: methoxymethyl
[0256] Me: methyl
[0257] Et: ethyl
Working Example 1
Synthesis of the Compound of the Following Formula [1]
##STR00084##
[0259] The methyl ester derivative (9.90 g, 17.2 mmol) of the
following formula:
##STR00085##
prepared by referring to the procedure of Working Example 110-2)
described in WO 02/02550, and benzyl mercaptan (2.63 mL, 22.4 mmol)
were dissolved in tetrahydrofuran (100 mL), and to this solution 1M
tetrahydrofuran solution (22.4 mL) in which lithium
hexamethyldisilazide was dissolved at room temperature, was
gradually added. The reaction solution was stirred at the same
temperature for 30 minutes, and then 1N aqueous sodium hydroxide
(100 mL) and methanol (100 mL) were added thereto; the reaction
solution was stirred at 60.degree. C. for 150 minutes. After the
reaction solution was cooled down to 0.degree. C., it was
neutralized using 1N hydrochloric acid. Saturated aqueous ammonium
chloride was added to the reaction solution and it was subjected to
extraction with chloroform. The organic layer was dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
resulting residue was purified by a column chromatography on silica
gel to obtain the above carboxylic acid derivative (11.4 g) as a
pale yellow solid.
##STR00086##
[0260] Triethylamine (79 .mu.L, 561 .mu.mol) and 5-amino-1-pentanol
(29 mg, 281 .mu.mol) were added to a chloroform solution (1 mL)
containing the carboxylic acid derivative (100 mg, 151 .mu.mol)
prepared in the above (1). After that, a chloroform solution (1 mL)
of 2-chloro-1,3-dimethylimidazolinium chloride (47 mg, 281 .mu.mol)
was added dropwise thereto with stirring under ice-cooling. The
mixture was stirred at room temperature for 30 minutes, and then
concentrated in vacuo. The residue was purified by thin layer
chromatography to obtain the above amide derivative (102 mg) as a
pale yellow oil.
##STR00087##
[0261] The above amide derivative (102 mg, 136 .mu.mol) prepared in
the above (2) was dissolved in chloroform (2 mL). After the
solution was cooled to 0.degree. C., 3-chloroperbenzoic acid (about
80%, 23 mg, 136 .mu.mol) was added. The reaction solution was
stirred at the same temperature for 1 hour, and triethylamine (114
.mu.L, 816 .mu.mol) and trichloroacetic anhydride (99 .mu.L, 544
.mu.mol) were added. Then, the temperature of the reaction solution
was raised to room temperature, and the solution was stirred for 30
minutes, followed by addition of methanol (4 mL). After the
reaction solution was stirred under heating at reflux for 1 hour,
and the temperature of the reaction solution was lowered to room
temperature. The reaction solution was diluted with chloroform, and
washed with water and saturated brine. The organic layer was dried
over anhydrous magnesium sulfate, filtered, and the filtrate was
concentrated. The resulting residue was purified by a thin layer
chromatography to obtain the above benzoisothiazolone derivative
(80 mg) as a yellow solid.
##STR00088##
[0262] The benzoisothiazolone derivative (80 mg, 122 .mu.mol)
obtained in the above (3) was dissolved in chloroform (2 mL) and
methanol (1 mL), and to this solution 4N hydrogen
chloride/1,4-dioxane (3 mL) was added, and then the mixture was
stirred at room temperature for 3 hours. The resulting reaction
solution was neutralized with aqueous sodium hydrogencarbonate
under ice-cooling, extracted with chloroform, and the organic layer
was washed with saturated brine. Then, the organic layer was dried
over anhydrous magnesium sulfate, filtered, and the filtrate was
concentrated. The residue was purified by a thin layer
chromatography to obtain the above phenol derivative (52 mg) as a
yellow solid.
##STR00089##
[0263] To tetrahydrofuran solution (1 nL) containing the phenol
derivative (10 mg, 19 .mu.mol) obtained in the above (4) were added
triphenylphosphine (15 mg, 57 .mu.mol) and 40% toluene solution (25
.mu.L) containing diethyl azodicarboxylate, and the mixture was
stirred at room temperature for 30 minutes. The reaction solution
was concentrated, and the resulting residue was purified by a thin
layer chromatography to obtain the above cyclic compound (10 mg) as
a yellow solid.
##STR00090##
[0264] The cyclic compound obtained in the above (5) was dissolved
in 4N hydrogen chloride/1,4-dioxane solution (2 mL), and the
solution was stirred in a sealed tube at 100.degree. C. for 2
hours. Diethyl ether was added to the reaction solution, and the
resulting precipitated solid was filtered off to obtain the
objective compound [1] (6.3 mg) as a yellow solid.
[0265] Spectral data of the compound of the above formula [1] are
shown below.
[0266] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.80-2.40 (6H, m),
3.79-3.90 (2H, m), 4.15-4.30 (2H, m), 6.81-6.97 (2H, m), 7.40-7.62
(2H, m), 7.99 (1H, d, J=7.7 Hz), 9. 27 (1H, d, J=7.7 Hz), 12.8 (1H,
brs).
mass: 380 (M+1).sup.+
Working Example 2
Synthesis of the Compound of the Following Formula [2]
##STR00091##
[0268] According to a method similar to the procedure described in
Working Example 1, the objective compound [2] (20 mg) which is a
racemate was obtained as a yellow solid from the above carboxylic
acid derivative (100 mg, 154 .mu.mol) obtained in Working Example
1-(1) and racemic 5-amino-1-hexanol synthesized by referring to the
method described in J. Med. Chem., 25(8) 964 (1982).
[0269] Spectral data of the compound of the above formula [2] are
shown below.
[0270] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.24 (3H, d, J=6.6 Hz),
1.70-2.05 (3H, m), 2.20-2. 65 (3H, m), 4.05-4.65 (3H, m), 6.95-6.98
(2H, m), 7.51 (1H, t, J=8.2 Hz), 7.61 (1H, t, J=7.7 Hz), 8.02 (1H,
d, J=7.7 Hz), 9.42 (1H, d, J=8.0 Hz), 12.8 (1H, s).
[0271] mass: 394 (M+1).sup.+
Working Example 3
Synthesis of the Compound of the Following Formula [3]
##STR00092##
[0273] According to a method similar to the procedures described in
Working Examples 1-(2) to 1-(3), the above benzoisothiazolone
derivative (480 mg) was obtained as a yellow solid from the
carboxylic acid derivative (1.08 g, 1.46 mmol) obtained in Working
Example 1-(1) and 2-aminoethanol.
##STR00093##
[0274] To chloroform solution (1 mL) containing the above
benzoisothiazolone derivative (30 mg, 48 .mu.mol) obtained in the
above (1) were added triphenylphosphine (38 mg, 98 .mu.mol), the
sulfonamide derivative [A-3-1] (38 mg, 101 mmol) and 40% toluene
solution containing diethyl azodicarboxylate (43 .mu.L, 98
.mu.mol), and the mixture was stirred at room temperature for 4
hours. The resulting solution was purified by thin layer
chromatography to obtain the above benzoisothiazolone (41 mg) as a
yellow solid.
##STR00094##
[0275] According to a method similar to the procedures described in
Working Examples 1-(4) to 1-(5), the above cyclic derivative (11
mg) was obtained as a yellow solid from the above
benzoisothiazolone derivative (29 mg, 30 .mu.mol).
##STR00095##
[0276] To N,N-dimethylformamide solution (1 mL) of the cyclic
derivative (11 mg, 15 .mu.mol) obtained in the above (3) were added
thiophenol (19 .mu.L, 18 .mu.mol) and sodium carbonate (6 mg, 55
.mu.mol), and the mixture was stirred at room temperature for 15
hours. After addition of water, the resulting reaction solution was
extracted with chloroform and the organic layer was washed with
saturated brine. Then, the organic layer was dried over anhydrous
magnesium sulfate, filtered and the filtrate was concentrated. The
resulting residue was purified by a thin layer chromatography to
obtain the amine derivative (7 mg) as a yellow solid.
##STR00096##
[0277] According to a method similar to the procedure described in
Working Example 1-(6), the hydrochloride (2 mg) of the objective
compound [3] was obtained as a yellow solid from the amine
derivative (3 mg, 5.7 .mu.mol) obtained in the above (4).
[0278] Spectral data of the compound of the above formula [3] are
shown below.
[0279] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.41 (3H, d, J=6.0 Hz),
3.20-3.90 (4H, m), 4.00-4.20 (1H, m), 4.35-4.50 (1H, m), 5.05-5.18
(1H, m), 7.00-7.15 (2H, m), 7.52-7.78 (2H, m), 8.15 (1H, d, J=7.5
Hz), 9.42 (1H, d, J=7.7 Hz), 13.0 (1H, s).
[0280] mass: 395 (M+1).sup.+.
Example 4
Synthesis of the Compound of the Following Formula [4]
##STR00097##
[0282] According to a method similar to the procedures described in
Working Example 3-(2) to 3-(5), the hydrochloride (2 mg) of the
objective compound [4] was obtained as a yellow solid from the
benzoisothiazolone derivative (15 mg, 24 .mu.mol) obtained in
Working Example 3-(1) and the sulfonamide derivative [A-3-2] (19
mg, 51 .mu.mol).
[0283] Spectral data of the compound of the above formula [4] are
shown below.
[0284] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.41 (3H, d, J=6.0 Hz),
3.20-3.90 (4H, m), 4.00-4. 20 (1H, m), 4.35-4.50 (1H, m), 5.05-5.18
(1H, m), 7.00-7.15 (2H, m), 7.52-7.78 (2H, m), 8.15 (1H, d, J=7.5
Hz), 9.42 (1H, d, J=7.7 Hz), 13.0 (1H, s).
[0285] mass: 395 (M+1).sup.+.
Working Example 5
Synthesis of the Compound of the Following Formula [5]
##STR00098##
[0287] According to a method similar to the procedures described in
Working Examples 3-(2) to 3-(5), the hydrochloride (2 mg) of the
objective compound [5] was obtained as a yellow solid from the
benzoisothiazolone derivative (15 mg, 24 .mu.mol) obtained in
Working Example 3-(1) and the sulfonamide derivative [A-3-3] (19
mg, 51 .mu.mol).
[0288] Spectral data of the compound of the above formula [5] are
shown below.
[0289] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.44 (3H, d, J=6.2 Hz),
3.10-4.55 (7H, m), 7.04-7. 13 (2H, m), 7.58-7.77 (2H, m), 8.15 (1H,
d, J=7.7 Hz), 8.43 (1H, brs), 9.39 (1H, d, J=7.8 Hz), 9.98 (1H,
brs), 13.0 (1H, s).
[0290] mass: 395 (M+1).sup.+.
Working Example 6
Synthesis of the Compound of the Following Formula [6]
##STR00099##
[0292] To methanol solution (500 .mu.L) containing the amine
derivative (4 mg, 7.6 .mu.mol) obtained in Working Example 3-(4)
was added 35% aqueous formalin solution (8 .mu.L), and then
methanol solution (500 .mu.L) containing zinc chloride (10 mg, 75
.mu.mol) and sodium cyanotrihydroborate (9.4 mg, 150 .mu.mol) was
added dropwise thereto. The mixture was stirred at room temperature
for 1 hour. The reaction solution was purified by a thin layer
chromatography to obtain the above N-methyl derivative (4 mg) as a
yellow solid.
##STR00100##
[0293] According to a method similar to the procedure of Working
Example 1-(6), the hydrochloride (3 mg) of the objective compound
[6] was obtained as a yellow solid from the N-methyl derivative (4
mg, 7.4 mmol) obtained in the above (1).
[0294] Spectral data of the compound of the above formula [6] are
shown below.
[0295] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.41 (3H, d, J=6.0 Hz),
2.37 (3H, s), 2.40-4.30 (6H, m), 4.85-4.98 (1H, m), 6.90-7.01 (2H,
m), 7.45-7.61 (2H, m), 8.02 (1H, d, J=7.6 Hz), 9.34 (1H, d, J=8.1
Hz), 12.7 (1H, brs).
[0296] mass: 409 (M+1).sup.+.
Working Example 7
Synthesis of the Compound of the Following Formula [7]
##STR00101##
[0298] According to a method similar to the procedures of Working
Examples 3-(2) to 3-(4) and 6, the hydrochloride (3 mg) of the
objective compound [7] was obtained as a yellow solid from the
benzoisothiazolone derivative (15 mg, 24 .mu.mol) obtained in
Working Example 3-(1) and the sulfonamide derivative [A-3-4] (19
mg, 51 .mu.mol).
[0299] Spectral data of the compound of the above formula [7] are
shown below.
[0300] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.90-1.40 (3H, m),
2.20-4.40 (10H, m), 6.90-7.05 (2H, m), 7.50-7.70 (2H, m), 8.00-8.15
(1H, m), 9.37 (1H, d, J=7.9 Hz), 12.8 (1H, brs).
[0301] mass: 409 (M+1).sup.+.
Working Example 8
Synthesis of the Compound of the Following Formula [8]
##STR00102##
[0303] According to a method similar to the procedures described in
Working Examples 3-(2) to 3-(4) and 6, the hydrochloride (2 mg) of
the objective compound [8] was obtained as a yellow solid from the
benzoisothiazolone derivative (15 mg, 24 .mu.mol) obtained in
Working Example 3-(1) and the sulfonamide derivative [A-3-3] (19
mg, 51 .mu.mol).
[0304] Spectral data of the compound of the above formula [8] are
shown below.
[0305] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.90-1.40 (3H, m),
2.20-4.40 (10H, m), 6.90-7.05 (2H, m), 7.50-7.70 (2H, m), 8.00-8.15
(1H, m), 9.37 (1H, d, J=7.9 Hz), 12.8 (1H, brs).
[0306] mass: 409 (M+1).sup.+.
Working Example 9
Synthesis of the Compound of the Following Formula [9]
##STR00103##
[0308] According to a method similar to the procedures described in
Working Example 3-(2) to 3-(4) and 6, the hydrochloride (2 mg) of
the objective compound [9] was obtained as a yellow solid from the
benzoisothiazolone derivative (15 mg, 24 .mu.mol) obtained in
Working Example 3-(1) and the sulfonamide derivative [A-3-5] (19
mg, 51 .mu.mol).
[0309] Spectral data of the compound of the above formula [9] are
shown below.
[0310] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.30-4.90 (11H, m),
6.82-7.18 (2H, m), 7.40-7.80 (2H, m), 7.95-8.20 (1H, m), 9.38 (1H,
d, J=7.8 Hz), 12.7-13.1 (1H, m).
[0311] mass: 395 (M+1).sup.+
Working Example 10
Synthesis of the Compound of the Following Formula [10]
##STR00104##
[0313] According to a method similar to the procedures described in
Working Examples 1-(2) to 1-(3), the above benzoisothiazolone
derivative (1.94 g) was obtained as a yellow solid from the
calboxylic acid derivative (2.00 g, 3.00 mmol) obtained in Working
Example 1-(1) and aminoacetaldehyde diethylacetal (873 .mu.L, 6.02
mmol).
##STR00105##
[0314] To tetrahydrofuran solution (600 mL) of the
benzoisothiazolone derivative (1.94 g, 2.82 mmol) obtained in the
above (1) was added water (50 mL), and then 4N hydrogen
chloride/1,4-dioxane (50 mL) was added thereto. The mixture was
stirred at room temperature for 15 hours. The reaction solution was
concentrated to about 100 mL, and the resulting yellow solid was
filtered off. After that, this solid was washed with diethylether,
and dried in vacuo to obtain the above aldehyde derivative (1.01 g)
as a yellow solid.
##STR00106##
[0315] To methanol solution (5 mL) containing the aldehyde
derivative (100 mg, 207 .mu.mol) obtained in the above (2) was
added racemic 3-hydroxypyrrolidine (34 .mu.L, 414 .mu.mol), and
then methanol solution (2.8 mL) containing zinc chloride (56 mg,
414 .mu.mol) and sodium cyanotrihydroborate (52 mg, 828 .mu.mol)
were added dropwise thereto. The mixture was stirred at room
temperature for 15 hours, and the reaction solution was
concentrated. The resulting residue was purified by a thin layer
chromatography to obtain the above racemic amine derivative (95 mg)
as a yellow solid.
##STR00107##
[0316] According to a method similar to the procedures described in
Working Examples 1-(5) to 1-(6), the hydrochloride (31 mg) of the
objective compound [10] as a racemate was obtained as a yellow
solid from the racemic amine derivative (95 mg, 171 .mu.mol)
obtained in the above (3).
[0317] Spectral data of the compound of the above formula [10] are
shown below.
[0318] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.80-4.00 (8H, m),
4.00-4.40 (2H, m), 5.38-5.42 (1H, m), 6.80-7.30 (2H, m), 7.40-7.80
(2H, m), 7.95-8.18 (1H, m), 9.24-9.36 (1H, m), 12.7 (1H, s).
[0319] mass: 407 (M+1).sup.+.
Working Example 11
Synthesis of the Compound of the Following Formula [11]
##STR00108##
[0321] To toluene solution (4 mL) containing the keto ester
derivative [A-2] (515 mg, 2.03 mmol) and the phenylenediamine
derivative [A-1] (643 mg, 2.03 mmol) was added acetic acid (0.4
mL), and the mixture was stirred at room temperature for 3 days.
The resulting precipitates were filtered off, washed with diethyl
ether and toluene, and dried in vacuo to obtain the above
quinoxalinone derivative (340 mg) as a white solid.
##STR00109##
[0322] The quinoxalinone derivative (101 mg, 0.20 mmol) obtained in
the above (1) was suspended in thionyl chloride (1 mL), and
N,N-dimethylformamide (15.5 .mu.L, 0.20 mmol) was added thereto.
Then, the reaction solution was heated under reflux for 20 minutes.
After this reaction solution was cooled to room temperature, the
thionyl chloride was removed by evaporation in vacuo. The resulting
residue was diluted with ethyl acetate, washed successively with
water, sodium hydrogencarbonate and saturated brine. The organic
layer was dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo to obtain the above chloroquinoxaline
derivative (106 mg) as a pale yellow solid.
##STR00110##
[0323] The chloroquinoxaline derivative (53 mg, 0.10 mmol) obtained
in the above (2) and chloromethyl methyl ether (23 .mu.L, 0.30
mmol) were dissolved in tetrahydrofuran (2 mL), and then 1.0M
tetrahydrofuran solution (0.2 mL, 0.20 mmol) containing tetrabutyl
ammonium fluoride was added dropwise at room temperature. After the
dropwise addition was completed, the reaction solution was cooled
in an ice-bath, methanol (1 mL) was added, and sodium hydride (14
mg, 60% dispersion in oil, 0.35 mmol) was gradually added thereto.
The resulting reaction solution was stirred at room temperature for
1 hour, and saturated aqueous ammonium chloride was added to stop
the reaction. The whole reaction solution was poured into water,
and extracted with ethyl acetate. The organic layer was washed
successively with water and saturated brine. Then, the organic
layer was dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo to obtain the above methoxyquinoxaline
derivative (49 mg) as a white solid.
##STR00111##
[0324] The methoxyquinoxaline derivative (45 mg, 100 mmol) obtained
in the above (3) was dissolved in toluene (3 mL), and to this
solution were added tributylvinyltin (36 .mu.L, 120 .mu.mol) and
tetrakis(triphenylphosphine)palladium(0) (16 mg, 2.5 .mu.mol). The
mixture was heated at reflux for 4 hours. The resulting reaction
solution was cooled down to room temperature, and filtered through
a Celite pad. The filtrate was concentrated in vacuo, and the
resulting residue was purified by thin layer chromatography to
obtain the above vinyl derivative (30 mg) as a pale yellow
solid.
##STR00112##
[0325] To acetonitrile solution (3 mL) containing the vinyl
derivative (20 mg, 50 .mu.mol) obtained in the above (4) were added
water (1 mL), 50% aqueous solution (15 .mu.L, 65 .mu.mol) of
N-methylmorpholine N-oxide, and 0.05M aqueous osmium tetraoxide
solution (50 .mu.L, 0.25 .mu.mol). After the resulting solution was
stirred at room temperature for 16 hours, saturated aqueous sodium
thiosulfate solution was added thereto, and the mixture was stirred
at room temperature for 30 minutes. After this solution was
extracted with ethyl acetate, the organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate, filtered,
and concentrated. The resulting residue was purified by a thin
layer chromatography to obtain the above diol derivative (18 mg) as
a pale yellow solid.
##STR00113##
[0326] To tetrahydrofuran solution (2 mL) containing the diol
derivative (18 mg) obtained in the above (5) were added water (2
mL) and potassium periodate (13 mg, 54 .mu.mol). The resulting
mixture was stirred at room temperature for 2 hours, and water was
added thereto. This solution was extracted with ethyl acetate, and
the organic layer was washed with saturated brine. Then, the
organic layer was dried over anhydrous magnesium sulfate, filtered,
and the filtrate was concentrated. The resulting residue was
purified by a thin layer chromatography to obtain the above
aldehyde derivative (12 mg) as a pale yellow solid.
##STR00114##
[0327] The aldehyde derivative (640 mg, 1.59 mmol) obtained in the
above (6) was dissolved in chloroform (15 mL) and methanol (10 mL),
and then sodium tetrahydroborate (120 mg, 3.18 mmol) was added
thereto under ice-cooling. The resulting reaction solution was
stirred for 15 minutes under ice-cooling. After saturated aqueous
ammonium chloride was added to the reaction solution, the mixture
was extracted with chloroform. The organic layer was washed
successively with water and saturated brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The resulting
residue was purified by a column chromatography on silica gel to
obtain the above benzyl alcohol derivative (416 mg) as a pale
yellow solid.
##STR00115##
[0328] The benzyl alcohol derivative (11.0 g, 27.3 mmol) obtained
in the above (7) was dissolved in chloroform (120 mL), and to this
solution were added 3,4-dihydro-2H-pyran (60 mL) and pyridinium
p-toluenesulfonate (1.50 g, 5.97 mmol) at room temperature. The
resulting reaction solution was stirred at room temperature for 4
hours, and diluted with ethyl acetate. The organic layer was washed
successively with aqueous sodium hydrogencarbonate and saturated
brine, dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo to obtain the above tetrahydropyranyl ether
derivative (11.1 g) as a white solid.
##STR00116##
[0329] The tetrahydropyranyl ether derivative (3.00 g, 6.17 mmol)
obtained in the above (8) was dissolved in tetrahydrofuran (50 mL)
and methanol (50 mL), and then 1N aqueous sodium hydroxide (50 mL)
was added. The mixture was stirred for 30 minutes. The resulting
reaction solution was diluted with ethyl acetate, and washed
successively with 1N hydrochloric acid, water, and saturated brine.
The resulting organic layer was dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo to obtain the above
carboxylic acid derivative (3.00 g) as a white solid.
##STR00117##
[0330] To chloroform solution (60 mL) containing the carboxylic
acid derivative (1.50 g, 3.17 mmol) obtained in the above (9) was
added pyridine (1.54 mL, 19.0 mmol), and then chloroform solution
(10 mL) containing 2-chloro-1,3-dimethylimidazolinium chloride
(1.07 g, 6.35 mmol) was added dropwise thereto with stirring under
ice-cooling. The mixture was stirred at room temperature for 15
minutes. After that, chloroform solution (20 mL) containing the
hydrazine derivative [A-17] (2.59 g, 9.51 mmol) was added to the
solution, and the mixture was stirred at room temperature for 5
hours. Water was added to the resulting reaction solution, and the
mixture was extracted with ethyl acetate. The organic layer was
washed successively with 1N hydrochloric acid, water, and saturated
brine, and purified by a silica gel chromatography to obtain the
above hydrazide derivative (1.59 g) as a pale yellow oil.
##STR00118##
[0331] To tetrahydrofuran solution (20 mL) containing the hydrazide
derivative (1.59 g, 2.18 mmol) obtained in the above (10) were
added diethylamine (1.13 mL, 10.9 mmol) and formic acid (0.411 mL),
and then tetrakis(triphenylphosphine)palladium(0) (252 mg, 0.218
mmol) was added thereto. After stirring the solution at room
temperature for 2 hours, water was added to the reaction solution,
and the mixture was extracted with ethyl acetate. The organic layer
was washed successively with aqueous sodium hydrogencarbonate,
water, and saturated brine, and purified by a silica gel
chromatography to obtain the above de-Alloc derivative (1.10 g) as
a pale yellow oil.
##STR00119##
[0332] N,N-diisopropylethylamine (509 .mu.L, 2.92 mmol) was added
to N,N-dimethylformamide solution (50 mL) containing the de-Alloc
derivative (628 mg, 974 .mu.mol) obtained in the above (11), and
the mixture was stirred at 120.degree. C. for 3 hours. After that,
the resulting reaction solution was cooled down to room
temperature, and concentrated in vacuo. Chloroform (10 mL) was
added to the resulting residue, and the resulting solid was
filtered off. This solid was dried in vacuo to obtain the above
3-indazolinone derivative (251 mg) as a yellow solid.
##STR00120##
[0333] To chloroform solution (10 mL) containing the 3-indazolinone
derivative (250 mg, 489 .mu.mol) obtained in the above (12) was
added N,N-diisopropylethylamine (426 .mu.L, 2.45 mmol), and then
methanesulfonyl chloride (113 .mu.L, 1.47 mmol) was added thereto,
followed by stirring for 30 minutes under ice-cooling. After
addition of water to the resulting reaction solution, the organic
layer was separated, and washed successively with 0.5N hydrochloric
acid, water, and saturated brine. Then, the organic layer was dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
resulting residue was dissolved in N-methylpyrrolidone (2.5 mL),
and then (R)-3-hydroxypyrrolidine (250 mg, 2.87 mmol) was added.
The mixture was stirred at 70.degree. C. for 1 hour, and cooled
down to room temperature. After that, aqueous sodium
hydrogencarbonate was added to the solution, and the solution was
extracted with ethyl acetate, and washed successively with water
and saturated brine. The organic layer was dried over anhydrous
magnesium sulfate, filtered, and concentrated. The resulting
residue was purified by a silica gel chromatography to obtain the
above amine (176 mg) as a yellow solid.
##STR00121##
[0334] N,N-diisopropylethylamine (264 .mu.L, 1.52 mmol) was added
to tetrahydrofuran solution (3.5 mL) of the amine derivative (176
mg, 303 .mu.mol) obtained in the above (13), and then
methanesulfonyl chloride (70.5 .mu.L, 910 mmol) was added thereto
under ice-cooling. The solution was stirred for 30 minutes under
ice-cooling, and 1N aqueous sodium hydroxide (3.5 mL) was added
dropwise to the solution, followed by addition of methanol (3.5
mL). The solution was stirred for 15 minutes under ice-cooling, and
then water was added. The solution was extracted with chloroform,
and washed with saturated brine. The organic layer was dried over
anhydrous magnesium sulfate, filtered, and concentrated to obtain
the above mesylated derivative (170 mg) as a yellow solid.
##STR00122##
[0335] The mesylated derivative (170 mg, 258 .mu.mol) obtained in
the above (14) was dissolved in trifluoroacetic acid (15 mL) and
water (1.5 mL), and the solution was stirred at room temperature
for 1 hour. The resulting reaction solution was concentrated in
vacuo, followed by azeotropic evaporation with ethanol and toluene
to obtain the above phenol derivative (170 mg) as a yellow
solid.
##STR00123##
[0336] The phenol (170 mg) obtained in the above (15) was dissolved
in N,N-dimethylformamide (35 mL), and then potassium carbonate (400
mg, 2.89 mmol) was added thereto. The mixture was stirred at
70.degree. C. for 1.5 hours. The resulting reaction solution was
cooled down to room temperature, filtered, and the mother liquor
was concentrated in vacuo. The resulting residue was dissolved in a
mixed solution of chloroform and methanol, and washed with
saturated brine. The organic layer was dried over anhydrous
magnesium sulfate, filtered, and concentrated. The resulting
residue obtained again was purified by a silica gel chromatography
to obtain the above cyclic derivative (92 mg) as a yellow
solid.
##STR00124##
[0337] The cyclic compound (30 mg, 69 .mu.mol) prepared in the
above (16) was dissolved in chloroform (1 mL), and to this solution
were added N,N-diisopropylethylamine (48 .mu.L, 276 .mu.mol) and
methanesulfonyl chloride (13 .mu.L, 173 .mu.mol), then the mixture
was stirred for 30 minutes. An aqueous solution (1 mL) in which
sodium hydrogencarbonate (60 mg) was dissolved was added to the
reaction solution. In addition, after the amine [A-23] (30 mg) was
added to the solution, the mixture was stirred at 60.degree. C. for
1 hour. The reaction solution was cooled down to room temperature,
and the organic layer was separated, concentrated, and purified by
a thin layer chromatography to obtain the above benzylamine
derivative (30 mg) as a yellow solid.
##STR00125##
[0338] The benzylamine derivative obtained in the above (17) was
dissolved in trifluoroacetic acid (5 mL) and water (500 .mu.L), and
the solution was heated at reflux for 3 days. The reaction solution
was cooled down to room temperature, and concentrated in vacuo.
After the resulting residue was dissolved in a mixed solution of
chloroform and methanol, the solution was washed successively with
water and saturated brine. The organic layer was dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
resulting residue was purified by thin layer chromatography to give
a yellow solid. To a stirred solution of the solid in chloroform (5
mL) was added dropwise 4N hydrogen chloride/1,4-dioxan solution
(500 .mu.L), and the resulting precipitates were collected by
filtration, washed with diethyl ether; and dried in vacuo to obtain
the hydrochloride (26 mg) of the objective compound [11] as a
yellow solid.
[0339] Spectral data of the compound of the above formula [11] are
shown below.
[0340] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-4.50 (24H, m),
5.15-5.35 (1H, m), 7.00-7.50 (3H, m), 7.86 (1H, d, J=7.8 Hz), 9.25
(1H, bs), 9.51-9.68 (1H, brs), 11. 8 (1H, brs), 12.9 (1H, brs).
[0341] mass: 517 (M+1).sup.+.
Working Example 12
Synthesis of the Compound of the Following Formula [12]
##STR00126##
[0343] According to a method similar to the procedures described in
Working Examples 11-(17) to 11-(18), the hydrochloride (26 mg) of
the objective compound [12] was obtained as an orange solid from
the cyclic derivative (30 mg, 69 .mu.mol) obtained in Working
Example 1'-(16) and the amine derivative [A-24].
[0344] Spectral data of the compound of the above formula [12] are
shown below.
[0345] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-4.50 (24H, m),
5.15-5.35 (1H, m), 7.00-7.50 (3H, m), 7.86 (1H, d, J=7.8 Hz), 9.2.5
(1H, bs), 9.51-9.68 (1H, brs), 11.8 (1H, brs), 12.9 (1H, brs).
[0346] mass: 517 (M+1).sup.+.
