U.S. patent application number 13/180011 was filed with the patent office on 2011-11-03 for triazole derivative.
This patent application is currently assigned to TAISHO PHARMACEUTICAL CO., LTD.. Invention is credited to Hironori Katakai, Naoya ONO, Tomomi Ota, Masakazu Sato, Fumiyasu Shiozawa, Tetsuo Takayama, Tetsuya Yabuuchi, Makoto Yagi.
Application Number | 20110269960 13/180011 |
Document ID | / |
Family ID | 38327575 |
Filed Date | 2011-11-03 |
United States Patent
Application |
20110269960 |
Kind Code |
A1 |
ONO; Naoya ; et al. |
November 3, 2011 |
TRIAZOLE DERIVATIVE
Abstract
An object of the present invention is to provide a compound
having an action of inhibiting binding between S1P and its
receptor, Edg-1 (S1P.sub.1), and is useful as a pharmaceutical
compound. A compound or a pharmaceutically acceptable salt thereof,
which compound is represented by the formula below ##STR00001##
(where A represents an oxygen atom, a sulfur atom, a group
represented by Formula --SO--, a group represented by Formula
--SO.sub.2--, or the like, R.sup.1 represents a hydrogen atom, an
alkyl group having 1-6 carbon atoms, or the like, R.sup.1A
represents a hydrogen atom or the like, R.sup.2 represents an alkyl
group having 1-6 carbon atoms, a cycloalkyl group having 3-6 carbon
atoms, or the like, R.sup.3 represents an aryl group, R.sup.4
represents a hydrogen atom or an alkyl group having 1-6 carbon
atoms and optionally substituted with a carboxyl group, and R.sup.5
represents an alkyl group having 1-10 carbon atoms, a cycloalkyl
group having 3-8 carbon atoms, an aryl group which is optionally
substituted, or the like).
Inventors: |
ONO; Naoya; (Tokyo, JP)
; Takayama; Tetsuo; (Tokyo, JP) ; Shiozawa;
Fumiyasu; (Tokyo, JP) ; Katakai; Hironori;
(Tokyo, JP) ; Yabuuchi; Tetsuya; (Tokyo, JP)
; Ota; Tomomi; (Tokyo, JP) ; Yagi; Makoto;
(Tokyo, JP) ; Sato; Masakazu; (Tokyo, JP) |
Assignee: |
TAISHO PHARMACEUTICAL CO.,
LTD.
Tokyo
JP
|
Family ID: |
38327575 |
Appl. No.: |
13/180011 |
Filed: |
July 11, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12278054 |
Aug 1, 2008 |
8022091 |
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PCT/JP2007/051951 |
Feb 5, 2007 |
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13180011 |
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Current U.S.
Class: |
544/131 ;
544/132; 544/281; 544/310; 544/316; 544/366; 546/146; 546/148;
546/158; 546/172; 546/19; 546/210; 546/272.4; 548/126; 548/127;
548/178; 548/185; 548/186; 548/235; 548/243; 548/247; 548/264.2;
548/264.8; 548/267.2 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 1/04 20180101; A61P 37/06 20180101; A61P 9/10 20180101; A61P
43/00 20180101; A61P 17/00 20180101; A61P 19/02 20180101; A61P
37/08 20180101; A61P 27/02 20180101; A61P 17/06 20180101; C07D
249/08 20130101; A61P 35/00 20180101; A61P 29/00 20180101; A61P
37/00 20180101; A61P 9/00 20180101; A61P 9/06 20180101; A61P 37/02
20180101; A61P 25/00 20180101 |
Class at
Publication: |
544/131 ;
544/132; 544/281; 544/310; 544/316; 544/366; 546/19; 546/146;
546/148; 546/158; 546/172; 546/210; 546/272.4; 548/126; 548/127;
548/178; 548/185; 548/186; 548/235; 548/243; 548/247; 548/264.2;
548/264.8; 548/267.2 |
International
Class: |
C07D 249/12 20060101
C07D249/12; C07D 413/12 20060101 C07D413/12; C07D 487/04 20060101
C07D487/04; C07D 491/113 20060101 C07D491/113; C07D 401/12 20060101
C07D401/12; C07D 417/14 20060101 C07D417/14; C07D 249/08 20060101
C07D249/08; C07D 403/12 20060101 C07D403/12; C07D 409/12 20060101
C07D409/12; C07D 405/12 20060101 C07D405/12; C07D 409/14 20060101
C07D409/14; C07D 403/14 20060101 C07D403/14; C07D 401/14 20060101
C07D401/14; C07D 405/14 20060101 C07D405/14; C07D 413/14 20060101
C07D413/14 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 3, 2006 |
JP |
2006/027799 |
Claims
1. A compound represented by Formula (I) ##STR00897## or a
pharmaceutically acceptable salt thereof, wherein A represents: an
oxygen atom, R.sup.1 represents: a hydrogen atom, an alkyl group
having from 1 to 6 carbon atoms and optionally substituted with a
substituent(s) selected from the group consisting of: a hydroxyl
group, a halogen atom, an alkoxy group having from 1 to 6 carbon
atoms, said alkoxy group optionally substituted with a phenyl
group, and a phenyl group, optionally substituted with a
substituent(s) selected from the group consisting of a halogen atom
and an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl
group having from 3 to 8 carbon atoms, an alkenyl group having from
2 to 8 carbon atoms, an alkynyl group having from 2 to 8 carbon
atoms, or a phenyl group; R.sup.1A represents: a hydrogen atom or
an alkyl group having from 1 to 6 carbon atoms; R.sup.1 and
R.sup.1A optionally form, together with a carbon atom to which said
R.sup.1 and R.sup.1A are attached, a cycloalkyl group having from 3
to 6 carbon atoms; R.sup.2 represents: a hydrogen atom, an alkyl
group having from 1 to 6 carbon atoms, an alkenyl group having from
2 to 8 carbon atoms, an alkynyl group having from 2 to 8 carbon
atoms, or a cycloalkyl group having from 3 to 6 carbon atoms;
R.sup.3 represents: a 2-naphthyl group, optionally substituted with
a substituent(s) selected from the group consisting of a halogen
atom and an alkyl group having from 1 to 6 carbon atoms, a
3-pyrazolyl group, optionally substituted with a substituent(s)
selected from the group consisting of an alkyl group having from 1
to 6 carbon atoms, a trifluoromethyl group, and a halogen atom, or
a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a
7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a
7-quinolinyl group, a 3-pyridyl group, or an indolyl group, each
optionally substituted with an alkyl group(s) having from 1 to 6
carbon atoms, an unsubstituted phenyl group, or a substituted
phenyl group (A) or (B) below: (A) a phenyl group substituted at 4
position with a substituent selected from the group consisting of:
an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group
having from 3 to 8 carbon atoms, an alkoxy group having from 1 to 6
carbon atoms, said alkoxy group optionally substituted with a
substituent(s) selected from the group consisting of an amino group
substituted with two alkyl groups each having from 1 to 4 carbon
atoms, a morpholino group, and a phenyl group, a halogen atom, a
trifluoromethoxy group, a phenoxy group, a phenyl group, a
1-pyrrolyl group, and --NR.sup.AR.sup.B, wherein each of R.sup.A
and R.sup.3 is an alkyl group having from 1 to 6 carbon atoms, or
R.sup.A and R.sup.B optionally form, together with the nitrogen
atom to which said R.sup.A and R.sup.B are attached, a 3- to
5-membered saturated hydrocarbon ring, wherein said phenyl group
substituted at 4 position is further optionally substituted at 3
position with a substituent selected from the group consisting of
an alkyl group having from 1 to 6 carbon atoms, a halogen atom, and
an alkoxy group having from 1 to 6 carbon atoms; and (B) a phenyl
group substituted at 3 position with a substituent selected from
the group consisting of: a hydroxyl group, an alkyl group having
from 1 to 6 carbon atoms, and an alkoxy group having from 1 to 6
carbon atoms, said alkoxy group optionally substituted with a
substituent(s) selected from the group consisting of an amino group
substituted with two alkyl groups each having from 1 to 4 carbon
atoms, a morpholino group, and a phenyl group, wherein said phenyl
group substituted at 3 position is further optionally substituted
with one or two alkyl groups each having from 1 to 6 carbon atoms,
or is further optionally substituted at 4 position with a halogen
atom; R.sup.4 represents: a hydrogen atom or an alkyl group having
from 1 to 6 carbon atoms and optionally substituted with a carboxyl
group; R.sup.5 represents: (i) an alkyl group having from 1 to 10
carbon atoms, (ii) an alkyl group having from 1 to 10 carbon atoms
and substituted with 1 to 2 substituents selected from the group
consisting of: a cycloalkyl group having from 3 to 8 carbon atoms,
a pyridyl group, and a phenyl group, a phenoxy group, and a
naphthyl group, each optionally substituted with 1 to 2
substituents selected from the group consisting of a halogen atom
and an alkoxy group having from 1 to 6 carbon atoms, (iii) a
cycloalkyl group having from 3 to 8 carbon atoms, (iv) an alkenyl
group having from 2 to 8 carbon atoms, (v) an alkenyl group having
from 2 to 8 carbon atoms and substituted with a phenyl group, (vi)
an alkynyl group having from 2 to 8 carbon atoms, (vii) an alkynyl
group having from 2 to 8 carbon atoms and substituted with a phenyl
group, or (viii) an optionally substituted aryl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein, in Formula (I): R.sup.1 represents: a hydrogen
atom, an alkyl group having from 1 to 6 carbon atoms, an alkyl
group having from 1 to 6 carbon atoms and substituted with a phenyl
group, a cycloalkyl group having from 3 to 8 carbon atoms, an
alkenyl group having from 2 to 8 carbon atoms, an alkynyl group
having from 2 to 8 carbon atoms, or a phenyl group; R.sup.1A
represents a hydrogen atom; R.sup.2 represents: an alkyl group
having from 1 to 6 carbon atoms, an alkenyl group having from 2 to
8 carbon atoms, an alkynyl group having from 2 to 8 carbon atoms,
or a cycloalkyl group having from 3 to 6 carbon atoms; R.sup.4
represents: a hydrogen atom, or an alkyl group having from 1 to 6
carbon atoms; R.sup.5 represents: (i) an alkyl group having from 1
to 10 carbon atoms, (ii) an alkyl group having from 1 to 10 carbon
atoms and substituted with 1 to 2 substituents selected from the
group consisting of: a cycloalkyl group having from 3 to 8 carbon
atoms, a phenyl group, a naphthyl group, a pyridyl group, and a
phenyl group substituted with 1 to 2 substituents selected from the
group consisting of a halogen atom and an alkoxy group having from
1 to 6 carbon atoms, (iii) a cycloalkyl group having from 3 to 8
carbon atoms, (iv) an alkenyl group having from 2 to 8 carbon
atoms, (v) an alkenyl group having from 2 to 8 carbon atoms and
substituted with a phenyl group, (vi) an alkynyl group having from
2 to 8 carbon atoms, (vii) an alkynyl group having from 2 to 8
carbon atoms and substituted with a phenyl group, or (viii) an
optionally substituted aryl group.
3. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein: R.sup.1 represents an alkyl group having from 1
to 6 carbon atoms and optionally substituted with a substituent(s)
selected from the group consisting of: a hydroxyl group, a halogen
atom, an alkoxy group having from 1 to 6 carbon atoms, said alkoxy
group optionally substituted with a phenyl group; and a phenyl
group, optionally substituted with a substituent(s) selected from
the group consisting of a halogen atom and an alkyl group having
from 1 to 6 carbon atoms; R.sup.1A represents: a hydrogen atom; or
an alkyl group having from 1 to 6 carbon atoms; and R.sup.1 and
R.sup.1A optionally form, together with a carbon atom to which said
R.sup.1 and R.sup.1A are attached, a cycloalkyl group having from 3
to 6 carbon atoms.
4. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein: R.sup.1 is: an alkyl group having from 1 to 6
carbon atoms and optionally substituted with a halogen atom(s), or
a benzyl group optionally substituted with a substituent(s)
selected from the group consisting of a halogen atom and an alkyl
group having from 1 to 6 carbon atoms; and R.sup.1A is a hydrogen
atom.
5. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is a methyl group or an ethyl group, and
R.sup.1A is a hydrogen atom.
6. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is a hydrogen atom.
7. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is an alkyl group having from 1 to 6
carbon atoms, or a cycloalkyl group having from 3 to 6 carbon
atoms.
8. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is an ethyl group or a cyclopropyl
group.
9. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is: (i) an alkyl group having from 1 to 10
carbon atoms, (ii) an alkyl group having from 1 to 10 carbon atoms
and substituted with 1 to 2 substituents selected from the group
consisting of: a cycloalkyl group having from 3 to 8 carbon atoms,
a pyridyl group, and a phenyl group, a phenoxy group, and a
naphthyl group, each optionally substituted with 1 to 2
substituents selected from the group consisting of a halogen atom
and an alkoxy group having from 1 to 6 carbon atoms; (iii) an
alkenyl group having from 2 to 8 carbon atoms and optionally
substituted with a phenyl group, or (iv) a phenyl group, a naphthyl
group, a thienyl group, a pyrrolyl group, a pyrazolyl group, a
pyridyl group, a furanyl group, a benzothienyl group, an
isoquinolinyl, an isoxazolyl group, a thiazolyl group, a
benzothiadiazolyl group, a benzoxadiazolyl group, a
dihydrobenzodioxepinyl group, a dihydrobenzodioxynyl group, a
benzodioxolyl group, a dihydrobenzofuranyl group, an indanyl group,
an uracil group, a coumaryl group, a chromanyl group, a
dihydroindolyl group, a tetrahydronaphthyl group, or a
tetrahydroisoquinolinyl group, each optionally substituted with 1
to 5 substituents selected from the group consisting of: an alkyl
group having from 1 to 6 carbon atoms and optionally substituted
with a fluorine atom(s), an alkenyl group having from 2 to 8 carbon
atoms, a halogen atom, an alkoxy group having from 1 to 6 carbon
atoms and optionally substituted with a fluorine atom(s), a
pyrazolyl group, an oxazolyl group, an isoxazolyl group, a
thiadiazolyl group, and a pyrimidinyl group, each optionally
substituted with a substituent(s) selected from Group X consisting
of a methyl group, a trifluoromethyl group, a halogen atom, and a
methylsulfanyl group, an alkylthio group having from 1 to 6 carbon
atoms, an alkylsulfonyl group having from 1 to 6 carbon atoms, a
benzenesulfonyl group, a morpholinosulfonyl group, a
morpholinocarbonylamino group, an aminosulfonyl group, an
alkoxycarbonyl group having from 2 to 10 carbon atoms, a morpholino
group optionally substituted with an alkyl group(s) having from 1
to 6 carbon atoms a phenyl group optionally substituted with an
alkoxy group(s) having from 1 to 6 carbon atoms, a phenoxy group, a
pyridinecarbonyl group, a pyridineoxy group, a cyano group, an
alkanoyl group having from 2 to 7 carbon atoms and optionally
substituted with a fluorine atom(s), and an alkanoylamino group
having from 2 to 7 carbon atoms.
10. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is: an alkyl group having from 1 to 10
carbon atoms and substituted with a cycloalkyl group having from 3
to 8 carbon atoms, an alkyl group having from 1 to 10 carbon atoms
and substituted with a naphthyl group, an alkenyl group having from
2 to 8 carbon atoms and substituted with a phenyl group, a phenyl
group or a naphthyl group, each optionally substituted with 1 to 5
substituents selected from the group consisting of: an alkyl group
having from 1 to 6 carbon atoms; a halogen atom, an alkoxy group
having from 1 to 6 carbon atoms; a trifluoromethoxy group, a
difluoromethoxy group, a trifluoromethyl group, an alkenyl group
having from 1 to 6 carbon atoms, an alkylsulfonyl group having from
1 to 6 carbon atoms, an alkanoyl group having from 2 to 7 carbon
atoms, an alkoxycarbonyl group having from 2 to 7 carbon atoms, and
a cyano group, a pyrrolyl group optionally substituted with a
substituent(s) selected from the group consisting of an alkyl group
having from 1 to 6 carbon atoms and a methoxycarbonyl group; a
furanyl group optionally substituted with a substituent(s) selected
from the group consisting of an alkyl group having from 1 to 6
carbon atoms, a trifluoromethyl group, and a halogen atom; a
thienyl group optionally substituted with a substituent (s)
selected from the group consisting of an alkyl group having from 1
to 6 carbon atoms, a trifluoromethyl group, a thiadiazolyl group,
an oxazolyl group, and a halogen atom; or a benzothienyl group, a
dihydrobenzodioxepinyl group, a benzodioxolyl group, a
dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a
tetrahydronaphthyl group, an indanyl group, a thiadiazolyl group, a
benzoxadiazolyl group, or a benzothiadiazolyl group, each
optionally substituted with a substituent(s) selected from the
group consisting of an alkyl group having from 1 to 6 carbon atoms
and a halogen atom.
11. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is: an alkyl group having from 1 to 6
carbon atoms and substituted with a naphthyl group, an alkenyl
group having from 2 to 6 carbon atoms and substituted with a phenyl
group; an unsubstituted phenyl group, a phenyl group substituted
with 1 to 5 substituents selected from the group consisting of a
methyl group, a methoxy group, and a halogen atom, a phenyl group
substituted with 1 to 3 substituents selected from the group
consisting of an alkyl group having from 1 to 6 carbon atoms, a
halogen atom, a methoxy group, a trifluoromethoxy group, a
difluoromethoxy group, a trifluoromethyl group, an alkenyl group
having from 1 to 6 carbon atoms, a methylsulfonyl group, an acetyl
group, a methoxycarbonyl group, and a cyano group, said phenyl
group substituted at either 3 or 4 position or both; a naphthyl
group optionally substituted with a substituent(s) selected from
the group consisting of: a halogen atom, an alkyl group having from
1 to 6 carbon atoms, a cyano group, and an alkylsulfonyl group
having from 1 to 6 carbon atoms, or a benzothienyl group, a
benzoxadiazolyl group, a benzodioxolyl group, a
dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, an indanyl
group, or a benzothiadiazolyl group, each optionally substituted
with a substituent(s) selected from the group consisting of an
alkyl group having from 1 to 6 carbon atoms and a halogen atom.
12. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is: a phenyl group substituted at 3 and 4
positions each with a halogen atom, or a naphthyl group optionally
substituted with a substituent(s) selected from the group
consisting of a halogen atom, an alkyl group having from 1 to 6
carbon atoms, and a cyano group.
13. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is a phenyl group substituted at 4
position with a fluorine atom or a chlorine atom.
14. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is a 6-indolyl group.
15. A pharmaceutical preparation, comprising the compound of claim
1 or a pharmaceutically acceptable salt thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional application of U.S. application Ser.
No. 12/278,054 filed Aug. 1, 2008, which is a National Stage of
International Application No. PCT/JP2007/051951 filed Feb. 5, 2007,
which claims priority to Japanese Application No. 2006/027799,
filed Feb. 3, 2006. The contents of all of the prior applications
are incorporated herein by reference in their entirety.
TECHNICAL FIELD
[0002] The present invention relates to novel triazole derivatives
which have an inhibitory effect on the binding between
sphingosine-1-phosphate having various physiological actions and
its receptor Edg-1 (Endothelial differentiation gene receptor
type-1, S1P1). The present invention also relates to pharmaceutical
preparations comprising these compounds as active ingredients, and
synthetic intermediates for these compounds.
BACKGROUND ART
[0003] Sphingosine-1-phosphate (hereinafter referred to as "SIP")
is a physiologically active lipid which is generated when
sphingolipids (typified by sphingomyelin) are metabolized in cells.
SIP is known to have a wide variety of actions such as cell
differentiation induction, cell growth stimulation, cell motility
inhibition and apoptosis inhibition, and is also known to show
physiological actions such as angiogenesis, bradycardia induction,
inflammatory cell activation and platelet activation (Non-patent
Document 1).
[0004] As SIP receptors, the following 5 subtypes have been
reported: Edg-1(S1P1), Edg-3(S1P3), Edg-5(S1P2), Edg-6(S1P4) and
Edg-8(S1P5) (Non-patent Document 2).
[0005] Among these subtypes, Edg-1(S1P1) is highly expressed in
immunocytes (e.g., T cells, dendritic cells) and vascular
endothelial cells, suggesting that Edg-1 (S1P1) contributes deeply
to SIP-stimulated T cell migration (Non-patent Document 3), mast
cell migration (Non-patent Document 4), T and B cell egress from
lymphoid organs (Non-patent Document 5) and angiogenesis
(Non-patent Document 6), and is involved in autoimmune diseases
such as Crohn's disease, irritable colitis, Sjogren's syndrome,
multiple sclerosis and systemic lupus erythematosus, as well as
other diseases such as rheumatoid arthritis, asthma, atopic
dermatitis, rejection after organ transplantation, cancer,
retinopathy, psoriasis, osteoarthritis, age-related macular
degeneration, etc.
[0006] Thus, ligands for Edg-1(S1P1) would be effective for
treatment or prevention of these diseases.
[0007] Edg-1(S1P1) ligands previously known include certain types
of thiophene derivatives (Non-patent Document 7), phosphoric acid
derivatives (Patent Documents 1 and 2, Nonpatent Documents 8 and 9)
and thiazolidine derivatives (Patent Document 3), carboxylic acid
derivatives (Patent Documents 4, 5, 6 and 8, Non-patent Documents
10 and 11), amino group-containing derivatives (Patent Document 7),
and pyrrole derivatives (Patent Document 9). [0008] Patent Document
1: WO2002-18395 [0009] Patent Document 2: JP 2003-137894 A [0010]
Patent Document 3: JP 2002-332278 A [0011] Patent Document 4:
WO2002-092068 [0012] Patent Document 5: WO2003-105771 [0013] Patent
Document 6: WO2004-058149 [0014] Patent Document 7: WO2004-103279
[0015] Patent Document 8: WO2005-058848 [0016] Patent Document 9:
WO2005-123677 [0017] Non-patent Document 1: J Biol Chem. 2004, 279:
20555, FASEB J 2002, 16: 625, Proceedings of the Japanese Society
for Immunology 2003, 33: 2-J-W30-20-P [0018] Non-patent Document 2:
Pharmacol Res 2003, 47: 401 [0019] Non-patent Document 3: FASEB J
2002, 16:1874 [0020] Non-patent Document 4: J Exp Med 2004, 199:
959 [0021] Non-patent Document 5: Nature 2004, 427: 355 [0022]
Non-patent Document 6: J Clin Invest 2000, 106: 951, Biocchim
Biophys Acta 2002, 1582: 222 [0023] Non-patent Document 7: J Biol
Chem 2004, 279: 13839 [0024] Non-patent Document 8: Bioorg Med Chem
Lett 2003, 13: 3401 [0025] Non-patent Document 9: J Med Chem. 2004,
47: 6662 [0026] Non-patent Document 10: J Med Chem. 2005, 48: 6169
[0027] Non-patent Document 11: J Biol Chem. 2005; 280: 9833
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
[0028] The present invention has as an object to provide a compound
with a new skeletal structure, which compound has an action of
inhibiting binding between S1P and its receptor Edg-1 (S1P.sub.1)
and is useful as a pharmaceutical product.
Means for Solving the Problems
[0029] The inventors of the present invention have diligently
studied in an attempt to find ligand compounds for Edg-1
(S1P.sub.1). As a result, they find that the object is attained
with a triazole derivative of Formula (I) below or a
pharmaceutically acceptable salt thereof (a feature is that R.sup.3
in the formula is an optionally substituted aryl group). This
finding has led to the accomplishment of the present invention. The
triazole derivative of Formula (I) below with this feature is a
completely new compound. Although compounds having an alkyl group
corresponding to R.sup.3 of Formula (I) are commercially available
from Bionet as reagents, they differ in structure from that of the
compound of the subject application, and pharmaceutical use of the
compounds of Bionet has not been known at all.
[0030] The following are embodiments of the triazole derivatives of
Formula (I) and compounds of Formula (II), which are intermediates
of the triazole derivatives (hereinafter, all of them will be
referred to as "compounds of the present invention").
1. A compound represented by Formula (I)
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein A
represents: [0031] an oxygen atom, [0032] a sulfur atom, [0033] a
group represented by Formula --SO--, [0034] a group represented by
Formula --SO.sub.2--, [0035] a group represented by Formula
--CH.sub.2--, or [0036] a group represented by Formula
--NR.sup.6--, wherein R.sup.6 represents a hydrogen atom or an
alkyl group having from 1 to 6 carbon atoms; R.sup.1 represents:
[0037] a hydrogen atom, [0038] an alkyl group having from 1 to 6
carbon atoms and optionally substituted with a substituent(s)
selected from the group consisting of: [0039] a hydroxyl group,
[0040] a halogen atom, [0041] an alkoxy group having from 1 to 6
carbon atoms, said alkoxy group optionally substituted with a
phenyl group, and [0042] a phenyl group, optionally substituted
with a substituent(s) selected from the group consisting of a
halogen atom and an alkyl group having from 1 to 6 carbon atoms,
[0043] a cycloalkyl group having from 3 to 8 carbon atoms, [0044]
an alkenyl group having from 2 to 8 carbon atoms, [0045] an alkynyl
group having from 2 to 8 carbon atoms, or a phenyl group; R.sup.1A
represents: [0046] a hydrogen atom or [0047] an alkyl group having
from 1 to 6 carbon atoms; R.sup.1 and R.sup.1A optionally form,
together with a carbon atom to which said R.sup.1 and R.sup.1A are
attached, a cycloalkyl group having from 3 to 6 carbon atoms;
R.sup.2 represents: [0048] a hydrogen atom, [0049] an alkyl group
having from 1 to 6 carbon atoms, [0050] an alkenyl group having
from 2 to 8 carbon atoms, [0051] an alkynyl group having from 2 to
8 carbon atoms, or [0052] a cycloalkyl group having from 3 to 6
carbon atoms; R.sup.3 represents an optionally substituted aryl
group; R.sup.4 represents: [0053] a hydrogen atom or [0054] an
alkyl group having from 1 to 6 carbon atoms and optionally
substituted with a carboxyl group; R.sup.5 represents: [0055] (i)
an alkyl group having from 1 to 10 carbon atoms, [0056] (ii) an
alkyl group having from 1 to 10 carbon atoms and substituted with 1
to 2 substituents selected from the group consisting of: [0057] a
cycloalkyl group having from 3 to 8 carbon atoms, a pyridyl group,
and [0058] a phenyl group, a phenoxy group, and a naphthyl group,
each optionally substituted with 1 to 2 substituents selected from
the group consisting of a halogen atom and an alkoxy group having
from 1 to 6 carbon atoms, [0059] (iii) a cycloalkyl group having
from 3 to 8 carbon atoms, [0060] (iv) an alkenyl group having from
2 to 8 carbon atoms, [0061] (v) an alkenyl group having from 2 to 8
carbon atoms and substituted with a phenyl group, [0062] (vi) an
alkynyl group having from 2 to 8 carbon atoms, [0063] (vii) an
alkynyl group having from 2 to 8 carbon atoms and substituted with
a phenyl group, or [0064] (viii) an optionally substituted aryl
group. 2. The compound of Embodiment 1, or a pharmaceutically
acceptable salt thereof, wherein, in Formula (I): R.sup.1
represents: [0065] a hydrogen atom, [0066] an alkyl group having
from 1 to 6 carbon atoms, [0067] an alkyl group having from 1 to 6
carbon atoms and substituted with a phenyl group, [0068] a
cycloalkyl group having from 3 to 8 carbon atoms, [0069] an alkenyl
group having from 2 to 8 carbon atoms, [0070] an alkynyl group
having from 2 to 8 carbon atoms, or [0071] a phenyl group; R.sup.1A
represents a hydrogen atom; R.sup.2 represents: [0072] an alkyl
group having from 1 to 6 carbon atoms, [0073] an alkenyl group
having from 2 to 8 carbon atoms, [0074] an alkynyl group having
from 2 to 8 carbon atoms, or [0075] a cycloalkyl group having from
3 to 6 carbon atoms; R.sup.4 represents: [0076] a hydrogen atom, or
[0077] an alkyl group having from 1 to 6 carbon atoms; R.sup.5
represents: [0078] (i) an alkyl group having from 1 to 10 carbon
atoms, [0079] (ii) an alkyl group having from 1 to 10 carbon atoms
and substituted with 1 to 2 substituents selected from the group
consisting of: [0080] a cycloalkyl group having from 3 to 8 carbon
atoms, a phenyl group, [0081] a naphthyl group, [0082] a pyridyl
group, and [0083] a phenyl group substituted with 1 to 2
substituents selected from the group consisting of a halogen atom
and an alkoxy group having from 1 to 6 carbon atoms, [0084] (iii) a
cycloalkyl group having from 3 to 8 carbon atoms, [0085] (iv) an
alkenyl group having from 2 to 8 carbon atoms, [0086] (v) an
alkenyl group having from 2 to 8 carbon atoms and substituted with
a phenyl group, [0087] (vi) an alkynyl group having from 2 to 8
carbon atoms, [0088] (vii) an alkynyl group having from 2 to 8
carbon atoms and substituted with a phenyl group, or [0089] (viii)
an optionally substituted aryl group. 3. The compound of Embodiment
1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is
an oxygen atom or a group represented by Formula --NR.sup.6--. 4.