Working Example 13
Synthesis of the compound of the following formula [13]
##STR00127##
[0348] According to a method similar to the procedures described in
Working Examples 11-(17) to 11-(18), the hydrochloride (25 mg) of
the objective compound [13] was obtained as an orange solid from
the cyclic compound derivative (30 mg, 69 .mu.mol) obtained in
Working Example 1'-(16) and morpholine.
[0349] Spectral data of the compound of the above formula [13] are
shown below.
[0350] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.60-4.20 (18H, m), 4.41
(2H, s), 5.15-5.40 (1H, m), 7.00-7.96 (4H, m), 9.10-9.40 (1H, m),
10.8-12.0 (2H, m), 12.8-13.0 (1H, m).
[0351] mass: 489 (M+1).sup.+.
Working Example 14
Synthesis of the Compound of the Following Formula [14]
##STR00128##
[0353] The quinoxalinone derivative (100 mg, 0.20 mmol) obtained in
Working Example 11-(1) was dissolved in tetrahydrofuran (5 mL), and
then chloromethyl 2-(trimethylsilyl)ethyl ether (37 .mu.L, 0.30
mmol) was added to the solution. Then, the solution was stirred at
room temperature, and to this solution was added potassium
t-butoxide (29 mg, 0.26 mmol) at 0.degree. C. The resulting
reaction solution was warmed up to room temperature, and stirred
for 30 minutes. After chloromethyl 2-(trimethylsilyl)ethyl ether
(37 .mu.L, 0.30 mmol) was added thereto, and then 1M
tetrabutylammonium fluoride/tetrahydrofuran (260 .mu.L, 0.26 mmol)
was added thereto. The resulting reaction solution was stirred at
room temperature for 40 minutes. Then chloromethyl
2-(trimethylsilyl)ethyl ether (37 .mu.L, 0.30 mmol) was added
thereto, and the mixture was stirred at room temperature for 2
hours. Water was added to the resulting reaction solution, and the
solution was extracted with chloroform, and the extract was washed
with saturated brine. The organic layer was dried over anhydrous
magnesium sulfate, filtered in vacuo, and concentrated. The
resulting residue was purified by a thin layer chromatography on
silica gel to obtain the above protected derivative with SEM (83
mg) as a white solid.
##STR00129##
[0354] According to a method similar to the procedures described in
Working Example 1-(1), the above carboxylic acid derivative (121
mg) was obtained as a pale yellow solid from the protected
derivative with SEM (100 mg, 0.15 mmol) obtained in the above
(1).
##STR00130##
[0355] The carboxylic acid derivative (3.78 g, 5.08 mmol) obtained
in the above (2) was dissolved in chloroform (30 mL), and to this
solution were added 1-hydroxybenzotriazole (1.01 g, 6.60 mmol) and
1-{(3-dimethylamino)propyl}-3-ethylcarbodiimide hydrochloride (1.36
g, 6.60 mmol). After this solution was stirred at room temperature
for 5 minutes, 3-aminopropionitrile (0.49 mL, 6.60 mmol) was added
thereto. The resulting solution was stirred at the same temperature
for 4 hours, diluted with chloroform, and washed successively with
aqueous sodium hydrogencarbonate and saturated aqueous ammonium
chloride. The resulting organic layer was dried over anhydrous
magnesium sulfate, filtered, and concentrated. The resulting
residue was purified by a column chromatography on silica gel to
obtain the above amide derivative (3.28 g) as a pale yellow
solid.
##STR00131##
[0356] According to a method similar to the procedure described in
Working Example 1-(3), the above benzisothiazolone derivative (2.93
g) was obtained as a yellow solid from the amide derivative (3.28
g, 4.12 mmol) obtained in the above (3).
##STR00132##
[0357] The benzoisothiazolone derivative (2.33 g, 3.31 mmol)
obtained in the above (4) was dissolved in a mixed solution of
N,N-dimethylformamide (25 mL) and methanol (25 mL), and then sodium
hydrogencarbonate (800 mg, 9.93 mmol) was added. After substituting
the reaction system with nitrogen gas, palladium(II) acetate (75
mg, 0.33 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (185 mg,
0.33 mmol) were added to the reaction solution at room temperature
under a nitrogen atmosphere. Then, the atmosphere in the reaction
system was substituted with carbon monoxide. This reaction solution
was stirred at 70.degree. C. for 2 hours, cooled down to room
temperature, diluted with chloroform, and washed successively with
water and saturated aqueous ammonium chloride. The resulting
organic layer was dried over anhydrous magnesium sulfate, filtered,
and concentrated. The resulting residue was purified by a column
chromatography on silica gel to obtain the above ester derivative
(2.03 g) as a yellow solid.
##STR00133##
[0358] The ester derivative (2.03 g, 2.97 mmol) obtained in the
above (5) was dissolved in a mixed solution of tetrahydrofuran (150
mL) and methanol (50 mL), and then 1N sodium hydroxide (50 mL) was
added thereto at room temperature. After the resulting reaction
solution was stirred at room temperature for 1 hour, the pH of the
solution was adjusted to 2 using 1N hydrochloric acid. After
removal of the tetrahydrofuran and methanol from the solution by
evaporation in vacuo, the resulting precipitates were filtered off.
The precipitates were washed with water, and dried in vacuo to
obtain the above carboxylic acid derivative (1.78 g) as a yellow
solid.
##STR00134##
[0359] The carboxylic acid derivative (50 mg, 75 .mu.mol) obtained
in the above (6) was dissolved in tetrahydrofuran (5 mL), and to
this solution were added
benzotriazo-1-yloxytripyrrolidinophosphonium hexafluorophosphate
(47 mg, 90 .mu.mol) and N,N-diisopropylethylamine (17 .mu.L, 97
.mu.mol) at room temperature. After the resulting reaction solution
was stirred at the same temperature for 5 minutes, 2M
tetrahydrofuran solution (80 .mu.L) containing lithium
tetrahydroborate was added, and the solution was stirred for 20
minutes. This reaction solution was poured into aqueous ammonium
chloride solution, and extracted with chloroform. The organic layer
was dried over anhydrous magnesium sulfate, filtered, and
concentrated. The resulting residue was purified by a thin layer
chromatography to obtain the above benzyl alcohol derivative (33.5
mg) as a pale yellow oil.
##STR00135##
[0360] The benzyl alcohol derivative (675 mg, 1.03 mmol) obtained
in the above (7) was dissolved in N,N-dimethylformamide (8 mL), and
to the solution were added successively imidazole (106 mg, 1.55
mmol) and t-butyldimethylsilyl chloride (202 mg, 1.34 mmol) in an
ice-bath, and then the reaction solution was stirred at room
temperature overnight. The resulting reaction solution was diluted
with ethyl acetate, and washed successively with water and
saturated brine. The organic layer was dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo to obtain
the above protected derivative with TBS (812 mg) as a yellow
oil.
##STR00136##
[0361] The protected derivative (78 mg) with TBS obtained in the
above (8) was dissolved in tetrahydrofuran (2 mL), and to this
solution was dropwise added 1M tetrahydrofuran solution (0.30 mL,
0.30 mmol) containing lithium hexamethyldisilazide in an ice-bath.
After the resulting solution was stirred for 20 minutes in an
ice-bath, saturated aqueous ammonium chloride was added thereto to
stop the reaction. The whole solution was poured into water,
extracted with ethyl acetate, and the organic layer was washed
successively with water and saturated brine. The organic layer was
dried over anhydrous magnesium sulfate, filtered, and concentrated
in vacuo to obtain the above de-propionitrile derivative (73 mg) as
an orange solid.
##STR00137##
[0362] The de-propionitrile derivative (296 mg) obtained in the
above (9) and the mesylated derivative [A-5] (258 mg) were
dissolved in 1,4-dioxane (15 mL), and then 4N aqueous lithium
hydroxide (103 .mu.L, 413 .mu.mol) was added to the solution. After
the solution was heated at reflux for 5 hours, it was cooled down
to room temperature, and 4N aqueous lithium hydroxide (824 .mu.L,
3.30 mmol) was added thereto, whereby the reaction solution was
suspended. After 1,4-dioxan and water were added to the reaction
solution to dissolve the suspension, the solution was heated at
reflux for 1 hour. Then, the reaction solution was cooled down to
room temperature, and saturated aqueous ammonium chloride was added
thereto. The solution was extracted with chloroform. The resulting
organic layer was washed with saturated brine, dried over anhydrous
magnesium sulfate, and filtered. The filtrate was concentrated, and
the resulting residue was purified by a column chromatography on
silica gel to obtain the above N-alkylbenzoisothiazolone derivative
(247 mg) as a yellow solid.
##STR00138##
[0363] The N-alkylbenzoisothiazolone derivative (247 mg, 346
.mu.mol) obtained in the above (10) was dissolved in chloroform (25
mL), and to the solution were added successively imidazole (28 mg,
415 .mu.mol) and t-butyldimethylsilyl chloride (52 mg, 346 .mu.mol)
in an ice-bath. The reaction solution was stirred overnight at room
temperature. The resulting reaction solution was diluted with ethyl
acetate, and washed successively with water and saturated brine.
The organic layer was dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo. The resulting residue was
purified by a chromatography on silica gel to obtain the above
protected derivative (170 mg) with TBS as a yellow solid.
##STR00139##
[0364] The protected derivative (170 mg, 205 .mu.mol) with TBS
obtained in the above (11) was dissolved in chloroform (5 mL), and
to the solution were added triethylamine (57 .mu.L, 410 .mu.mol)
and methanesulfonyl chloride (24 .mu.L, 308 .mu.mol) under
ice-cooling, and the mixture was stirred for 1 hour. After aqueous
sodium hydrogencarbonate was added the resulting reaction solution,
the mixture was extracted with chloroform. This organic layer was
washed with saturated brine, dried over anhydrous magnesium
sulfate, and filtered. The filtrate was concentrated to obtain a
yellow oil. The resulting yellow oil was dissolved in chloroform (4
mL) and methanol (2 mL), and then 4N hydrogen chloride in
1,4-dioxane (4 mL) was added thereto. The solution was stirred for
3 hours at room temperature. This solution was neutralized with
aqueous sodium hydrogencarbonate under ice-cooling, extracted with
chloroform, and the organic layer was washed with saturated brine.
After the organic layer was filtered, it was concentrated. The
resulting residue was purified by a column chromatography on silica
gel to obtain the above mesylated derivative (82 mg) as a yellow
solid.
##STR00140##
[0365] The mesylated derivative (82 mg, 154 .mu.mol) obtained in
the above (12) was dissolved in N-methylpyrrolidone (4 mL), and to
the solution was added potassium carbonate (64 mg, 462 .mu.mol).
The solution was stirred at 90.degree. C. for 5 hours. The
resulting reaction was cooled down to room temperature, and ethyl
acetate was added thereto. The organic layer was washed
successively with water and saturated brine. After the solution was
filtered and the filtrate was concentrated, and the resulting
residue was purified by a thin layer chromatography to obtain the
above cyclic derivative (23 mg) as a yellow solid.
##STR00141##
[0366] The cyclic derivative (23 mg, 40.6 .mu.mol) obtained in the
above (13) was dissolved in chloroform (1 mL), and to the solution
were added triethylamine (11 .mu.L, 81.3 .mu.mol) and
methanesulfonyl chloride (6.3 .mu.L, 81.3 .mu.mol) under
ice-cooling. After stirring the solution for 30 minutes, piperidine
(40 .mu.L, 406 .mu.mol) was added to the resulting reaction
solution. The mixture was heated at reflux for 30 minutes. The
reaction solution was cooled down to room temperature, and purified
by a thin layer chromatography to obtain the above benzylamine
derivative (24 mg) as a yellow solid.
##STR00142##
[0367] According to a method similar to the procedure described in
Working Example 1-(6), the hydrochloride (21 mg) of the objective
compound [14] was obtained from the benzylamine derivative (21 mg)
obtained in the above (14).
[0368] Spectral data of the compound of the above formula [14] are
shown below.
[0369] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.30-1.47 (1H, m),
1.60-2.39 (14H, m) 2.80-3.00 (2H, m), 3.25-3.40 (2H, m), 3.70-4.22
(2H, m), 4.30-4.45 (2H, m), 5.39 (1H, m), 7.02 (1H, s), 7.43 (1H,
s), 7.65 (1H, t, J=7.7 Hz), 8.06 (1H, d, J=7.7 Hz), 9.30 (1H, d,
J=7.7 Hz), 10.2 (1H, brs), 13.0 (1H, s).
[0370] mass: 503 (M+1).sup.+.
Working Example 15
Synthesis of the Compound of the Following Formula [15]
##STR00143##
[0372] In the above formula, the stereo chemistry of the position
with the symbol * is of cis-configuration (hereinafter, the same
until Working Example 19).
##STR00144##
[0373] According to a method similar to the procedure described in
Working Example 11-(8), the above tetrahydropyranyl ether
derivative (78 mg) was obtained as a yellow solid from the benzyl
alcohol derivative (65 mg, 0.10 mmol) obtained in Working Example
14-(7).
##STR00145##
[0374] According to a method similar to the procedure described in
Working Example 14-(9), the above de-propionitrile derivative (73
mg) was obtained as an orange solid from the tetrahydropyranyl
ether derivative (78 mg, 0.10 mmol) obtained in the above (1).
##STR00146##
[0375] According to a method similar to the procedure described in
Working Example 14-(10), the above racemic
N-alkylbenzoisothiazolone derivative (1.4 g) was obtained as a
yellow solid from the de-propionitrile derivative (3.1 g, 4.6 mmol)
and the racemic mesylated derivative [A-12] (3.7 g, 9.2 mmol)
obtained in the above (2).
##STR00147##
[0376] The racemic N-alkylbenzoisothiazolone derivative (2.2 g, 2.2
mmol) obtained in the above (3) was dissolved in tetrahydrofuran
(30 mL), and to the solution was added 1M tetrahydrofuran solution
(16 mL) containing tetrabutylammonium fluoride. The solution was
stirred at room temperature for 2 hours. The resulting reaction
solution was diluted with chloroform (150 mL) and washed with 0.1M
phosphate buffer (pH 6.8) and saturated brine. The organic layer
was dried over anhydrous magnesium sulfate, filtered, and the
filtrate was concentrated. The resulting residue was purified by a
column chromatography on silica gel to obtain the above racemic
alcohol derivative (1.53 g) as a yellow solid.
##STR00148##
[0377] According to a method similar to the procedures described in
Working Examples 14-(12) to 14-(13), the above racemic cyclic
derivative (124 mg) was obtained as a yellow solid from the racemic
alcohol derivative (1.53 g, 1.7 mmol) obtained in the above
(4).
##STR00149##
[0378] According to a method similar to the procedure described in
Working Example 14-(14), the above benzylamine derivative as a
diastereomer mixture (64 mg) was obtained as a yellow oil from the
racemic cyclic derivative (100 mg, 150 .mu.mol) and the racemic
amine derivative [A-25] obtained in the above (5).
##STR00150##
[0379] The above benzylamine derivative as a diastereomer mixture
(64 mg, 80 .mu.mol) obtained in the above (6) was dissolved in
chloroform (1 mL), and to the solution were added
dichlorobis(triphenylphosphine)palladium(II) (23 mg, 30 .mu.mol),
acetic acid (20 mg, 340 .mu.mol), tributyltin hydride (73 mg, 250
.mu.mol). The mixture was stirred at room temperature for 30
minutes. The resulting reaction solution was purified by a thin
layer chromatography to obtain the above de-Alloc derivative as a
diastereomer mixture (50 mg) as a yellow oil.
##STR00151##
[0380] According to a method similar to the procedure described in
Working Example 1-(6), the above hydrochloride (27 mg) of the
objective compound [15] as a diastereomer mixture was obtained as a
yellow solid from the de-Alloc derivative (50 mg, 70 .mu.mol) as a
diastereomer mixture obtained in the above (7).
[0381] Spectral data of the compound of the above formula [15] are
shown below.
[0382] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.60-2.40 (9H, m),
2.60-3.80 (11H, m), 4.20-4.80 (6H, m), 7.15 (1H, J=4.8 Hz), 7.75
(2H, m), 8.18 (1H, d, J=7.7 Hz), 9.43 (1H, d, J=7.7 Hz), 11.2 (1H,
brs), 13.2 (1H, brs).
[0383] mass: 548 (M+1).sup.+.
Working Example 16
Synthesis of the Compound of the Following Formula [16]
##STR00152##
[0385] According to a method similar to the procedure described in
Working Example 6-(1), the hydrochloride (6.4 mg) of the objective
compound [16] as a diastereomer mixture was obtained as a yellow
solid from the compound (10 mg, 20 .mu.mol) obtained as a
diastereomer mixture in Working Example 15.
[0386] Spectral data of the compound of the above formula [16] are
shown below.
[0387] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.60-2.20 (9H, m),
2.20-3.00 (4H, m), 3.00-3.80 (10H, m), 4.00-4.60 (6H, m), 7.06 (1H,
s), 7.60 (2H, m), 8.07 (1H, d, J=7. 6 Hz), 9.37 (1H, d, J=7.6 Hz),
10.0 (1H, brs), 13.0 (1H, brs)
[0388] mass: 562 (M+1).sup.+.
Working Example 17
Synthesis of the Compound of the Following Formula [17]
##STR00153##
[0390] According to a method similar to the procedure described in
Working Example 14-(14), the above benzylamine derivative (183 mg)
as a diastereomer mixture was obtained as a yellow oil from the
racemic cyclic derivative (210 mg, 320 .mu.mol) obtained in Working
Example 15-(5) and the racemic amine derivative [A-22] (147 mg, 970
.mu.mol).
##STR00154##
[0391] According to a method similar to the procedure described in
Working Example 15-(7), the above de-Alloc derivative (131 mg) as a
diastereomer mixture was obtained as a yellow oil from the
benzylamine derivative as a diastereomer mixture (183 mg, 240
.mu.mol) obtained in the above (1).
##STR00155##
[0392] According to a method similar to the procedure described in
Working Example 11-(18), the hydrochloride (51.4 mg) of the
objective compound [17] was obtained as a yellow solid from the
de-Alloc derivative (131 mg, 240 .mu.mol) as a diastereomer mixture
obtained in the above (2).
[0393] Spectral data of the compound of the above formula [17] are
shown below.
[0394] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.60-2.40 (12H, m),
3.20-3.80 (7H, m), 4.20-4.80 (5H, m), 7.20 (1H, m), 7.75 (2H, m),
8.18 (1H, d, J=8.0 Hz), 9.42 (1H, d, J=8.0 Hz), 9.80 (1H, brs),
11.7 (1H, brs).
[0395] mass: 534 (M+1).sup.+.
Working Example 18
Synthesis of the Compound of the Following Formula [18]
##STR00156##
[0397] According to a method similar to the procedure described in
Working Example 14-(14), the above racemic benzylamine derivative
(22 mg) was obtained as a yellow solid from the racemic cyclic
derivative (65 mg, 100 .mu.mol) obtained in the Working Example
15-(5) and piperidine.
##STR00157##
[0398] The racemic benzylamine derivative (22 mg, 30 .mu.mol)
obtained in the above (1) was dissolved in tetrahydrofuran (1 mL),
and to the solution were added formic acid (7 mg, 150 .mu.mol),
diethylamine (16 .mu.L, 830 .mu.mol) and
tetrakis(triphenylphosphine)palladium(0) (1.73 mg, 1.5 .mu.mol)
under ice-cooling. The mixture was stirred at room temperature for
3 hours. Aqueous sodium hydrogencarbonate was added to the
resulting reaction solution, followed by extraction with
chloroform. The organic layer was washed with saturated brine,
dried over anhydrous magnesium sulfate, and filtered. The filtrate
was concentrated, and purified by a thin layer chromatography to
obtain the above racemic N-allyl derivative (7.1 mg, 11 .mu.mol) as
a yellow solid and the above racemic N--H derivative (6.9 mg) as a
yellow solid, respectively.
##STR00158##
[0399] According to a method similar to the procedure described in
Working Example 1-(6), the hydrochloride (5.6 mg) of the racemic
objective derivative [18] was obtained as a yellow solid from the
racemic N--H derivative (6.9 mg, 11 .mu.mol) obtained in the above
(2).
[0400] Spectral data of the compound of the above formula [18] are
shown below.
[0401] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20-2.50 (10H, m),
2.60-3.80 (4H, m), 4.20-4.80 (8H, m), 7.17 (1H, s), 7.75 (1H, t,
J=7.7 Hz), 7.75 (1H, s), 8.18 (1H, d, J=7.7 Hz), 9.42 (1H, d, J=7.7
Hz), 11.2 (1H, brs), 13.2 (1H, brs).
[0402] mass: 506 (M+1).sup.+.
Working Example 19
Synthesis of the Compound of the Following Formula
##STR00159##
[0404] According to a method similar to the procedure described in
Working Example 1-(6), the hydrochloride (4.5 mg, 11 .mu.mol) of
the racemic objective derivative [19] was obtained as a yellow
solid from the racemic N-allyl derivative (7.1 mg, 11 .mu.mol)
obtained in Working Example 18-(2).
[0405] Spectral data of the compound of the above formula [19] are
shown below.
[0406] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20-2.20 (10H, m),
2.20-3.10 (4H, m), 3.10-4.60 (10H, m), 5.10-5.40 (2H, m), 6.05 (1H,
m), 7.06 (1H, s), 7.51 (1H, s), 7.63 (1H, t, J=7.5 Hz), 8.06 (1H,
d, J=7.7 Hz), 9.37 (1H, d, J=7.7 Hz), 10.8 (1H, brs), 13.0 (1H,
brs).
[0407] mass: 544 (M+1).sup.+.
Working Example 20
Synthesis of the Compound of the Following Formula [20]
##STR00160##
[0409] According to a method similar to the procedures described in
Working Example 15-(3) to 15-(5), the above cyclic derivative (82
mg) was obtained as an orange solid from the de-propionitrile
derivative (617 mg, 0.900 mmol) obtained in the Working Example
15-(2) and the mesylated derivative [A-13].
##STR00161##
[0410] According to a method similar to the procedures described in
Working Examples 14-(14) and 1-(6), the hydrochloride (36 mg) of
the objective compound [20] was obtained as a yellow solid from the
cyclic derivative (82 mg, 0.145 mmol) obtained in the above
(1).
[0411] Spectral data of the compound of the above formula [20] are
shown below.
[0412] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.30-2.10 (13H, m),
2.90-3.10 (4H, m), 3.30-3.40 (2H, m), 4.20-4.40 (4H, m), 4.83 (1H,
s), 7.05 (1H, s), 7.39 (1H, s), 7.63 (1H, t, J=8.0 Hz), 8.09 (1H,
d, J=8.0 Hz), 9.18 (1H, d, J=8.0 Hz), 10.6 (1H, brs), 13.0 (1H,
s).
[0413] mass: 503 (M+1).sup.+.
Working Example 21
Synthesis of the Compound of the Following Formula [21]
##STR00162##
[0415] According to a method similar to the procedures described in
Working Example 20, the hydrochloride (90 mg) of the objective
compound [21] was obtained as a yellow solid from the
de-propionitrile derivative (547 mg, 0.797 mmol) obtained in the
Example 15-(2) and the mesylated derivative [A-8].
[0416] Spectral data of the compound of the above formula [21] are
shown below.
[0417] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.23 (3H, d, J=8.0 Hz),
1.30-2.00 (9H, m) 2.30-2.60 (3H, m), 2.80-3.00 (2H, m), 3.20-3.40
(2H, m), 4.15 (1H, t, J=10.0 Hz), 4.30-4.60 (4H, m), 7.03 (1H, s),
7.51 (1H, s), 7.62 (1H, t, J=8.0 Hz), 8.03 (1H, d, J=8.0 Hz), 9.41
(1H, d, J=8.0 Hz), 10.8 (1H, brs), 13.1 (1H, s).
[0418] mass: 491 (M+1).sup.+.
Working Example 22
Synthesis of the Compound of the Following Formula [22]
##STR00163##
[0420] According to a method similar to the procedure described in
Working Example 20, the hydrochloride (130 mg) of the objective
compound [0.22] was obtained as a yellow solid from the
de-propionitrile derivative (755 mg, 1.10 mol) obtained in the
Working Example 15-(2) and the mesylated derivative [A-9].
[0421] Spectral data of the compound of the above formula [22] are
shown below.
[0422] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.22 (3H, d, J=8.0 Hz),
1.30-2.00 (9H, m), 2.30-2.60 (3H, m), 2.80-3.00 (2H, m), 3.20-3.40
(2H, m), 4.14 (1H, t, J=10.0 Hz), 4.32-4.34 (2H, m), 4.43-4.48 (1H,
m), 4.55-4.60 (1H, m), 7.02 (1H, s), 7.50 (1H, s), 7.61 (1H, t,
J=8.0 Hz), 8.02 (1H, d, J=8.0 Hz), 9.40 (1H, d, J=8.0 Hz), 10.8
(1H, brs), 13.0 (1H, s).
[0423] mass: 491 (M+1).sup.+.
Working Example 23
Synthesis of the Compound of the Following Formula [23]
##STR00164##
[0425] According to a method similar to the procedure described in
Working Example 20, the hydrochloride (59 mg) of the objective
compound [23] was obtained as a yellow solid from the
de-propionitrile derivative (523 mg, 762 .mu.mol) obtained in
Working Example 15-(2) and the mesylated derivative [A-4].
[0426] Spectral data of the compound of the above formula [23] are
shown below.
[0427] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-1.70 (1H, m),
1.90-2.30 (8H, m), 2.40-2.58 (2H, m), 2.60-3.00 (4H, m), 3.10-3.30
(2H, m), 3.50-3.80 (2H, m), 4.58-4.64 (3H, m), 4.82-5.00 (1H, m),
5.18-5.22 (1H, m), 7.36 (1H, s), 7.80 (1H, s), 7.90 (1H, t, J=7.7
Hz), 8.30 (1H, d, J=7.7 Hz) 9.54 (1H, d, J=7.7H z), 13.2 (1H,
s).
[0428] mass: 503 (M+1).sup.+.
Working Example 24
Synthesis of the Compound of the Following Formula [24]
##STR00165##
[0430] According to a method similar to the same procedure as
Working Example 23, the hydrochloride (59 mg) of the objective
compound [24] was obtained from the de-propionitrile derivative
obtained in Working Example 15-(2) and the mesylated derivative
[A-6].
[0431] Spectral data of the compound of the above formula [24] are
shown below.
[0432] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-1.70 (1H, m),
1.90-2.30 (8H, m), 2.40-2.58 (2H, m), 2.60-3.00 (4H, m), 3.10-3.30
(2H, m), 3.50-3.80 (2H, m), 4.58-4.64 (3H, m), 4.82-5.00 (1H, m),
5.18-5.22 (1H, m), 7.36 (1H, s), 7.80 (1H, s), 7.90 (1H, t, J=7.7
Hz), 8.30 (1H, d, J=7.7 Hz) 9.54 (1H, d, J=7.7H z), 10.8 (1H, brs),
13.2 (1H, s).
[0433] mass: 503 (M+1).sup.+.
Working Example 25
Synthesis of the Compound of the Following Formula [25]
##STR00166##
[0435] According to a method similar to the procedures described in
Working Examples 14-(10) to 14-(14) and 1-(6), the hydrochloride
(14 mg) of the objective compound [25] was obtained as a yellow
solid from the de-propionitrile derivative (145 mg) obtained in
Working Example 14-(9) and the mesylated derivative [A-7] (193
mg).
[0436] Spectral data of the compound of the above formula [25] are
shown below.
[0437] .sup.1HNMR (DMSO-d.sub.6) .delta.: 1.30-1.55 (2H, m),
1.60-1.75 (4H, m), 1.75-2.05 (5H, m), 2.32 (2H, m), 2.65 (4H, m),
2.85-2.95 (2H, m), 4.00-4.15 (1H, m), 4.30-4.40 (2H, m), 4.50-4.60
(1H, m), 5.27 (1H, m), 7.00 (1H, s), 7.16 (1H, s), 7.63 (1H, m),
8.08 (1H, d, J=7.6 Hz), 9.31 (1H, d, J=7.2 Hz), 9.88 (1H, brs).
[0438] mass: 503 (M+1).sup.+.
Working Example 26
Synthesis of the Compound of the Following Formula [26]
##STR00167##
[0440] According to a method similar to the procedures described in
Working Examples 14-(10) to 4-(14), and 1-(6), the hydrochloride
(63.9 mg) of the objective compound [26] was obtained as a yellow
solid from the de-propionitrile derivative (456 mg, 637 .mu.mol)
obtained in Working Example 14-(9) and the mesylated derivative
[A-10].
[0441] Spectral data of the compound of the above formula [26] are
shown below.
[0442] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.39-1.50 (4H, m),
1.69-1.86 (7H, m), 2.08-2.11 (4H, m), 2.88-2.93 (2H, m), 3.25-3.37
(2H, m), 3.55-3.70 (1H, m), 4.01-4.41 (3H, m), 4.91-4.92 (1H, m),
6.96 (1H, s), 7.44 (1H, s), 7.50-7.62 (1H, m), 7.95 (1H, d, J=7.3
Hz), 9.27 (1H, d, J=8.1 Hz), 13.0 (1H, brs).
[0443] mass: 491 (M+1).sup.+.
Working Example 27
Synthesis of the Compound of the Following Formula [27]
##STR00168##
[0445] According to a method similar to the procedure as Working
Example 26, the hydrochloride (63 mg) of the objective compound
[27] was obtained from the mesylated derivative [A-11] and the
de-propionitile derivative obtained in Working Example 14-(9).
[0446] Spectral data of the compound of the above formula [27] are
shown below.
[0447] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.39-1.50 (4H, m),
1.69-1.86 (7H, m), 2.08-2.11 (4H, m), 2.88-2.93 (2H, m), 3.25-3.37
(2H, m), 3.55-3.70 (1H, m), 4.01-4.41 (3H, m), 4.91-4.92 (1H, m),
6.96 (1H, s), 7.44 (1H, s), 7.50-7.62 (1H, m), 7.95 (1H, d, J=7.3
Hz), 9.27 (1H, d, J=8.1 Hz), 13.0 (1H, brs).
[0448] mass: 491 (M+1).sup.+.
Working Example 28
Synthesis of the Compound of the Following Formula [28]
##STR00169##
[0450] According to a method similar to the procedure described in
Working Example 1-(1), the above carboxylic acid derivative (2.98
g) was obtained as a white solid from the tetrahydropyranyl ether
derivative (3.00 g, 6.17 mmol) obtained in Working Example
11-(8).
##STR00170##
[0451] According to a method similar to the procedures described in
Working Examples 1-(2) to 1-(4), the above benzoisothiazolone
derivative (120 mg) was obtained as a yellow solid from the
carboxylic acid derivative (426 mg, 740 .mu.mol) obtained in the
above (1) and the amine derivative [A-14].