The compound of Embodiment 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein A is an oxygen atom. 5. The compound of
Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof,
wherein A is a group represented by Formula --NH--. 6. The compound
of any one of Embodiments 1 and 3-5, or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 represents an alkyl group
having from 1 to 6 carbon atoms and optionally substituted with a
substituent(s) selected from the group consisting of: [0090] a
hydroxyl group, [0091] a halogen atom, [0092] an alkoxy group
having from 1 to 6 carbon atoms, said alkoxy group optionally
substituted with a phenyl group; and [0093] a phenyl group,
optionally substituted with a substituent(s) selected from the
group consisting of a halogen atom and an alkyl group having from 1
to 6 carbon atoms; R.sup.1A represents: [0094] a hydrogen atom; or
[0095] an alkyl group having from 1 to 6 carbon atoms; and R.sup.1
and R.sup.1A optionally form, together with a carbon atom to which
said R.sup.1 and R.sup.1A are attached, a cycloalkyl group having
from 3 to 6 carbon atoms. 7. The compound of any one of Embodiments
1 and 3-5, or a pharmaceutically acceptable salt thereof,
wherein:
R.sup.1 is:
[0096] an alkyl group having from 1 to 6 carbon atoms and
optionally substituted with a halogen atom(s), or
[0097] a benzyl group optionally substituted with a substituent(s)
selected from the group consisting of a halogen atom and an alkyl
group having from 1 to 6 carbon atoms; and
R.sup.1A is a hydrogen atom. 8. The compound of any one of
Embodiments 1-5, or a pharmaceutically acceptable salt thereof,
wherein R.sup.1 is a methyl group or an ethyl group, and R.sup.1A
is a hydrogen atom. 9. The compound of any one of Embodiments 1-8,
or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is a
hydrogen atom. 10. The compound of any one of Embodiments 1-9, or a
pharmaceutically acceptable salt thereof, wherein R.sup.2 is an
alkyl group having from 1 to 6 carbon atoms, or a cycloalkyl group
having from 3 to 6 carbon atoms. 11. The compound of any one of
Embodiments 1-9, or a pharmaceutically acceptable salt thereof,
wherein R.sup.2 is an ethyl group or a cyclopropyl group. 12. The
compound of any one of Embodiments 1 and 3-11, or a
pharmaceutically acceptable salt thereof, wherein R.sup.5 is:
[0098] (i) an alkyl group having from 1 to 10 carbon atoms, [0099]
(ii) an alkyl group having from 1 to 10 carbon atoms and
substituted with 1 to 2 substituents selected from the group
consisting of: [0100] a cycloalkyl group having from 3 to 8 carbon
atoms, a pyridyl group, and [0101] a phenyl group, a phenoxy group,
and a naphthyl group, each optionally substituted with 1 to 2
substituents selected from the group consisting of a halogen atom
and an alkoxy group having from 1 to 6 carbon atoms; [0102] (iii)
an alkenyl group having from 2 to 8 carbon atoms and optionally
substituted with a phenyl group, or [0103] (iv) a phenyl group, a
naphthyl group, a thienyl group, a pyrrolyl group, a pyrazolyl
group, a pyridyl group, a furanyl group, a benzothienyl group, an
isoquinolinyl, an isoxazolyl group, a thiazolyl group, a
benzothiadiazolyl group, a benzoxadiazolyl group, a
dihydrobenzodioxepinyl group, a dihydrobenzodioxynyl group, a
benzodioxolyl group, a dihydrobenzofuranyl group, an indanyl group,
an uracil group, a coumaryl group, a chromanyl group, a
dihydroindolyl group, a tetrahydronaphthyl group, or a
tetrahydroisoquinolinyl group, each optionally substituted with 1
to 5 substituents selected from the group consisting of: [0104] an
alkyl group having from 1 to 6 carbon atoms and optionally
substituted with a fluorine atom(s), [0105] an alkenyl group having
from 2 to 8 carbon atoms, a halogen atom, [0106] an alkoxy group
having from 1 to 6 carbon atoms and optionally substituted with a
fluorine atom(s), [0107] a pyrazolyl group, an oxazolyl group, an
isoxazolyl group, a thiadiazolyl group, and a pyrimidinyl group,
each optionally substituted with a substituent(s) selected from
Group X consisting of a methyl group, a trifluoromethyl group, a
halogen atom, and a methylsulfanyl group, [0108] an alkylthio group
having from 1 to 6 carbon atoms, [0109] an alkylsulfonyl group
having from 1 to 6 carbon atoms, [0110] a benzenesulfonyl group,
[0111] a morpholinosulfonyl group, [0112] a morpholinocarbonylamino
group, [0113] an aminosulfonyl group, [0114] an alkoxycarbonyl
group having from 2 to 10 carbon atoms, [0115] a morpholino group
optionally substituted with an alkyl group(s) having from 1 to 6
carbon atoms [0116] a phenyl group optionally substituted with an
alkoxy group(s) having from 1 to 6 carbon atoms, [0117] a phenoxy
group, [0118] a pyridinecarbonyl group, [0119] a pyridineoxy group,
[0120] a cyano group, [0121] an alkanoyl group having from 2 to 7
carbon atoms and optionally substituted with a fluorine atom(s),
and [0122] an alkanoylamino group having from 2 to 7 carbon atoms.
13. The compound of any one of Embodiments 1-11, or a
pharmaceutically acceptable salt thereof, wherein R.sup.5 is:
[0123] an alkyl group having from 1 to 10 carbon atoms and
substituted with a cycloalkyl group having from 3 to 8 carbon
atoms,
[0124] an alkyl group having from 1 to 10 carbon atoms and
substituted with a naphthyl group,
[0125] an alkenyl group having from 2 to 8 carbon atoms and
substituted with a phenyl group,
[0126] a phenyl group or a naphthyl group, each optionally
substituted with 1 to 5 substituents selected from the group
consisting of: [0127] an alkyl group having from 1 to 6 carbon
atoms; [0128] a halogen atom, [0129] an alkoxy group having from 1
to 6 carbon atoms; [0130] a trifluoromethoxy group, [0131] a
difluoromethoxy group, [0132] a trifluoromethyl group, [0133] an
alkenyl group having from 1 to 6 carbon atoms, [0134] an
alkylsulfonyl group having from 1 to 6 carbon atoms, [0135] an
alkanoyl group having from 2 to 7 carbon atoms, [0136] an
alkoxycarbonyl group having from 2 to 7 carbon atoms, and [0137] a
cyano group,
[0138] a pyrrolyl group optionally substituted with a
substituent(s) selected from the group consisting of an alkyl group
having from 1 to 6 carbon atoms and a methoxycarbonyl group;
[0139] a furanyl group optionally selected from a substituent(s)
selected from the group consisting of an alkyl group having from 1
to 6 carbon atoms, a trifluoromethyl group, and a halogen atom;
[0140] a thienyl group optionally substituted with a substituent
(s) selected from the group consisting of an alkyl group having
from 1 to 6 carbon atoms, a trifluoromethyl group, a thiadiazolyl
group, an oxazolyl group, and a halogen atom; or
[0141] a benzothienyl group, a dihydrobenzodioxepinyl group, a
benzodioxolyl group, a dihydrobenzodioxynyl group, a
dihydrobenzofuranyl group, a tetrahydronaphthyl group, an indanyl
group, a thiadiazolyl group, a benzoxadiazolyl group, or a
benzothiadiazolyl group, each optionally substituted with a
substituent(s) selected from the group consisting of an alkyl group
having from 1 to 6 carbon atoms and a halogen atom.
14. The compound of any one of Embodiments 1-11, or a
pharmaceutically acceptable salt thereof, wherein R.sup.5 is:
[0142] an alkyl group having from 1 to 6 carbon atoms and
substituted with a naphthyl group,
[0143] an alkenyl group having from 2 to 6 carbon atoms and
substituted with a phenyl group;
[0144] an unsubstituted phenyl group,
[0145] a phenyl group substituted with 1 to 5 substituents selected
from the group consisting of a methyl group, a methoxy group, and a
halogen atom,
[0146] a phenyl group substituted with 1 to 3 substituents selected
from the group consisting of: [0147] an alkyl group having from 1
to 6 carbon atoms, [0148] a halogen atom, [0149] a methoxy group,
[0150] a trifluoromethoxy group, [0151] a difluoromethoxy group,
[0152] a trifluoromethyl group, [0153] an alkenyl group having from
1 to 6 carbon atoms, [0154] a methylsulfonyl group, [0155] an
acetyl group, [0156] a methoxycarbonyl group, and [0157] a cyano
group, [0158] said phenyl group substituted at either 3 or 4
position or both;
[0159] a naphthyl group optionally substituted with a
substituent(s) selected from the group consisting of: [0160] a
halogen atom, [0161] an alkyl group having from 1 to 6 carbon
atoms, [0162] a cyano group, and [0163] an alkylsulfonyl group
having from 1 to 6 carbon atoms, or
[0164] a benzothienyl group, a benzoxadiazolyl group, a
benzodioxolyl group, a dihydrobenzodioxynyl group, a
dihydrobenzofuranyl group, an indanyl group, or a benzothiadiazolyl
group, each optionally substituted with a substituent(s) selected
from the group consisting of an alkyl group having from 1 to 6
carbon atoms and a halogen atom. 15. The compound of any one of
Embodiments 1-11, or a pharmaceutically acceptable salt thereof,
wherein R.sup.5 is:
[0165] a phenyl group substituted at 3 and 4 positions each with a
halogen atom, or
[0166] a naphthyl group optionally substituted with a
substituent(s) selected from the group consisting of a halogen
atom, an alkyl group having from 1 to 6 carbon atoms, and a cyano
group.