##STR00171##
[0452] According to a method similar to the procedure described in
Working Example 11-(9), the above alcohol derivative (120 mg) was
obtained as a pale yellow solid from the benzoisothiazolone
derivative (120 mg, 171 mmol) obtained in the above (2).
##STR00172##
[0453] According to a method similar to the procedures described in
Working Examples 14-(12) to 14-(13), the above cyclic derivative
(32 mg) was obtained as a yellow solid from the alcohol derivative
(120 mg) obtained in the above (3).
##STR00173##
[0454] According to a method similar to the procedures described in
Working Examples 14-(14) and 11-(18), the above hydrochloride (34
mg) of the objective compound [28] was obtained as a yellow solid
from the cyclic derivative (32 mg, 70.9 .mu.mol) obtained in the
above (4) and the amine derivative [A-27].
[0455] Spectral data of the compound of the above formula [28] are
shown below.
[0456] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-2.10 (10H, m),
2.20-4.80 (16H, m), 7.07 (1H, s), 7.37 (1H, s), 7.64 (1H, t, J=7.7
Hz), 8.07 (1H, d, J=7.7 Hz), 9.33 (1H, d, J=7.7 Hz), 10.3 (1H,
brs), 13.0 (1H, brs).
[0457] mass: 549 (M+1).sup.+.
Working Example 29
Synthesis of the Compound of the Following Formula [29]
##STR00174##
[0459] According to a method similar to the procedures described in
Working Examples 1-(2) to 1-(3), the above benzoisothiazolone
derivative (1.81 g) was obtained as a pale yellow solid from the
carboxylic acid derivative (1.31 g, 2.26 mmol) obtained in Working
Example 28-(1) and the amine derivative [A-15].
##STR00175##
[0460] According to a method similar to the procedure described in
Working Example 15-(4), the above alcohol derivative (1.08 g) was
obtained as a yellow solid from the benzoisothiazolone derivative
(1.81 g, 1.89 mmol) obtained in the above (1).
##STR00176##
[0461] According to a method similar to the procedures described in
Working Examples 14-(12) to 14-(13), the above cyclic derivative
(740 mg) was obtained as a yellow solid from the alcohol derivative
(1.08 g, 1.81 mmol) obtained in the above (2).
##STR00177##
[0462] According to a method similar to the procedures described in
Working Examples 14-(14) and 11-(18), the trifluoroacetate (20 mg)
of the objective compound [29] as a diastereomer mixture was
obtained as a yellow solid from the cyclic derivative (42 mg, 93
.mu.mol) obtained in the above (3) and the racemic amine derivative
[A-22].
[0463] Spectral data of the compound of the above formula [29] are
shown below.
[0464] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.45-1.95 (5H, m),
2.25-2.31 (2H, m), 2.80-3.15 (4H, m), 3.20-3.29 (3H, m), 3.57-3.69
(2H, m), 3.82-3.95 (2H, m), 4.02-4.43 (5H, m), 5.60 (1H, m), 7.11
(1H, s), 7.43 (1H, s), 7.61 (1H, t, J=7.6 Hz), 8.05 (1H, d, J=7.6
Hz), 9.31 (1H, d, J=7.6 Hz), 9.49 (1H, brs), 13.0 (1H, brs).
[0465] mass: 535 (M+1).sup.+.
Working Example 30
Synthesis of the Compound of the Following Formula [30]
##STR00178##
[0467] According to a method similar to the procedures described in
Working Examples 14-(14) and 11-(18), the trifluoroacetate (17 mg)
of the objective compound [30] as a diastereomer mixture was
obtained as a yellow solid from the alcohol derivative (49 mg, 109
.mu.mol) obtained in Working Example 29-(3) and the racemic amine
derivative [A-26].
[0468] Spectral data of the compound of the above formula [30] are
shown below.
[0469] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.42-1.65 (2H, m),
1.64-1.80 (3H, m), 1.94 (1H, m), 2.80-3.15 (3H, m), 3.40 (3H, m),
3.55-3.65 (4H, m), 3.82-3.95 (4H, m), 4.05-4.30 (4H, m), 4.70 (1H,
m), 5.6 (1H, m), 7.09 (1H, s), 7.39 (1H, s), 7.61 (1H, t, J=7.6
Hz), 8.05 (1H, d, J=7.6 Hz), 9.31 (1H, d, J=7.6 Hz), 9.35 (1H,
brs), 13.0 (1H, brs).
[0470] mass: 549 (M+1).sup.+.
Working Example 31
Synthesis of the Compound of the Following Formula [31]
##STR00179##
[0472] According to a method similar to the procedure described in
Working Example 3-(1), the above benzoisothiazolone derivative (313
mg) was obtained as a pale yellow solid from the carboxylic acid
derivative (576 mg, 1.00 mmol) obtained in Working Example
28-(1).
##STR00180##
[0473] The benzoisothiazolone derivative (278 mg, 520 .mu.mol)
obtained in the above (1) was dissolved in methylene chloride (5
mL), and to the solution were added triethylamine (220 .mu.L, 1.56
mmol) and methanesulfonyl chloride (60 .mu.L, 780 .mu.mol) with
stirring at 0.degree. C. The mixture was stirred at the same
temperature for 1 hour. 1N aqueous potassium hydrogensulfate was
added the resulting reaction solution, and the solution was stirred
at room temperature for 30 minutes. Then, the reaction solution was
extracted with chloroform. The organic layer was washed with
saturated brine, dried with anhydrous sodium sulfate, and filtered.
The filtrate was concentrated, and the resulting residue was dried
with a vacuumpump, and dissolved in N,N-dimethylformamide (10 mL).
After potassium carbonate (222 mg, 1.56 mmol) and
(R)-3-hydroxypyrrolidine hydrochloride (200 mg, 1.56 mmol) were
added thereto, the mixture was heated with stirring at 70.degree.
C. for 4 hours. To this reaction solution was added 1N aqueous
potassium hydrogensulfate, and the mixture was stirred at room
temperature for 30 minutes, then extracted with chloroform. The
organic layer was washed with saturated brine, dried over an
hydrous sodium sulfate, and filtered. The filtrate was
concentrated, and the resulting residue was purified by a column
chromatography on silica gel to obtain the above amine derivative
(114 mg) as a pale yellow solid.
##STR00181##
[0474] According to a method similar to the procedures described in
Working Example 14-(12) to 14-(13), the above cyclic derivative (10
mg) was obtained as a yellow oil from the amine derivative (13 mg,
21 .mu.mol) obtained in the above (2).
##STR00182##
[0475] According to a method similar to the procedures described in
Working Examples 14-(14) and 11-(18), the hydrochloride (13 mg) of
the objective compound [31] was obtained as a yellow solid from the
cyclic derivative (12 mg, 21 .mu.mol) obtained in the above (3) and
piperidine.
[0476] Spectral data of the compound of the above formula [31] are
shown below.
[0477] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20-2.10 (8H, m),
2.20-3.50 (8H, m), 3.50-4.40 (6H, m), 5.50 (1H, m), 6.98-7.10 (1H,
m), 7.50-7.80 (2H, m), 7.98-8.10 (1H, m), 9.28 (1H, d, J=8.2
Hz).
[0478] mass: 504 (M+1).sup.+.
Working Example 32
Synthesis of the Compound of the Following Formula [32]
##STR00183##
[0480] According to a method similar to the procedures described in
Working Examples 14-(14) and 11-(18), the hydrochloride (88 mg) of
the objective compound [32.] was obtained as a yellow solid from
the cyclic derivative (143 mg, 317 .mu.mol) obtained in Working
Example 31-(3) and morpholine.
[0481] Spectral data of the compound of the above formula [32] are
shown below.
[0482] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.80-2.60 (6H, m),
2.80-3.50 (3H, m), 3.50-4.30 (10H, m), 4.30-4.50 (1H, m) 5.50 (1H,
m), 6.90-7.05 (1H, m), 7.40-7.80 (2H, m), 7.90-8.10 (1H, m),
9.20-9.30 (1H, m).
[0483] mass: 506 (M+1).sup.+.
Working Example 33
Synthesis of the Compound of the Following Formula [33]
##STR00184##
[0485] According to a method similar to the procedures as Working
Examples 31-(2) and 32-(3), the above cyclic derivative was
obtained from the benzoisothiazolone derivative obtained in Working
Example 31-(1) and (S)-3-hydroxypyrrolidine hydrochloride.
##STR00185##
[0486] According to a method similar to the procedures described in
Working Examples 14-(14) and 11-(18), the trifluoroacetate (37 mg)
of the objective compound [33] as a diastereomer mixture was
obtained as a yellow solid from the cyclic derivative (68 mg, 151
.mu.mol) obtained in the above (1) and the racemic amine derivative
[A-22].
[0487] Spectral data of the compound of the above formula [33] are
shown below.
[0488] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.80-1.20 (2H, m),
1.40-2.60 (8H, m), 2.60-3.80 (8H, m), 3.20 (3H, s), 4.10-4.50 (3H,
m) 5.30 (1H, m), 6.90-7.02 (1H, m), 7.10-7.20 (1H, m), 7.58 (1H,
m), 8.01-8.02 (1H, m), 9.30 (1H, m), 9.48 (1H, brs), 13.0 (1H,
brs).
[0489] mass: 534 (M+1).sup.+.
Working Example 34
Synthesis of the Compound of the Following Formula [34]
##STR00186##
[0491] According to a method similar to the procedures described in
Working Examples 14-(14) and 11-(18), the trifluoroacetate (27 mg)
of the objective compound [34] was obtained as a yellow solid from
the cyclic derivative (60 mg, 133 .mu.mol) obtained in Working
Example 31-(3) and the racemic amine derivative [A-23].
[0492] Spectral data of the compound of the above formula [34] are
shown below.
[0493] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.50-2.09 (5H, m),
2.25-2.33 (1H, m), 2.71-3.22 (3H, m), 3.24-3.28 (3H, m), 3.31-3.43
(3H, m), 3.66-3.73 (2H, m), 3.80-4.00 (2H, m), 4.05-4.50 (5H, m),
5.31-5.43 (1H, m), 7.00-7.29 (1H, m), 7.55-7.75 (2H, m), 8.03-8.15
(1H, m), 9.30-9.35 (1H, m), 9.65 (1H, brs), 12.9-13.2 (1H, m).
[0494] mass: 534 (M+1).sup.+.
Working Example 35
Synthesis of the Compound of the Following Formula [35]
##STR00187##
[0496] According to a method similar to the procedures described in
Working Examples 14-(14) and 11-(18), the trifluoroacetate (25 mg)
of the objective compound [35] was obtained as a yellow solid from
the cyclic derivative (60 mg, 133 .mu.mol) obtained in Working
Example 31-(3) and the amine derivative [A-24].
[0497] Spectral data of the compound of the above formula [35] are
shown below.
[0498] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.17-1.96 (5H, m),
2.12-2.40 (1H, m), 2.72-3.23 (3H, m), 3.23-3.28 (3H, m), 3.38-3.60
(5H, m), 3.60-3.74 (2H, m), 4.12-4.43 (5H, m), 5.35-5.41 (1H, m),
7.06-7.30 (1H, m), 7.50-7.80 (2H, m), 8.03-8.06 (1H, m), 9.31-9.34
(1H, m), 9.64 (1H, brs), 12.9-13.0 (1H, m).
[0499] mass: 534 (M+1).sup.+.
Working Example 36
Synthesis of the Compound of the Following Formula [36]
##STR00188##
[0501] According to a method similar to the procedures described in
Working Examples 14-(14) and 11-(18), the trifluoroacetate (41 mg)
of the objective compound [36] was obtained as a yellow solid from
the cyclic derivative (70 mg, 150 .mu.mol) obtained in Working
Example 31-(3) and the amine derivative [A-27].
[0502] Spectral data of the compound of the above formula [36] are
shown below.
[0503] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.30-1.80 (7H, m)
2.06-2.93 (7H, m), 3.06-3.87 (10H, m), 4.25-4.39 (2H, m), 5.35 (1H,
brs), 7.02 (1H, s), 7.19 (1H, s), 7.57 (1H, t, J=7.2 Hz), 8.03 (1H,
d, J=7.2 Hz), 9.30 (1H, d, J=7.2 Hz), 12.9 (1H, s).
[0504] mass: 548 (M+1).sup.+.
Working Example 37
Synthesis of the Compound of the Following Formula [37]
##STR00189##
[0506] According to a method similar to the procedures described in
Working Examples 14-(14) and 11-(18), the trifluoroacetate (41 mg)
of the objective derivative [37] was obtained as a yellow solid
from the cyclic derivative (70 mg, 150 .mu.mol) obtained in Working
Example 31-(3) and the amine derivative [A-28].
[0507] Spectral data of the compound of the above formula [37] are
shown below.
[0508] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.30-1.80 (7H, m),
2.06-2.93 (7H, m), 3.06-3.87 (10H, m), 4.25-4.39 (2H, m), 5.35 (1H,
brs), 7.02 (1H, s), 7.19 (1H, s), 7.57 (1H, t J=7.2 Hz), 8.03 (1H,
d, J=7.2 Hz), 9.30 (1H, d, J=7.2 Hz), 12.9 (1H, s).
[0509] mass: 548 (M+1).sup.+.
Working Example 38
Synthesis of the Compound of the Following Formula [38]
##STR00190##
[0511] According to a method similar to the procedure described in
Working Example 1-(2), the above amide derivative (250 mg) was
obtained as an orange solid from the carboxylic acid derivative
(200 mg, 340 .mu.mol) obtained in Working Example 28-(1) and the
amine derivative [A-16].
##STR00191##
[0512] The amide derivative (190 mg, 0.26 mmol) obtained in the
above (1) was dissolved in methylene chloride (5.0 mL) under a
nitrogen atmosphere, and N-methylpyrrolidine (104 .mu.L, 1.04 mmol)
was added thereto. The reaction solution was cooled to -78.degree.
C., and a solution of sulfuryl chloride in methylene chloride (1.04
mL, 0.5M, 0.52 mmol) was added dropwise at -78.degree. C. The
reaction solution was stirred at the same temperature for 1 hour.
The resulting reaction solution was poured into an aqueous solution
of sodium sulfite and potassium carbonate, and then extracted with
chloroform twice. The organic layer was dried over anhydrous sodium
sulfate, filtered, and concentrated. The resulting residue was
purified by a column chromatography on silica gel to obtain the
above benzoisothiazolone derivative (169 mg) as a yellow solid.
##STR00192##
[0513] According to a method similar to the procedures described in
Working Examples 11-(9), and 14-(12) to 14-(13), the above cyclic
derivative (46 mg) was obtained as a yellow solid from the
benzoisothiazolone derivative (225 mg, 340 .mu.mol) obtained in the
above (2).
##STR00193##
[0514] According to a method similar to the procedures described in
Working Examples 14-(14) and 11-(18), the trifluoroacetate (41 mg)
of the objective compound [38] was obtained as a yellow solid from
the cyclic derivative (70 mg, 150 .mu.mol) obtained in the above
(3) and the amine derivative [A-23].
[0515] Spectral data of the compound of the above formula [38] are
shown below.
[0516] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.23-2.25 (9H, m),
2.90-3.14 (2H, m), 3.25 (3H, s), 3.28-3.38 (2H, m), 3.43-3.58 (2H,
m), 3.63-3.78 (2H, m), 4.10-5.10 (6H, m), 5.43 (1H, brs), 7.02-7.14
(1H, m), 7.32-7.46 (1H, m), 7.66-7.75 (1H, m), 8.08-8.18 (1H, m),
9.46-9.52 (1H, m), 12.9 (1H, s).
[0517] mass: 548 (M+1).sup.+.
Working Example 39
Synthesis of the Compound of the Following Formula [39]
##STR00194##
[0519] According to a method similar to the procedures described in
Working Examples 14-(14) and 11-(18), the hydrochloride (14 mg) of
the objective compound [39] was obtained as a yellow solid from the
cyclic derivative (46 mg, 100 .mu.mol) obtained in Working Example
38-(3) and morpholine.
[0520] Spectral data of the compound of the above formula [39] are
shown below.
[0521] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.08-2.33 (4H, m),
3.03-3.80 (12H, m), 3.84-4.03 (4H, m), 4.20-4.55 (2H, m), 5.58 (1H,
brs), 7.03 (1H, s), 7.66 (1H, t, J=8.0 Hz), 7.89 (1H, s), 8.07 (1H,
d, J=8.0 Hz), 9.42 (1H, d, J=8.0 Hz), 12.9 (1H, s).
[0522] mass: 520 (M+1).sup.+.
Working Example 40
Synthesis of the Compound of the Following Formula [40]
##STR00195##
[0524] According to a method similar to the procedures of Working
Examples 1-(2) to 1-(5), the above racemic cyclic derivative (2.01
g) was obtained as a yellow solid from the carboxylic acid
derivative (6.61 g, 8.88 mmol) prepared in Working Example 14-(2)
and a racemate of 5-amino-1-hexanol synthesized by referring to a
method similar to the method described in J. Med. Chem., 25(8) 964
(1982).
##STR00196##
[0525] According to a method similar to the procedures described in
Working Examples 14-(5) to 14-(6), the above racemic carboxylic
acid derivative (464 mg) was obtained as an orange solid from the
racemic cyclic derivative (529 mg, 880 mmol) obtained in the above
(1).
##STR00197##
[0526] The racemic carboxylic acid derivative (464 mg, 820 .mu.mol)
obtained in the above (2) was dissolved in tetrahydrofuran (50 mL)
and N,N-dimethylformamide (14 mL), and then
1,1'-carbonylbis-1H-imidazole (199 mg, 1.23 mmol) was added
thereto. The reaction solution was stirred at room temperature for
11 hours, and then lithium tetrahydroborate (35.6 mg, 1.64 mmol)
was added. Lithium tetrahydroborate (35.6 mg, 1.64 mmol) was added
to the resulting reaction solution, and the mixture was stirred at
room temperature for 30 minutes. After that, lithium
tetrahydroborate (35.6 mg, 1.64 mmol) was further added thereto,
and the mixture was stirred at room temperature for 30 minutes, and
then chloroform (50 mL) was added to the reaction solution. After
addition of saturated aqueous ammonium chloride (30 mL), the
solution was extracted with chloroform. The organic layer was
washed with saturated brine, and dried over anhydrous magnesium
sulfate, and filtered. The filtrate was concentrated in vacuo, and
the resulting residue was evaporated azeotropically using toluene.
The resulting residue was dissolved in methylene chloride (30 mL)
and chloroform (30 mL). After manganese dioxide (214 mg, 2.45 mmol)
was added to this solution, the mixture was stirred at room
temperature for 2 hours. The resulting reaction solution was
filtered through a Celite pad, and then concentrated in vacuo. The
residue was purified by a column chromatography on silica gel to
obtain the above racemic benzyl alcohol derivative (298 mg) as a
yellowish brown solid.
##STR00198##
[0527] The racemic benzyl alcohol derivative (298 mg, 540 .mu.mol)
obtained in the above (3) was dissolved in chloroform (20 mL), and
manganese dioxide (468 mg, 5.38 mmol) was added thereto. The
mixture was stirred at room temperature for 11 hours. The resulting
reaction solution was filtered through a Celite pad, and the
filtrate was concentrated in vacuo. The resulting residue was
purified by a thin layer chromatography to obtain the above racemic
aldehyde (175 mg) as a yellowish brown solid.
##STR00199##
[0528] To chloroform solution (20 mL) containing the racemic
aldehyde derivative (100 mg, 180 .mu.mol) obtained in the above (4)
and pyrrolidine (121 .mu.L, 1.45 mmol) was added methanol solution
(2.42 mL) containing zinc chloride (50 mg, 364 .mu.mol) and sodium
cyanotrihydroborate (47 mg, 726 .mu.mol), and the mixture was
stirred at room temperature for 12 hours. The resulting reaction
solution was concentrated, and the resulting residue was diluted
with chloroform, and washed with water and saturated brine. The
organic layer was dried over anhydrous magnesium sulfate, and
filtered. The filtrate was concentrated in vacuo, and the resulting
residue was purified by a thin layer chromatography to obtain the
above racemic benzylamine derivative (70 mg) as a yellowish brown
solid.
##STR00200##
[0529] According to a method similar to the procedure described in
Working Example 1-(6), the hydrochloride (49 mg) of the objective
compound [40] as a racemate was obtained as a yellow solid from the
racemic benzylamine derivative (70 mg, 120 .mu.mol) obtained in the
above (5).
[0530] Spectral data of the compound of the above formula [40] are
shown below.
[0531] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.24 (3H, d, J=6.6 Hz),
1.80-2.08 (10H, m), 3.05-3.12 (2H, m), 3.38-3.45 (2H, m), 4.14-4.21
(1H, m), 4.43-4.52 (3H, m), 4.58-4.63 (1H, m), 7.06 (1H, s), 7.39
(1H, s), 7.65 (1H, t, J=7.8 Hz), 8.06 (1H, d, J=7.8 Hz), 9.45 (1H,
d, J=7.8 Hz), 10.8 (1H, brs), 13.0 (1H, s).
[0532] mass: 477 (M+1).sup.+.
Working Example 41
Synthesis of the Compound of the Following Formula [41]
##STR00201##
[0534] According to a method similar to the procedures described in
Working Examples 40-(5) to 40-(6), the hydrochloride (12 mg) of the
objective compound [41] as a racemate was obtained as a yellowish
brown solid from the racemic aldehyde derivative (20 mg, 36
.mu.mol) obtained in Working Example 40-(4) and morpholine.
[0535] Spectral data of the compound of the above formula [41] are
shown below.
[0536] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.22 (3H, d, J=6.3 Hz),
1.76-1.97 (4H, m), 2.24-2.43 (2H, m), 3.11-3.29 (4H, m), 3.81-3.95
(4H, m), 4.11-4.17 (1H, m), 4.41-4.47 (3H, m), 4.56-4.59 (1H, m),
7.02 (1H, s), 7.49 (1H, s), 7.60 (1H, t, J=7.8 Hz), 8.01 (1H, d,
J=7.8 Hz), 9.44 (1H, d, J=7.8 Hz), 11.5 (1H, b rs), 13.0 (1H,
s).
[0537] mass: 493 (M+1).sup.+.
Working Example 42
Synthesis of the Compound of the Following Formula [42]
##STR00202##
[0539] According to a method similar to the procedures described in
Working Examples 14-(14) and 1-(6), the hydrochloride (40 mg) of
the objective compound [42] as a racemate was obtained as a
yellowish brown solid from the racemic benzyl alcohol derivative
(177 mg, 140 mmol) obtained in Working Example 40-(3) and
4-methylpiperidine.
[0540] Spectral data of the compound of the above formula [42] are
shown below.
[0541] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.91 (3H, d, J=6.3 Hz),
1.24 (3H, d, J=6.9 Hz), 1.38-1.64 (4H, m), 1.74-2.01 (5H, m),
2.25-2.40 (2H, m), 2.88-3.00 (2H, m), 3.11-3.18 (1H, m), 3.25-3.45
(1H, m), 4.15-4.22 (1H, m), 4.33-4.38 (2H, m), 4.45-4.51 (1H, m),
4.58-4.64 (1H, m), 7.04 (1H, s), 7.34 (1H, s), 7.66 (1H, t, J=7.8
Hz), 8.07 (1H, d, J=7.8 Hz), 9.45 (1H, d, J=7.8 Hz), 10.1 (1H,
brs), 13.1 (1H, s).
[0542] mass: 505 (M+1).sup.+.
Working Example 43
Synthesis of the Compound of the Following Formula [43]
##STR00203##
[0544] The racemic cyclic derivative (143 mg, 51 .mu.mol) obtained
in Working Example 40-(1) was dissolved in toluene (1.5 mL), and to
this solution were added N-methylpiperazine (136 .mu.L, 122
.mu.mol), (R)-(+)-2,2'-bis(di-4-tolylphosphino)-1,1'-binaphthyl
(9.5 mg, 15 .mu.mol), tris(dibenzylideneacetone)
dipalladium(0)-chloroform adduct (5.3 mg, 5 .mu.mol) and sodium
t-butoxide (9.8 mg, 102 .mu.mol). The mixture was stirred at
80.degree. C. for 5 hours. The resulting reaction solution was
cooled down to room temperature, extracted with chloroform, and the
extract was washed successively with water and saturated brine. The
organic layer was dried over anhydrous magnesium sulfate, filtered,
and concentrated in vacuo. The resulting residue was purified by a
thin layer chromatography to obtain the above racemic 6-piperazine
derivative (30 mg) as a yellowish brown liquid.
##STR00204##
[0545] According to a method similar to the procedure described in
Working Example 1-(6), the hydrochloride (11 mg) of the objective
compound [43] as a racemate was obtained as a yellowish brown solid
from the racemic 6-piperazine derivative (30 mg, 48 .mu.mol)
obtained in the above (1).
[0546] Spectral data of the compound of the above formula [43] are
shown below.
[0547] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.22 (3H, d, J=6.6 Hz),
1.78-1.90 (4H, m), 2.23-2.39 (2H, m), 2.83 (3H, d, J=3.9 Hz),
3.14-3.39 (6H, m), 3.96-4.11 (3H, m), 4.38-4.44 (1H, m), 4.53-4.58
(1H, m), 6.31 (1H, s), 6.68 (1H, s), 7.57 (1H, t, J=7.8 Hz), 7.94
(1H, d, J=7.8 Hz), 9.27 (1H, d, J=7.8 Hz), 10.9 (1H, brs), 12.5
(1H, s).
[0548] mass: 492 (M+1).sup.+.
Working Example 44
Synthesis of the Compound of the Following Formula [44]
##STR00205##
[0550] According to a method similar to the procedure described in
Working Example 11-(4), the above racemic vinyl derivative (60 mg)
was obtained as an orange solid from the racemic cyclic derivative
(116 mg, 139 .mu.mol) obtained in Working Example 40-(1).
##STR00206##
[0551] Pyrrolidine (4 mL) was added to the racemic vinyl derivative
(23.5 mg, 43 .mu.mol) obtained in the above (1), and the mixture
was heated in a sealed tube at 120.degree. C. for 15 hours. The
resulting reaction solution was concentrated in vacuo, and the
resulting residue was diluted with chloroform, and washed with
water and saturated brine. The organic layer was dried over
anhydrous magnesium sulfate, and filtered, and concentrated in
vacuo. The resulting residue was purified by a thin layer
chromatography to obtain the above racemic pyrrolidinylethyl
derivative (6.3 mg) as a yellowish brown solid.
##STR00207##
[0552] According to a method similar to the procedure described in
Working Example 1-(6), the hydrochloride (2.9 mg) of the objective
compound [44] as a racemate was obtained as a yellowish brown solid
from the racemic pyrrolidinylethyl derivative (6.3 mg, 10 .mu.mol)
obtained in the above (2).
[0553] Spectral data of the compound of the above formula [44] are
shown below.
[0554] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.23 (3H, d, J=6.3 Hz),
1.85-2.02 (6H, m), 2.26-2.62 (4H, m), 3.05-3.12 (2H, m), 3.25-3.59
(6H, m), 4.10-4.25 (1H, m), 4.40-4.48 (1H, m), 4.54-4.68 (1H, m),
6.84 (1H, s), 6.98 (1H, s), 7.63 (1H, t, J=7.8 Hz), 8.03 (1H, d,
J=7.8 Hz), 9.41 (1H, d, J=7.8 Hz), 10.5 (1H, brs), 12.9 (1H,
s).
[0555] mass: 491 (M+1).sup.+.
Working Example 45
Synthesis of the Compound of the Following Formula [45]
##STR00208##
[0557] The cyclic derivative (18.9 mg, 42 .mu.mol) obtained in
Working Example 31-(3) and methyl iodide (4 .mu.L, 63 mmol) were
dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (2.0 mg,
60% dispersion in oil, 50 .mu.mol) was added to this solution in an
ice-bath, and the solution was stirred at the same temperature for
2 hours. After methyl iodide (12 .mu.L, 189 .mu.mol) and sodium
hydride (6.0 mg, 60% dispersion in oil, 150 .mu.mol) were further
added thereto in an ice-bath, the solution was stirred at room
temperature for 7.5 hours. After saturated aqueous ammonium
chloride was added to the resulting reaction solution, it was
extracted with chloroform. The organic layer was washed with water
and saturated brine, dried over anhydrous magnesium sulfate, and
filtered. The filtrate was concentrated in vacuo, and the residue
was evaporated azeotropically using toluene, and the resulting
residue was purified by a thin layer chromatography to obtain the
above methoxymethyl derivative (15.6 mg) as a yellowish brown
oil.
##STR00209##
[0558] According to a method similar to the procedure described in
Working Example 11-(18), the hydrochloride (6.9 mg) of the
objective compound [45] was obtained as a yellowish brown solid
from the methoxymethyl derivative (15.6 mg, 33 .mu.mol) obtained in
the above (1).
[0559] Spectral data of the compound of the above formula [45] are
shown below.
[0560] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.93-2.06 (1H, m),
2.21-2.30 (1H, m), 2.72-3.16 (4H, m), 3.25-3.45 (4H, m), 3.59-4.10
(2H, m), 4.10-4.15 (1H, m), 4.46-4.55 (2H, m), 5.33-5.43 (1H, m),
6.78-7.04 (2H, m), 7.54-7.71 (1H, m), 8.00-8.12 (1H, m), 9.31 (1H,
brs), 12.8 (1H, s).
[0561] mass: 451 (M+1).sup.+.
Working Example 46
Synthesis of the Compound of the Following Formula [46]
##STR00210##
[0563] According to a method similar to the procedures described in
Working Examples 11-(10) to 11-(12), the above 3-indazolinone
derivative (737 mg) was obtained as an orange solid from the
carboxylic acid derivative (944 mg, 2.0 mmol) obtained in Working
Example 11-(9) and the hydrazine derivative [A-18].
##STR00211##
[0564] According to a method similar to the procedure described in
Working Example 11-(9), the above alcohol derivative (531 mg) was
obtained as an orange solid from the 3-indazolinone derivative (737
mg) obtained in the above (1).
##STR00212##
[0565] According to a method similar to the procedure described in
Working Examples 11-(14) to 11-(18), the hydrochloride (95 mg) of
the objective compound [46] was obtained as a purple solid from the
alcohol derivative (531 mg, 940 .mu.mol) obtained in the above (2)
and piperidine.
[0566] Spectral data of the compound of the above formula [46] are
shown below.