16. The compound of any one of Embodiments 1-15, or a
pharmaceutically acceptable salt thereof, wherein R.sup.3 is a
phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group,
an indolyl group, a benzothiazolyl group, a benzothiadiazolyl
group, a pyrazolopyrimidinyl group, a quinolinyl group, an
isoquinolinyl group, a benzothienyl group, or a dihydroquinolinonyl
group, each optionally substituted with 1 to 3 substituents
selected from the group consisting of the following
substituents:
[0167] an alkyl group having from 1 to 6 carbon atoms and
optionally substituted with a fluorine atom(s),
[0168] a cycloalkyl group having from 3 to 8 carbon atoms,
[0169] a halogen atom,
[0170] an alkoxy group having from 1 to 6 carbon atoms, said alkoxy
group optionally substituted with a substituent(s) selected from
the group consisting of a fluorine atom, a phenyl group, an amino
group substituted with two alkyl groups each having from 1 to 4
carbon atoms, and a morpholino group;
[0171] a phenoxy group,
[0172] a phenyl group,
[0173] a carboxyl group,
[0174] an alkoxycarbonyl group having from 2 to 10 carbon
atoms,
[0175] a hydroxyl group,
[0176] a monocylic saturated hydrocarbon group having from 2 to 7
carbon atoms and having a nitrogen atom(s) as a ring atom(s), said
saturated hydrocarbon group optionally substituted with an alkyl
group(s) having from 1 to 6 carbon atoms,
[0177] a nitrogen-containing monocylic unsaturated hydrocarbon
group,
[0178] a morpholinyl group optionally substituted with an alkyl
group(s) having from 1 to 6 carbon atoms,
[0179] a piperazino group optionally substituted with a
substituent(s) selected from the group consisting of: [0180] an
alkyl group having from 1 to 6 carbon atoms, said alkyl group
optionally substituted with an amino group optionally substituted
with one or two alkyl groups each having from 1 to 6 carbon atoms,
a morpholino group, a hydroxyl group, or an alkoxy group having
from 1 to 6 carbon atoms, [0181] a formyl group, [0182] an alkanoyl
group having from 2 to 7 carbon atoms, [0183] a carbamoyl group
optionally substituted with one or two alkyl groups each having
from 1 to 4 carbon atoms, [0184] an aminosulfonyl group optionally
substituted with one or two alkyl groups each having from 1 to 6
carbon atoms, and [0185] an alkylsulfonyl group having from 1 to 6
carbon atoms, and
[0186] Formula --NR.sup.7R.sup.8, wherein: [0187] R.sup.7 and
R.sup.8 each represent: [0188] a hydrogen atom, [0189] an alkyl
group having from 1 to 6 carbon atoms, said alkyl group optionally
substituted with an amino group optionally substituted with one or
two alkyl groups each having from 1 to 6 carbon atoms, a hydroxyl
group, or an alkoxy group having from 1 to 6 carbon atoms, [0190]
an alkanoyl group having from 1 to 6 carbon atoms, [0191] a
carbamoyl group optionally substituted with one or two alkyl groups
each having from 1 to 4 carbon atoms, [0192] a morpholinocarbonyl
group, [0193] an aminosulfonyl group optionally substituted with
one or two alkyl groups each having from 1 to 6 carbon atoms, or
[0194] an alkylsulfonyl group having from 1 to 6 carbon atoms, or
[0195] R.sup.7 and R.sup.8 optionally form, together with the
nitrogen atom to which said R.sup.7 and R.sup.8 are attached, a 3-
to 8-membered saturated hydrocarbon ring, said ring optionally
substituted with a substituent(s) selected from the group
consisting of a dimethylenedioxy group, an oxo group, and a
hydroxyl group. 17. The compound of any one of Embodiments 1-15, or
a pharmaceutically acceptable salt thereof, wherein R.sup.3 is:
[0196] a 2-naphthyl group, optionally substituted with a
substituent(s) selected from the group consisting of a halogen atom
and an alkyl group having from 1 to 6 carbon atoms,
[0197] a 3-pyrazolyl group, optionally substituted with a
substituent(s) selected from the group consisting of an alkyl group
having from 1 to 6 carbon atoms, a trifluoromethyl group, and a
halogen atom, or
[0198] a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a
7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a
7-quinolinyl group, a 3-pyridyl group, or an indolyl group, each
optionally substituted with an alkyl group(s) having from 1 to 6
carbon atoms,
[0199] an unsubstituted phenyl group, or
[0200] a substituted phenyl group (A), (B), or (C) below:
[0201] (A) a phenyl group substituted at 4 position with a
substituent selected from the group consisting of: [0202] an alkyl
group having from 1 to 6 carbon atoms, [0203] a cycloalkyl group
having from 3 to 8 carbon atoms, [0204] an alkoxy group having from
1 to 6 carbon atoms, said alkoxy group optionally substituted with
a substituent(s) selected from the group consisting of an amino
group substituted with two alkyl groups each having from 1 to 4
carbon atoms, a morpholino group, and a phenyl group, [0205] a
halogen atom, [0206] a trifluoromethoxy group, [0207] a phenoxy
group, [0208] a phenyl group, [0209] a 1-pyrrolyl group, and [0210]
--NR.sup.AR.sup.B, wherein each of R.sup.A and R.sup.B is an alkyl
group having from 1 to 6 carbon atoms, or R.sup.A and R.sup.B
optionally form, together with the nitrogen atom to which said
R.sup.A and R.sup.B are attached, a 3- to 5-membered saturated
hydrocarbon ring,
[0211] wherein said phenyl group substituted at 4 position is
further optionally substituted at 3 position with a substituent
selected from the group consisting of an alkyl group having from 1
to 6 carbon atoms, a halogen atom, and an alkoxy group having from
1 to 6 carbon atoms;
[0212] (B) a phenyl group substituted at 3 position with a
substituent selected from the group consisting of: [0213] a
hydroxyl group, [0214] an alkyl group having from 1 to 6 carbon
atoms, and [0215] an alkoxy group having from 1 to 6 carbon atoms,
said alkoxy group optionally substituted with a substituent(s)
selected from the group consisting of an amino group substituted
with two alkyl groups each having from 1 to 4 carbon atoms, a
morpholino group, and a phenyl group,
[0216] wherein said phenyl group substituted at 3 position is
further optionally substituted with one or two alkyl groups each
having from 1 to 6 carbon atoms, or is further optionally
substituted at 4 position with a halogen atom; and
[0217] (C) a phenyl group substituted at 3 position with a
substituent selected from the group consisting of
nitrogen-containing groups (i)-(v) below, said phenyl group further
optionally substituted at 4 position with a halogen atom: [0218]
(i) a monocylic saturated hydrocarbon group having from 2 to 7
carbon atoms and having a nitrogen atom(s) as a ring atom(s), said
saturated hydrocarbon group optionally substituted with an alkyl
group(s) having from 1 to 6 carbon atoms, [0219] (ii) a
nitrogen-containing monocylic unsaturated hydrocarbon group, [0220]
(iii) a morpholinyl group optionally substituted with an alkyl
group(s) having from 1 to 6 carbon atoms, [0221] (iv) a piperazino
group, optionally substituted with an alkanoyl group having from 2
to 7 carbon atoms or an alkyl group having from 1 to 6 carbon atoms
and optionally substituted with a substituent(s) selected from the
group consisting of: [0222] an amino group substituted with two
alkyl groups each having from 1 to 4 carbon atoms, and [0223] a
morpholino group, and [0224] (v) Formula --NR.sup.7R.sup.8,
wherein: [0225] R.sup.7 and R.sup.8 each represent: [0226] a
hydrogen atom, [0227] an alkyl group having from 1 to 6 carbon
atoms, said alkyl group optionally substituted with an amino group
optionally substituted with one or two alkyl groups each having
from 1 to 6 carbon atoms, a morpholino group, a hydroxyl group, or
an alkoxy group having from 1 to 6 carbon atoms, an alkanoyl group
having from 1 to 6 carbon atoms, [0228] a carbamoyl group
optionally substituted with one or two alkyl groups each having
from 1 to 4 carbon atoms, [0229] a morpholinocarbonyl group, [0230]
an aminosulfonyl group optionally substituted with one or two alkyl
groups each having from 1 to 6 carbon atoms, or [0231] an
alkylsulfonyl group having from 1 to 6 carbon atoms, or [0232]
R.sup.7 and R.sup.8 optionally form, together with the nitrogen
atom to which said R.sup.7 and R.sup.8 are attached, a 3- to
8-membered saturated hydrocarbon ring, said ring optionally
substituted with a substituent(s) selected from the group
consisting of a dimethylenedioxy group, an oxo group, and a
hydroxyl group. 18. The compound of any one of Embodiments 1-15, or
a pharmaceutically acceptable salt thereof, wherein R.sup.3 is a
phenyl group substituted at 3 position with a substituent selected
from the group consisting of nitrogen-containing groups (i)-(v)
below, said phenyl group further optionally substituted at 4
position with a halogen atom:
[0233] (i) a monocylic saturated hydrocarbon group having from 2 to
7 carbon atoms and having a nitrogen atom(s) as a ring atom(s),
said saturated hydrocarbon group optionally substituted with an
alkyl group(s) having from 1 to 6 carbon atoms,
[0234] (ii) a nitrogen-containing monocylic unsaturated hydrocarbon
group,
[0235] (iii) a morpholinyl group optionally substituted with an
alkyl group(s) having from 1 to 6 carbon atoms,
[0236] (iv) a piperazino group, optionally substituted with an
alkanoyl group having from 2 to 7 carbon atoms or an alkyl group
having from 1 to 6 carbon atoms and optionally substituted with a
substituent(s) selected from the group consisting of: [0237] an
amino group substituted with two alkyl groups each having from 1 to
4 carbon atoms, and [0238] a morpholino group, and
[0239] (v) Formula --NR.sup.7R.sup.8, wherein: [0240] R.sup.7 and
R.sup.8 each represent: [0241] a hydrogen atom, [0242] an alkyl
group having from 1 to 6 carbon atoms, said alkyl group optionally
substituted with an amino group optionally substituted with one or
two alkyl groups each having from 1 to 6 carbon atoms, a morpholino
group, a hydroxyl group, or an alkoxy group having from 1 to 6
carbon atoms, [0243] an alkanoyl group having from 1 to 6 carbon
atoms, [0244] a carbamoyl group optionally substituted with one or
two alkyl groups each having from 1 to 4 carbon atoms, [0245] a
morpholinocarbonyl group, [0246] an aminosulfonyl group optionally
substituted with one or two alkyl groups each having from 1 to 6
carbon atoms, or [0247] an alkylsulfonyl group having from 1 to 6
carbon atoms, or
[0248] R.sup.7 and R.sup.8 optionally form, together with the
nitrogen atom to which said R.sup.7 and R.sup.8 are attached, a 3-
to 8-membered saturated hydrocarbon ring, said ring optionally
substituted with a substituent(s) selected from the group
consisting of a dimethylenedioxy group, an oxo group, and a
hydroxyl group.
19. The compound of any one of Embodiments 1-15, or a
pharmaceutically acceptable salt thereof, wherein R.sup.3 is a
phenyl group substituted at 4 position with a fluorine atom or a
chlorine atom. 20. The compound of any one of Embodiments 1-15, or
a pharmaceutically acceptable salt thereof, wherein R.sup.3 is a
6-indolyl group. 21. A pharmaceutical preparation, comprising the
compound of any one of Embodiments 1-20 or a pharmaceutically
acceptable salt thereof. 22. The pharmaceutical preparation of
Embodiment 21, which is for treatment of an autoimmune disease,
such as Crohn disease, hypersensitivity colitis, Sjogren's
syndrome, multiple sclerosis, and systemic lupus erythematosus,
rheumatoid arthritis, asthma, atopic dermatitis, organ transplant
rejection, cancer, retinopathy, psoriasis, osteoarthritis, or
age-related macular degeneration. 23. A compound represented by
Formula (II)
##STR00003##
or a salt thereof, wherein R.sup.1, R.sup.1A, R.sup.2, and R.sup.3
are as defined in Embodiment 1, and A' represents an oxygen atom or
NH. 24. The compound of Embodiment 23, or a salt thereof, wherein,
in Formula (II): A' represents an oxygen atom; R.sup.1
represents:
[0249] a hydrogen atom,
[0250] an alkyl group having from 1 to 6 carbon atoms,
[0251] an alkyl group having from 1 to 6 carbon atoms and
substituted with a phenyl group,
[0252] a cycloalkyl group having from 3 to 8 carbon atoms,
[0253] an alkenyl group having from 2 to 8 carbon atoms,
[0254] an alkynyl group having from 2 to 8 carbon atoms, or
[0255] a phenyl group;
R.sup.1A represents a hydrogen atom; and R.sup.2 represents:
[0256] an alkyl group having from 1 to 6 carbon atoms,
[0257] an alkenyl group having from 2 to 8 carbon atoms,
[0258] an alkynyl group having from 2 to 8 carbon atoms, or
[0259] a cycloalkyl group having from 3 to 6 carbon atoms.
25. The compound of Embodiment 23, or a salt thereof, wherein, in
Formula (II): A' represents NH; R.sup.1 represents:
[0260] a hydrogen atom,
[0261] an alkyl group having from 1 to 6 carbon atoms,
[0262] an alkyl group having from 1 to 6 carbon atoms and
substituted with a phenyl group,
[0263] a cycloalkyl group having from 3 to 8 carbon atoms,
[0264] an alkenyl group having from 2 to 8 carbon atoms,
[0265] an alkynyl group having from 2 to 8 carbon atoms, or
[0266] a phenyl group;
R.sup.1A represents a hydrogen atom; and R.sup.2 represents:
[0267] an alkyl group having from 1 to 6 carbon atoms,
[0268] an alkenyl group having from 2 to 8 carbon atoms,
[0269] an alkynyl group having from 2 to 8 carbon atoms, or
[0270] a cycloalkyl group having from 3 to 6 carbon atoms.
26. The compound of Embodiment 23, or a salt thereof, wherein:
R.sup.1 represents an alkyl group having from 1 to 6 carbon atoms
and optionally substituted with a substituent(s) selected from the
group consisting of:
[0271] a hydroxyl group,
[0272] a halogen atom,
[0273] an alkoxy group having from 1 to 6 carbon atoms, said alkoxy
group optionally substituted with a phenyl group, and
[0274] a phenyl group, optionally substituted with a substituent(s)
selected from the group consisting of a halogen atom and an alkyl
group having from 1 to 6 carbon atoms;
R.sup.1A represents a hydrogen atom or an alkyl group having from 1
to 6 carbon atoms; and R.sup.1 and R.sup.1A optionally form,
together with a carbon atom to which said R.sup.1 and R.sup.1A are
attached, a cycloalkyl group having from 3 to 6 carbon atoms. 27.
The compound of Embodiment 23, or a salt thereof, wherein: R.sup.1
is an alkyl group having from 1 to 6 carbon atoms and optionally
substituted with a halogen atom(s), or a benzyl group optionally
substituted with a substituent(s) selected from the group
consisting of a halogen atom and an alkyl group having from 1 to 6
carbon atoms; and R.sup.1A is a hydrogen atom. 28. The compound of
any one of Embodiments 23-25, or a salt thereof, wherein R.sup.1 is
a methyl group or an ethyl group, and R.sup.1A is a hydrogen atom.
29. The compound of any one of Embodiments 23-28, or a salt
thereof, wherein R.sup.2 is an alkyl group having from 1 to 6
carbon atoms, or a cycloalkyl group having from 3 to 8 carbon
atoms. 30. The compound of any one of Embodiments 23-28, or a salt
thereof, wherein R.sup.2 is an ethyl group or a cyclopropyl group.
31. The compound of any one of Embodiments 23-30, or a salt
thereof, wherein:
[0275] R.sup.3 is a phenyl group, a naphthyl group, a pyrazolyl
group, a pyridyl group, an indolyl group, a benzothiazolyl group, a
benzothiadiazolyl group, a pyrazolopyrimidinyl group, a quinolinyl
group, an isoquinolinyl group, a benzothienyl group, or a
dihydroquinolinonyl group, each optionally substituted with 1 to 3
substituents selected from the group consisting of the following
substituents:
[0276] an alkyl group having from 1 to 6 carbon atoms and
optionally substituted with a fluorine atom(s),
[0277] a cycloalkyl group having from 3 to 8 carbon atoms,
[0278] a halogen atom,
[0279] an alkoxy group having from 1 to 6 carbon atoms, said alkoxy
group optionally substituted with a substituent(s) selected from
the group consisting of a fluorine atom, a phenyl group, an amino
group substituted with two alkyl groups each having from 1 to 4
carbon atoms, and a morpholino group, a phenoxy group,
[0280] a phenyl group,
[0281] a carboxyl group,
[0282] an alkoxycarbonyl group having from 2 to 10 carbon
atoms,
[0283] a hydroxyl group,
[0284] a monocylic saturated hydrocarbon group having from 2 to 7
carbon atoms and having a nitrogen atom(s) as a ring atom(s), said
saturated hydrocarbon group optionally substituted with an alkyl
group(s) having from 1 to 6 carbon atoms;
[0285] a nitrogen-containing monocylic unsaturated hydrocarbon
group,
[0286] a morpholinyl group optionally substituted with an alkyl
group(s) having from 1 to 6 carbon atoms,
[0287] a piperazino group optionally substituted with a
substituent(s) selected from the group consisting of: [0288] an
alkyl group having from 1 to 6 carbon atoms, said alkyl group
optionally substituted with an amino group optionally substituted
with one or two alkyl groups each having from 1 to 6 carbon atoms,
a morpholino group, a hydroxyl group, or an alkoxy group having
from 1 to 6 carbon atoms, [0289] a formyl group, [0290] an alkanoyl
group having from 2 to 7 carbon atoms, [0291] a carbamoyl group
optionally substituted with one or two alkyl groups each having
from 1 to 4 carbon atoms, [0292] an aminosulfonyl group optionally
substituted with one or two alkyl groups each having from 1 to 6
carbon atoms, and [0293] an alkylsulfonyl group having from 1 to 6
carbon atoms; and
[0294] Formula --NR.sup.7R.sup.8, wherein: [0295] R.sup.7 and
R.sup.8 each represent: [0296] a hydrogen atom, [0297] an alkyl
group having from 1 to 6 carbon atoms, said alkyl group optionally
substituted with an amino group optionally substituted with one or
two alkyl groups each having from 1 to 6 carbon atoms, a hydroxyl
group, or an alkoxy group having from 1 to 6 carbon atoms, [0298]
an alkanoyl group having from 1 to 6 carbon atoms, [0299] a
carbamoyl group optionally substituted with one or two alkyl groups
each having from 1 to 4 carbon atoms, [0300] a morpholinocarbonyl
group, [0301] an aminosulfonyl group optionally substituted with
one or two alkyl groups each having from 1 to 6 carbon atoms, or
[0302] an alkylsulfonyl group having from 1 to 6 carbon atoms,
or
[0303] R.sup.7 and R.sup.8 optionally form, together with the
nitrogen atom to which said R.sup.7 and R.sup.8 are attached, a 3-
to 8-membered saturated hydrocarbon ring, said ring optionally
substituted with a substituent(s) selected from the group
consisting of a dimethylenedioxy group, an oxo group, and a
hydroxyl group.
32. The compound of any one of Embodiments 23-30, or a salt
thereof, wherein R.sup.3 is:
[0304] a 2-naphthyl group, optionally substituted with a
substituent(s) selected from the group consisting of a halogen atom
and an alkyl group having from 1 to 6 carbon atoms;
[0305] a 3-pyrazolyl group, optionally substituted with a
substituent(s) selected from the group consisting of an alkyl group
having from 1 to 6 carbon atoms, a trifluoromethyl group, and a
halogen atom;
[0306] a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a
7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a
7-quinolinyl group, a 3-pyridyl group, or an indolyl group, each
optionally substituted with an alkyl group(s) having from 1 to 6
carbon atoms;
[0307] an unsubstituted phenyl group; or
[0308] a substituted phenyl group (A), (B), or (C) below:
[0309] (A) a phenyl group substituted at 4 position with a
substituent selected from the group consisting of: [0310] an alkyl
group having from 1 to 6 carbon atoms, [0311] a cycloalkyl group
having from 3 to 8 carbon atoms, [0312] an alkoxy group having from
1 to 6 carbon atoms, said alkoxy group optionally substituted with
a substituent(s) selected from the group consisting of an amino
group substituted with two alkyl groups each having from 1 to 4
carbon atoms, a morpholino group, and a phenyl group, [0313] a
halogen atom, [0314] a trifluoromethoxy group, [0315] a phenoxy
group, [0316] a phenyl group, [0317] a 1-pyrrolyl group, and [0318]
--NR.sup.AR.sup.B, wherein each of R.sup.A and R.sup.B is an alkyl
group having from 1 to 6 carbon atoms, or R.sup.A and R.sup.B
optionally form, together with the nitrogen atom to which said
R.sup.A and R.sup.B are attached, a 3- to 5-membered saturated
hydrocarbon ring,
[0319] wherein said phenyl group substituted at 4 position is
further optionally substituted at 3 position with a substituent
selected from the group consisting of an alkyl group having from 1
to 6 carbon atoms, a halogen atom, and an alkoxy group having from
1 to 6 carbon atoms;
[0320] (B) a phenyl group substituted at 3 position with a
substituent selected from the group consisting of: [0321] a
hydroxyl group, [0322] an alkyl group having from 1 to 6 carbon
atoms, and [0323] an alkoxy group having from 1 to 6 carbon atoms,
said alkoxy group optionally substituted with a substituent(s)
selected from the group consisting of an amino group substituted
with two alkyl groups each having from 1 to 4 carbon atoms, a
morpholino group, and a phenyl group,
[0324] wherein said phenyl group substituted at 3 position is
further optionally substituted with one or two alkyl groups each
having from 1 to 6 carbon atoms, or is further optionally
substituted at 4 position with a halogen atom; and
[0325] (C) a phenyl group substituted at 3 position with a
substituent selected from the group consisting of
nitrogen-containing groups (i)-(v) below, said phenyl group further
optionally substituted at 4 position with a halogen atom: [0326]
(i) a monocylic saturated hydrocarbon group having from 2 to 7
carbon atoms and having a nitrogen atom(s) as a ring atom(s), said
saturated hydrocarbon group optionally substituted with an alkyl
group(s) having from 1 to 6 carbon atoms, [0327] (ii) a
nitrogen-containing monocylic unsaturated hydrocarbon group, [0328]
(iii) a morpholinyl group optionally substituted with an alkyl
group(s) having from 1 to 6 carbon atoms, [0329] (iv) a piperazino
group, optionally substituted with an alkanoyl group having from 2
to 7 carbon atoms or an alkyl group having from 1 to 6 carbon atoms
and optionally substituted with a substituent(s) selected from the
group consisting of: [0330] an amino group substituted with two
alkyl groups each having from 1 to 4 carbon atoms; and [0331] a
morpholino group, and [0332] (v) Formula --NR.sup.7R.sup.8,
wherein: [0333] R.sup.7 and R.sup.8 each represent: [0334] a
hydrogen atom, [0335] an alkyl group having from 1 to 6 carbon
atoms, said alkyl group optionally substituted with an amino group
optionally substituted with one or two alkyl groups each having
from 1 to 6 carbon atoms, a morpholino group, a hydroxyl group, or
an alkoxy group having from 1 to 6 carbon atoms; [0336] an alkanoyl
group having from 1 to 6 carbon atoms, [0337] a carbamoyl group
optionally substituted with one or two alkyl groups each having
from 1 to 4 carbon atoms, [0338] a morpholinocarbonyl group, [0339]
an aminosulfonyl group optionally substituted with one or two alkyl
groups each having from 1 to 6 carbon atoms, or [0340] an
alkylsulfonyl group having from 1 to 6 carbon atoms, or [0341]
R.sup.7 and R.sup.8 optionally form, together with the nitrogen
atom to which said R.sup.7 and R.sup.8 are attached, a 3- to
8-membered saturated hydrocarbon ring, said ring optionally
substituted with a substituent(s) selected from the group
consisting of a dimethylenedioxy group, an oxo group, and a
hydroxyl group.
[0342] The present invention is described in detail as follows.
[0343] The term "halogen atom" means a fluorine atom, a chlorine
atom, a bromine atom, or an iodine atom.
[0344] The term "alkyl group having from 1 to 6 carbon atoms"
refers to a linear or branched alkyl group containing 1 to 6 carbon
atoms. Examples include a methyl group, an ethyl group, a n-propyl
group, an isopropyl group, a n-butyl group, an isobutyl group, a
tert-butyl group, a sec-butyl group, a n-pentyl group, an isopentyl
group, a neopentyl group, a tert-pentyl group, and a n-hexyl
group.
[0345] The term "cycloalkyl group having from 3 to 8 carbon atoms"
refers to a cycloalkyl group containing 3 to 8 carbon atoms.
Examples include a cyclopropyl group, a cyclobutyl group, a
cyclopentyl group, and a cyclohexyl group.
[0346] The term "alkenyl group having from 2 to 8 carbon atoms"
refers to a linear or branched alkenyl group containing 2 to 8
carbon atoms. Examples include a vinyl group, an allyl group, a
1-propenyl group, an isopropenyl group, a 1-butenyl group, a
2-butenyl group, a 3-butenyl group, a 1,3-butadienyl group, a
2-methylallyl group, a 2-methyl-propenyl group, a 2-pentenyl group,
and a 3-methyl-but-2-enyl group.
[0347] The term "alkynyl group having from 2 to 8 carbon atoms"
refers to a linear or branched alkynyl group containing 2 to 8
carbon atoms. Examples include an ethynyl group, a 2-propynyl
group, a 2-butynyl group, a 1-methyl-prop-2-ynyl group, a
2-pentynyl group, and a 4-pentynyl group.
[0348] The term "alkoxy group having from 1 to 6 carbon atoms"
refers to a linear or branched alkoxy group containing 1 to 6
carbon atoms. Examples include a methoxy group, an ethoxy group, a
propoxy group, an isopropoxy group, a butoxy group, an isobutoxy
group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group,
and a hexyloxy group.
[0349] The term "alkyl group having from 1 to 10 carbon atoms"
refers to a linear or branched alkyl group containing 1 to 10
carbon atoms. Examples include a methyl group, an ethyl group, a
n-propyl group, an isopropyl group, a n-butyl group, an isobutyl
group, a tert-butyl group, a sec-butyl group, a n-pentyl group, an
isopentyl group, a neopentyl group, a tert-pentyl group, a n-hexyl
group, a n-heptyl group, a n-octyl group, and a n-hexadecyl
group.
[0350] The term "alkylthio group having from 1 to 6 carbon atoms"
refers to a linear or branched alkylthio group containing 1 to 6
carbon atoms. Examples include a methylthio group, an ethylthio
group, a propylthio group, an isopropylthio group, a butylthio
group, an isobutylthio group, a pentylthio group, and a hexylthio
group.
[0351] The term "alkylsulfonyl group having from 1 to 6 carbon
atoms" refers to a linear or branched alkylsulfonyl group
containing 1 to 6 carbon atoms. Examples include a methanesulfonyl
group, an ethanesulfonyl group, a propane-2-sulfonyl group, and a
hexanesulfonyl group.
[0352] The term "alkoxycarbonyl group having from 2 to 10 carbon
atoms" refers to a linear or branched alkoxycarbonyl group
containing 2 to 10 carbon atoms. Examples include alkanoyl group
having from 2 to 7 carbon atoms such as a methoxycarbonyl group, an
ethoxycarbonyl group and a t-butoxycarbonyl group, as well as an
octyloxycarbonyl group.
[0353] The term "alkanoyl group having from 2 to 7 carbon atoms"
refers to a linear or branched alkanoyl group containing 2 to 7
carbon atoms. Examples include an acetyl group, a propanoyl group,
a butanoyl group, and a hexanoyl group.
[0354] The term "alkanoyl group having from 1 to 6 carbon atoms"
refers to a linear or branched alkanoyl group containing 1 to 6
carbon atoms. Examples include a formyl group, an acetyl group, a
propanoyl group, and a butanoyl group.