[0567] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.30-1.44 (1H, m), 1.48
(3H, d, J=6.0 Hz), 1.65-2.00 (10H, m), 2.05-2.15 (1H, m), 2.82-2.96
(2H, m), 3.20-3.28 (1H, m), 3.30-3.38 (1H, m), 3.86-3.98 (1H, m),
4.12-4.22 (1H, m), 4.24-4.34 (1H, m), 4.36-4.44 (1H, m), 4.76-4.88
(1H, m), 6.95 (1H, s), 7.17 (1H, t, J=8.0 Hz), 7.45 (1H, s), 7.83
(1H, d, J=8.0 Hz), 9.22 (1H, d, J=8.0 Hz), 10.8-10.9 (1H, brs),
11.4 (1H, s), 12.8 (1H, s).
[0568] mass: 474 (M+1).sup.+.
Working Example 47
Synthesis of the Compound of the Following Formula [47]
##STR00213##
[0570] According to a method similar to the procedures as Working
Example 46, the hydrochloride of the objective compound [47] was
obtained from the carboxylic acid derivative obtained in Working
Example 11-(9) and the hydrazine derivative [A-19].
[0571] Spectral data of the compound of the above formula [47] are
shown below.
[0572] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.30-1.44 (1H, m), 1.48
(3H, d, J=6.0 Hz), 1.65-2.00 (10H, m), 2.05-2.15 (1H, m), 2.82-2.96
(2H, m), 3.20-3.28 (1H, m), 3.30-3.38 (1H, m), 3.86-3.98 (1H, m),
4.12-4.22 (1H, m), 4.24-4.34 (1H, m), 4.36-4.44 (1H, m), 4.76-4.88
(1H, m), 6.95 (1H, s), 7.17 (1H, t, J=8.0 Hz), 7.45 (1H, s), 7.83
(1H, d, J=8.0 Hz), 9.22 (1H, d, J=8.0 Hz), 10.8-10.9 (1H, brs),
11.4 (1H, s), 12.8 (1H, s).
[0573] mass: 474 (M+1).sup.+.
Working Example 48
Synthesis of the Compound of the Following Formula [48]
##STR00214##
[0575] Triethylamine (167 .mu.L, 1.20 mmol) and
2-chloro-1,3-dimethylimidazolinium chloride (102 mg, 602 .mu.L)
were added to chloroform solution (5 mL) of the carboxylic acid
derivative (200 mg, 367 mmol) obtained by reference to Working
Example 110-2) described in WO02/02550, and the mixture was stirred
for 10 minutes. After that, to this solution was added the
hydrazine derivative [A-20] (275 mg, 602 .mu.L), and the mixture
was stirred at room temperature for 2 hours. The resulting reaction
solution was purified by a thin layer chromatography to obtain the
above hydrazide derivative (213 mg) as a yellow oil.
##STR00215##
[0576] 10% hydrochloric acid/methanol (2 mL) was added to the
hydrazide derivative (50 mg, 50.9 .mu.mol) obtained in the above
(1), and the mixture was stirred at room temperature for 15 hours.
The resulting reaction solution was concentrated, and the resulting
residue was purified by a thin layer chromatography to obtain the
above de-Boc derivative (28 mg) as a yellow oil.
##STR00216##
[0577] According to a method similar to the procedure described in
Working Example 11-(12), the above 3-indazolinone derivative (14
mg, 27 .mu.mol) was obtained as an orange solid from the de-Boc
derivative (28 mg) obtained in the above (2).
##STR00217##
[0578] According to a method similar to the procedures described in
Working Examples 1-(5) to 1-(6), the objective compound [48] (8 mg)
was obtained as an orange solid from the 3-indazolinone derivative
(14 mg, 27 .mu.mol) obtained in the above (3).
[0579] Spectral data of the compound of the above formula [48] are
shown below.
[0580] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.73-2.10 (6H, m),
4.00-4.11 (2H, m), 4.15-4.23 (2H, m), 6.84-6.90 (2H, m), 7.17 (1H,
t, J=7.7 Hz), 7.45 (1H, t, J=8.2 Hz), 7.83 (1H, d, J=7.7 Hz), 9.24
(1H, d, J=7.7 Hz), 11.6 (1H, s), 12.6 (1H, b rs).
[0581] mass: 363 (M+1).sup.+
Working Example 49
Synthesis of the Compound of the Following Formula [49]
##STR00218##
[0583] According to a method similar to the procedure described in
Working Example 11-(9), the above carboxylic acid derivative (8.42
g) was obtained as a pale yellow solid from the protected
derivative (10 g) with SEM obtained in Working Example 14-(1).
##STR00219##
[0584] According to a method similar to the procedures including
the steps of up to the macrocyclization described in Working
Examples 48-(1) to 48-(4), the above racemic cyclic derivative (6.9
mg) was obtained as a yellowish brown solid from the carboxylic
acid derivative (15.6 mg, 33 .mu.mol) obtained in the above (1) and
the racemic hydrazine derivative [A-21].
##STR00220##
[0585] According to a method similar to the procedure described in
Working Example 14-(5) to 14-(6), the above racemic carboxylic acid
derivative (188 mg) was obtained as an orange solid from the
racemic cyclic derivative (192 mg, 326 .mu.mol) obtained in the
above (2).
##STR00221##
[0586] The racemic carboxylic acid derivative (188 mg, 340 .mu.mol)
obtained in the above (3) was dissolved in tetrahydrofuran (10 mL),
and to the solution was added 1,1'-carbonylbis-1H-imidazole (83 mg,
510 .mu.mol). The mixture was stirred at room temperature for 17
hours. To the resulting reaction solution were slowly added sodium
tetrahydroborate (26 mg, 680 .mu.mol) and water (10 mL), and the
mixture was stirred at room temperature for 20 minutes. After
saturated aqueous ammonium chloride solution was added to this
reaction solution, the mixture was extracted with chloroform. The
organic layer was washed with saturated brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo. The
resulting residue was purified by a thin layer chromatography. The
resulting compound was dissolved in methylene chloride (6 mL), and
manganese dioxide (133 mg, 1.53 mmol) was added thereto. The
mixture was stirred at room temperature for 18 hours. The resulting
reaction solution was filtered through a Celite pad and the
filtrate was concentrated in vacuo. The resulting residue was
purified by a thin layer chromatography to obtain the above racemic
aldehyde derivative (44 mg) as an orange solid.
##STR00222##
[0587] According to a method similar to the procedures described in
Working Examples 40-(5) to 40-(6), the hydrochloride (12 mg) of the
racemic objective compound [49] as a racemate was obtained as a
deep purple solid from the racemic aldehyde derivative (22 mg, 41
.mu.mol) obtained in the above (4) and pyrrolidine.
[0588] Spectral data of the compound of the above formula [49] are
shown below.
[0589] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.05 (3H, d, J=5.7 Hz),
1.71-1.85 (6H, m), 1.92-2.17 (4H, m), 2.96-3.05 (2H, m), 3.25-3.45
(2H, m), 4.08-4.15 (1H, m), 4.31-4.39 (3H, m), 4.48-4.54 (1H, m),
6.95 (1H, s), 7.16 (1H, t, J=7.8 Hz), 7.35 (1H, s), 7.75 (1H, d,
J=7.8 Hz), 9.02 (1H, d, J=7.8 Hz), 10.5 (1H, brs), 10.9 (1H, s),
12.8 (1H, s).
[0590] mass: 460 (M+1).sup.+.
Working Example 50
Synthesis of the Compound of the Following Formula [50]
##STR00223##
[0592] According to a method similar to the procedures described in
Working Example 40-(5) to 40-(6), the hydrochloride (79 mg) of the
racemic objective compound [50] as a racemate was obtained as a
deep green solid from the racemic aldehyde derivative (102 mg, 169
.mu.mol) obtained in Working Example 49-(4) and piperidine.
[0593] Spectral data of the compound of the above formula [50] are
shown below.
[0594] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.14 (3H, d, J=6.0 Hz),
1.75-1.86 (10H, m), 2.05-2.19 (2H, m), 2.88-2.95 (2H, m), 3.25-3.56
(2H, m), 4.17-4.24 (1H, m), 4.32-4.46 (3H, m), 4.56-4.73 (1H, m),
7.04 (1H, s), 7.25 (1H, t, J=7.8 Hz), 7.46 (1H, s), 7.85 (1H, d,
J=7.8 Hz), 9.10 (1H, d, J=7.8 Hz), 10.2 (1H, brs), 11.0 (1H, s),
12.9 (1H, s).
[0595] mass: 474 (M+1).sup.+.
Working Example 51
Synthesis of the Compound of the Following Formula [51]
##STR00224##
[0597] According to a method similar to the procedures up to the
step of the macrocyclization described in Working Examples 48-(1)
to 48-(4), and 14-(5) to 14-(6), the above carboxylic acid
derivative (580 mg) was obtained as a yellowish brown solid from
the carboxylic acid derivative (2.48 g, 3.87 mmol) obtained in
Working Example 49-(1).
##STR00225##
[0598] The carboxylic acid derivative (580 mg, 1.08 mmol) obtained
in the above (1) was dissolved in tetrahydrofuran (60 mL) and
N,N-dimethylformamide (60 mL), and to this solution was added
1,1'-carbonylbis-1H-imidazole (262 mg, 1.62 mmol). The mixture was
stirred at 60.degree. C. for 30 minutes, and further at room
temperature for 11 hours. Lithium tetrahydroborate (47 mg, 2.16
mmol) was added to the resulting reaction solution, and it was
stirred at room temperature for 30 minutes. After that, lithium
tetrahydroborate (500 mg, 23 mmol) was further added to this
solution, and the mixture was stirred at room temperature for 1
hour, followed by addition of chloroform (100 mL). Then, saturated
aqueous ammonium chloride solution (50 mL) was added to this
solution, and the mixture was extracted with chloroform. The
organic layer was washed with saturated brine, dried over anhydrous
magnesium sulfate, and filtered. The filtrate was concentrated in
vacuo and evaporated azeotropically using toluene. The resulting
residue was dissolved in chloroform (100 mL), and then manganese
dioxide (282 mg, 3.24 mmol) was added to the solution. The mixture
was stirred at room temperature for 1 hour. The resulting reaction
solution was filtered through a Celite pad and concentrated in
vacuo. The resulting residue was purified by a column
chromatography on silica gel to obtain the above benzyl alcohol
derivative (320 mg) as an orange liquid.
##STR00226##
[0599] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (55 mg) of
the objective compound [51] was obtained as a deep purple solid
from the benzyl alcohol derivative (88 mg, 168 .mu.mol) obtained in
the above (2) and piperidine.
[0600] Spectral data of the compound of the above formula [51] are
shown below.
[0601] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.35-1.40 (1H, m),
1.66-2.26 (11H, m), 2.88-2.94 (2H, m), 3.25-3.45 (2H, m), 4.04-4.10
(2H, m), 4.24-4.30 (2H, m), 4.31-4.37 (2H, m), 7.00 (1H, s), 7.21
(1H, t, J=7.8 Hz), 7.30 (1H, s), 7.87 (1H, d, J=7.8 Hz), 9.26 (1H,
d, J=7.8 Hz), 10.3 (1H, brs), 11.6 (1H, s), 12.9 (1H, s).
[0602] mass: 460 (M+1).sup.+.
Working Example 52
Synthesis of the Compound of the Following Formula [52]
##STR00227##
[0604] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (28 mg) of
the objective compound [52] was obtained as a deep green solid from
the benzyl alcohol derivative (66 mg, 127 .mu.mol) obtained in the
above (2) and piperidine in Working Example 51-(2) and
pyrrolidine.
[0605] Spectral data of the compound of the above formula [52] are
shown below.
[0606] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.83-1.90 (6H, m),
1.92-2.03 (4H, m), 3.03-3.10 (2H, m), 3.36-3.44 (2H, m), 4.05-4.09
(2H, m), 4.22-4.26 (2H, m), 4.41-4.43 (2H, m), 7.00 (1H, s), 7.19
(1H, t, J=7.8 Hz), 7.33 (1H, s), 7.85 (1H, d, J=7.8 Hz), 9.25 (1H,
d, J=7.8 Hz), 11.0 (1H, brs), 11.6 (1H, s), 12.9 (1H, s).
[0607] mass: 446 (M+1).sup.+.
Working Example 53
Synthesis of the Compound of the Following Formula [53]
##STR00228##
[0609] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (7 mg) of the
objective compound [53] was obtained as a yellow green solid from
the benzyl alcohol derivative (10 mg, 19 .mu.mol) obtained in
Working Example 51-(2) and morpholine.
[0610] Spectral data of the compound of the above formula [53] are
shown below.
[0611] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.81-1.95 (4H, m),
2.04-2.26 (2H, m), 3.11-3.21 (4H, m), 3.69-3.81 (2H, m), 3.91-3.99
(2H, m), 4.05-4.10 (2H, m), 4.26-4.31 (2H, m), 4.41-4.46 (2H, m),
7.02 (1H, s), 7.21 (1H, t, J=7.8 Hz), 7.26 (1H, s), 7.88 (1H, d,
J=7.8 Hz), 9.28 (1H, d, J=7.8 Hz), 10.7 (1H, brs), 11.6 (1H, s),
12.9 (1H, s).
[0612] mass: 462 (M+1).sup.+.
Working Example 54
Synthesis of the Compound of the Following Formula [54]
##STR00229##
[0614] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (6 mg) of the
racemic objective compound [53] as a racemate was obtained as a
deep green solid from the benzyl alcohol derivative (10 mg, 19
.mu.mol) obtained in Working Example 51-(2) and a racemic
2-methylpiperidine.
[0615] Spectral data of the compound of the above formula [54] are
shown below.
[0616] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.36-1.50 (3H, m),
1.66-1.92 (10H, m), 1.94-2.08 (2H, m), 2.71-2.82 (1H, m), 3.01-3.11
(2H, m), 4.03-4.13 (3H, m), 4.23-4.35 (2H, m), 4.71-4.77 (1H, m),
6.99-7.18 (1H, m), 7.21 (1H, t, J=7.8 Hz), 7.31-7.40 (1H, m), 7.87
(1H, d, J=7.8 Hz), 9.26 (1H, d, J=7.8 Hz), 10.2 (1H, brs), 11.6
(1H, s), 12.9 (1H, s).
[0617] mass: 474 (M+1).sup.+.
Working Example 55
Synthesis of the Compound of the Following Formula [55]
##STR00230##
[0619] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (7 mg) of the
objective compound [55] as a racemate was obtained as a green solid
from the benzyl alcohol derivative (10 mg, 19 .mu.mol) obtained in
Example 51-(2) and a racemic 3-methylpiperidine.
[0620] Spectral data of the compound of the above formula [55] are
shown below.
[0621] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.86 (3H, d, J=6.6 Hz),
1.75-2.12 (11H, m), 3.20-3.40 (4H, m), 4.04-4.10 (2H, m), 4.25-4.28
(2H, m), 4.32-4.34 (2H, m), 6.99 (1H, s), 7.20 (1H, t, J=7.8 Hz),
7.32 (1H, s), 7.87 (1H, d, J=7.8 Hz), 9.26 (1H, d, J=7.8 Hz), 10.4
(1H, brs), 11.6 (1H, s), 12.9 (1H, s).
[0622] mass: 474 (M+1).sup.+.
Working Example 56
Synthesis of the Compound of the Following Formula [56]
##STR00231##
[0624] According to a method similar to the procedures described in
Working Example 11-(17) and 1-(6), the hydrochloride (8 mg) of the
objective compound [56] as a racemate was obtained as a yellow
green solid from the benzyl alcohol derivative (10 mg, 19 .mu.mol)
obtained in Working Example 51-(2) and a racemic
3-methoxycarbonylpiperidine.
[0625] Spectral data of the compound of the above formula [56] are
shown below.
[0626] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.17 (3H, t, J=7.2 Hz),
1.44-1.49 (1H, m), 1.72-1.97 (6H, m), 2.01-2.12 (3H, m), 2.89-3.09
(4H, m), 3.50-3.58 (1H, m), 4.04-4.12 (4H, m), 4.25-4.31 (2H, m),
4.40-4.44 (2H, m), 7.01 (1H, s), 7.22 (1H, t, J=7.8 Hz), 7.24 (1H,
s), 7.89 (1H, d, J=7.8 Hz), 9.29 (1H, d, J=7.8 Hz), 10.3 (1H, brs),
11.6 (1H, s), 12.9 (1H, s).
[0627] mass: 532 (M+1).sup.+.
Working Example 57
Synthesis of the Compound of the Following Formula [57]
##STR00232##
[0629] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (6 mg) of the
objective compound [57] was obtained as a deep green solid from the
benzyl alcohol derivative (10 mg, 19 .mu.mol) obtained in Working
Example 51-(2) and (S)-2-methoxymethylpyrrolidine.
[0630] Spectral data of the compound of the above formula [57] are
shown below.
[0631] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.67-2.07 (9H, m),
2.12-2.25 (1H, m), 3.06-3.28 (2H, m), 3.32 (3H, s), 3.66-3.92 (3H,
m), 3.95-4.10 (2H, m), 4.11-4.34 (3H, m), 4.57-4.63 (1H, m), 6.97
(1H, s), 7.16 (1H, t, J=7.8 Hz), 7.29-7.69 (1H, m), 7.83 (1H, d,
J=7.8 Hz), 9.21 (1H, d, J=7.8 Hz), 10.8 (1H, brs), 11.5 (1H, s),
12.8 (1H, s).
[0632] mass: 490 (M+1).sup.+.
Working Example 58
Synthesis of the Compound of the Following Formula [58]
##STR00233##
[0634] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (9 mg) of the
objective compound [58] was obtained as a deep green solid from the
benzyl alcohol derivative (10 mg, 19 .mu.mol) obtained in Working
Example 51-(2) and (R)-2-methoxymethylpyrrolidine.
[0635] Spectral data of the compound of the above formula [58] are
shown below.
[0636] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.68-2.20 (10H, m),
3.12-3.19 (2H, m), 3.32 (3H, s), 3.61-3.83 (3H, m), 4.03-4.06 (2H,
m), 4.22-4.34 (3H, m), 4.58-4.63 (1H, m), 7.00 (1H, s), 7.19 (1H,
t, J=7.8 Hz), 7.29 (1H, m), 7.83 (1H, d, J=7.8 Hz), 9.25 (1H, d,
J=7.8 Hz), 10.6 (1H, brs), 11.6 (1H, s), 12.9 (1H, s).
[0637] mass: 490 (M+1).sup.+.
Working Example 59
Synthesis of the Compound of the Following Formula [59]
##STR00234##
[0639] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (8 mg) of the
objective compound [59] was obtained as a deep purple solid from
the benzyl alcohol derivative (10 mg, 19 .mu.mol) obtained in
Working Example 51-(2) and thiomorpholine.
[0640] Spectral data of the compound of the above formula [59] are
shown below.
[0641] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.83-1.90 (4H, m),
2.03-2.08 (2H, m), 2.71-2.87 (2H, m), 3.05-3.21 (2H, m), 3.40-3.45
(2H, m), 3.56-3.75 (2H, m), 4.05-4.11 (2H, m), 4.23-4.32 (2H, m),
4.40-4.49 (2H, m), 7.02 (1H, s), 7.21 (1H, t, J=7.8 Hz), 7.29 (1H,
s), 7.88 (1H, d, J=7.8 Hz), 9.27 (1H, d, J=7.8 Hz), 10.7 (1H, brs),
11.6 (1H, s), 12.9 (1H, s).
[0642] mass: 478 (M+1).sup.+.
Working Example 60
Synthesis of the Compound of the Following Formula [60]
##STR00235##
[0644] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (6 mg) of the
objective compound [60] was obtained as an ocher solid from the
benzyl alcohol derivative (10 mg, 19 .mu.mol) obtained in Working
Example 51-(2) and the amine derivative [A-29].
[0645] Spectral data of the compound of the above formula [60] are
shown below.
[0646] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.55-1.65 (1H, m),
1.81-1.98 (5H, m), 2.02-2.27 (4H, m), 2.95-3.22 (5H, m), 3.26 (3H,
s), 4.05-4.11 (2H, m), 4.25-4.30 (2H, m), 4.35-4.42 (2H, m),
7.00-7.04 (1H, m), 7.21 (1H, t, J=7.8 Hz), 7.27 (1H, s), 7.88 (1H,
d, J=7.8 Hz), 9.28 (1H, d, J=7.8 Hz), 10.2 (1H, brs), 11.6 (1H, s),
12.9 (1H, s).
[0647] mass: 490 (M+1).sup.+.
Working Example 61
Synthesis of the Compound of the Following Formula [61]
##STR00236##
[0649] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (8 mg) of the
objective compound [61] as a racemate was obtained as a green solid
from the benzyl alcohol derivative (10 mg, 19 .mu.mol) obtained in
Working Example 51-(2) and the racemic amine derivative [A-22].
[0650] Spectral data of the compound of the above formula [61] are
shown below.
[0651] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.21-1.23 (1H, m),
1.38-1.56 (1H, m), 1.61-1.95 (6H, m), 2.01-2.10 (2H, m), 2.95-3.20
(1H, m), 3.20-3.56 (5H, m), 3.56-3.80 (2H, m), 4.02-4.10 (2H, m),
4.18-4.24 (2H, m), 4.24-4.41 (2H, m), 6.97-7.04 (1H, m), 7.15-7.40
(2H, m), 7.85-7.86 (1H, m), 9.24-9.25 (1H, m), 11.2 (1H, brs), 11.6
(1H, s), 12.8-12.9 (1H, m).
[0652] mass: 490 (M+1).sup.+.
Working Example 62
Synthesis of the Compound of the Following Formula [62]
##STR00237##
[0654] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (7 mg) of the
objective compound [62] as a racemate was obtained as a green solid
from the benzyl alcohol derivative (10 mg, 19 .mu.mol) obtained in
Working Example 51-(2) and the racemic amine derivative [A-25].
[0655] Spectral data of the compound of the above formula [62] are
shown below.
[0656] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.12-1.24 (1H, m),
1.66-1.74 (1H, m), 1.78-1.96 (6H, m), 2.00-2.07 (2H, m), 2.17-2.26
(1H, m), 2.67-2.87 (2H, m), 3.20 (3H, s), 3.61-3.81 (4H, m),
4.06-4.09 (2H, m), 4.22-4.25 (2H, m), 4.33-4.36 (2H, m), 6.98 (1H,
s), 7.19 (1H, t, J=7.8 Hz), 7.34 (1H, s), 7.86 (1H, d, J=7.8 Hz),
9.26 (1H, d, J=7.8 Hz), 10.6 (1H, brs), 11.6 (1H, s), 12.9 (1H,
s).
[0657] mass: 504 (M+1).sup.+.
Working Example 63
Synthesis of the Compound of the Following Formula [63]
##STR00238##
[0659] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (6 mg) of the
objective compound [63] as a racemate was obtained as a deep purple
solid from the benzyl alcohol derivative (10 mg, 19 .mu.mol)
obtained in Working Example 52-(2) and the racemic amine derivative
[A-26].
[0660] Spectral data of the compound of the above formula [63] are
shown below.
[0661] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.40-2.00 (10H, m),
2.00-2.12 (2H, m), 2.82-3.18 (2H, m), 3.40 (3H, s), 3.77-3.88 (2H,
m), 4.02-4.10 (2H, m), 4.11-4.40 (4H, m), 4.66-4.73 (1H, m),
7.01-7.07 (1H, m), 7.18-7.24 (2H, m), 7.88 (1H, d, J=7.8 Hz), 9.28
(1H, d, J=7.8 Hz), 9.96 (1H, brs), 11.6 (1H, s), 12.9 (1H, s).
[0662] mass: 504 (M+1).sup.+.
Working Example 64
Synthesis of the Compound of the Following Formula [64]
##STR00239##
[0664] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (8 mg) of the
objective compound [64] was obtained as a deep purple solid from
the benzyl alcohol derivative (10 mg, 19 .mu.mol) obtained in
Working Example 51-(2) and 4,4-difluoropiperidine.
[0665] Spectral data of the compound of the above formula [64] are
shown below.
[0666] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.81-1.96 (4H, m),
2.03-2.10 (2H, m), 2.25-2.45 (2H, m), 2.45-2.56 (2H, m), 3.18-3.29
(4H, m), 4.05-4.11 (2H, m), 4.25-4.31 (2H, m), 4.44-4.73 (2H, m),
7.01 (1H, s), 7.21 (1H, t, J=7.8 Hz), 7.32 (1H, s), 7.88 (1H, d,
J=7.8 Hz), 9.27 (1H, d, J=7.8 Hz), 11.0 (1H, brs), 11.6 (1H, s),
12.9 (1H, s).
[0667] mass: 496 (M+1).sup.+.
Working Example 65
Synthesis of the Compound of the Following Formula [65]
##STR00240##
[0669] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (5 mg) of the
objective compound [65] was obtained as a brown solid from the
benzyl alcohol derivative (10 mg, 19 .mu.mol) obtained in Working
Example 51-(2) and 4-fluoropiperidine.
[0670] Spectral data of the compound of the above formula [65] are
shown below.
[0671] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.80-2.00 (4H, m),
2.01-2.20 (6H, m), 3.02-3.35 (4H, m), 4.05-4.09 (2H, m), 4.25-4.29
(2H, m), 4.30-4.44 (2H, m), 4.92-5.08 (1H, m), 7.03 (1H, s), 7.21
(1H, t, J=7.8 Hz); 7.32 (1H, s), 7.88 (1H, d, J=7.8 Hz), 9.27 (1H,
d, J=7.8 Hz), 10.6 (1H, brs), 11.6 (1H, s), 12.9 (1H, s).
[0672] mass: 478 (M+1).sup.+.
Working Example 66
Synthesis of the Compound of the Following Formula [66]
##STR00241##
[0674] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (5 mg) of the
objective compound [66] was obtained as a brown solid from the
benzyl alcohol derivative (10 mg, 19 .mu.mol) obtained in Working
Example 51-(2) and diethylamine.
[0675] Spectral data of the compound of the above formula [66] are
shown below.
[0676] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.25 (6H, t, J=7.5 Hz)
1.82-1.93 (4H, m), 2.00-2. 10 (2H, m), 3.06-3.23 (4H, m), 4.05-4.11
(2H, m), 4.24-4.30 (2H, m), 4.37-4.40 (2H, m), 7.03 (1H, s), 7.22
(1H, t, J=7.8 Hz), 7.24 (1H, s), 7.88 (1H, d, J=7.8 Hz), 9.28 (1H,
d, J=7.8 Hz), 9.94 (1H, brs), 11.6 (1H, s), 12.9 (1H, s).
[0677] mass: 448 (M+1).sup.+.
Working Example 67
Synthesis of the Compound of the Following Formula [67]
##STR00242##
[0679] According to a method similar to the procedure described in
Working Example 43, the hydrochloride (8.1 mg) of the objective
compound [67] as a racemate was obtained was obtained as a deep
green solid from the racemic cyclic derivative (30 mg, 51 .mu.mol)
obtained in Working Example 49-(2).
[0680] Spectral data of the compound of the above formula [67] are
shown below.
[0681] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.14 (3H, d, J=6.3 Hz),
1.76-1.86 (4H, m), 2.08-2. 28 (2H, m), 2.84 (3H, d, J=4.8 Hz)
3.13-3.29 (4H, m), 3.40-3.60 (2H, m), 3.99-4.10 (2H, m), 4.10-4.17
(1H, m), 4.38-4.45 (1H, m), 4.60-4.66 (1H, m), 6.33 (1H, s), 6.88
(1H, s) 7.21 (1H, t, J=7.8 Hz), 7.75 (1H, d, J=7.8 Hz), 8.98 (1H,
d, J=7.8 Hz), 10.6 (1H, brs), 11.0 (1H, s), 12.5 (1H, s).
[0682] mass: 475 (M+1).sup.+.
Working Example 68
Synthesis of the Compound of the Following Formula [68]
##STR00243##
[0684] According to a method similar to the procedure described in
Working Example 43, the hydrochloride (11 mg) of the objective
compound [68] as a racemate was obtained as a deep green solid from
the racemic cyclic derivative (20 mg, 34 .mu.mol) obtained in
Working Example 49-(2) and morpholine.
[0685] Spectral data of the compound of the above formula [68] are
shown below.
[0686] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.14 (3H, d, J=6.0 Hz)
1.71-1.86 (4H, m), 2.06-2. 27 (2H, m), 3.17-3.31 (4H, m), 3.75-3.80
(4H, m), 4.01-4.17 (1H, m), 4.37-4.43 (1H, m), 4.58-4.64 (1H, m),
6.28 (1H, s), 6.80 (1H, s), 7.19 (1H, t, J=7.8 Hz), 7.73 (1H, d,
J=7.8 Hz), 8.96 (1H, d, J=7.8 Hz), 11.0 (1H, s), 12.4 (1H, s).
[0687] mass: 462 (M+1).sup.+.
Working Example 69
Synthesis of the Compound of the Following Formula [69]
##STR00244##
[0689] According to a method similar to the procedure described in
Working Example 43, the hydrochloride (11 mg) of the objective
compound [69] as a racemate was obtained as a deep green solid from
the racemic cyclic derivative (20 mg, 34 .mu.mol) obtained in
Working Example 49-(2) and piperidine.
[0690] Spectral data of the compound of the above formula [69] are
shown below.
[0691] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.14 (3H, d, J=6.3 Hz),
1.73-1.87 (6H, m), 2.06-2. 28 (4H, m), 2.72-2.85 (2H, m), 3.12-3.36
(2H, m), 4.01-4.18 (3H, m), 4.38-4.45 (1H, m), 4.53-4.65 (1H, m),
6.32 (1H, s), 6.88 (1H, s), 7.21 (1H, t, J=7.8 Hz), 7.75 (1H, d,
J=7.8 Hz), 8.98 (1H, d, J=7.8 Hz), 10.6 (1H, brs), 11.0 (1H, s),
12.5 (1H, s).
[0692] mass: 460 (M+1).sup.+.
Working Example 70
Synthesis of the Compound of the Following Formula [70]
##STR00245##
[0694] According to a method similar to the procedure described in
Working Example 1-(2), the above hydroxylamide (71 mg) was obtained
as a pale yellow oil from the carboxylic acid derivative (82 mg,
190 .mu.mol) which is a starting material in Working Example 48-(1)
and the above hydroxylamine derivative [A-30] (98 mg, 282
.mu.mol).
##STR00246##
[0695] According to a method similar to the procedure described in
Working Example 15-(4), the above 3-benzoisoxazolone derivative (40
mg) was obtained as a yellow solid from the hydroxylamide
derivative (71 mg, 80 .mu.mol) obtained in the above (1).
##STR00247##
[0696] According to a method similar to the procedures described in
Working Examples 1-(4) to 1-(6), the objective compound [70] (9 mg)
was obtained as a yellow solid from the 3-benzoisoxazolone
derivative (40 mg) obtained in the above (2).
[0697] Spectral data of the compound of the above formula [70] are
shown below.