[0355] The phrase "amino group optionally substituted with one or
two alkyl groups each having from 1 to 6 carbon atoms" is intended
to include, for example, an amino group, a methylamino group, an
ethylamino group, an isopropylamino group, a hexylamino group, a
dimethylamino group, a diethylamino group, a diisopropylamino
group, and a dihexylamino group.
[0356] The phrase "aminosulfonyl group optionally substituted with
one or two alkyl groups each having from 1 to 6 carbon atoms" is
intended to include, for example, a sulfamoyl group, a
dimethylaminosulfonyl group, and a diethylaminosulfonyl group.
[0357] The phrase "carbamoyl group optionally substituted with an
alkyl group(s) having from 1 to 4 carbon atoms" is intended to
include a carbamoyl group, a methylcarbamoyl group, an
ethylcarbamoyl group, and a propylcarbamoyl group.
[0358] The phrase "piperazino group which may be substituted" or
"optionally substituted piperazino group" refers to a piperazino
group which may be substituted (preferably on its nitrogen atom)
with a substituent(s) selected from the group consisting of an
alkyl group having 1-6 carbon atoms (wherein said alkyl group may
be substituted with an amino group which may be substituted with
one or two alkyl groups each having 1-6 carbon atoms, a morpholino
group, a hydroxyl group, or an alkoxy group having 1-6 carbon
atoms), a formyl group, an alkanoyl group having 2-7 carbon atoms,
a carbamoyl group which may be substituted with one or two alkyl
groups each having 1-4 carbon atoms, an aminosulfonyl group
optionally substituted with one or two alkyl groups each having 1-6
carbon atoms, and an alkylsulfonyl group having 1-6 carbon atoms.
Specific examples include a piperazino group, a methylpiperazino
group, an isopropylpiperazino group, a dimethylaminoethylpiperazino
group, and an acetylpiperazino group.
[0359] The term "monocylic saturated hydrocarbon group having from
2 to 7 carbon atoms and having a nitrogen atom(s) as a ring
atom(s)" means a 3- to 9-membered monocylic saturated hydrocarbon
group containing one or two nitrogen atoms as ring-forming atoms
and substituted at a ring carbon atom. Examples of the monocylic
saturated hydrocarbon group include aziridinyl groups, azetidinyl
groups, pyrrolidinyl groups, and piperidinyl groups (e.g.,
4-piperidinyl groups).
[0360] The term "nitrogen-containing monocyclic unsaturated
hydrocarbon group" refers to a 5- or 6-membered unsaturated ring
containing 1 to 3 nitrogen atoms as its ring members. Examples
include a pyrrolyl group (e.g., a pyrrol-1-yl group), an
imidazol-1-yl group (e.g., an imidazolyl group), a pyrazolyl group,
a triazol-4-yl group (e.g., a [1,2,4]triazol-4-yl group), and a
pyridyl group.
[0361] The 3- to 5-membered saturated hydrocarbon ring formed by
R.sup.A and R.sup.B together with the nitrogen atom to which
R.sup.A and R.sup.B are attached is intended to include an
aziridinyl group, an azetidinyl group, and a pyrrolidinyl
group.
[0362] The 3- to 8-membered saturated hydrocarbon ring formed by
R.sup.7 and R.sup.8 (or R.sup.C and R.sup.D) together with the
nitrogen atom to which R.sup.7 and R.sup.8 (or R.sup.C and R.sup.D)
are attached is intended to include an aziridinyl group, an
azetidinyl group, a pyrrolidinyl group, and a piperidinyl
group.
[0363] The term "aryl group" as used herein refers to an aromatic
hydrocarbon group, a partially saturated aromatic hydrocarbon
group, an aromatic heterocyclic group, or a partially saturated
aromatic heterocyclic ring. The aromatic hydrocarbon group refers
to, for example, an aromatic hydrocarbon group containing 6-14
carbon atoms, including a phenyl group, a naphthyl group, and an
anthryl group.
[0364] The partially saturated aromatic hydrocarbon group refers to
a group obtained by partial saturation of a polycyclic aromatic
hydrocarbon group having 6-14 carbon atoms. Examples include a
tetrahydronaphthyl group and an indanyl group.
[0365] The aromatic heterocyclic group refers to a monocylic or
polycyclic aromatic heterocyclic group containing 2-13 carbon atoms
and having 1-6 hetero atoms (e.g., oxygen, sulfur and/or nitrogen
atoms). Examples include a thienyl group, a furanyl group, a
pyrrolyl group, an isothiazolyl group, an isoxazolyl group, a
pyrazolyl group, a thiazolyl group, an oxazolyl group, an
imidazolyl group, a pyridyl group, a pyridazinyl group, a
pyrimidinyl group, a pyrazinyl group, a benzothienyl group, a
benzofuranyl group, an indolyl group, a benzothiazolyl group, a
benzoxazolyl group, a benzimidazolyl group, a quinolinyl group, an
isoquinolinyl group, a benzoxadiazolyl group, a benzothiadiazolyl
group, and a pyrazolopyrimidinyl group (e.g., a
5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl group).
[0366] The partially saturated aromatic heterocyclic ring refers to
a heterocyclic ring obtained by partial saturation of a polycyclic
aromatic heterocyclic group. Such a heterocyclic ring may be
substituted with an oxo group. Examples include a
dihydroquinolinonyl group:
##STR00004##
a dihydrobenzofuranyl group, a dihydrobenzodioxinyl group, a
dihydrobenzodioxepinyl group, a benzodioxolyl group, a
dihydrobenzoxazolyl group, and a dihydrobenzoxazinyl group.
[0367] In a case where such an aryl group is substituted,
substituents for the aryl group include those listed below and the
aryl group can be substituted with 1 to 5 of these
substituents:
[0368] a halogen atom, a cyano group, a nitro group, a sulfamoyl
group, a hydroxyl group, a carboxyl group, an alkyl group having
1-6 carbon atoms, a trifluoromethyl group, a methoxycarbonylethyl
group, an alkoxy group having 1-6 carbon atoms (the alkoxy group is
optionally substituted with a phenyl group, an alkylamino group
having 1-6 carbon atoms, a dialkylamino group having 2-12 carbon
atoms, or a morpholino group), a trifluoromethoxy group, a
difluoromethoxy group, a cyanoethoxy group,
[0369] an alkenyl group having 2-8 carbon atoms, an alkynyl group
having 2-8 carbon atoms,
[0370] a cycloalkyl group having 3-8 carbon atoms, an alkanoyl
group having 2-7 carbon atoms, a trifluoroacetyl group, an
alkoxycarbonyl group having 2-10 carbon atoms,
[0371] a phenyl group (the phenyl group is optionally substituted
with an alkanoyl group having 2-7 carbon atoms or an alkoxy group
having 1-6 carbon atoms),
[0372] a phenoxy group optionally substituted with an alkoxy group
having 1-6 carbon atoms,
[0373] a pyrazolyl group, a
1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl group, a
methylpyrimidinyl group, a 2-methylsulfanyl-pyrimidin-4-yl groups,
an oxazolyl group (e.g., oxazol-5-yl group), an isooxazol-5-yl
group, a 5-trifluoromethyl-isooxazol-3-yl group, a pyridyloxy group
(e.g., 4-pyridyloxy group), a pyridinecarbonyl group, a benzoyl
group, a pyrrolyl group (e.g., pyrrol-1-yl group), an imidazolyl
group (e.g., imidazol-1-yl group), a thiazolyl group, a
[1,2,3]thiadiazol-4-yl group, a triazolyl group (e.g.,
[1,2,4]triazol-4-yl group), an alkylthio group having 1-6 carbon
atoms (e.g., methylthio group), an alkylsulfonyl group having 1-6
carbon atoms (e.g., methanesulfonyl group), a benzenesulfonyl
group, a pyrrolidinesulfonyl group, a morpholinylsulfonyl group, a
4-piperidinyl group optionally substituted with an alkyl group
having 1-6 carbon atoms, a morpholino group optionally substituted
with an alkyl group having 1-6 carbon atoms, a piperazino group
substituted with an alkyl group having 1-6 carbon atoms or an alkyl
group having 1-6 carbon atoms and substituted with a dimethylamino
group, or a group represented by Formula --NR.sup.7R.sup.8, where
R.sup.7 and R.sup.8 each represent a hydrogen atom, an alkyl group
having 1-6 carbon atoms (the alkyl group is optionally substituted
with an alkoxy group having 1-6 carbon atoms or a dimethylamino
group), an alkanoyl group having 1-6 carbon atoms, a carbamoyl
group, a carbamoyl group substituted with an alkyl group(s) having
1-4 carbon atoms, a morpholinocarbonyl group, a
dimethylaminosulfonyl group, or an alkylsulfonyl group having 1-6
carbon atoms, or R.sup.7 and R.sup.8 optionally form, together with
the nitrogen atom to which R.sup.7 and R.sup.8 are attached, to
form a 3- to 8-membered saturated hydrocarbon ring, which ring is
optionally substituted with a dimethylenedioxy group, an oxo group,
or a hydroxyl group, (e.g., acetamide groups, dimethylamino groups,
methylureido groups, butylureido groups, trimethylureido groups,
morpholinylcarbonylamino), a methoxyethylureido group, a
pyridylethoxycarbonylamino group.
[0374] The term "pharmaceutically acceptable salt" refers to a salt
with an alkali metal, an alkaline earth metal, ammonium or an
alkylammonium, or a salt with a mineral acid or an organic acid.
Examples include a sodium salt, a potassium salt, a calcium salt,
an ammonium salt, an aluminum salt, a triethylammonium salt, an
acetate salt, a propionate salt, a butyrate salt, a formate salt, a
trifluoroacetate salt, a maleate salt, a tartrate salt, a citrate
salt, a stearate salt, a succinate salt, an ethylsuccinate salt, a
lactobionate salt, a gluconate salt, a glucoheptate salt, a
benzoate salt, a methanesulfonate salt, an ethanesulfonate salt, a
2-hydroxyethanesulfonate salt, a benzenesulfonate salt, a
paratoluenesulfonate salt, a lauryl sulfate salt, a malate salt, an
aspartate salt, a glutamate salt, an adipate salt, a salt with
cysteine, a salt with N-acetylcysteine, a hydrochloride salt, a
hydrobromide salt, a phosphate salt, a sulfate salt, a hydroiodide
salt, a nicotinate salt, an oxalate salt, a picrate salt, a
thiocyanate salt, an undecanoate salt, a salt with an acrylate
polymer, and a salt with a carboxyvinyl polymer.
[0375] The compounds of the present invention may have
stereoisomers including optical isomers, diastereoisomers and
geometrical isomers. All of these stereoisomers and mixtures
thereof also fall within the scope of the present invention. Some
of the compounds and intermediates of the present invention may
also exist, e.g., as keto-enol tautomers.
[0376] As shown in Test Example below, the compounds of the present
invention show strong activity in an action of inhibiting binding
between SIP and its receptor, Edg-1 (S1P1). Thus, the compounds are
expected to have preventive or therapeutic effects on autoimmune,
diseases, such as Crohn disease, hypersensitivity colitis,
Sjogren's syndrome, multiple sclerosis, and systemic lupus
erythematosus, and diseases such as rheumatoid arthritis, asthma,
atopic dermatitis, organ transplant rejection, cancer, retinopathy,
psoriasis, osteoarthritis, and age-related macular
degeneration.
[0377] Preferred embodiments of the compound of the present
invention are described as follows.
[0378] A preferred example of A is an oxygen atom or --NR.sup.6--
(it is preferable that R.sup.6 be hydrogen). A more preferred
example of A is an oxygen atom.
[0379] A preferred example of R.sup.1 is an alkyl group having 1-6
carbon atoms which may be substituted with a halogen atom(s), or a
benzyl group which may be substituted with a substituent(s)
selected from the group consisting of a halogen atom and an alkyl
group having 1-6 carbon atoms. More preferred is a methyl group, an
ethyl group, or a benzyl group which may be substituted with a
halogen atom(s), and even more preferred is a methyl group.
[0380] A preferred example of R.sup.1A is a hydrogen atom.
[0381] Preferred examples of R.sup.2 are an ethyl group and a
cyclopropyl group.
[0382] A preferred example of R.sup.4 is a hydrogen atom.
[0383] In a preferred embodiment, R.sup.3 is: a optionally
substituted phenyl group; a 2-naphthyl group (the naphthyl group is
optionally substituted with a substituent(s) selected from the
group consisting of a halogen atom and an alkyl group having 1-6
carbon atoms); a 3-pyrazolyl group (the pyrazolyl group is
optionally substituted with a substituent(s) selected from the
group consisting of an alkyl group having 1-6 carbon atoms
(preferably a methyl group), a trifluoromethyl group, and a halogen
atom); or a 5-benzothiazolyl group, a 5-benzothiadiazolyl group, a
7-dihydroquinolinonyl group, a 7-isoquinolinyl group, a
7-quinolinyl group, a 3-pyridyl group, or an indolyl group
(preferably a 6-indolyl group), each optionally substituted with an
alkyl group(s) having 1-6 carbon atoms (preferably a methyl
group).