[0698] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.82 (4H, m), 2.05 (2H,
m), 4.05 (2H, m), 4.20 (2H, m), 6.91 (2H, m), 7.44 (2H, m), 7.87
(1H, d, J=7.6 Hz), 9.05 (1H, d=7.6 Hz), 12.6 (1H, s).
[0699] mass: 364 (M+1).sup.+.
Working Example 71
Synthesis of the Compound of the Following Formula [71]
##STR00248##
[0701] According to a method similar to the procedure described in
Working Example 48, the hydrochloride (84 mg) of the objective
compound [71] was obtained as a yellow solid from the carboxylic
acid derivative (711 mg, 1.27 mmol) which is a starting material in
Working Example 48-(1) and the hydrazine derivative [A-31] (576 mg,
1.65 mmol).
[0702] Spectral data of the compound of the above formula [71] are
shown below.
[0703] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 3.00 (3H, brs),
3.55-3.75 (2H, m), 4.20-4.65 (6H, m), 6.93 (1H, d, J=7.5 Hz), 6.98
(1H, d, J=7.5 Hz), 7.26 (1H, d, J=7.5 Hz), 7.53 (1H, t, J=7.5 Hz),
7.87 (1H, d, J=7.5 Hz), 9.24 (1H, d, J=7.5 Hz), 9.78 (1H, brs),
11.5 (1H, brs), 12.8 (1H, s).
[0704] mass: 378 (M+1).sup.+.
Working Example 72
Synthesis of the Compound of the Following Formula [72]
##STR00249##
[0706] According to a method similar to the procedures described in
Working Examples 48-(1) to 48-(3), the above racemic diol
derivative (121 mg) was obtained as a yellow oil from the
carboxylic acid (287 mg, 0.50 mmol) which is a starting material in
Working Example 48-(1) and the racemic hydrazine derivative
[A-21].
##STR00250##
[0707] The racemic diol derivative (370 mg, 0.705 mmol) obtained in
the above (1) was dissolved in tetrahydrofuran (10 mL), and to this
solution were added 1N sodium hydroxide (1 mL) and 35% aqueous
formalin solution (2.5 mL) at room temperature. The mixture was
stirred at room temperature overnight, and the resulting reaction
solution was stirred at 50.degree. C. for 2 hours. This reaction
solution was cooled down to room temperature, diluted with ethyl
acetate, and washed successively with water and saturated brine.
The organic layer was dried over anhydrous magnesium sulfate,
filtered and concentrated in vacuo to obtain the racemic triol
derivative (366 mg) as an orange oil.
##STR00251##
[0708] The racemic triol derivative (55 mg, 0.10 mmol) obtained in
the above (2) was dissolved in toluene (3 mL), and to the solution
were added acetic acid (0.3 mL) and pyrrolidine (0.3 mL). The
solution was stirred under heating at 50.degree. C. for 2 days. The
resulting reaction solution was cooled down to room temperature,
poured into water, and extracted twice with ethyl acetate. The
organic layer was washed with saturated brine, dried over anhydrous
magnesium sulfate, filtered and then concentrated in vacuo. The
resulting residue was purified by a thin layer chromatography to
obtain the racemic benzylamine derivative (46 mg) as an orange
oil.
##STR00252##
[0709] According to a method similar to the procedures described in
Working Examples 1-(5) to 1-(6), the hydrochloride (5 mg) of the
objective compound [72] as a racemate was obtained as a yellow
solid from the racemic benzylamine derivative (10 mg, 17 .mu.mol)
obtained in the above (3).
[0710] Spectral data of the compound of the above formula [72] are
shown below.
[0711] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.20 (3H, d, J=6.5 Hz)
1.30-1.50 (2H, m), 1.80-2. 10 (7H, m), 2.20-2.40 (1H, m), 3.02-3.25
(2H, m), 3.30-3.42 (1H, m), 3.42-3.55 (1H, m), 4.00-4.10 (2H, m),
4.30-4.50 (3H, m), 7.23 (1H, d, J=8.0 Hz), 7.25 (1H, t, J=8.0 Hz),
7.87 (1H, d, J=8.0 Hz), 7.88 (1H, d, J=8.0 Hz), 9.20 (1H, d, J=8.0
Hz), 10.50-10.60 (1H, m), 10.84 (1H, s), 12.94 (1H, s).
[0712] mass: 460 (M+1).sup.+.
Working Example 73
Synthesis of the Compound of the Following Formula [73]
##STR00253##
[0714] According to a method similar to the procedures described in
Working Examples 72-(3), and 1-(5) to 1-(6), the hydrochloride (28
mg) of the objective compound [73] as a racemate was obtained as a
yellow solid from the racemic triol derivative (55 mg, 0.10 mmol)
obtained in Working Example 72-(2) and piperidine.
[0715] Spectral data of the compound of the above formula [73] are
shown below.
[0716] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.19 (3H, d, J=6.5 Hz),
1.30-1.50 (2H, m) 1.60-2. 05 (9H, m), 2.20-2.38 (1H, m), 2.80-2.95
(1H, m), 2.95-3.10 (1H, m), 3. 22-3.32 (1H, m), 3.36-3.46 (1H, m),
4.00-4.05 (2H, m), 4.30-4.50 (3H, m), 7.24 (1H, d, J=8.0 Hz), 7.26
(1H, t, J=8.0 Hz), 7.87 (1H, d, J=8.0 Hz), 7.93 (1H, d, J=8.0 Hz),
9.20 (1H, d, J=8.0 Hz), 10.15-10.25 (1H, m), 10.84 (1H, s), 12.95
(1H, s).
[0717] mass: 474 (M+1).sup.+.
Working Example 74
Synthesis of the Compound of the Following Formula [74]
##STR00254##
[0719] According to a method similar to the procedure of Example
11-(1), a mixture (21.6 g) of the above 5-nitroquinoxalin-2-one
derivative and the above 8-nitroquinoxalin-2-one derivative was
obtained as a yellow solid from ethyl
(2-fluoro-3-iodophenyl)oxoacetate (21.5 g, 66.8 mmol) obtained
according to a method similar to the method of the general formula
(II-d) described in WO 02/02550 and 3-nitrophenylenediamine (10.2
g, 66.6 mmol).
##STR00255##
[0720] Chloromethyl 2-(trimethylsilyl)ethyl ether (10.0 mL, 56.3
mmol) was added to tetrahydrofuran solution (500 mL) containing a
mixture (21.6 g) of the 5-nitroquinoxalin-2-one derivative and the
8-nitroquinoxalin-2-one derivative obtained in the above (1), and
then sodium hydride (2.30 g, 60% dispersion in oil, 57.3 mmol) was
added thereto under ice-cooling. After the resulting reaction
solution was stirred at room temperature for 1.5 hours, aqueous
ammonium chloride solution was added thereto, and the mixture was
extracted with chloroform. After the organic layer was washed with
saturated brine, it was dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo. To the resulting residue was
added 4N hydrogen chloride/1,4-dioxane solution (100 mL), and the
solution was stirred at room temperature for 1 hour. After removal
of the insolubles by filtration, the filtrate was concentrated in
vacuo. The resulting residue was purified by a column
chromatography on silica gel to obtain the above
5-nitroquinoxaline-2-one derivative (11.6 g) protected with SEM, as
a yellow solid.
##STR00256##
[0721] According to a method similar to the procedure described in
Working Example 14-(5), the above ester derivative (8.06 g) was
obtained as a yellow solid from the protected derivative with SEM
(11.6 g, 21.4 mmol) obtained in the above (2).
##STR00257##
[0722] The ester derivative (191 mg, 0.40 mmol) obtained in the
above (3) was dissolved in ethanol (10 mL), and to this solution
were added saturated aqueous ammonium chloride solution (2 mL) and
iron powder (110 mg). After the resulting reaction solution was
heated under reflux for 20 minutes, saturated aqueous ammonium
chloride solution (2 mL) and iron powder (300 mg) were added
thereto. Further, after this reaction solution was heated under
reflux for 20 minutes, iron powder (500 mg) was added thereto.
Then, the resulting reaction solution was heated under reflux for
20 minutes, cooled down to room temperature, and water and
chloroform were added. After the reaction solution was filtered,
the filtrate was extracted with chloroform, and dried over
anhydrous magnesium sulfate. After removal of the insolubles by
filtration, the filtrate was concentrated in vacuo to obtain the
aniline derivative (168 mg) as a yellow solid.
##STR00258##
[0723] Hydrazine monohydrate (5 mL) was added to ethanol solution
(20 mL) containing the aniline derivative (1.60 g, 3.61 mmol)
obtained in the above (4), and the mixture was stirred at room
temperature for 2 hours. The resulting reaction solution was
concentrated in vacuo to obtain the above hydrazide derivative
(1.60 g) as a yellow solid.
##STR00259##
[0724] According to a method similar to the procedure described in
Working Example 11-(12), the above 3-indazolinone derivative (684
mg) was obtained as a yellow solid from the hydrazide derivative
(1.60 g, 3.61 mmol) obtained in the above (5).
##STR00260##
[0725] The 3-indazolinone derivative (10 mg, 24 .mu.mol) obtained
in the above (6) was dissolved in N,N-dimethylformamide (1 mL), and
then 1,5-diiodopentane (50 .mu.L, 340 .mu.mol) was added thereto.
The mixture was stirred at 100.degree. C. for 3.5 hours. After the
resulting reaction solution was cooled down to room temperature, it
was concentrated in vacuo. The resulting residue was purified by a
thin layer chromatography to obtain the cyclic derivative (2.5 mg)
as a yellow solid.
##STR00261##
[0726] According to a method similar to the procedure described in
Working Example 1-(6), the objective compound [74] (1.8 mg) was
obtained as a yellow solid from the cyclic derivative (2.5 mg, 5.1
.mu.mol) obtained in the above (7).
[0727] Spectral data of the compound of the above formula [74] are
shown below.
[0728] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.62 (2H, m), 1.95 (4H,
m), 3.20 (4H, m) 7.19 (1H, t, J=7.8 Hz), 7.20-7.70 (4H, m), 7.86
(1H, d, J=7.8 Hz), 9.18 (1H, br), 12.18 (1H, br), 12.78 (1H,
br).
[0729] mass: 362 (M+1).sup.+.
Working Example 75
Synthesis of the Compound of the Following Formula [75]
##STR00262##
[0731] According to a method similar to the procedures described in
Working Examples 1-(2) to 1-(6), the objective compound [75] (10
mg) was obtained as a yellow solid from the carboxylic acid
derivative (30 mg, 45 .mu.mol) obtained in Working Example 1-(1)
and 6-amino-1-hexanol.
[0732] Spectral data of the compound of the above formula [75] are
shown below.
[0733] .sup.1H-NMR (DMSO) .delta.: 1.60-2.00 (8H, m), 3.80-3.90
(2H, m), 4.15-4.30 (2H, m), 6.90-6.98 (2H, m), 7.43-7.65 (2H, m),
8.01 (1H, d, J=7.6 Hz), 9.51 (1H, d, J=7.8 Hz), 12.8 (1H, brs).
[0734] mass: 394 (M+1).sup.+.
Working Example 76
Synthesis of the Compound of the Following Formula [76]
##STR00263##
[0736] Diisoproylethylamine (2.90 mL, 16.7 mmol), trioctylsilane
(5.98 mL, 13.3 mmol) and dichloro-bistriphenylphosphine palladium
(777 mg, 1.11 mmol) were successively added to a mixed solution of
N,N-dimethylformamide (75 mL) and 1,4-dioxane (75 mL) containing
the methoxyquinoxaline derivative (5.00 g, 11.1 mmol) obtained in
Working Example 11-(3). The resulting reaction solution was stirred
at 90.degree. C. for 30 minutes, and then cooled down to room
temperature. After hexane and water were added to this reaction
solution, it was filtered through a Celite pad and the filtrate was
extracted with ethyl acetate. The resulting organic layer was
washed with saturated brine, dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The resulting residue
was purified by a column chromatography on silica gel to obtain the
reduced derivative (4.10 g) as a gray solid.
##STR00264##
[0737] According to a method similar to the procedures described in
Working Examples 11-(9) to 11-(12), the above alcohol derivative
(2.13 g) was obtained as a yellow solid from the reduced derivative
(4.10 g) obtained in the above (1).
##STR00265##
[0738] According to a method similar to the procedures described in
Working Examples 11-(13) to 11-(16), and 11-(18), the hydrochloride
(510 mg) of the objective compound [76] was obtained as a yellow
solid from the reduced derivative (2.13 g) obtained in the above
(2).
[0739] Spectral data of the compound of the above formula [76] are
shown below.
[0740] .sup.1H-NMR (DMSO) .delta.: 1.75-2.40 (3H, m), 2.40-2.55
(1H, m), 3.00-3.35 (2H, m), 3.50-3.80 (1H, m), 3.82-4.35 (3H, m),
5.34-5.42 (1H, m), 6.96-7.27 (3H, m), 7.49-7.56 (1H, m), 7.84 (1H,
d, J=7.8 Hz), 9.20-9.30 (1H, m), 11.8-12.0 (1H, m), 12.7-12.8 (1H,
m).
[0741] mass: 390 (M+1).sup.+.
Working Example 77
Synthesis of the Compound of the Following Formula [77]
##STR00266##
[0743] In the formula, the stereo chemistry of the position with
the symbol * is of cis-configuration.
##STR00267##
[0744] According to a method similar to the procedures described in
Working Examples 1-(2) to 1-(3), the racemic benzoisothiazolone
derivative (177 mg) was obtained as a yellow oil from the
carboxylic acid derivative (665 mg, 1.00 mmol) obtained in Working
Example 1-(1) and the racemate derivative [A-32].
##STR00268##
[0745] According to a method similar to the procedures described in
Working Examples 14-(12) to 14-(13), and 1-(6), the objective
compound [77] (6 mg) as a racemate was obtained as a yellow solid
from the racemic benzoisothiazolone derivative (177 mg, 264
.mu.mol) obtained in the above (1).
[0746] Spectral data of the compound of the above formula [77] are
shown below.
[0747] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.78-1.90 (1H, m),
1.95-2.04 (2H, m), 2.61-2.70 (2H, m), 2.85-2.92 (2H, m), 4.50-4.58
(1H, m), 4.70-4.82 (2H, m), 7.00-7.02 (2H, m), 7.50-7.65 (2H, m),
8.05 (1H, d, J=7.3 Hz), 9.01 (1H, d, J=6.6 Hz), 12.8 (1H, brs).
[0748] mass: 392 (M+1).sup.+.
Example 78
Synthesis of the Compound of the Following Formula [78]
##STR00269##
[0750] According to a method similar to the procedures described in
Working Examples 3-(1) to 3-(4) and 6, the hydrochloride (6 mg) of
the objective compound [78] was obtained as a yellow solid from the
carboxylic acid derivative (475 mg, 0.64 mmol) obtained in Working
Example 14-(2) and the sulfonamide derivative [A-3-5].
[0751] Spectral data of the compound of the above formula [78] are
shown below.
[0752] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.30-4.80 (11H, m), 7.10
(1H, s), 7.45-7.70 (2H, m), 7.97-8.05 (1H, m), 9.25-9.32 (1H, m),
12.9 (1H, brs).
[0753] mass: 473 (M+1).sup.+.
Working Example 79
Synthesis of the Compound of the Following Formula [79]
##STR00270##
[0755] According to a method similar to the procedure described in
Working Example 1-(4), the above phenol derivative (774 mg) was
obtained as a white solid from the methyl ester derivative (1.00 g,
1.74 mmol) which is a starting material of Example 1-(1).
##STR00271##
[0756] To tetrahydrofuran solution (20 mL) of the phenol derivative
(774 mg, 1.74 mmol) obtained in the above (1) was added 40% toluene
solution (1.52 mL) containing triphenylphosphine (912 mg, 3.48
mmol), allyl alcohol (202 mg, 3.48 mmol) and diethyl
azodicarboxylate, and the mixture was stirred at room temperature
for 30 minutes. After addition of water (100 .mu.L), the reaction
solution was concentrated in vacuo, and the resulting residue was
purified by a column chromatography on silica gel to obtain the
allyl ether derivative (725 mg) as a white solid.
##STR00272##
[0757] Xylene solution (100 mL) containing the allyl ether
derivative (725 mg, 1.50 mmol) obtained in the above (2) was
stirred at 180.degree. C. for 3 days. The reaction solution was
concentrated, and the resulting residue was purified by a column
chromatography on silica gel to obtain the above allyl
rearrangement derivative (543 mg) as a white solid.
##STR00273##
[0758] Chloromethyl 2-(trimethylsilyl)ethyl ether (400 .mu.L, 2.26
mmol) was added to tetrahydrofuran solution (20 mL) of the allyl
rearrangement derivative (543 mg, 1.13 mmol) obtained in the above
(3), under ice-cooling, and sodium hydride (90 mg, 60% dispersion
in oil, 2.26 mmol) was added thereto. The mixture was stirred at
room temperature for 2 hours. After saturated aqueous ammonium
chloride solution was added to the reaction solution, it was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous magnesium sulfate,
and filtered. The filtrate was concentrated and the resulting
residue was purified by a column chromatography on silica gel to
obtain the protected derivative (695 mg) with SEM as a white
solid.
##STR00274##
[0759] Ozone was bubbled at -78.degree. C. through a mixed solution
of dichloromethane (14 mL) and methanol (6 mL) containing the
derivative (1.00 g, 1.63 mmol) protected with SEM obtained in the
above (4), and the mixture was stirred at the same temperature for
30 minutes. Nitrogen gas was bubbled through the solution, and
dimethyl sulfide (5 ml) was added dropwise thereto. The reaction
solution was warmed up to room temperature. After sodium
tetrahydroborate (100 mg) was added thereto under ice-cooling, the
mixture was stirred for 1 hour. After saturated aqueous ammonium
chloride solution was added to the reaction solution, it was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous magnesium sulfate,
and filtered. The filtrate was concentrated, and the resulting
residue was purified by silica gel chromatography on to obtain the
hydroxyethyl derivative (800 mg) as a pale yellow solid.
##STR00275##
[0760] According to a method similar to the procedure described in
Working Example 11-(8), the above derivative (820 mg) protected
with THP was obtained as a pale yellow solid from the hydroxyethyl
derivative (800 mg, 1.29 mmol) obtained in the above (5).
##STR00276##
[0761] According to a method similar to the procedures described in
Working Examples 1-(1) to 1-(3), the above benzoisothiazolone
derivative (129 mg) was obtained as a yellow solid from the
derivative protected with THP (820 mg, 1.16 mmol) obtained in the
above (6).
##STR00277##
[0762] According to a method similar to the procedures described in
Working Examples 11-(19), and 14-(12) to 14-(13), the above cyclic
derivative (42 mg) was obtained as a yellow solid from the
benzoisothiazolone derivative (110 mg, 118 .mu.mol) obtained in the
above (7).
##STR00278##
[0763] According to a method similar to the procedure described in
Working Example 11-(14), the above mesylated derivative (3.0 mg)
was obtained as a yellow solid from the cyclic derivative (3.0 mg,
5.42 .mu.mol) obtained in the above (8).
##STR00279##
[0764] The mesylated derivative (3.0 mg, 4.75 .mu.mol) obtained in
the above (9) was dissolved in toluene (450 .mu.L), and to this
solution were added pyrrolidine (45 .mu.L) and aqueous sodium
hydrogencarbonate solution (45 mg, 450 .mu.L)) at room temperature.
The mixture was stirred in a sealed tube at 130.degree. C. for 12
hours. After this reaction solution was cooled down to room
temperature. it was extracted with ethyl acetate. The organic layer
was washed with saturated brine, dried over anhydrous magnesium
sulfate, and filtered. The filtrate was concentrated, and the
resulting residue was purified by a column chromatography on silica
gel to obtain the pyrrolidinoethyl derivative (3.0 mg) as a pale
yellow solid.
##STR00280##
[0765] According to a method similar to the procedure described in
Working Example 1-(6), the above hydrochloride (2 mg) of the
objective compound [79] was obtained as a yellow solid from the
pyrrolidinoethyl derivative (2.5 mg, 4.12 .mu.mol) obtained in the
above (10).
[0766] Spectral data of the compound of the above formula [79] are
shown below.
[0767] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.80-2.12 (9H, m),
2.18-2.33 (3H, m), 3.01-3.20 (4H, m), 3.53-3.70 (2H, m), 3.71-3.85
(2H, m), 4.30-4.41 (2H, m), 7.20 (1H, d, J=8.7 Hz), 7.59 (1H, d,
J=8.7 Hz), 7.66 (1H, dd, J=7.6 Hz, 8.0 Hz), 8.08 (1H, d, J=7.6 Hz),
9.53 (1H, d, J=8.0 Hz), 10.15-10.32 (1H, m), 12. 94 (1H, s).
[0768] mass: 477 (M+1).sup.+.
Working Example 80
Synthesis of the Compound of the Following Formula [80]
##STR00281##
[0770] According to a method similar to the procedures described in
Working Examples 79-(10) and 1-(6), the hydrochloride (2.0 mg) of
the objective compound [80] was obtained as a yellow solid from the
mesylated derivative (3 mg, 19 .mu.mol) obtained in Working Example
79-(9) and piperidine (45 .mu.L).
[0771] Spectral data of the compound of the above formula [80] are
shown below.
[0772] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.30-2.18 (11H, m),
2.19-2.36 (3H, m), 2.90-3.06 (2H, m), 3.10-3.21 (2H, m), 3.50-3.65
(2H, m), 3.72-3.88 (2H, m), 4.28-4.42 (2H, m), 7.21 (1H, d, J=8.7
Hz), 7.57 (1H, d, J=8.7 Hz), 7.66 (1H, d d, J=7.4 Hz, 7.9 Hz), 8.08
(1H, d, J=7.4 Hz), 9.53 (1H, d, J=7.9 Hz), 9.70-9.90 (1H, m), 12.93
(1H, s).
[0773] mass: 491 (M+1).sup.+.
Working Example 81
Synthesis of the Compound of the Following Formula [81]
##STR00282##
[0775] According to a method similar to the procedure described in
Working Examples 79-(10) and 1-(6), the hydrochloride (1.2 mg) of
the objective compound [81] was obtained as a yellow solid from the
mesylated derivative (3 mg, 19 .mu.mol) obtained in Working Example
79-(9) and N-methylpiperazine (45 .mu.L).
[0776] Spectral data of the compound of the above formula [81] are
shown below.
[0777] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.90-4.00 (23H, m),
4.28-4.42 (2H, m), 7.20 (1H, d, J=8.7 Hz), 7.55-7.75 (2H, m), 8.08
(1H, d, J=7.5 Hz), 9.30-9.48 (1H, m), 9.53 (1H, d, J=8.0 Hz), 12.94
(1H, s).
[0778] mass: 506 (M+1).sup.+.
Working Example 82
Synthesis of the Compound of the Following Formula [82]
##STR00283##
[0780] According to a method similar to the procedures described in
Working Examples 79-(10) and 1-(6), the hydrochloride (14.5 mg) of
the objective compound [82] was obtained as a yellow solid from the
mesylated derivative (20 mg, 19 .mu.mol) obtained in Working
Example 79-(9) and 4,4-difluoropiperidine (300 .mu.L).
[0781] Spectral data of the compound of the above formula [82] are
shown below.
[0782] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.92-2.18 (4H, m),
2.20-2.78 (6H, m), 3.12-3.38 (5H, m), 3.70-3.88 (5H, m), 4.28-4.42
(2H, m), 7.21 (1H, d, J=8.5 Hz), 7. 57 (1H, d, J=8.9 Hz), 7.66 (1H,
dd, J=7.4 Hz, 8.2 Hz), 8.08 (1H, d, J=7.4H z), 9.53 (1H, d, J=8.2
Hz), 10.70-10.88 (1H, m), 12.93 (1H, s).
[0783] mass: 527 (M+1).sup.+.
Working Example 83
Synthesis of the Compound of the Following Formula [83]
##STR00284##
[0785] N,N-Diisopropylethylamine (12.8 mL, 73.5 mmol) was added to
chloroform solution (300 mL) containing the 3-indazolidinone
derivative (10.0 g, 19.6 mmol) obtained in Working Example 11-(12),
and methanesulfonyl chloride (5.00 mL, 64.6 mmol) was added
dropwise thereto under ice-cooling. The mixture was stirred for 30
minutes. Water was added to the resulting reaction solution, and
the organic layer was separated, washed successively with saturated
aqueous sodium hydrogencarbonate, water and saturated brine, dried
over anhydrous magnesium sulfate and filtered. The filtrate was
concentrated. The resulting residue was dissolved in ethyl acetate,
and the solution was washed with water. The resulting organic layer
was dried over anhydrous magnesium sulfate, filtered, and
concentrated. The resulting residue was dissolved in 1,4-dioxane
(30 mL), and the pyrrolidine derivative [A-33] (11.9 g, 118 mmol)
was added thereto. The mixture was stirred at 85.degree. C. for 2
hours and then cooled down to room temperature. The reaction
solution was concentrated and the resulting residue was purified by
a column chromatography on silica gel to produce the above amine
derivative (9.61 g) as a yellow solid.
##STR00285##
[0786] According to a method similar to the procedures described in
Working Examples 11-(14) to 11-(16), the above cyclic derivative
(4.68 g) was obtained as a yellow solid from the amine derivative
(9.61 g, 16.2 mmol) obtained in the above (1).
##STR00286##
[0787] According to a method similar to the procedure described in
Working Example 40-(4), the above aldehyde derivative (1.62 g) was
obtained as an orange solid from the cyclic derivative (2.34 g,
5.23 mmol) obtained in the above (2).
##STR00287##
[0788] To tetrahydrofuran solution (3 mL) containing the aldehyde
derivative (171 mg, 384 .mu.mol) obtained in the above (3) were
added 2M isopropanol solution (6.2 mL) containing ammonia and
anhydrous magnesium sulfate (1.49 g). After the reaction solution
was stirred for 1 hour, manganese dioxide (1.27 g) was added
thereto, and the mixture was stirred for 15 hours. The resulting
reaction solution was filtered through a Celite pad, and the mother
liquor was concentrated. The residue was purified by a silica gel
chromatography to obtain the above nitrile derivative (106 mg) as
an orange solid.
##STR00288##
[0789] To tetrahydrofuran solution (1 mL) containing the nitrile
derivative (11 mg, 24.8 .mu.mol) obtained in the above (4) was
added 1M tetrahydrofuran solution (1 mL) containing lithium
bis(trimethylsilyl)amide at room temperature, and the solution was
stirred for 15 minutes. The reaction solution was subjected to
ice-cooling, and 6N hydrogen chloride/ethanol (1 mL) was added
dropwise. The solution was stirred at room temperature for 30
minutes. After the reaction solution was diluted in diethyl ether,
the resulting precipitates were filtered off, and washed with
diethyl ether. The resulting precipitates were dissolved in
methanol, and the solution was diluted with ethyl acetate and
water. After N,N-diisopropylethylamine (3 mL) and sodium chloride
were added to the mixed solution until the aqueous layer was
saturated with them, the organic layer was separated. The resulting
organic layer was washed with saturated brine, dried over anhydrous
magnesium sulfate, and filtered. The filtrate was concentrated, and
chloroform (2 mL) was added to the resulting residue. The mixture
was stirred for 15 minutes to give a suspension. After 4N hydrogen
chloride/1,4-dioxane (100 .mu.L) was added dropwise to the
suspension, diethyl ether (3 mL) was added thereto. The resulting
precipitates were filtered off, washed with diethyl ether, and
dried in vacuo to obtain the above amidine derivative (9.7 mg) as a
purple solid.
##STR00289##
[0790] The amidine derivative (4.6 mg, 8.63 .mu.mol) obtained in
the above (5) was suspended in 1,1,3,3-tetramethoxypropane (500
.mu.L). The suspension was stirred in a sealed tube at 180.degree.
C. for 2 hours. The reaction solution was cooled down to room
temperature, and diluted with methanol. After triethylamine (1 mL)
was added to the suspension, it was concentrated in vacuo. The
resulting residue was purified by a silica gel chromatography to
obtain the hydrochloride (0.90 mg) of the objective compound [83]
as an orange solid.
[0791] Spectral data of the compound of the above formula [83] are
shown below.
[0792] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.60-0.80 (3H, m),
1.00-4.00 (8H, m) 4.40-4.55 (1H, m), 5.32-5.42 (1H, m), 7.12-7.23
(1H, m), 7.48-7.57 (1H, m), 7.84-7.95 (2H, m), 8.09 (1H, s),
8.95-9.03 (2H, m), 9.42-9.53 (1H, m), 12.29-12.40 (1H, m), 12.81
(1H, brs).
[0793] mass: 482 (M+1).sup.+.
Working Example 84
Synthesis of the Compound of the Following Formula [84]
##STR00290##
[0795] The amidine derivative (5.0 mg, 9.4 .mu.mol) obtained in
Working Example 83-(5) was suspended in acetonitrile (2 mL). To the
suspension were added .beta.-trifluoromethyl vinamidinium chloride
(4.4 mg, 18.8 .mu.mol) synthesized according to a method similar to
the method described in Tetrahedron Lett., 37(11) 1829 (1996) and
1.0 M methanol solution (22.5 .mu.L, 22.5 .mu.mol) containing
sodium methoxide. The mixture was stirred at room temperature for
2.5 hours. Water was added to the reaction solution, and it was
extracted with a mixed solvent of chloroform:methanol=9:1. The
organic layer was washed with saturated brine, dried over anhydrous
sodium sulfate, and filtered. The filtrate was concentrated, and
the resulting residue was purified by a thin layer chromatography,
followed by treatment according to a method similar to the
procedure described in Working Example 1-(6), thereby to obtain the
hydrochloride (2.5 mg) of the objective compound [84] as a brown
solid
[0796] Spectral data of the compound of the above formula [84] are
shown below.
[0797] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.64-0.78 (3H, m),
1.35-1.45 (1H, m), 2.23-2.40 (2H, m), 2.52-2.63 (1H, m), 2.71-2.85
(1H, m), 2.94-3.08 (1H, m), 3.77-3.91 (2H, m), 4.44-4.51 (1H, m),
5.35-5.39 (1H, m), 7.13-7.20 (1H, m), 7.84-7.91 (2H, m), 8.12 (1H,
s), 9.39 (2H, s), 9.45 (1H, d, J=7.8 Hz), 12.28-12.30 (1H, m), 12.9
(1H, s).
[0798] mass: 550 (M+1).sup.+.
Working Example 85
Synthesis of the Compound of the Following Formula [85]
##STR00291##
[0800] 3-(Dimethylamino)-2-methyl-2-propenal (4.5 mg, 39.4 .mu.mol)
and 1.0 M methanol solution (47.3 .mu.L, 47.3 .mu.mol) containing
sodium methoxide were added to methanol solution (3.0 mL)
containing the amidine derivative (10.5 mg, 19.7 .mu.mol) obtained
in Working Example 83-(5). The solution was heated at reflux with
stirring for 6.5 hours. Further,
3-(dimethylamino)-2-methyl-2-propenal (27.0 mg, 238 .mu.mol) and
1.0 M methanol solution (284 .mu.L, 284 .mu.mol) containing sodium
methoxide were added thereto. The mixture was heated at reflux with
stirring for 18 hours. After the resulting reaction solution was
cooled down to room temperature, water was added to the solution,
which was then extracted with a mixed solvent of
chloroform:methanol=9:1. The organic layer was washed with
saturated brine, dried over anhydrous sodium sulfate, filtered. The
filtrate was concentrated, and the resulting residue was purified
by a thin layer chromatography, followed by treatment according to
a method similar to the procedure described in Working Example
1-(6), thereby to obtain the hydrochloride (4.8 mg) of the
objective compound [85] as a deep purple solid.
[0801] Spectral data of the compound of the above formula [85] are
shown below.
[0802] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.66-0.90 (3H, m),
1.38-1.47 (1H, m) 2.31 (3H, s), 2.25-2.41 (2H, m), 2.75-3.20 (2H,
m), 3.82-3.93 (2H, m), 4.25-4.56 (2H, m), 5.36-5.42 (1H, m),
7.15-7.23 (1H, m), 7.87 (1H, d, J=7.8 Hz), 7. 89 (1H, s), 8.06 (1H,
s), 8.81 (2H, s), 9.40-9.47 (1H, m), 12.2-12.4 (1H, m), 12.8 (1H,
s).
[0803] mass: 496 (M+1).sup.+.
Working Example 86
Synthesis of the Compound of the Following Formula [86]
##STR00292##
[0805] The amidine derivative (9.9 mg, 18.6 .mu.mol) obtained in
Working Example 83-(5) was suspended in ethanol (3 mL), and to the
suspension were added 2-methoxymethylene cyclohexanone (5.2 mg,
37.2 .mu.mol) synthesized according to a method similar to the
method described in J. Heterocycl. Chem., 27, 1537 (1990) and
sodium acetate (3.7 mg, 44.6 .mu.mol). The mixture was stirred
under heating at reflux for 6.5 hours. Then, after further addition
of 2-methoxymethylene cyclohexanone (10.4 mg, 74.3 .mu.mol) and
sodium acetate (37.3 mg, 89.3 mmol), the mixture was stirred under
heating at reflux for 10 hours. The resulting reaction solution was
cooled down to room temperature, and 10% aqueous sodium carbonate
solution (2 mL) was added thereto. The mixture was stirred at room
temperature for 5 minutes and then extracted with a mixed solvent
of chloroform:methanol=9:1. The organic layer was washed with water
and saturated brine, dried over anhydrous sodium sulfate, and
filtered. The filtrate was concentrated, and the resulting residue
was purified by thin layer chromatography, followed by treatment
according to a method similar to the procedure described in Working
Example 1-(6), thereby to obtain the hydrochloride (0.4 mg) of the
objective compound [86] as a brown solid.
[0806] Spectral datum of the compound of the above formula [86] is
shown below.
[0807] mass: 536 (M+1).sup.+.
Working Example 87
Synthesis of the Compound of the Following Formula [87]
##STR00293##
[0809] To methanol solution (3.0 mL) containing the amidine
derivative (10.0 mg, 18.8 .mu.mol) obtained in Working Example
83-(5) were added acetylacetaldehyde dimetyhlacetal (5.0 .mu.L,
37.6 .mu.mol) and 1.0 M methanol solution (45.1 .mu.L, 45.1
.mu.mol) containing sodium methoxide. The mixture was stirred at
50.degree. C. for 4.5 hours. Then, acetylacetaldehyde
dimetyhlacetal (10.0 .mu.L, 75.2 .mu.mol) and 1.0 M methanol
solution (90.2 .mu.L, 90.2 .mu.mol) containing sodium methoxide
were added thereto. The mixture was stirred at 50.degree. C. for 13
hours. After the resulting reaction solution was cooled down to
room temperature, water was added thereto, and the reaction
solution was extracted with a mixed solvent of
chloroform:methanol=9:1. The organic layer was washed with
saturated brine, dried over anhydrous sodium sulfate, and filtered.
The filtrate was concentrated and the resulting residue was
purified by a thin layer chromatography, followed by treatment
according to a method similar to the procedure described in Working
Example 1-(6), thereby to obtain the hydrochloride (7.2 mg) of the
objective compound [87] as a deep purple solid.
[0810] Spectral data of the compound of the above formula [87] are
shown below.
[0811] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.67-0.82 (3H, m),
1.40-1.45 (1H, m), 2.25-2.42 (2H, m), 2.58 (3H, s), 2.56-3.07 (3H,
m), 3.83-3.98 (2H, m), 4.50-4.65 (1H, m), 5.34-5.41 (1H, m),
7.15-7.24 (1H, m), 7.40 (1H, d, J=5.1 Hz), 7. 88 (1H, d, J=8.1 Hz),
7.92 (1H, s), 8.10 (1H, s), 8.80 (1H, d, J=5.1 Hz), 9.38-9.45 (1H,
m), 12.2-12.3 (1H, m), 12.8 (1H, s).
[0812] mass: 496 (M+1).sup.+.
Working Example 88
Synthesis of the Compound of the Following Formula [88]
##STR00294##
[0814] Acetylacetone (7.7 .mu.L, 75.1 .mu.mol) and acetic acid (8.6
.mu.L, 150 .mu.mol) were added to 1-pentanol solution (4.0 mL)
containing the amidine derivative (10.0 mg, 18.8 .mu.mol) obtained
in Working Example 83-(5). The mixture was stirred at 135.degree.
C. for 1.5 hours. Acetylacetone (77.2 .mu.L, 751 .mu.mol) and
acetic acid (86.0 .mu.L, 1.50 mmol) were further added thereto. The
mixture was stirred at 135.degree. C. for 27 hours. The resulting
reaction solution was cooled down to room temperature, and
saturated aqueous sodium hydrogencarbonate was added to the
reaction solution. The solution was extracted with a mixed solvent
of chloroform:methanol=9:1. The organic layer was washed with water
and saturated brine, dried over anhydrous sodium sulfate, and
filtered. The filtrate was concentrated and the resulting residue
was purified by a thin layer chromatography, followed by treatment
according to a method similar to the procedure described in Working
Example 1-(6), thereby to obtain the hydrochloride (1.3 mg) of the
objective compound [88] as a deep purple solid.
[0815] Spectral data of the compound of the above formula [88] are
shown below.
[0816] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.65-0.79 (3H, m),
1.38-1.59 (1H, m), 2.08-2.50 (3H, m), 2.55 (6H, s), 2.78-3.08 (2H,
m), 3.71-3.90 (2H, m), 4.44-4.49 (1H, m), 5.32-5.38 (1H, m),
7.13-7.26 (1H, m), 7.27 (1H, s), 7.90 (1H, d, J=8.1 Hz), 7.90 (1H,
s), 8.10 (1H, s), 9.40-9.47 (1H, m), 12.2-12.4 (1H, m), 12.7 (1H,
s).
[0817] mass: 510 (M+1).sup.+.
Working Example 89
Synthesis of the Compound of the Following Formula [89]
##STR00295##
[0819] Hydroxylamine (12.6 mg, 181 .mu.mol) and triethylamine (25.2
.mu.g, 181 .mu.mol) were added to methanol solution (4.0 mL)
containing the nitrile derivative (20 mg, 45.2 .mu.mol) obtained in
Working Example 83-(4). The mixture was stirred at room temperature
for 10 hours. Hydroxylamine (12.6 mg, 181 .mu.mol) and
triethylamine (25.2 .mu.g, 181 .mu.mol) were further added thereto.
The mixture was stirred at room temperature for 3 days. The
resulting reaction solution was concentrated in vacuo. Acetic
anhydride (15 mL) was added to the resulting residue, and the
mixture was stirred at 100.degree. C. for 24 hours. After the
resulting reaction solution was concentrated in vacuo, it was
evaporated azeotropically using toluene. The resulting residue was
dissolved in tetrahydrofuran (10 mL) and methanol (10 mL), and 1N
sodium hydroxide (10 mL) was added to the solution. The solution
was stirred at room temperature for 30 minutes. After the resulting
reaction solution was neutralized using 1N hydrochloric acid, it
was extracted with a mixed solvent of chloroform:methanol=9:1. The
organic layer was washed with water and saturated brine, dried over
anhydrous sodium sulfate, and filtered. The filtrate was
concentrated and the resulting residue was purified by a thin layer
chromatography, followed by treatment according to a method similar
to the procedure described in Working Example 1-(6), thereby to
obtain the hydrochloride (8.4 mg) of the objective compound [89] as
an ocher solid.
[0820] Spectral data of the compound of the above formula [89] are
shown below.
[0821] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.65-0.76 (3H, m),
1.35-1.41 (1H, m), 2.25-2.45 (2H, m), 2.69 (3H, s), 2.55-2.80 (2H,
m), 2.91-3.05 (1H, m), 3.77-3.94 (2H, m), 4.42-4.51 (1H, m),
5.36-5.41 (1H, m), 7.14-7.21 (1H, m), 7.48 (1H, s), 7.62 (1H, s),
7.85 (1H, d, J=7.8 Hz), 9.44 (1H, d, J=7.8 Hz), 12.25-12.29 (1H,
m), 12.8 (1H, s).
[0822] mass: 486 (M+1).sup.+.
Working Example 90
Synthesis of the Compound of the Following Formula [90]
##STR00296##
[0824] According to a method similar to the procedures described in
Working Examples 11-(10) to 11-(11), the above hydrazide derivative
(24.3 g) was obtained as an orange solid from the carboxylic acid
derivative (24.4 g, 36.9 mmol) obtained in Working Example
49-(1).
##STR00297##
[0825] N,N-Diisopropylethylamine (13.3 mL, 76.3 mmol) was added to
n-butanol solution (200 mL) containing the hydrazide derivative
(22.2 g, 27.3 mmol) obtained in the above (1). The mixture was
stirred at 120.degree. C. for 5 hours. After that, the resulting
reaction solution was cooled down to room temperature, and
concentrated in vacuo to give a residue, to which was added ether
(200 mL). The resulting solid was filtered off and dried in vacuo,
followed by treatment according to a method similar to the
procedure described in Working Example 15-(4), thereby to obtain
the above alcohol derivative (17.5 g, 25.8 mmol) as a yellow
solid
##STR00298##
[0826] According to a method similar to the procedure described in
Working Example 83-(1), the above amine derivative (10.6 g) was
obtained as a yellow solid from the alcohol derivative (12.5 g,
18.4 mmol) obtained in the above (2).
##STR00299##
[0827] According to a method similar to the procedures described in
Working Examples 1-(4) to 1-(5), the above cyclic derivative (7.06
g) was obtained as a yellow solid from the amine derivative (9.78
g, 12.8 mmol) obtained in the above (3).
##STR00300##
[0828] The cyclic derivative (15 mg, 24.5 .mu.mol) obtained in the
above (4) was dissolved in a mixture of 1,2-dimethoxyethane and
water (9:1) (1 mL). To the solution were added
tetrakis(triphenylphospine)palladium (10 mg), potassium carbonate
(10 mg) and dimethyl 2-pyridylboronate (10 mg), and the mixture was
stirred at 85.degree. C. for 12 hours. Water and ethyl acetate were
added to the resulting reaction solution, and the organic layer was
separated, then washed successively with water and saturated brine.
This organic layer was dried over anhydrous magnesium sulfate,
filtered, and concentrated. The resulting residue was purified by a
silica gel chromatography to obtain the above pyridine derivative
(5 mg) as a yellow solid.
##STR00301##
[0829] According to a method similar to the procedure described in
Working Example 11-(18), the trifluoroacetate (2.4 mg) of the
objective compound [90] was obtained as a dark yellow solid from
the pyridine derivative (5 mg, 8.19 .mu.mol) obtained in the above
(5).
[0830] Spectral data of the compound of the above formula [90] are
shown below.
[0831] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.68-0.70 (3H, m)
1.38-1.44 (1H, m), 2.24-2.38 (1H, m), 2.40-2.60 (2H, m), 2.70-2.79
(1H, m), 2.90-3.02 (1H, m), 3.76-3.86 (2H, m), 4.41-4.48 (1H, m),
5.38-5.40 (1H, m), 7.12-7.18 (1H, m), 7.40-7.42 (1H, m), 7.66 (1H,
s), 7.70 (1H, s), 7.81-7.84 (1H, m), 7.90-8.00 (1H, m), 8.01-8.02
(1H, m), 8.70-8.72 (1H, m), 9.42-9.44 (1H, m), 12.3 (1H, bs), 12.7
(1H, bs).
[0832] mass: 481 (M+1).sup.+.
Working Example 91
Synthesis of the Compound of the Following Formula [91]
##STR00302##
[0834] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (1.9 mg)
of the objective compound (911 was obtained as a dark yellow solid
from the cyclic derivative (15 mg, 24.5 .mu.mol) obtained in
Working Example 90-(4) and pyrimidine-5-boronic acid.
[0835] Spectral datum of the compound of the above formula [91] is
shown below.
[0836] mass: 482 (M+1).sup.+.
Working Example 92
Synthesis of the Compound of the Following Formula [92]
##STR00303##
[0838] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the hydrochloride (7.7 mg) of
the objective compound [92] was obtained as a dark yellow solid
from the cyclic derivative (50 mg, 81.6 .mu.mol) obtained in
Working Example 90-(4) and thiazole-2-boronic acid.
[0839] Spectral datum of the compound of the above formula [92] is
shown below.
[0840] mass: 487 (M+1).sup.+.
Working Example 93
Synthesis of the Compound of the Following Formula [93]
##STR00304##
[0842] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (2.6 mg)
of the objective compound [93] was obtained as a dark yellow solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 5-acetyl-2-thiopheneboronic acid.
[0843] Spectral datum of the compound of the above formula [93] is
shown below.
[0844] mass: 528 (M+1).sup.+.
Working Example 94
Synthesis of the Compound of the Following Formula [94]
##STR00305##
[0846] According to a method similar to the procedures described in
Example 90-(5) and 11-(18), the trifluoroacetate (7.3 mg) of the
objective compound [94] was obtained as a dark purple solid from
the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in Working
Example 90-(4) and pyridine-3-boronic acid.
[0847] Spectral datum of the compound of the above formula [94] is
shown below.
[0848] mass: 481 (M+1).sup.+.
Working Example 95
Synthesis of the Compound of the Following Formula [95]
##STR00306##
[0850] According to a method similar to the procedures described in
Example 90-(5) and 11-(18), the trifluoroacetate (5.9 mg) of the
objective compound [95] was obtained as a dark yellow solid from
the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in Working
Example 90-(4) and pyridine-4-boronic acid.
[0851] Spectral datum of the compound of the above formula [95] is
shown below.
[0852] mass: 481 (M+1).sup.+.
Working Example 96
Synthesis of the Compound of the Following Formula [96]
##STR00307##
[0854] The cyclic derivative (20 mg, 32.7 .mu.mol) obtained in
Working Example 90-(4) was dissolved in 1,4-dioxane (1 mL). To this
solution were added 2-pyrrolidinone (4.97 .mu.L, 65.4 .mu.mol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.68 mg, 9.81
.mu.mol), tris(dibenzylideneacetone)dipalladium(0)-chloroform
adduct (3.38 mg, 3.27 .mu.mol) and cesium carbonate (23.4 mg, 71.9
.mu.mol). The mixture was stirred at 110.degree. C. for 1 hour
under an argon atmosphere. The resulting reaction solution was
cooled down to room temperature and concentrated in vacuo. The
resulting residue was purified by a thin layer chromatography to
obtain the above amide derivative (18 mg) as a yellow solid.
##STR00308##
[0855] According to a method similar to the procedure described in
Working Example 1-(6), the hydrochloride (14 mg) of the objective
compound [96] was obtained as a dark purple solid from the amide
derivative (18 mg, 29.2 .mu.mol) obtained in the above (1).
[0856] Spectral data of the compound of the above formula [96] are
shown below.
[0857] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.58-0.75 (3H, m),
1.22-1.45 (1H, m), 2.00-4.00 (13H, m), 4.35-4.53 (1H, m), 5.18-5.28
(1H, m), 7.07-7.20 (1H, m), 7.29-7.42 (2H, m), 7.78-7.86 (1H, m),
9.37-9.43 (1H, m), 12.25 (1H, brs), 12.56 (1H, s).
[0858] mass: 487 (M+1).sup.+.
Working Example 97
Synthesis of the Compound of the Following Formula [97]
##STR00309##
[0860] According to a method similar to the procedures described in
Working Examples 96-(1) and 1-(6), the hydrochloride (3.3 mg) of
the objective compound [97] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and indole.
[0861] Spectral datum of the compound of the above formula [97] is
shown below.
[0862] mass: 519 (M+1).sup.+.
Working Example 98
Synthesis of the Compound of the Following Formula [98]
##STR00310##
[0864] According to a method similar to the procedures described in
Working Examples 96-(1) and 1-(6), the trifluoroacetate (5.9 mg) of
the objective compound [98] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 3,5-dimethylpyrazole.
[0865] Spectral datum of the compound of the above formula [98] is
shown below.
[0866] mass: 498 (M+1).sup.+.
Working Example 99
Synthesis of the Compound of the Following Formula [99]
##STR00311##
[0868] According to a method similar to the procedures described in
Working Examples 96-(1) and 1-(6), the trifluoroacetate (4.6 mg) of
the objective compound [99] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and indazole.
[0869] Spectral datum of the compound of the above formula [99] is
shown below.
[0870] mass: 520 (M+1).sup.+.
Working Example 100
Synthesis of the Compound of the Following Formula [100]
##STR00312##
[0872] According to a method similar to the procedures described in
Working Examples 96-(1) and 1-(6), the trifluoroacetate (6.3 mg) of
the objective compound [100] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 7-azaindole.
[0873] Spectral datum of the compound of the above formula [100] is
shown below.
[0874] mass: 520 (M+1).sup.+.
Working Example 101
Synthesis of the Compound of the Following Formula [101]
##STR00313##
[0876] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the hydrochloride (14.5 mg) of
the objective compound [101] was obtained as a dark purple solid
from the cyclic derivative (30 mg, 49.0 .mu.mol) obtained in
Working Example 90-(4) and 3,5-dimethylphenylboronic acid.
[0877] Spectral datum of the compound of the above formula [101] is
shown below.
[0878] mass: 508 (M+1).sup.+.
Working Example 102
Synthesis of the Compound of the Following Formula [102]
##STR00314##
[0880] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the hydrochloride (7.0 mg) of
the objective compound [102] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and phenylboronic acid.
[0881] Spectral datum of the compound of the above formula [102] is
shown below.
[0882] mass: 480 (M+1).sup.+.
Working Example 103
Synthesis of the Compound of the Following Formula [103]
##STR00315##
[0884] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (5.1 mg)
of the objective compound [103] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 3-(trifluoromethoxy)phenylboronic
acid.
[0885] Spectral datum of the compound of the above formula [103] is
shown below.
[0886] mass: 564 (M+1).sup.+.
Working Example 104
Synthesis of the Compound of the Following Formula [104]
##STR00316##
[0888] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (9.0 mg)
of the objective compound [104] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 3,4-dimethoxyphenylboronic acid.
[0889] Spectral datum of the compound of the above formula [104] is
shown below.
[0890] mass: 540 (M+1).sup.+.
Working Example 105
Synthesis of the Compound of the Following Formula [105]
##STR00317##
[0892] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the hydrochloride (5.2 mg) of
the objective compound [105] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 2,2-difluorobenzodioxole-5-boronic
acid.
[0893] Spectral datum of the compound of the above formula [105] is
shown below.
[0894] mass: 560 (M+1).sup.+.
Working Example 106
Synthesis of the Compound of the Following Formula [106]
##STR00318##
[0896] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the hydrochloride (1.1 mg) of
the objective compound [106] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 4-(difluoromethoxy)phenylboronic
acid.
[0897] Spectral datum of the compound of the above formula [106] is
shown below.
[0898] mass: 546 (M+1).sup.+.
Working Example 107
Synthesis of the Compound of the Following Formula [107]
##STR00319##
[0900] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (20.9 mg)
of the objective compound [107] was obtained as a dark purple solid
from the cyclic derivative (20 mg, 32.6 .mu.mol) obtained in
Working Example 90-(4) and 3-methoxyphenylboronic acid.
[0901] Spectral datum of the compound of the above formula [107] is
shown below.
[0902] mass: 510 (M+1).sup.+.
Working Example 108
Synthesis of the Compound of the Following Formula [108]
##STR00320##
[0904] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (14.3 mg)
of the objective compound [108] was obtained as a dark purple solid
from the cyclic derivative (20 mg, 32.6 .mu.mol) obtained in
Working Example 90-(4) and 3-acetylphenylboronic acid.
[0905] Spectral datum of the compound of the above formula [108] is
shown below.
[0906] mass: 522 (M+1).sup.+.
Working Example 109
Synthesis of the Compound of the Following Formula [109]
##STR00321##
[0908] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (13.2 mg)
of the objective compound [109] was obtained as a dark purple solid
from the cyclic derivative (20 mg, 32.6 .mu.mol) obtained in
working Example 90-(4) and 3-acetamidophenylboronic acid.
[0909] Spectral datum of the compound of the above formula [109] is
shown below.
[0910] mass: 537 (M+1).sup.+.
Working Example 110
Synthesis of the Compound of the Following Formula [110]
##STR00322##
[0912] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (8.8 mg)
of the objective compound [110] was obtained as a dark purple solid
from the cyclic derivative (20 mg, 32.6 .mu.mol) obtained in
Working Example 90-(4) and 3-isopropylphenylboronic acid.
[0913] Spectral datum of the compound of the above formula [110] is
shown below.
[0914] mass: 522 (M+1).sup.+.
Working Example 111
Synthesis of the Compound of the Following Formula [111]
##STR00323##
[0916] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (10.7 mg)
of the objective compound [111] was obtained as a dark purple solid
from the cyclic derivative (20 mg, 32.6 .mu.mol) obtained in
Working Example 90-(4) and 3,5-difluorophenylboronic acid.
[0917] Spectral datum of the compound of the above formula [111] is
shown below.
[0918] mass: 516 (M+1).sup.+.
Working Example 112
Synthesis of the Compound of the Following Formula [112]
##STR00324##
[0920] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (8.6 mg)
of the objective compound [112] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 2-methoxyphenylboronic acid.
[0921] Spectral datum of the compound of the above formula [112] is
shown below.
[0922] mass: 510 (M+1).sup.+.
Working Example 113
Synthesis of the Compound of the Following Formula [113]
##STR00325##
[0924] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (5.3 mg)
of the objective compound [113] was obtained as a dark purple solid
from the cyclic c derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 4-methoxyphenylboronic acid.
[0925] Spectral datum of the compound of the above formula [113] is
shown below.
[0926] mass: 510 (M+1).sup.+.
Working Example 114
Synthesis of the Compound of the Following Formula [114]
##STR00326##
[0928] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (6.8 mg)
of the objective compound [114] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 2-nitrophenylboronic acid.
[0929] Spectral datum of the compound of the above formula [114] is
shown below.
[0930] mass: 525 (M+1).sup.+.
Working Example 115
Synthesis of the Compound of the Following Formula [115]
##STR00327##
[0932] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (8.5 mg)
of the objective compound [115] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 4-aminophenylboronic acid.
[0933] Spectral datum of the compound of the above formula [115] is
shown below.
[0934] mass: 495 (M+1).sup.+.
Working Example 116
Synthesis of the Compound of the Following Formula [116]
##STR00328##
[0936] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (1.3 mg)
of the objective compound [116] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 4-hydroxyphenylboronic acid.
[0937] Spectral datum of the compound of the above formula [116] is
shown below.
[0938] mass: 496 (M+1).sup.+.
Working Example 117
Synthesis of the Compound of the Following Formula [117]
##STR00329##
[0940] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (10.8 mg)
of the objective compound [117] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 3-aminophenylboronic acid.
[0941] Spectral datum of the compound of the above formula [117] is
shown below.
[0942] mass: 495 (M+1).sup.+.
Working Example 118
Synthesis of the Compound of the Following Formula [118]
##STR00330##
[0944] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (5.6 mg)
of the objective compound [118] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 4-(trifluoromethoxy)phenylboronic
acid.
[0945] Spectral datum of the compound of the above formula [118] is
shown below.
[0946] mass: 564 (M+1).sup.+.
Working Example 119
Synthesis of the Compound of the Following Formula [119]
##STR00331##
[0948] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (5.5 mg)
of the objective compound [119] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and
4-(N,N-dimethylaminocarbonyl)phenylboronic acid.
[0949] Spectral datum of the compound of the above formula [119] is
shown below.
[0950] mass: 551 (M+1).sup.+.
Working Example 120
Synthesis of the Compound of the Following Formula [120]
##STR00332##
[0952] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (4.8 mg)
of the objective compound [120] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 4-(pyrrolidine-1-carbonyl)phenylboronic
acid.
[0953] Spectral datum of the compound of the above formula [120] is
shown below.
[0954] mass: 577 (M+1).sup.+.
Working Example 121
Synthesis of the Compound of the Following Formula [121]
##STR00333##
[0956] According to a method similar to the procedures described in
Working Examples 90-(5) and 11-(18), the trifluoroacetate (7.3 mg)
of the objective compound [121] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 4-methylsulfonylphenylboronic acid.
[0957] Spectral datum of the compound of the above formula [121] is
shown below.
[0958] mass: 558 (M+1).sup.+.
Working Example 122
Synthesis of the Compound of the Following Formula [122]
##STR00334##
[0960] According to a method similar to the procedures described in
Working Examples 43-(1) and 1-(6), the trifluoroacetate (1.5 mg) of
the objective compound [122] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and pyrrolidine.
[0961] Spectral data of the compound of the above formula [122] are
shown below.
[0962] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.60-0.80 (3H, m),
1.30-1.50 (1H, m), 1.95-4.38 (15H, m), 4.38-4.50 (1H, m), 5.18-5.28
(1H, m), 5.93 (1H, s), 6.30 (1H, s), 7.02-7.18 (1H, m), 7.65-7.75
(1H, m), 9.22-9.30 (1H, m), 12.02-12. 23 (2H, m).
[0963] mass: 473 (M+1).sup.+.
Working Example 123
Synthesis of the Compound of the Following Formula [123]
##STR00335##
[0965] According to a method similar to the procedures described in
Working Examples 43-(1) and 1-(6), the trifluoroacetate (1.7 mg) of
the objective compound [123] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and (S)-2-methoxymethylpyrrolidine.
[0966] Spectral datum of the compound of the above formula [123] is
shown below.
[0967] mass: 517 (M+1).sup.+.
Working Example 124
Synthesis of the Compound of the Following Formula [124]
##STR00336##
[0969] According to a method similar to the procedures described in
Working Examples 43-(1) and 1-(6), the trifluoroacetate (1.5 mg) of
the objective compound [124] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 3-azabicyclo[3,2,2]nonane.
[0970] Spectral datum of the compound of the above formula [124] is
shown below.
[0971] mass: 527 (M+1).sup.+.
Working Example 125
Synthesis of the Compound of the Following Formula [125]
##STR00337##
[0973] According to a method similar to the procedures described in
Working Examples 43-(1) and 1-(6), the trifluoroacetate (1.9 mg) of
the objective compound [125] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and (R)-2-methoxymethylpyrrolidine.
[0974] Spectral datum of the compound of the above formula [125] is
shown below.
[0975] mass: 517 (M+1).sup.+.
Working Example 126
Synthesis of the Compound of the Following Formula [126]
##STR00338##
[0977] According to a method similar to the procedures described in
Working Examples 43-(1) and 1-(6), the trifluoroacetate (1.4 mg) of
the objective compound [126] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 4-methylpiperidine.
[0978] Spectral datum of the compound of the above formula [126] is
shown below.
[0979] mass: 501 (M+1).sup.+.
Working Example 127
Synthesis of the Compound of the Following Formula [127]
##STR00339##
[0981] According to a method similar to the procedures described in
Working Examples 43-(1) and 1-(6), the trifluoroacetate (1.7 mg) of
the objective compound [127] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and hexamethyleneimine.
[0982] Spectral datum of the compound of the above formula [127] is
shown below.
[0983] mass: 501 (M+1).sup.+.
Working Example 128
Synthesis of the Compound of the Following Formula [128]
##STR00340##
[0985] According to a method similar to the procedures described in
Working Examples 43-(1) and 1-(6), the trifluoroacetate (1.1 mg) of
the objective compound [128] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 1-(2-fluorophenyl)-piperazine.
[0986] Spectral datum of the compound of the above formula [128] is
shown below.
[0987] mass: 582 (M+1).sup.+.
Working Example 129
Synthesis of the Compound of the Following Formula [129]
##STR00341##
[0989] According to a method similar to the procedures described in
Working Examples 43-(1) and 1-(6), the trifluoroacetate (1.1 mg) of
the objective compound [129] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 .mu.mol) obtained in
Working Example 90-(4) and 1-(2-pyridyl)piperazine.
[0990] Spectral datum of the compound of the above formula [129] is
shown below.
[0991] mass: 565 (M+1).sup.+.
Working Example 130
Synthesis of the Compound of the Following Formula [130]
##STR00342##
[0993] According to a method similar to the procedures described in
Working Examples 43-(1) and 1-(6), the trifluoroacetate (1.0 mg) of
the objective compound [130] was obtained as a dark purple solid
from the cyclic derivative (10 mg, 16.3 mmol) obtained in Working
Example 90-(4) and 1-benzylpiperazine.
[0994] Spectral datum of the compound of the above formula [130] is
shown below.
[0995] mass: 578 (M+1).sup.+.
Working Example 131
Synthesis of the Compound of the Following Formula [131]
##STR00343##
[0997] The amine derivative (320 mg, 421 .mu.mol) obtained in
Working Example 90-(3) was dissolved in tetrahydrofuran (18 mL) and
methanol (6 mL), and 10% palladium-carbon catalyst (64 mg) was
added thereto under a nitrogen atmosphere. The reaction system was
substituted by hydrogen gas, and the mixture was stirred at room
temperature for 1 hour. The resulting reaction solution was
filtered through a Celite pad to remove the catalyst. The filtrate
was concentrated in vacuo and the resulting residue was purified by
a silica gel chromatography to obtain the reduced derivative (290
mg) as a yellowish brown solid.
##STR00344##
[0998] According to a method similar to the procedure described in
Working Example 1-(4), the above phenol derivative (200 mg) was
obtained as a yellowish brown solid from the reduced derivative
(290 mg, 421 .mu.mol) obtained in the above (1).