[0384] The "optionally substituted phenyl group" in the preferred
embodiment of R.sup.3 includes unsubstituted phenyl groups and
substituted phenyl groups (A)-(C) below:
(A) a phenyl group substituted at 4 position with a substituent
selected from the group consisting of an alkyl group having 1-6
carbon atoms, a cycloalkyl group having 3-8 carbon atoms, an alkoxy
group having 1-6 carbon atoms (the alkoxy group is optionally
substituted with a substituent(s) selected from the group
consisting of an amino group substituted with two alkyl groups each
having 1-4 carbon atoms, a morpholino group, and a phenyl group), a
halogen atom, a trifluoromethoxy group, a phenoxy group, a phenyl
group, a 1-pyrrolyl group, and --NR.sup.AR.sup.B (R.sup.A and
R.sup.B are alkyl groups each having 1-6 carbon atoms, or R.sup.A
and R.sup.B optionally form, together with the nitrogen atom to
which R.sup.A and R.sup.B are attached, a 3- to 5-membered
saturated hydrocarbon ring), which phenyl group substituted at 4
position is optionally further substituted at 3 position with a
substituent selected from the group consisting of an alkyl group
having 1-6 carbon atoms, a halogen atom, and an alkoxy group having
1-6 carbon atoms; (B) a phenyl group substituted at 3 position with
a substituent selected from the group consisting of a hydroxyl
group, an alkyl group having 1-6 carbon atoms, and an alkoxy group
having 1-6 carbon atoms (the alkoxy group is optionally substituted
with a substituent(s) selected from the group consisting of an
amino group substituted with two alkyl groups each having 1-4
carbon atoms, a morpholino group, and a phenyl group), which phenyl
group substituted at 3 position is optionally further substituted
with one or two alkyl groups each having 1-6 carbon atoms, or is
optionally further substituted at 4 position with a halogen atom;
and (C) a phenyl group substituted at 3 position with a substituent
selected from the group consisting of nitrogen-containing groups
(i)-(v) below and, in some cases, optionally further substituted at
4 position with a halogen atom, which nitrogen-containing groups
preferably have a tertiary nitrogen and are attached to the phenyl
group at a nitrogen atom: [0385] (i) a monocylic saturated
hydrocarbon group having 2-7 carbon atoms, having a nitrogen
atom(s) as a ring atom(s), and substituted with a phenyl group at a
carbon atom (the saturated hydrocarbon group is optionally
substituted with an alkyl group(s) having 1-6 carbon atoms) (e.g.,
a piperidinyl group optionally substituted with an alkyl group(s)
having 1-6 carbon atoms, such as a 4-piperidinyl group); [0386]
(ii) a nitrogen-containing monocylic unsaturated hydrocarbon group
(e.g., a pyrrolyl group, an imidazolyl group); [0387] (iii) a
morpholinyl group optionally substituted with an alkyl group(s)
having 1-6 carbon atoms, such as a morpholino group; [0388] (iv) an
optionally substituted piperazino group (e.g., a piperazino group
optionally substituted (preferably on a nitrogen atom constituting
a ring) with a substituent(s) selected from the group consisting of
an alkyl group having 1-6 carbon atoms (the alkyl group is
optionally substituted with a substituent(s) selected from the
group consisting of an amino group substituted with two alkyl
groups each having 1-4 carbon atoms, and a morpholino group), and
an alkanoyl group having 2-7 carbon atoms); and [0389] (v) Formula
--NR.sup.7R.sup.8, in which R.sup.7 and R.sup.8 each represent a
hydrogen atom, an alkyl group having 1-6 carbon atoms (the alkyl
group is optionally substituted with an amino group optionally
substituted with one or two alkyl groups each having 1-6 carbon
atoms, a morpholino group, a hydroxyl group, or an alkoxy group
having 1-6 carbon atoms), an alkanoyl group having 1-6 carbon
atoms, a carbamoyl group optionally substituted with one or two
alkyl groups each having 1-4 carbon atoms, a morpholinocarbonyl
group, an aminosulfonyl group optionally substituted with one or
two alkyl groups each having 1-6 carbon atoms, or an alkylsulfonyl
group having 1-6 carbon atoms, or R.sup.7 and R.sup.8 optionally
form, together with the nitrogen atom to which R.sup.7 and R.sup.8
are attached, a 3- to 8-membered saturated hydrocarbon ring, which
ring is optionally substituted with a substituent(s) selected from
the group consisting of a dimethylenedioxy group, an oxo group, and
a hydroxyl group.
[0390] It is preferable that Formula --NR.sup.7R.sup.8 in item (v)
above be --NR.sup.CR.sup.D as defined below.
[0391] R.sup.C and R.sup.D each represent a hydrogen atom, an alkyl
group having 1-6 carbon atoms (the alkyl group is optionally
substituted with an amino group optionally substituted with one or
two alkyl groups each having 1-4 carbon atoms, a hydroxyl group, or
an alkoxy group having 1-4 carbon atoms), a formyl group, an acetyl
group, an aminocarbonyl group, a dimethylaminosulfonyl group, or a
methylsulfonyl group, or R.sup.C and
R.sup.D optionally form, together with the nitrogen atom to which
R.sup.C and R.sup.D are attached, a 3- to 8-membered saturated
hydrocarbon ring, which ring is optionally substituted with a
substituent(s) selected from the group consisting of a
dimethylenedioxy group, an oxo group, and a hydroxyl group.
[0392] In an especially preferred embodiment, R.sup.3 is a phenyl
group substituted at 4 position with a fluorine atom or a chlorine
atom, a 6-indolyl group, and nitrogen-containing groups (i), (iv),
and (v) shown in item (C) above, which phenyl group substituted
with a substituent selected from the above group is optionally
further substituted at 4 position with a halogen atom.
[0393] In a preferred embodiment, R.sup.5 is: an alkyl group having
1-10 carbon atoms (preferably 1-6 carbon atoms) and substituted
with a cycloalkyl group having 3-8 carbon atoms; an alkyl group
having 1-10 carbon atoms (preferably 1-6 carbon atoms) and
substituted with a naphthyl group; an alkenyl group having 2-8
carbon atoms (preferably 2-6 carbon atoms) and substituted with a
phenyl group; a phenyl group or a naphthyl group (preferably
2-naphthyl group) each optionally substituted with 1-5 substituents
selected from the group consisting of an alkyl group having 1-6
carbon atoms, a halogen atom, an alkoxy group having 1-6 carbon
atoms, a trifluoromethoxy group, a difluoromethoxy group, a
trifluoromethyl group, an alkenyl group having 1-6 carbon atoms, an
alkylsulfonyl group having 1-6 carbon atoms, an alkanoyl group
having 2-7 carbon atoms, an alkoxycarbonyl group having 2-7 carbon
atoms, and a cyano group; a pyrrolyl group optionally substituted
with a substituent(s) selected from the group consisting of an
alkyl group having 1-6 carbon atoms (preferably a methyl group) and
a methoxycarbonyl group; a furanyl group optionally substituted
with a substituent(s) selected from the group consisting of an
alkyl group having 1-6 carbon atoms (preferably a methyl group), a
trifluoromethyl group, and a halogen atom; a thienyl group
optionally substituted with a substituent(s) selected from the
group consisting of an alkyl group having 1-6 carbon atoms
(preferably a methyl group), a trifluoromethyl group, a
thiadiazolyl group, an oxazolyl group, and a halogen atom; or a
benzothienyl group (preferably a 2-benzothienyl group), a phenyl
group condensed with a 5- to 7-membered saturated hydrocarbon ring
which may contain one or two oxygen atoms as ring-forming atoms
(e.g., a dihydrobenzodioxepinyl group, a benzodioxolyl group, a
dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a
tetrahydronaphthyl group, an indanyl group), a thiadiazolyl group,
a benzoxadiazolyl group, or a benzothiadiazolyl group (preferably
5-benzothiadiazolyl groups), each optionally substituted with a
substituent(s) selected from the group consisting of an alkyl group
having 1-6 carbon atoms (preferably a methyl group) and a halogen
atom.
[0394] In a preferred embodiment of R.sup.5, examples of the
"phenyl group which is optionally substituted" include an
unsubstituted phenyl group, a phenyl group substituted with 1-5
substituents selected from the group consisting of an alkyl group
having 1-6 carbon atoms (preferably a methyl group), an alkoxy
group having 1-6 carbon atoms (preferably a methoxy group), and a
halogen atom, and a phenyl group substituted at either 3 or 4
position or both and substituted with 1-3 substituents selected
from the group consisting of an alkyl group having 1-6 carbon
atoms, a halogen atom, an alkoxy group having 1-6 carbon atoms
(preferably a methoxy group), a trifluoromethoxy group, a
difluoromethoxy group, a trifluoromethyl group, an alkenyl group
having 1-6 carbon atoms, an alkylsulfonyl group having 1-6 carbon
atoms (preferably a methylsulfonyl group), a methoxycarbonyl group,
an acetyl group, and a cyano group, preferably a halogen atom, a
methyl group, and a methoxy group, and more preferably a halogen
atom.
[0395] In a preferred embodiment of R.sup.5, an example of the
"naphthyl group which is optionally substituted" is a naphthyl
group optionally substituted with a substituent(s) (preferably 1-3
substituents) selected from the group consisting of a halogen atom,
an alkyl group having 1-6 carbon atoms (preferably a methyl group),
a cyano group, and an alkylsulfonyl group having 1-6 carbon atoms
(preferably a methylsulfonyl group). More preferably, it is a
naphthyl group optionally substituted with a substituent(s)
selected from the group consisting of a halogen atom, an alkyl
group having 1-6 carbon atoms (preferably a methyl group), and a
cyano group. Examples in a case of a 2-naphthyl group include an
unsubstituted 2-naphthyl group and a 2-naphthyl group substituted
with a substituent(s) selected from the group consisting of an
alkyl group having 1-6 carbon atoms (substituted at any position,
preferably at 5, 7 and/or 8 position) and other substituents
(substituted at 5, 7 and/or 8 position). Examples in a case of a
1-naphthyl group include an unsubstituted 1-naphthyl group and a
1-naphthyl group substituted with a substituent(s) selected from
the group consisting of an alkyl group having 1-6 carbon atoms
(substituted at any position) and other substituents, preferably a
halogen atom (substituted preferably at 4 position).
[0396] In an especially preferred embodiment, R.sup.5 is a phenyl
group substituted at 3 and 4 positions with a halogen atom, an
unsubstituted 2-naphthyl group, and a 2-naphthyl group substituted
at 5, 7 and/or 8 position with a substituent(s) selected from the
group consisting of a halogen atom, an alkyl group having 1-6
carbon atoms (preferably a methyl group), and a cyano group.
[0397] The following are combinations of R.sup.3 and R.sup.5 that
are especially preferred. In a case in which R.sup.3 is a phenyl
group substituted at 4 position with a fluorine atom or a chlorine
atom, R.sup.5 is: an alkyl group having 1-10 carbon atoms
(preferably 1-6 carbon atoms) and substituted with a naphthyl
group; an alkenyl group having 2-8 carbon atoms (preferably 2-6
carbon atoms) and substituted with a phenyl group; a substituted
phenyl group (e.g., a phenyl group substituted with 1-5 methyl
groups, a phenyl group substituted at either 3 or 4 position or
both and substituted with 1-3 substituents selected from the group
consisting of an alkyl group having 1-6 a carbon atom (preferably a
methyl group, an ethyl group, a propyl group), a halogen atom, a
methoxy group, a trifluoromethoxy group, a difluoromethoxy group, a
trifluoromethyl group, an alkenyl group having 1-6 carbon atoms
(preferably a vinyl group), a methoxycarbonyl group, an acetyl
group, and a cyano group; a benzothienyl group; a naphthyl group
optionally substituted with a substituent(s) selected from the
group consisting of a halogen atom, an alkyl group having 1-6
carbon atoms (preferably a methyl group), a cyano group, and an
alkylsulfonyl group having 1-6 carbon atoms (preferably a
methylsulfonyl group); a pyrrolyl group optionally substituted with
a substituent(s) selected from the group consisting of a methyl
group and a methoxycarbonyl group; a thienyl group substituted with
an alkyl group(s) having 1-6 carbon atoms (preferably a methyl
group); a benzodioxolyl group; a dihydrobenzodioxynyl group; a
dihydrobenzofuranyl group; a tetrahydronaphthyl group; an indanyl
group; or a benzothiadiazolyl group (preferably a
5-benzothiadiazolyl group).
[0398] In a case in which R.sup.3 is a 6-indolyl group, R.sup.5 is:
an alkyl group having 1-10 carbon atoms (preferably 1-6 carbon
atoms) and substituted with a naphthyl group; an alkenyl group
having 2-8 carbon atoms (preferably 2-6 carbon atoms) and
substituted with a phenyl group; a phenyl group which is optionally
substituted (e.g., an unsubstituted phenyl group, a phenyl group
substituted with 1-5 methyl groups, a phenyl group substituted at
either 3 or 4 position or both and substituted with 1-3
substituents selected from the group consisting of an alkyl group
having 1-6 carbon atoms (preferably a methyl group, an ethyl group,
a propyl group), a halogen atom, a methoxy group, a
trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl
group, an alkenyl group having 1-6 carbon atoms (preferably a vinyl
group), a methoxycarbonyl group, an acetyl group, and a cyano
group); a benzothienyl group; a naphthyl group optionally
substituted with a substituent(s) selected from the group
consisting of a halogen atom, an alkyl group having 1-6 carbon
atoms (preferably a methyl group), a cyano group, and an
alkylsulfonyl group having 1-6 carbon atoms (preferably a
methylsulfonyl group); a pyrrolyl group optionally substituted with
a substituent(s) selected from the group consisting of an alkyl
group having 1-6 carbon atoms (preferably a methyl group) and a
methoxycarbonyl group; or a benzodioxolyl group, a
dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a
tetrahydronaphthyl group, an indanyl group, or a benzothiadiazolyl
group (preferably, 5-benzothiadiazolyl group), each optionally
substituted with a substituent(s) selected from the group
consisting of an alkyl group having 1-6 carbon atoms (preferably a
methyl group) and a halogen atom.