##STR00345##
[0999] According to the procedure described in Working Example
72-(2), the above hydroxymethyl derivative (210 mg) was obtained as
a ocher solid from the phenol derivative (200 mg, 363 .mu.mol)
obtained in the above (2).
##STR00346##
[1000] To a stirred chloroform suspension (10 mL) of the
hydroxymethyl derivative (210 mg, 363 .mu.mol) obtained in the
above (3) were added triethylamine (202 .mu.L, 725 .mu.mol),
4-dimethylaminopyridine (8.9 mg, 72.5 .mu.mol) and
t-butyldiphenylsilyl chloride (141 .mu.L, 544 .mu.mol) at 0.degree.
C., and the mixture was stirred at room temperature for 30 minutes.
After further addition of triethylamine (606 .mu.L, 2.17 mmol),
4-dimethylaminopyridine (16.7 mg, 217 .mu.mol) and
t-butyldiphenylsilyl chloride (324 .mu.L, 1.63 mmol) with stirring
at 0.degree. C., the reaction solution was stirred at room
temperature for 1.5 hours. After addition of water, the resulting
reaction solution was extracted with chloroform. The organic layer
was washed with saturated brine, dried over anhydrous sodium
sulfate and filtered. The filtrate was concentrated, and the
resulting residue was purified by a column chromatography on silica
gel to obtain the protected derivative with TBDPS (257 mg) as a
yellowish brown solid.
##STR00347##
[1001] According to a method similar to the procedures described in
Working Examples 1-(5) and 15-(4), the above alcohol derivative
(130 mg) was obtained as a yellowish brown solid from the
derivative protected with TBDPS (257 mg, 313 .mu.mol) obtained in
the above (4).
##STR00348##
[1002] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (4.6 mg) of
the objective compound [131] was obtained as a yellow green solid
from the alcohol derivative (11.3 mg, 20.1 .mu.mol) obtained in the
above (5) and piperidine.
[1003] Spectral data of the compound of the above formula [131] are
shown below.
[1004] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.60-0.68 (3H, m),
1.24-1.43 (1H, m), 1.63-1.85 (6H, m), 2.00-2.26 (1H, m), 2.71-3.46
(8H, m), 3.54-3.77 (1H, m), 3.78-3.97 (1H, m), 4.30-4.52 (3H, m),
5.33-5.43 (1H, m), 7.18-7.24 (1H, m), 7.21 (1H, d, J=8.4 Hz),
7.75-7.90 (1H, m), 7.88 (1H, d, J=7.5 Hz), 9.43-9.59 (1H, m),
9.98-10.0 (1H, m), 12.7-12.9 (1H, m), 12.9 (1H, s).
[1005] mass: 501 (M+1).sup.+.
Working Example 132
Synthesis of the Compound of the Following Formula [132]
##STR00349##
[1007] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (6.9 mg) of
the objective compound [132] was obtained as a dark green solid
from the alcohol derivative (18.4 mg, 32.7 .mu.mol) obtained in
Working Example 131-(5) and N-methylpiperazine.
[1008] Spectral datum of the compound of the above formula [132] is
shown below.
[1009] mass: 516 (M+1).sup.+.
Working Example 133
Synthesis of the Compound of the Following Formula [133]
##STR00350##
[1011] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (11.7 mg) of
the objective compound [133] was obtained as a dark green solid
from the alcohol derivative (20.7 mg, 36.8 .mu.mol) obtained in
Working Example 131-(5) and N-acetylpiperazine.
[1012] Spectral datum of the compound of the above formula [133] is
shown below.
[1013] mass: 544 (M+1).sup.+.
Working Example 134
Synthesis of the Compound of the Following Formula [134]
##STR00351##
[1015] According to a method similar to the procedures described in
Working Examples 83-(1), 11-(14) to 11-(16) and 11-(18), the
hydrochloride (9.6 mg) of the objective compound [134] was obtained
as a dark green solid from the alcohol derivative (140 mg, 351
.mu.mol) obtained in Working Example 76-(2).
[1016] Spectral data of the compound of the above formula [134] are
shown below.
[1017] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.68 (3H, m), 1.34 (1H,
m), 2.00-3.10 (5H, m), 3.40-4.00 (2H, m), 4.46 (1H, m), 5.24 (1H,
brs), 6.94 (2H, m), 7.14 (1H, m), 7.48 (1H, m), 7.83 (1H, d, J=8.4
Hz), 9.43 (1H, m), 12.2 (1H, brs), 12.6 (1H, brs).
[1018] mass: 404 (M+1).sup.+.
Working Example 135
Synthesis of the Compound of the Following Formula [135]
##STR00352##
[1020] According to a method similar to the procedure described in
Working Example 11-(14), the above mesylated derivative (270 mg)
was obtained as a yellow solid from the cyclic derivative (240 mg,
536 .mu.mol) obtained in Working Example 83-(2).
##STR00353##
[1021] According to a method similar to the procedure described in
Working Example 131-(1), the above methyl derivative (24 mg) was
obtained as a yellow solid from the mesylated derivative (90 mg,
171 .mu.mol) obtained in the above (1).
##STR00354##
[1022] According to a method similar to the procedure described in
Working Example 1-(6), the hydrochloride (15 mg) of the objective
compound [135] was obtained as a dark purple solid from the methyl
derivative (24 mg, 55.6 .mu.mol) obtained in the above (2).
[1023] Spectral data of the compound of the above formula [135] are
shown below.
[1024] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.60-0.75 (3H, m),
1.25-1.41 (1H, m), 2.20-2.61 (6H, m), 2.63-2.82 (1H, m), 2.85-3.10
(1H, m), 3.55-3.90 (2H, m), 4.38-4.50 (1H, m), 5.18-5.25 (1H, m),
6.72-6.79 (1H, m), 6.82-6.90 (1H, m), 7.02-7.22 (1H, m), 7.80-7.86
(1H, m), 9.35-9.45 (1H, m), 12.20-12.31 (1H, m), 12.55-12.65 (1H,
m).
[1025] mass: 418 (M+1).sup.+.
Working Example 136
Synthesis of the Compound of the Following Formula [136]
##STR00355##
[1027] According to a method similar to the procedure described in
Working Examples 11-(17) and 1-(6), the hydrochloride (49 mg) of
the objective compound [136] was obtained as a yellow solid from
the mesylated derivative (80 mg, 179 .mu.mol) obtained in Working
Example 135-(1) and morpholine.
[1028] Spectral data of the compound of the above formula [136] are
shown below.
[1029] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.62-0.78 (3H, m),
1.30-1.42 (1H, m), 2.22-3.40 (9H, m), 3.60-4.00 (6H, m), 4.35-4.52
(3H, m), 5.12-5.23 (1H, m), 7.05 (1H, d, J=0.9 Hz), 7.17 (1H, dd,
J=7.9 Hz, 8.3 Hz), 7.37 (1H, d, J=0.9 Hz), 7.88 (1H, d, J=7.9 Hz),
9.44 (1H, d, J=8.3 Hz), 10.82-11.01 (1H, m), 12. 24 (1H, s), 12.89
(1H, s).
[1030] mass: 503 (M+1).sup.+.
Working Example 137
Synthesis of the Compound of the Following Formula [137]
##STR00356##
[1032] To tetrahydrofuran solution (5 mL) containing the mesylated
derivative (80 mg, 179 .mu.mol) obtained in Example 135-(1) was
added 1M methanol solution containing sodium methoxide at room
temperature. The mixture was stirred at 60.degree. C. for 3 hours.
The reaction solution was cooled down to room temperature, diluted
with chloroform, and washed successively with water and saturated
brine. The organic layer was dried over anhydrous magnesium sulfate
and filtered. The filtrate was concentrated in vacuo and the
resulting residue was purified by a silica gel chromatography to
produce the methoxymethyl derivative (56 mg) as a yellow solid.
##STR00357##
[1033] According to a method similar to the procedure described in
Working Example 11-(18), the hydrochloride (40 mg) of the objective
compound [137] was obtained as a purple solid from the
methoxymethyl derivative (56 mg, 121 .mu.mol) obtained in the above
(1).
[1034] Spectral data of the compound of the above formula [137] are
shown below.
[1035] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.60-0.80 (3H, m),
1.20-1.50 (1H, m), 2.20-3.10 (5H, m), 3.56 (3H, s), 3.72-4.60 (5H,
m), 5.20-5.31 (1H, m), 6.89-7.00 (2H, m), 7.10-7.22 (1H, m),
7.80-7.88 (1H, m), 9.38-9.48 (1H, m), 12.20-12.38 (1H, m),
12.62-12.70 (1H, m).
[1036] mass: 448 (M+1).sup.+.
Working Example 138
Synthesis of the Compound of the Following Formula [138]
##STR00358##
[1038] To tetrahydrofuran solution (5 mL) containing the mesylated
derivative (50 mg, 95 .mu.mol) obtained in Example 135-(1) was
added 1M tetrahydrofuran solution (5 mL) containing sodium
2-methoxyethoxide at room temperature, and the mixture was stirred
at 60.degree. C. for 3 hours. The reaction solution was cooled down
to room temperature, diluted with chloroform, and washed
successively with water and saturated brine. The organic layer was
dried over anhydrous magnesium sulfate, and filtered. The filtrate
was concentrated in vacuo, and the resulting residue was purified
by a silica gel chromatography to obtain the methoxyethoxymethyl
derivative (12 mg) as a yellow solid.
##STR00359##
[1039] According to a method similar to the procedure described in
Working Example 11-(18), the hydrochloride (6.2 mg) of the
objective compound [138] was obtained as a dark purple solid from
the methoxyethoxymethyl derivative (12 mg, 23.7 .mu.mol) obtained
in the above (1).
[1040] Spectral data of the compound of the above formula [138] are
shown below.
[1041] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.60-0.78 (3H, m),
1.20-1.50 (1H, m), 2.20-4.20 (14H, m), 4.38-4.52 (1H, m), 4.59 (2H,
s), 5.19-5.27 (1H, m), 6.90-6.98 (2H, m), 7.08-7.12 (1H, m),
7.81-7.87 (1H, m), 9.35-9.45 (1H, m), 12.18-12.32 (1H, m),
12.55-12.70 (1H, m).
[1042] mass: 492 (M+1).sup.+.
Working Example 139
Synthesis of the Compound of the Following Formula [139]
##STR00360##
[1044] To tetrahydrofuran solution (100 mL) containing the aldehyde
derivative (197 mg, 442 .mu.mol) obtained in Working Example 83-(3)
was dropwise added 1M diethyl ether solution (2.64 mL) containing
allyl magnesium bromide at -78.degree. C., and the mixture was
stirred at the same temperature for 15 minutes. After acetic acid
(500 .mu.L) was added dropwise to the reaction solution, it was
warmed up to room temperature. This reaction solution was
concentrated in vacuo, and the resulting residue was purified by a
silica gel chromatography to obtain the diol derivative (127 mg),
which was a diastereomer mixture, as a yellow solid.
##STR00361##
[1045] The alcohol derivative (74 mg) which was a diastereomer
mixture obtained in the above (1) was resolved by Chiralpack AD to
produce the chiral alcohol derivative A (430 mg) with a shorter
retention time as a yellow solid and the chiral alcohol derivative
B (38 mg) with a longer retention time as a yellow solid.
##STR00362##
[1046] To N,N-dimethylformamide solution (15 mL) containing the
chiral alcohol derivative A (30 mg, 61.5 .mu.mol) obtained in the
above (2) was added sodium hydride (16 mg, 60% dispersion in oil)
at 70.degree. C., and the mixture was stirred at the same
temperature for 10 minutes. The resulting reaction solution was
kept at 0.degree. C., and allyl bromide (34 .mu.L) was added
thereto, and then the mixture was further stirred for 30 minutes.
After acetic acid (100 .mu.L) was added dropwise, pyrrolidine (55
.mu.L) was added dropwise thereto. This reaction solution was
diluted with ethyl acetate, and the organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate and
filtered. The filtrate was concentrated in vacuo, and the resulting
residue was purified by a column chromatography on silica gel to
obtain the allyl ether derivative (5.1 mg) as a yellow solid.
##STR00363##
[1047] To dichloromethane solution (3 mL) containing the allyl
ether derivative (5.1 mg, 9.77 mmol) obtained in the above (3) was
added benzylidene-bis(tricyclohexylphosphine)dichlorolutenium (795
.mu.g) at room temperature under an argon atmosphere, and the
mixture was stirred for 15 hours. The resulting reaction solution
was purified by a column chromatography on silica gel to obtain the
cyclic derivative (5.0 mg) as a yellow solid.
##STR00364##
[1048] According to a method similar to the procedure described in
Working Example 131-(1), the above tetrahydropyran derivative (5.0
mg) was obtained as a yellow solid from the cyclic derivative (5.0
mg, 10.0 .mu.mol) obtained in the above (4).
##STR00365##
[1049] According to a method similar to the procedure described in
Working Example 1-(6), the hydrochloride (2.0 mg) of the objective
compound [139] was obtained as a dark purple solid from the
tetrahydropyran derivative (2.0 mg, 3.98 .mu.mol) obtained in the
above (5).
[1050] Spectral data of the compound of the above formula [139] are
shown below.
[1051] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.52-0.78 (3H, m),
1.22-1.98 (8H, m), 2.88-3.08 (1H, m), 3.50-4.11 (6H, m), 4.35-4.53
(3H, m), 5.18-5.35 (1H, m), 6.90-7.00 (2H, m), 7.10-7.22 (1H, m),
7.81-7.88 (1H, m), 9.38-9.48 (1H, m), 12.20-12.35 (1H, m), 12.61
(1H, brs).
[1052] mass: 488 (M+1).sup.+.
Working Example 140
Synthesis of the Compound of the Following Formula [140]
##STR00366##
[1054] According to a method similar to the procedures described in
Working Examples 139-(3) to 139-(4), 131-(1) and 1-(6), the
hydrochloride (3.2 mg) of the objective compound [140] was obtained
as a dark purple solid from the chiral alcohol derivative (38 mg,
77.9 .mu.mol) obtained in Working Example 139-(2).
[1055] Spectral datum of the compound of the above formula [140] is
shown below.
[1056] mass: 488 (M+1).sup.+.
Working Example 141
Synthesis of the Compound of the Following Formula [141]
##STR00367##
[1058] According to a method similar to the procedures described in
working Examples 11-(14), 131-(1) and 1-(6), the hydrochloride (1.8
mg) of the objective compound [141] was obtained as a dark purple
solid from the cyclic derivative (8.5 mg) obtained in Working
Example 11-(16).
[1059] Spectral data of the compound of the above formula [141] are
shown below.
[1060] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 2.00-2.70 (7H, m),
2.80-4.40 (6H, m) 5.32 (1H, m), 6.80-7.40 (3H, m), 7.80 (1H, m),
9.18 (1H, m), 11.8 (1H, m), 12.6 (1H, m).
[1061] mass: 404 (M+1).sup.+.
Working Example 142
Synthesis of the Compound of the Following Formula [142]
##STR00368##
[1063] According to a method similar to the procedures described in
Working Examples 11-(10) to 11-(11), 90-(2) and 15-(4), the
indazolinone derivative (250 mg) was obtained as a yellowish brown
viscous liquid from the carboxylic acid (382 mg, 696 .mu.mol) which
is a starting material of Example 48-(1), and the hydrazine
derivative [A-34] (304 mg, 1.05 mmol).
##STR00369##
[1064] According to a method similar to the procedure described in
Working Example 83-(1), the above amine derivative (6.8 mg) was
obtained as a yellowish brown viscous liquid from the indazolinone
derivative (38.0 mg, 62.0 .mu.mol) obtained in the above (1).
##STR00370##
[1065] According to a method similar to the procedures described in
Working Examples 1-(4) to 1-(6), the hydrochloride (1.4 mg) of the
objective compound [142] was obtained as a dark purple solid from
the amine derivative (6.8 mg, 9.77 .mu.mol) obtained in the above
(2).
[1066] Spectral data of the compound of the above formula [142] are
shown below.
[1067] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.60-0.72 (3H, m),
1.25-1.49 (1H, m), 1.51 (3H, d, J=6.9 Hz), 2.20-2.30 (1H, m),
2.68-3.23 (4H, m), 3.66-3.82 (1H, m), 4.79-4.91 (1H, m), 5.21-5.25
(1H, m), 7.00 (1H, d, J=8.1 Hz), 7.09-7.19 (2H, m), 7.51 (1H, d,
J=8.1 Hz), 7.85 (1H, d, J=7.2 Hz), 9.33-9.42 (1H, m), 12.15-12.24
(1H, m), 12.7 (1H, s).
[1068] mass: 418 (M+1).sup.+.
Working Example 143
Synthesis of the Compound of the Following Formula [143]
##STR00371##
[1070] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (6.4 mg) of
the objective compound [143] was obtained as a yellowish green
solid from the alcohol derivative (10.0 mg, 17.7 .mu.mol) obtained
in Working Example 131-(5) and cyclopentylamine.
[1071] Spectral data of the compound of the above formula [143] are
shown below.
[1072] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.52-0.74 (3H, m),
1.06-1.29 (1H, m), 1.46-1.59 (2H, m), 1.59-1.80 (4H, m), 1.97-2.07
(2H, m), 2.09-2.27 (1H, m), 2.82-3.16 (2H, m), 3.46-3.59 (2H, m),
3.60-3.95 (3H, m), 4.09-4.39 (2H, m), 4.39-4.46 (1H, m), 5.21-5.42
(1H, m), 7.15-7.22 (1H, m), 7.19 (1H, d, J=8.4 Hz), 7.77-7.84 (1H,
m), 7.87 (1H, d, J=7.5 Hz), 9.05-9.15 (1H, m), 9.23-9.34 (1H, m),
9.42-9.55 (1H, m), 12.66-12.70 (1H, m), 12.8 (1H, s).
[1073] mass: 501 (M+1).sup.+.
Example 144
Synthesis of the Compound of the Following Formula [144]
##STR00372##
[1075] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (4.7 mg) of
the objective compound [144] was obtained as a yellowish green
solid from the alcohol derivative (10.0 mg, 17.7 .mu.mol) obtained
in Working Example 131-(5) and cyclopropylamine.
[1076] Spectral data of the compound of the above formula [144] are
shown below.
[1077] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.60-0.90 (5H, m),
0.90-0.96 (2H, m) 11.10-1.30 (1H, m), 2.05-2.25 (1H, m), 2.61-2.80
(2H, m), 2.93-3.15 (2H, m), 3.55-3.80 (1H, m), 3.82-4.02 (2H, m),
4.27-4.51 (3H, m), 5.24-5.42 (1H, m), 7.14-7.23 (1H, m), 7.17 (1H,
d, J=8.7 Hz), 7.73-7.80 (1H, m), 7.87 (1H, d, J=7.8 Hz), 9.35-9.60
(3H, m), 12.7-12.8 (1H, m), 12.9 (1H, s).
[1078] mass: 473 (M+1).sup.+.
Working Example 145
Synthesis of the Compound of the Following Formula [145]
##STR00373##
[1080] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (4.7 mg) of
the objective compound [145] was obtained as a yellowish green
solid from the alcohol derivative (10.0 mg, 17.7 .mu.mol) obtained
in Working Example 131-(5) and t-butylamine.
[1081] Spectral data of the compound of the above formula [145] are
shown below.
[1082] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.55-0.77 (3H, m),
1.05-1.39 (1H, m), 1.40 (9H, s), 2.03-2.31 (1H, m), 2.80-3.05 (2H,
m), 3.35-3.79 (2H, m), 3.80-4.03 (2H, m), 4.09-4.38 (2H, m),
4.39-4.51 (1H, m), 5.27-5.38 (1H, m), 7.14-7.23 (1H, m), 7.19 (1H,
d, J=8.7 Hz), 7.81-7.89 (1H, m), 7.86 (1H, d, J=7.8 Hz), 8.60-8.85
(1H, m), 9.05-9.25 (1H, m), 9.35-9.65 (1H, m), 12.7-12.9 (1H, m),
12.9 (1H, s).
[1083] mass: 489 (M+1).sup.+.
Working Example 146
Synthesis of the Compound of the Following Formula [146]
##STR00374##
[1085] According to a method similar to the procedures described in
Working Examples 11-(17) and 1-(6), the hydrochloride (5.0 mg) of
the objective compound [146] was obtained as a yellowish green
solid from the alcohol derivative (10.0 mg, 17.7 .mu.mol) obtained
in Working Example 131-(5) and trifluoroethylamine.
[1086] Spectral data of the compound of the above formula [146] are
shown below.
[1087] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 0.59-0.92 (3H, m),
1.05-1.54 (1H, m), 1.90-2.15 (1H, m), 2.85-3.20 (2H, m), 3.45-4.10
(6H, m), 4.10-4.39 (2H, m), 4.40-4.46 (1H, m), 5.21-5.42 (1H, m),
7.13-7.23 (1H, m), 7.16 (1H, d, J=8.7H z), 7.70-7.85 (1H, m), 7.87
(1H, d, J=7.5 Hz), 9.40-9.65 (1H, m), 12.6-12.8 (1H, m), 12.8 (1H,
s).
[1088] mass: 515 (M+1).sup.+.
Reference Example 1
Synthesis of the Compound of the Following Formula [A-1]
##STR00375##
[1090] 2-Amino-3-nitrophenol (77 mg, 0.50 mmol) was dissolved in
N,N-dimethylformamide (2 mL), and to this solution were added
successively imidazole (68 mg, 1.00 mmol) and t-butyldimethylsilyl
chloride (90 mg, 0.60 mmol) under ice-cooling. The mixture was
stirred at room temperature overnight. The resulting reaction
solution was diluted with ethyl acetate, and washed successively
with water and saturated brine. The organic layer was dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo to
obtain the above protected derivative with TBS (140 mg) as a deep
orange oil.
##STR00376##
[1091] The protected derivative with TBS (140 mg, 0.50 mmol)
obtained in the above (1) was dissolved in ethyl acetate (2 mL),
and to the solution was added gradually N-bromosuccinimide (98 mg,
0.55 mmol) in a water-bath. The reaction solution was stirred at
room temperature for 10 minutes. The resulting reaction solution
was diluted with ethyl acetate, and washed successively with
saturated aqueous sodium sulfite, aqueous sodium hydrogencarbonate
and saturated brine. The organic layer was dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo to obtain
the above brominated derivative (169 mg) as a deep yellow
solid.
##STR00377##
[1092] The brominated derivative (165 mg, 0.48 mmol) obtained in
the above (2) was dissolved in tetrahydrofuran (2 mL), and 5%
platinum carbon catalyst (33 mg) was added thereto under a nitrogen
atmosphere. After substitution of the atmosphere of the reaction
system with hydrogen, the solution was stirred at room temperature
for 8 hours. The resulting reaction solution was filtered through a
Celite pad to remove the catalyst, and the filtrate was
concentrated in vacuo to obtain the objective compound [A-1] (151
mg) as a deep brown oil.
Reference Example 2
Synthesis of the Compound of the Following Formula [A-2]
##STR00378##
[1094] Ethyl (2-fluoro-3-iodophenyl)oxoacetate (10.0 g, 31.1 mmol)
according to a method similar to the method of general formula
(II-d) described in WO 02/02550 pamphlet was dissolved in
N,N-dimethylformamide (100 mL) and methanol (100 mL), and to this
solution was added sodium hydrogencarbonate (7.84 g, 93.3 mmol).
The atmosphere in the reaction system was substituted with nitrogen
gas. Palladium acetate(II) (75 mg, 3.11 mmol) and
1,1'-bis(diphenylphosphino)ferrocene (185 mg, 3.11 mmol) were added
thereto at room temperature under a nitrogen atmosphere, and then
the atmosphere in the reaction system was substituted by carbon
monoxide gas. This solution was stirred at 70.degree. C. for 2
hours, cooled down to room temperature, diluted with chloroform,
and washed successively with water and saturated aqueous ammonium
chloride. The organic layer was dried over anhydrous magnesium
sulfate, filtered, and concentrated. The resulting residue was
purified by a column chromatography on silica gel to obtain the
objective compound [A-2] (2.90 g) as a yellow solid.
Reference Example 3
Synthesis of the Compounds of the Following Formulae [A-3-1] to
[A-3-5]
##STR00379##
[1096] According to a method similar to the method described in
Journal of Synthetic Organic Chemistry, Japan, 59(8) 779 (2001) and
the procedure of Reference Example 1-(1), (R)-1-amino-2-propanol,
(S)-1-amino-2-propanol, (R)-2-amino-1-propanol,
(S)-2-amino-1-propanol, and 2-aminoethanol were respectively
sulfonated and silylated to obtain the corresponding
O-silyl-sulfonamide derivatives [A-3-1] to [A-3-5].
Reference Example 4
Synthesis of the Compound of the Following Formula [A-4]
##STR00380##
[1098] According to a method similar to the method described in
Bull. Chem. Soc. Jpn., 57(7) 2019 (1984), the above TBS derivative
was obtained from (1R,3R)-3-(2'-hydroxyethyl)cyclopentanol
synthesized by the method described in J. Am. Chem. Soc., 99(5)
1625 (1977).
##STR00381##
[1099] The TBS derivative (9.8 g, 40 mmol) obtained in the above
(1) was dissolved in toluene (150 mL), and to the solution was
added 40% toluene solution (35 mL, 80 mmol) containing benzoic acid
(9.8 g, 80 mmol), triphenylphosphine (21 g, 80 mmol) and diethyl
azodicarboxylate under ice-cooling. The solution was stirred for 1
hour under ice-cooling, and water was added thereto. The solution
was stirred at room temperature for 30 minutes, and the resulting
solid was filtered off, and the filtrate was washed with saturated
brine. The organic layer was dried over anhydrous magnesium
sulfate, filtered, and concentrated. The resulting residue was
purified by a column chromatography on silica gel to obtain the
above benzoyl derivative (9.8 g) as a colorless oil.
##STR00382##
[1100] The benzoyl derivative (4.5 g, 12.9 mmol) obtained in the
above (2) was dissolved in methanol (20 mL), and then 0.05M
methanol solution (150 mL) containing sodium hydroxide was added
thereto under ice-cooling. The solution was stirred at room
temperature for 12 hours. The resulting reaction solution was
diluted with t-butyl methyl ether, and the organic layer was washed
successively with water and saturated brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The resulting
residue was purified by a column chromatography on silica gel to
obtain the above alcohol derivative (2.6 g) as a colorless oil.
##STR00383##
[1101] The alcohol derivative (566 mg, 2.31 mmol) obtained in the
above (3) was dissolved in chloroform (10 mL), and to the solution
were added triethylamine (414 .mu.L, 2.97 mmol) and
methanesulfonylchloride (231 .mu.L, 2.97 mmol) under ice-cooling.
The mixture was stirred for 1 hour. After aqueous sodium
hydrogencarbonate was added to the reaction solution, it was
extracted with chloroform. The organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate, filtered,
and concentrated to obtain the objective derivative [A-4] (746 mg)
as a pale yellow oil.
Reference Example 5
Synthesis of the Compound of the Following Formula [A-5]
##STR00384##
[1103] The above diol derivative was obtained from norcamphor
according to the method described in J. Am. Chem. Soc., 99(5) 1625
(1977).
##STR00385##
[1104] The above benzoyl compound was obtained from the diol
derivative obtained in the above (1) according to a method similar
to the procedures of Reference Examples 4-(1) to 4-(2).
##STR00386##
[1105] The benzoyl derivative (4.5 g, 12.9 mmol) obtained in the
above (2) was dissolved in chloroform (80 mL), and hydrochloric
acid/methanol (20 mL) was added thereto under ice-cooling. The
resulting reaction solution was stirred for 15 minutes under
ice-cooling, and chloroform was added thereto. The organic layer
was washed successively with water, saturated aqueous sodium
hydrogencarbonate and saturated brine. Then, the organic layer was
dried over anhydrous magnesium sulfate, filtered, and concentrated.
The resulting residue was purified by a column chromatography on
silica gel to obtain the above alcohol derivative (2.7 g) as a
colorless oil.
##STR00387##
[1106] The objective compound [A-5] (258 mg) was obtained as a pale
yellow oil from the alcohol derivative (194 mg, 826 .mu.mol)
obtained according to the procedure of Reference Example 4-(4).
Reference Example 6
Synthesis of the Compound of the Following Formula [A-6]
##STR00388##
[1108] According to a method similar to the procedures as Reference
Examples 4-(3) to 4-(4), the objective compound [A-6] was obtained
from the benzoyl derivative obtained in Reference Example
5-(2).
Reference Example 7
Synthesis of the Compound of the Following Formula [A-7]
##STR00389##
[1110] The TBS-derivative (4 g, 16 mmol) obtained in Reference
Example 4-(1) was dissolved in chloroform (80 mL), and to the
solution were added triethylamine (3.4 mL, 21 mmol),
4-dimethylaminopyridine (600 mg, 4.3 mmol), and benzoylchloride
(2.2 mL, 17 mmol). The mixture was stirred at room temperature for
3 hours. Aqueous sodium hydrogencarbonate solution was added to the
resulting reaction solution, and it was extracted with chloroform.
The organic layer was washed with saturated brine, dried over
anhydrous magnesium sulfate, filtered, and the filtrate was
concentrated. The resulting residue was purified by a column
chromatography on silica gel to obtain the above benzoyl derivative
(5.6 g) as a colorless oil.
##STR00390##
[1111] According to a method similar to the procedures of Reference
Examples 5-(3) to 5-(4), the objective compound [A-7] (670 mg) was
obtained as a colorless oil from the benzoyl derivative (583 mg,
1.68 mmol) obtained in the above (1)
Reference Example 8
Synthesis of the Compound of the Following Formula [A-8]
##STR00391##
[1113] According to a method similar to the procedure of Reference
Example 1-(1), the above TBDPS-derivative (88.2 g) was obtained as
a colorless oil from (S)-hexane-1,5-diol (29.9 g, 253 mmol)
synthesized by referring to the method described in J. Chem. Soc.
Perkin Trans. I, 20 2467 (1996) and t-butyldiphenylsilyl
chloride.
##STR00392##
[1114] According to a method similar to the procedure of Reference
Example 4-(4), the objective compound [A-8] (652 mg) was obtained
as a colorless oil from the TBDPS-derivative (535 mg, 1.5 mmol)
prepared in the above (1)
Reference Example 9
Synthesis of the Compound of the Following Formula [A-9]
##STR00393##
[1116] According to a method similar to the method as Reference
Example 8, the objective compound [A-9] was obtained from
(R)-hexane-1,5-diol.
Reference Example 10
Synthesis of the Compound of the Following Formula [A-10]
##STR00394##
[1118] According to a method similar to the procedure of Reference
Example 7-(1), the above benzoyl compound (2.6 g) was obtained as a
colorless oil from TBDPS-derivative (2 g, 5.6 mmol) obtained in
Reference Example 8-(1)
##STR00395##
[1119] The benzoyl derivative (2.5 g, 5.4 mmol) obtained in the
above (1) was dissolved in tetrahydrofuran (16 mL), and to this
solution was added 1M tetrahydrofuran solution (16 mL) containing
tetrabutylammonium fluoride. The solution was stirred at room
temperature for 2 hours. The resulting reaction solution was
diluted with diethyl ether (100 mL), and washed successively with
0.1M phosphate buffer (pH 6.8) and saturated brine. The organic
layer was dried over anhydrous magnesium sulfate, filtered, and the
filtrate was concentrated. The resulting residue was purified by a
column chromatography on silica gel to obtain the above alcohol
derivative (1.2 g) as a colorless oil.
##STR00396##
[1120] According to a method similar to the procedure of Reference
Example 4-(4), the objective compound [A-10] was obtained as a
colorless oil from the alcohol derivative (378 mg, 1.70 mmol)
prepared in the above (2). The product was used without separation
and purification.
Reference Example 11
Synthesis of the Compound of the Following Formula [A-11]
##STR00397##
[1122] According to a method similar to the procedures of Reference
Examples 8-(1) and 10, the objective compound [A-11] was obtained
from (R)-hexane-1,5-diol synthesized by referring to the method
described in J. Chem. Soc. Perkin Trans. I, 20 2467 (1996).
Reference Example 12
Synthesis of the Compound of the Following Formula [A-12]
##STR00398##
[1124] In the above formula, the stereo chemistry of the position
with the asterisk * is of cis configuration.
##STR00399##
[1125] Cis-2,5-di(ethoxycarbonyl)pyrrolidine (10.5 g, 49.1 mmol)
synthesized by referring to the method described in J. Org. Chem.,
26(5) 1500 (1961) was dissolved in pyridine (30 mL), and to the
solution was added allyl chloroformate (8.9 g, 73.6 mmol) under
ice-cooling. The solution was stirred for 30 minutes, and aqueous
sodium hydrogencarbonate was added to the resulting reaction
solution. The reaction solution was extracted with diethyl ether.
The organic layer was washed with saturated brine, dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
resulting residue was purified by a column chromatography on silica
gel to obtain the above protected derivative with Alloc (10.6 g) as
a colorless oil.
##STR00400##
[1126] The above protected derivative with Alloc (10.6 g, 35.4
mmol) obtained in the above (1) was dissolved in tetrahydrofuran
(170 mL), and then lithium tetrahydroborate (3.9 g, 177 mmol) was
added thereto. The mixture was stirred at room temperature for 2
hours. Methanol was gradually added dropwise to the resulting
reaction solution, and the reaction solution was diluted with
aqueous sodium hydrogencarbonate solution. This solution was
extracted with ethyl acetate, and the organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate, and
filtered. The filtrate was and concentrated, and the resulting
residue was purified by a column chromatography on silica gel to
obtain the above diol derivative (5.5 g) as a colorless oil.
##STR00401##
[1127] The diol derivative (5.5 g, 25.5 mmol) obtained in the above
(2) was dissolved in chloroform (250 mL), and to the solution were
added triethylamine (4.1 mL, 30 mmol), t-butyldimethylsilyl
chloride (4.0 g, 25.5 mmol), and 4-dimethylaminopyridine (940 mg,
7.7 mmol). The mixture was stirred at room temperature for 2 hours.
After aqueous sodium hydrogencarbonate solution was added to the
resulting reaction solution, it was extracted with chloroform. The
organic layer was washed with saturated brine, dried over anhydrous
magnesium sulfate, and filtered. The filtrate was concentrated, and
the resulting residue was purified by a column chromatography on
silica gel to obtain the above racemic TBS-derivative (3.5 g) as a
colorless oil.
##STR00402##
[1128] According to a method similar to the procedure of Reference
Example 4-(4), the objective compound [A-12] (4.6 g) was obtained
as a colorless oil from the compound (3.5 g, 11.5 mmol) obtained in
the above (3)
Reference Example 13
Synthesis of the Compound of the Following Formula [A-13]
##STR00403##
[1130] According to a method similar to the procedure of Reference
Example 12-(3), the above TBS-derivative (995 mg) was obtained as a
colorless oil from cis-4-hydroxymethylcyclohexanol (601 mg, 4.62
mmol) prepared by reference to the method described in J. Org.
Chem., 35(7) 2368 (1970)
##STR00404##
[1131] The TBS-derivative (489 mg, 2.00 mmol) obtained in the above
(1) and triethylamine (1.11 mL, 8.00 mmol) were dissolved in
dimethyl sulfoxide (5 mL), and then sulfur trioxide-pyridine
complex (637 mg, 4.00 mmol) was added thereto in a water-bath. The
resulting reaction solution was stirred at room temperature for 10
minutes, diluted with ethyl acetate, and washed successively with
water (twice) and saturated brine. The organic layer was dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo to
obtain the above ketone derivative (444 mg) as a colorless oil.
##STR00405##
[1132] The ketone derivative (121 mg, 160 .mu.mol) obtained in the
above (2) was dissolved in tetrahydrofuran (3 mL), and to the
solution was added dropwise 1M tetrahydrofuran solution (750 .mu.L,
750 .mu.mol) containing lithium tri-t-buthoxy-aluminium hydride at
-65.degree. C. The resulting reaction solution was warmed up to
0.degree. C., and saturated aqueous Rochelle salt and ethyl acetate
were added thereto. The mixture was stirred at room temperature for
1 hour. This reaction solution was extracted with ethyl acetate,
and the extract was washed successively with water and saturated
brine, dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo to obtain the above trans-alcohol derivative
(122 mg) as a pale yellow oil.
##STR00406##
[1133] According to a method similar to the procedure of Reference
Example 4-(4), the objective compound [A-13] (659 mg) was obtained
as a colorless oil from the trans-alcohol derivative (518 mg, 2.12
mmol) obtained in the above (3).
Reference Example 14
Synthesis of the Compound of the Following Formula [A-14]
##STR00407##
[1135] To a stirred solution of (R)-(-)-ribose (5.00 g, 33.3 mmol)
in N,N-dimethylformamide (10 mL) were added imidazole (4.50 g, 66.6
mmol) and t-butyldiphenylsilyl chloride (9.07 mL, 34.8 mmol) at
0.degree. C. The reaction solution was stirred at room temperature
overnight. 1N aqueous potassium hydrogensulfate was added to the
resulting reaction solution, and the solution was stirred at room
temperature for 30 minutes, and then extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over
anhydrous magnesium sulfate, filtered, and the filtrate was
concentrated. Pyridine (30 mL) and acetic anhydide (10 mL) were
added to the resulting residue, and the mixture was stirred at room
temperature for 2 hours. To this reaction solution was added 1N
aqueous potassium hydrogensulfate, and the reaction solution was
extracted with ethylacetate. The organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate, filtered,
and the filtrate was concentrated. The resulting residue was
purified by a column chromatography on silica gel to obtain the
above protected derivative with TBDPS (12.3 g) as a pale yellow
solid.
##STR00408##
[1136] The protected derivative with TBDPS (11 g, 21.4 mmol)
obtained in the above (1) was dissolved in methylene chloride (60
mL), and the reaction system was substituted with carbon monoxide.
To this solution were added diethylmethylsilane (22 mL, 215 mmol)
and dicobalt octacarbonyl (1.0 g, 2.92 mmol), and the mixture was
stirred at room temperature overnight, after which time water was
added thereto. The reaction solution was extracted with ethyl
acetate, and the organic layer was washed with saturated brine,
dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo. The resulting residue was purified by a column
chromatography on silica gel to obtain the above alcohol derivative
(5.37 g) as a pale yellow solid.
##STR00409##
[1137] To a stirred solution of the alcohol derivative (1.00 g,
2.05 mmol) obtained in the above (2) in methylene chloride (10 mL)
were added triethylamine (860 .mu.L, 6.15 mmol),
4,4'-dimethoxytrityl (692 mg, 780 .mu.mol) and
4-dimethylaminopyridine (251 mg, 2.05 mmol) at 0.degree. C. The
reaction solution was stirred at room temperature for 2 hours.
Water was added to the resulting reaction solution, and the
solution was stirred at room temperature for 30 minutes, and then
extracted with ethyl acetate. The organic layer was washed with
saturated brine, dried over anhydrous sodium sulfate, filtered, and
the filtrate was concentrated. The resulting residue was purified
by a column chromatography on silica gel to obtain the above
tritylated derivative (765 mg) as a pale yellow solid.
##STR00410##
[1138] According to a method similar to the procedure of Reference
Example 4-(3), the above diol derivative (511 mg) was obtained as a
pale yellow solid from the tritylated derivative (711 mg, 2.05
mmol) obtained in the above (3)
##STR00411##
[1139] To a stirred tetrahydrofuran solution (10 mL) containing the
diol derivative (511 mg, 720 .mu.mol) obtained in the above (4) was
added 60% sodium hydride dispersion in oil (116 mg, 2.90 mmol) at
0.degree. C., and the mixture was stirred at room temperature for
30 minutes. After addition of carbon disulfide (230 .mu.L, 3.02
mmol), the reaction solution was stirred at room temperature for 5
minutes, and methyl iodide (170 .mu.L, 2.73 mmol) was added
thereto. The mixture was stirred at room temperature for 1 hour,
and 1N aqueous potassium hydrogensulfate was added. The reaction
solution was extracted with ethyl acetate. The organic layer was
washed with saturated brine, dried over anhydrous sodium sulfate,
filtered, and the filtrate was concentrated. The resulting residue
was purified by a column chromatography on silica gel to obtain the
above dithiocarbonate derivative (585 mg) as a pale yellow
solid.
##STR00412##
[1140] To a stirred toluene solution (10 mL) containing the
dithiocarbonate derivative (585 mg, 660 .mu.mol) obtained in the
above (5) were added tributyltin hydride (360 .mu.L, 1.23 mmol) and
2,2'-azobisisobutyronitrile (24 mg, 140 .mu.mol) under a nitrogen
atmosphere, and the mixture was stirred overnight under heating at
reflux. Water was added to the reaction solution, and it was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, dried over anhydrous sodium sulfate, filtered, and
the filtrate was concentrated. The resulting residue was purified
by a column chromatography on silica gel to obtain the above
intra-olefin derivative (367 mg) as a pale yellow solid.
##STR00413##
[1141] To methylene chloride solution (30 mL) containing the above
intra-olefin derivative (665 mg, 990 .mu.mol) obtained in the above
(6) was added gradually trichloroacetic acid (160 mg, 979 .mu.mol).
The reaction solution was stirred at room temperature for 2 hours.
Aqueous sodium hydrogencarbonate solution was added to the
resulting reaction solution, and the solution was extracted with
chloroform. The organic layer was washed with saturated brine,
dried over anhydrous sodium sulfate, filtered, and the filtrate was
concentrated. The resulting residue was purified by a column
chromatography on silica gel to obtain the above alcohol derivative
(213 mg) as a pale yellow solid.
##STR00414##
[1142] The alcohol derivative (1.40 g, 3.77 mmol) obtained in the
above (7) was dissolved in tetrahydrofuran (30 mL) and methanol (30
mL), and to the solution was added platinum oxide catalyst (700 mg)
under a nitrogen atmosphere. After substitution of the reaction
system with hydrogen gas, the mixture was stirred at room
temperature for 15 hours. The resulting reaction solution was
filtered through a Celite pad to remove the catalyst, and the
filtrate was concentrated in vacuo. The resulting residue was
purified by a column chromatography on silica gel to obtain the
above tetrahydrofuran derivative (1.28 g) as a colorless oil.
##STR00415##
[1143] According to a method similar to the procedure of Reference
Example 7-(1), the above benzoyl derivative (421 mg) was obtained
as a colorless oil from the tetrahydrofuran derivative (402 mg,
1.08 mmol) obtained in the above (8).
##STR00416##
[1144] According to a method similar to the procedure of Reference
Example 10-(2), the above alcohol derivative (402 mg) was obtained
as a pale yellow oil from the benzoyl derivative (421 mg, 887
.mu.mol) obtained in the above (9)
##STR00417##
[1145] The alcohol derivative (402 mg) obtained in the above (10)
was dissolved in diethyl ether (5 mL), and then
N,N-diisopropylethylamine (223 .mu.L, 1.28 mmol) and
methanesulfonyl chloride (82 .mu.L, 1.06 mmol) were added thereto
under ice-cooling. The mixture was stirred for 2 hours. After
diethyl ether was added to the resulting reaction solution, the
organic layer was washed successively with 1N hydrochloric acid,
water, and saturated brine, dried over anhydrous magnesium sulfate,
and filtered. The filtrate was concentrated, and the resulting
residue was dissolved in N,N-dimethylformamide (5 mL), and then
sodium azide (115 mg, 1.77 mmol) was added thereto. The reaction
solution was stirred at 80.degree. C. for 12 hours, and cooled down
to room temperature. After addition of ethyl acetate to this
reaction solution, the organic layer was washed successively with
water and saturated brine, dried over anhydrous magnesium sulfate,
and filtered. The filtrate was concentrated, and the resulting
residue was dissolved in tetrahydrofuran (5 mL) and methanol (5
mL), and 10% palladium carbon catalyst (700 mg) was added thereto
under a nitrogen atmosphere. The atmosphere in the reaction system
was substituted with hydrogen gas, and the solution was stirred at
room temperature for 3 hours. The resulting solution was filtered
through a Celite pad to remove the catalyst, and the filtrate was
concentrated in vacuo. The resulting residue was purified by a
silica gel chromatography to obtain the objective compound [A-14]
(81 mg) as a colorless oil.
Reference Example 15
Synthesis of the Compound of the Following Formula [A-15]
##STR00418##
[1147]
Ethyl(3R,5S)-3-(t-butyldiphenylsilyloxy)tetrahydro-5-furanylacetate
(11.9 g, 29 mmol) prepared according to a method similar to the
method described in Tetrahedron Lett., 26(9) 1185 (1985) was
dissolved in ether (100 mL), and lithium aluminium hydride (660 mg,
1.7 mmol) was added thereto in an ice-bath. The reaction solution
was stirred at room temperature for 1 hour. Anhydrous sodium
sulfate decahydrate (3 g) was added thereto in an ice-bath, and the
mixture was stirred at room temperature for 2 hours. The reaction
solution was dried over anhydrous magnesium sulfate, and filtered
through a Celite pad to remove the insolubles. The filtrate was
concentrated in vacuo to obtain the above primary alcohol
derivative (9.52 g) as a colorless oil.
##STR00419##
[1148] According to a method similar to the procedure of Reference
Example 14-(11), the objective compound [A-15] (2.27 g) was
obtained as a colorless oil from the primary alcohol derivative
(2.50 g, 6.75 mmol) obtained in the above (1)
Reference Example 16
Synthesis of the Compound of the Following Formula [A-16]
##STR00420##
[1150] 4-Acetoxypiperidine hydrochloride (1.5 g, 8.6 mmol) prepared
by referring to EP122855 and t-butyl-N-(2-oxoethyl)carbamate (1.1
g, 6.9 mmol) were dissolved in methanol (20 mL). To the solution
was portionwise added sodium cyanotrihydroborate (641 mg, 10 mmol)
in an ice-water bath, and the mixture was stirred at room
temperature for 2 hours. The resulting reaction solution was
concentrated in vacuo, poured into aqueous sodium hydrogencarbonate
solution, and extracted with chloroform three times. The resulting
extract was dried over anhydrous sodium sulfate, and filtered. The
filtrate was concentrated in vacuo and the resulting residue was
purified by a column chromatography to obtain the above
N-alkylpiperidin derivative (850 mg) as a colorless oil.
##STR00421##
[1151] 4N hydrogen chloride/1,4-dioxane solution (5 mL) was added
to the N-alkylpiperidine derivative (850 mg, 3.0 mmol) obtained in
the above (1) at room temperature, and the mixture was stirred at
room temperature for 2 hours. The resulting reaction solution was
concentrated in vacuo to obtain the objective compound [A-16] (666
mg) as a white solid.
Reference Example 17
Synthesis of the Compound of the Following Formula [A-17]
##STR00422##
[1153] To a solution of (t-butyldimethylsilyloxy)acetaldehyde (5.00
g, 28.6 mmol) in chloroform (50 mL) was added the allyl carbazinate
derivative (5.00 g, 43.1 mmol) prepared by referring to JP
04117361, and the mixture was stirred at room temperature for 15
hours. After addition of saturated brine to the resulting reaction
solution, the organic layer was separated. The resulting organic
layer was dried over anhydrous magnesium sulfate, filtered, and the
filtrate was concentrated. To the resulting residue were added zinc
chloride (1.02 g, 75.0 mmol) and methanol solution (500 mL)
containing sodium cyanotrihydroborate (1.41 g, 150 mmol), and the
mixture was stirred at room temperature for 2 days. After hexane
and ethyl acetate were added to the resulting reaction solution, it
was filtered through a Celite pad, and the filtrate was washed with
water and saturated brine. The organic layer was dried over
anhydrous magnesium sulfate, filtered, and the filtrate was
concentrated. The resulting residue was purified by a
chromatography on silica gel to obtain the objective compound
[A-17] (5.03 g) as a colorless oil.
Reference Example 18
Synthesis of the Compound of the Following Formula [A-18]
##STR00423##
[1155] According to a method similar to the procedure of Reference
Example 13-(2), the above aldehyde derivative (1.51 g) was obtained
as a colorless oil from the de-TBDPS derivative (1.56 g, 7.0 mmol)
obtained in Reference Example 10-(2).
##STR00424##
[1156] According to a method similar to the procedure of Reference
Example 17, the objective compound [A-18] (1.33 g) was obtained as
a colorless oil from the aldehyde derivative (1.51 g, 6.9 mmol)
obtained in the above (1).
Reference Example 19
Synthesis of the Compound of the Following Formula [A-19]
##STR00425##
[1158] According to a method similar to the method as Reference
Examples 8-(1) and 10-(1) to 10-(2), the above primary alcohol
derivative was obtained from (R)-hexane-1,5-diol which is a
starting material of Reference Example 11
##STR00426##
[1159] According to a method similar to the procedure as Reference
Example 18, the objective compound [A-19] was obtained from the
primary alcohol derivative obtained in the above (1)
Reference Example 20
Synthesis of the Compound of the Following Formula [A-20]
##STR00427##
[1161] According to a method similar to the procedure of Reference
Example 17, the objective compound [A-20] (335 mg) was obtained as
a colorless oil from 5-t-butyldiphenylsilyloxy-1-pentanal (500 mg,
1.47 mmol) synthesized by referring to the method described in J.
Org. Chem., 59(2), 324 (1994) and t-butyl carbazinate (194 mg, 1.47
mmol)
Reference Example 21
Synthesis of the Compound of the Following Formula [A-21]
##STR00428##
[1163] According to a method similar to the procedure of Reference
Example 17, the objective compound [A-21] (7.40 g) was obtained as
a colorless oil from the ketone derivative (10.8 g, 30.4 mmol)
synthesized by referring to the method described in Tetrahedron
Lett., 56(8) 1065 (2000).
Reference Example 22
Synthesis of the Compound of the Following Formula [A-22]
##STR00429##
[1165] Racemic 3-hydroxypiperidine hydrochloride (662 mg, 4.81
mmol) was dissolved in a mixed solution of water (2 mL) and
1,4-dioxane (4 mL), and to this solution was added 4N aqueous
sodium hydroxide (3 mL). To this solution was added di-t-butyl
dicarbonate (1.11 mL, 4.81 mmol). After the solution was stirred at
room temperature for 7 hours, ethyl acetate was added to the
resulting reaction solution for extraction. The organic layer was
washed successively with water and saturated brine, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo to
obtain the above protected derivative with Boc (968 mg) as a
colorless oil.
[1166] The resulting protected derivative with Boc (968 mg, 4.81
mmol) was dissolved in N,N-dimethylformamide (5 mL), and then
methyl iodide (449 .mu.L, 7.22 mmol) was added thereto. After
addition of sodium hydride (231 mg, 60% dispersion in oil, 5.77
mmol) under ice-cooling, the mixture was stirred for 5 minutes at
the same temperature. The resulting reaction solution was warmed up
to room temperature, and stirred for further 10 hours. After
saturated aqueous ammonium chloride solution was added to this
solution, it was extracted with a mixed solvent of hexane and ethyl
acetate. The organic layer was washed with water and saturated
brine, dried over anhydrous magnesium sulfate, and filtered. The
filtrate was concentrated in vacuo, and azeotropic evaporation was
carried out using toluene. The residue was purified by a column
chromatography on silica gel to obtain the above methyl ether
derivative (885 mg) as a colorless liquid.
[1167] The resulting methyl ether derivative (885 mg) was dissolved
in chloroform (5 mL), and to this solution was added 4N hydrogen
chloride/1,4-dioxane solution (5 mL). The solution was stirred at
room temperature for 2 hours, and the resulting reaction solution
was concentrated in vacuo to obtain the racemic objective compound
[A-22] (596 mg) as a white solid.
Reference Example 23
Synthesis of the Compound of the Following Formula [A-23]
##STR00430##
[1169] According to a method similar to the procedure of Reference
Example 22, the objective compound [A-23] was obtained from
(R)-3-hydroxypiperidine hydrochloride.
Reference Example 24
Synthesis of the Compound of the Following Formula [A-24]
##STR00431##
[1171] According to a method similar to the procedure as Reference
Example 22, the objective compound [A-24] was obtained from
(S)-3-hydroxypiperidine synthesized according to the method
described in Tetrahedron Lett., 51(21) 5935 (1995).
Reference Example 25
Synthesis of the Compound of the Following Formula [A-25]
##STR00432##
[1173] According to a method similar to the procedure of Reference
Example 22, the racemic objective compound [A-25] (352 mg) was
obtained as a white solid from racemic 3-hydroxymethylpiperidine
(569 mg, 4.94 mmol).
Reference Example 26
Synthesis of the Compound of the Following Formula [A-26]
##STR00433##
[1175] According to a method similar to the procedure of Reference
Example 22, the racemic objective compound [A-26] (899 mg) was
obtained as a white solid from racemic 2-hydroxymethylpiperidine
(857 mg, 7.44 mmol).
Reference Example 27
Synthesis of the Compound of the Following Formula [A-27]
##STR00434##
[1177] According to a method similar to the procedure as Reference
Example 22, the objective compound [A-27] was obtained from
(R)-2-hydroxymethylpiperidine synthesized according to the method:
described in Heterocycles, 41(9) 1931 (1995).
Reference Example 28
Synthesis of the Compound of the Following Formula [A-28]
##STR00435##
[1179] According to a method similar to the procedure as Reference
Example 22, the objective compound [A-28] was obtained from
(S)-2-hydroxymethylpiperidine synthesized according to the method
described in Heterocycles, 41(9) 1931 (1995),
Reference Example 29
Synthesis of the Compound of the Following Formula [A-29]
##STR00436##
[1181] According to a method similar to the procedure of Reference
Example 22, the objective compound [A-29] (222 mg) was obtained as
a milky yellow solid from 4-hydroxypiperidine (251 mg, 2.48
mmol).
Reference Example 30
Synthesis of the Compound of the Following Formula [A-30]
##STR00437##
[1183] To a solution of 5-hydroxypentanal oxime (300 mg, 2.56 mmol)
in methanol (10 mL) was added sodium cyanotrihydroborate (193 mg,
3.07 mmol), and then a mixture of conc. hydrochloric acid and
methanol was added dropwise so as to adjust the pH to 3. The
mixture was stirred for 30 minutes. After this solution was
neutralized using aqueous sodium hydroxide, it was concentrated.
The resulting residue was purified by a column chromatography on
silica gel to obtain the above hydroxylamine derivative (299 mg) as
a colorless oil.
##STR00438##
[1184] According to a method similar to the procedure of Reference
Example 1-(1), the objective compound [A-30] (481 mg) was obtained
as a pale yellow oil from the hydroxylamine derivative (235 mg,
1.97 mmol) obtained in the above (1).
Reference Example 31
Synthesis of the Compound of the Following Formula [A-31]
##STR00439##
[1186] To a solution of t-butyl carbazinate (350 mg, 2.65 mmol) in
pyridine (5 mL) was added 4-nitrobenzenesulfonyl chloride (590 mg,
2.65 mmol) in an ice-bath, and the mixture was stirred at room
temperature for 1 hour. After the resulting reaction solution was
diluted with chloroform, it was washed successively with 1N
hydrochloric acid and saturated brine. The organic layer was dried
over anhydrous magnesium sulfate, filtered, and concentrated in
vacuo to obtain the above sulfone hydrazide derivative (910 mg) as
a white solid.
##STR00440##
[1187] According to a method similar to the procedure of Reference
Example 17, the above amine derivative (599 mg) was obtained from
(t-butyldimethylsilyloxy)acetaldehyde (500 .mu.L) and
N-methyl-2-aminoethanol (200 .mu.L)
##STR00441##
[1188] According to a method similar to the procedure of Reference
Example 4-(2), the above N-alkylsulfone hydrazide derivative (1.35
g) was obtained as a pale yellow solid from the sulfone hydrazide
derivative (815 mg, 2.57 mmol) obtained in the above (1) and the
amine derivative (599 mg, 2.57 mmol) obtained in the above (2)
##STR00442##
[1189] According to a method similar to the method described in
Journal of Synthetic Organic Chemistry, Japan 59(8) 779 (2001),
deprotection of the 4-nitrobenzenesulfonyl group was carried out to
obtain the objective compound [A-31] (576 mg) as a colorless oil
from the N-alkylsulfone hydrazide derivative (1.35 g) obtained in
the above (3)
Reference Example 32
Synthesis of the Compound of the Following Formula [A-32]
##STR00443##
[1191] In the structure, the stereo chemistry of the position with
the symbol * is of cis-configuration.
##STR00444##
[1192] To a solution of racemic 2-azabicyclo[2,2,1]hept-5-ene-3-one
(1.12 g, 10.2 mmol) in ethanol (20 mL) was added 10% palladium
carbon (250 mg), and atmosphere in the reaction system was
substituted with hydrogen gas. The mixture was stirred at room
temperature for 3 hours under normal pressure. The resulting
reaction solution was filtered through a Celite pad, and the
filtrate was concentrated to obtain the above racemic reduced
derivative (1.14 g) as a colorless oil.
##STR00445##
[1193] The racemic reduced derivative (1.85 g, 16.6 mmol) obtained
in the above (1) was dissolved in methylene chloride (30 mL), and
then di-t-butyl dicarbonate (3.63 g, 16.6 mmol), triethylamine
(6.00 mL, 43.1 mmol) and 4-dimethylaminopyridine (3.23 g, 26.4
mmol) were added to the solution at 0.degree. C. with stirring, and
the mixture was stirred overnight at room temperature. 1N potassium
hydrogensulfate solution was added to the resulting reaction
solution, and it was extracted with ethyl acetate. The organic
layer was washed with saturated brine, dried over anhydrous sodium
sulfate, and filtered. The filtrate was concentrated in vacuo to
obtain the above racemic protected derivative with Boc (2.24 g) as
a colorless solid.
##STR00446##
[1194] The racemic protected derivative with Boc (1.00 g, 4.73
mmol) obtained in the above (2) was dissolved in methanol (20 mL),
and to this solution was added potassium carbonate (654 mg, 4.73
mmol) at 0.degree. C. with stirring. The solution was stirred at
room temperature for 1 hour. Water was added the resulting reaction
solution, and it was extracted with ethyl acetate. The organic
layer was washed with saturated brine, dried over anhydrous sodium
sulfate, filtered, and the filtrate was concentrated in vacuo to
obtain the above racemic ester derivative (1.00 g) as a colorless
solid.
##STR00447##
[1195] According to a method similar to the procedure of Reference
Example 12-(2), the racemic alcohol derivative (884 mg) was
obtained as a colorless solid from the racemic ester derivative
(1.00 g, 4.11 mmol) prepared in the above (3)
##STR00448##
[1196] According to a method similar to the procedure of Reference
Example 16-(2), the racemic objective derivative [A-32] (151 mg)
was obtained as a yellow oil from the racemic alcohol derivative
(215 mg, 1.00 mmol) obtained in the above (4).
Reference Example 33
Synthesis of the Compound of the Following Formula [A-33]
##STR00449##
[1198] (2R,4R)-1-(buthoxycarbonyl)-4-hydroxy-2-methylpyrrolidine
(861 mg) prepared by referring to the method described in
Tetrahedron Lett., 54, 10029 (1988) was dissolved in 4N hydrogen
chloride/1,4-dioxane solution (3 mL), and the solution was stirred
at room temperature for 19 hours. The reaction solution was
concentrated, filtered, washed with diethyl ether, and dried to
obtain a white solid (338 mg). 0.5M methanol solution (5.4 mL)
containing sodium methoxide was added to this white solid, and the
mixture was stirred for 1 hour. The resulting reaction solution was
filtered, and the mother liquor was concentrated to give a residue,
to which was added chloroform (2 mL). The mixture was stirred for
30 minutes, and the resulting suspension was filtered. The mother
liquor was concentrated, and distilled to obtain the objective
compound [A-33] (205 mg) as a colorless clear oil.
Reference Example 34
Synthesis of the Compound of the Following Formula [A-34]
##STR00450##
[1200] According to a method similar to the procedure of Reference
Example 31-(1), the above sulfone hydrazide derivative (3.22 g) was
obtained as a white solid from the allyl carbazinate derivative
(2.00 g, 17.2 mmol) synthesized by referring to the method
described in JP 04117361.
##STR00451##
[1201] According to a method similar to the procedure of Reference
Example 4-(1), the above N-alkylsulfone hydrazide derivative (1.08
g) was obtained as a colorless oil from
(S)-1-(t-butyldimethylsiloxy)-2-propanol (678 mg, 3.56 mmol)
synthesized by referring to the method described in J. Org. Chem.,
53(10) 2300 (1988).
##STR00452##
[1202] Deprotection of the 4-nitrobenzenesulfonyl group of the
N-alkylsulfone hydrazide derivative (1.08 g) obtained in the above
(2) was carried out according to a method similar to the method
described in Journal of Synthetic Organic Chemistry, Japan 59(8)
779 (2001), to obtain the objective compound [A-34] (304 mg) as a
colorless oil.
INDUSTRIAL APPLICABILITY
[1203] As described above, the compounds of the present invention
have strong Cdk inhibitory activity. Since the compounds of the
present invention also show strong inhibitory activity of BrdU
uptake, they have clearly inhibitory activity of cell growth.
Therefore, the compounds of the present invention are useful as an
anti-cancer agent (agent for the treatment of cancers). That is, it
is considered that anti-cancer agents containing a new
quinoxalinone derivative or a salt or ester thereof of the present
invention are useful for the treatment of cancer patients.
* * * * *