[0399] In a case in which R.sup.3 is of the embodiment shown in
item (C) above, R.sup.5 is: an alkyl group having 1-6 carbon atoms
and substituted with a cycloalkyl group having 3-8 carbon atoms; an
alkyl group having 1-10 carbon atoms (preferably 1-6 carbon atoms)
and substituted with a naphthyl group; an alkenyl group having 2-8
carbon atoms (preferably 2-6 carbon atoms) and substituted with a
phenyl group; a optionally substituted phenyl group (e.g., an
unsubstituted phenyl group, a phenyl group substituted with 1-5
substituents selected from the group consisting of an alkyl group
having 1-6 carbon atoms (preferably a methyl group) and a halogen
atom, a phenyl group substituted at 3 or 4 position or both and
substituted with 1-3 substituents selected from the group
consisting of an alkyl group having 1-6 carbon atoms, a halogen
atom, a methoxy group, a trifluoromethoxy group, a difluoromethoxy
group, a trifluoromethyl group, an alkenyl group having 1-6 carbon
atoms, an alkylsulfonyl group having 1-6 carbon atoms (preferably a
methylsulfonyl group), a methoxycarbonyl group, an acetyl group,
and a cyano group; a naphthyl group optionally substituted with a
substituent(s) selected from the group consisting of a halogen
atom, an alkyl group having 1-6 carbon atoms (preferably a methyl
group), a cyano group, and an alkylsulfonyl group having 1-6 carbon
atoms (preferably a methylsulfonyl group); a pyrrolyl group
optionally substituted with a substituent(s) selected from the
group consisting of an alkyl group having 1-6 carbon atoms
(preferably a methyl group) and a methoxycarbonyl group; a thienyl
group optionally substituted with a substituent(s) selected from
the group consisting of an alkyl group having 1-6 carbon atoms
(preferably a methyl group), a trifluoromethyl group, a
thiadiazolyl group, an oxazolyl group, and a halogen atom; a
furanyl group optionally substituted with a substituent(s) selected
from the group consisting of an alkyl group having 1-6 carbon atoms
(preferably a methyl group), a trifluoromethyl group, and a halogen
atom; or a benzothienyl group, a benzodioxolyl group, a
dihydrobenzodioxynyl group, a dihydrobenzofuranyl group, a
tetrahydronaphthyl group, an indanyl group, a thiadiazolyl group
(preferably a 5-thiadiazolyl group), a benzoxadiazolyl group, or a
benzothiadiazolyl group (preferably a 5-benzothiadiazolyl group),
each optionally substituted with a substituent(s) selected from the
group consisting of an alkyl group having 1-6 carbon atoms
(preferably a methyl group) and a halogen atom.
[0400] A preferred optically-active compound of the present
compound having R.sup.1A being a hydrogen atom has the structure
below.
##STR00005##
[0401] The compound of the present invention can be synthesized by,
for instance, the method described below.
##STR00006##
(where R.sup.1, R.sup.1A, R.sup.2, R.sup.3, and R.sup.5 are as
defined above, R' represents an alkyl group having 1-6 carbon
atoms, R'' represents a protecting group for an amino group, which
protecting group is stable under a basic condition (e.g., a
t-butoxycarbonyl group, a benzyloxycarbonyl group), L represents a
leaving group (e.g., a halogen atom, such as a chlorine atom, a
bromine atom, and an iodine atom, an alkylsulfonyloxy group, such
as an a methanesulfonyloxy group and a p-toluenesulfonyloxy group,
an arylsulfonyloxy group, a 2-oxo-1-oxazolyl group), and A.sup.1
represents an oxygen atom, a sulfur atom, or a group represented by
--NR.sup.6--, where R.sup.6 represents a hydrogen atom or an alkyl
group having 1-6 carbon atoms.)
[0402] In the present invention, a compound having A being an
oxygen atom, a sulfur atom, or a group represented by --NR.sup.6--
can be synthesized by, for instance, the method shown in Scheme
1.
[0403] The compound represented by Formula (b) can be obtained by
allowing the compound represented by Formula (a) to react with
hydrazine in a solvent or in the absence of a solvent. The amount
of the hydrazine used is generally 1-30 equivalent weight with
respect to Compound (a), preferably 5-30 equivalent weight. A
solvent to be used when it is necessary is not particularly
limited, as long as it is inert. Examples of the solvent to be used
include alcohols such as methanol and ethanol. The reaction
temperature is generally a room temperature to a solvent reflux
temperature. The reaction time is generally 12-24 hours, but it
depends on the reaction temperature and starting compounds.
[0404] The compound represented by Formula (d) can be obtained by
allowing the compound represented by Formula (b) to react with the
compound represented by Formula (c) in a solvent or in the absence
of a solvent. The amount of the compound represented by Formula (c)
to be used is generally 1-3 equivalent weight with respect to the
compound represented by Formula (b), preferably 1.1-1.5 equivalent
weight. A solvent to be used when it is necessary is not
particularly limited, as long as it is inert. For instance,
alcohols, such as methanol and ethanol, and halogenated
hydrocarbons, such as dichloromethane and chloroform, are
preferably used. The reaction temperature is generally a room
temperature to a solvent reflux temperature. The reaction time is
generally 30 minutes to 24 hours, but it depends on the reaction
temperature and starting compounds.
[0405] The compound represented by Formula (e) can be obtained by
allowing the compound of Formula (d) to react with a base in a
solvent or in the absence of a solvent to cyclize. The base to be
used includes alkali metal hydroxides such as NaOH and KOH, and
alkali metal salts such as NaHCO.sub.3 and K.sub.2CO.sub.3. The
amount of the base used is 1-10 equivalent weight with respect to
the compound represented by Formula (d), preferably 1.1-1.5
equivalent weight. If a solvent is necessary, the following can be
used as the solvent: water, alcohols such as methanol and ethanol,
ethers such as dioxane and tetrahydrofuran (THF), and mixed
solvents thereof. The reaction temperature is generally a room
temperature to a solvent reflux temperature. The reaction time is
generally a period of 30 minutes to 24 hours, but it depends on the
reaction temperature and starting compounds.
[0406] The compound represented by Formula (g) can be obtained by
allowing, in a solvent or in the absence of a solvent, the compound
represented by Formula (e) to react with the compound represented
by Formula (f) in the presence of a base. The amount of the
compound represented by Formula (f) to be used is generally 1-5
equivalent weight, preferably 1.1-1.5 equivalent weight, with
respect to the compound represented by Formula (e). The base to be
used includes alkali metal hydroxides, such as NaOH and KOH, alkali
metal salts, such as NaHCO.sub.3 and K.sub.2CO.sub.3, and amines,
such as triethylamine, diisopropylethylamine, and diisopropylamine.
The amount of the base used is 1-10 equivalent weight with respect
to the compound represented by Formula (e), preferably 1.0-3.0
equivalent weight. The reaction temperature is 0.degree. C. to a
solvent reflux temperature, preferably 0.degree. C. to a room
temperature. A solvent to be used when it is necessary is not
particularly limited, as long as it is inert. Examples of the
solvent to be used include water, ethers such as dioxane and THF,
dimethylformamide (DMF), N,N'-dimethylacetamide (DMA),
N,N'-dimethylpropyleneurea (DMPU), hexamethylphosphoramide (HMPA),
and mixed solvents thereof. The reaction time is generally a period
of 30 minutes to 24 hours, but it depends on the reaction
temperature and starting compounds.
[0407] The compound represented by Formula (h) can be obtained by
allowing the compound represented by Formula (g) to react with an
oxidant in a solvent. Examples of the solvent to be used include
organic peroxyacids such as m-chloroperbenzoic acid, magnesium
monoperphthalate hexahydrate, peroxyacetic acid, and peroxyformic
acid, inorganic or organic peroxides such as hydrogen peroxide,
hydrogen peroxide urea adduct/phthalic anhydride,
tert-butylhydroperoxide, and cumenehydroperoxide, sodium periodate,
Oxone (registered trademark), N-bromosuccinimide,
N-chlorosuccinimide, chloramine-T, hypochlorite tert-butyl,
iodobenzene diacetate, and bromine-1,4-diazabicyclo[2,2,2]octane
addition complex. The amount of the oxidant used is 2-10 equivalent
weight with respect to the compound represented by Formula (g),
preferably 2-3 equivalent weight. A solvent to be used when it is
necessary is not particularly limited, as long as it is inert.
Examples of the solvent to be used include halogenated hydrocarbons
such as methylene chloride and chloroform. The reaction temperature
is 0.degree. C. to a solvent reflux temperature, preferably
0.degree. C.-40.degree. C. The reaction time is generally a period
of 30 minutes to 24 hours, but it depends on the reaction
temperature and starting compound.
[0408] The compound represented by Formula (i) or a salt of the
compound can be obtained by subjecting the compound represented by
Formula (h) to deprotection of an amino group in a solvent under a
conventional condition, e.g., allowing it to react with an acid.
Examples of the acid used include inorganic acids (e.g.,
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric
acid, nitric acid) and organic acids (e.g., trifluoroacetic acid,
p-toluenesulfonic acid, methanesulfonic acid). The amount of the
acid used is 1-50 equivalent weight with respect to the compound
represented by Formula (h). The reaction temperature is 0.degree.
C. to a solvent reflux temperature, preferably a room temperature
to 40.degree. C. A solvent to be used when it is necessary is not
particularly limited, as long as it is inert. Examples of the
solvent to be used include halogenated hydrocarbons such as
methylene chloride and chloroform. The reaction time is generally a
period of 30 minutes to 24 hours, but it depends on the reaction
temperature and starting compound.
[0409] The compound represented by Formula (k) or a
pharmaceutically acceptable salt of the compound can be obtained by
allowing, in a solvent or in the absence of a solvent, the compound
represented by Formula (i) to react with the compound represented
by Formula (j) (where A.sup.1 represents an oxygen atom, a sulfur
atom, or a group represented by Formula --NR.sup.6--, and R.sup.3
is as defined above) in the presence of a base and, when necessary,
forming a salt. The amount of the compound of Formula (j) to be
used is generally 1-5 equivalent weight with respect to the
compound represented by Formula (i), preferably 1-3 equivalent
weight. Examples of the base used include alkali metal salts, such
as sodium carbonate, potassium carbonate, cesium carbonate, sodium
hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide,
dimsyl sodium, sodium hydride, sodium amide, tert-butoxypotassium,
and tert-butoxysodium, amines, such as triethylamine,
diisopropylamine, pyrrolidine, and piperidine, sodium acetate, and
potassium acetate. The amount of the base used is generally 1-10
equivalent weight with respect to the compound represented by
Formula (i), preferably 1-3 equivalent weight. The reaction
temperature is 0.degree. C. to a solvent reflux temperature, and it
can be carried out under ordinary pressure, increased pressure,
microwave irradiation, or the like. The reaction solvent to be used
includes ethers such as dioxane and THF, DMF, DMA, DMPU, RMPA, or
the like, or mixed solvents thereof. The reaction time is generally
a period of 1-12 hours, but it depends on the reaction temperature
and starting compound.
[0410] The compound represented by Formula (m) or a
pharmaceutically acceptable salt of the compound can be obtained by
allowing, in a solvent or in the absence of a solvent, the compound
represented by Formula (k) to react with the compound represented
by Formula (l) in the presence of a base and, when necessary,
forming a salt. The amount of the compound represented by Formula
(l) used is 1-5 equivalent weight with respect to the compound
represented by Formula (k), preferably 1-1.2 equivalent weight. The
base to be used includes alkali metal hydroxides, such as NaOH and
KOH, alkali metal salts, such as NaHCO.sub.3 and K.sub.2CO.sub.3,
or amines, such as triethylamine, diisopropylethylamine, and
diisopropylamine. The amount of the base used is 1-10 equivalent
weight with respect to the compound represented by Formula (k),
preferably 1.0-3.0 equivalent weight. The reaction temperature is
0.degree. C. to a solvent reflux temperature, preferably 0.degree.
C. to a room temperature. A solvent to be used when it is necessary
is not particularly limited, as long as it is inert. Examples of
the solvent to be used include halogenated hydrocarbons such as
methylene chloride and chloroform, ethers such as dioxane and THF,
and mixed solvents thereof. The reaction time is generally a period
of 30 minutes to 24 hours, but it depends on the reaction
temperature and starting compound.
##STR00007## ##STR00008##
(where R.sup.1, R.sup.1A, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R',
R'', A, and L are as defined above, R.sup.41 is the same as R.sup.4
excluding the hydrogen atom).
[0411] In the present invention, a compound having A represented by
Formula --SO-- or Formula --SO.sub.2-- can be synthesized by the
method shown in Scheme 2.
[0412] The compound represented by Formula (m2), the compound
represented by Formula (m3), or pharmaceutically acceptable salts
of the compounds can be obtained by allowing, among the compounds
obtained in Scheme 1 and represented by Formula (m), the compound
represented by Formula (m1) having A.sup.1 being a sulfur atom to
react with an oxidant and, when necessary, forming a salt. Examples
of the oxidant to be used include organic peroxyacids such as
m-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate,
peroxyacetic acid, and peroxyformic acid, inorganic or organic
peroxides such as hydrogen peroxide, hydrogen peroxide urea
adduct/phthalic anhydride, tert-butylhydroperoxide, and
cumenehydroperoxide, sodium periodate, Oxone (registered
trademark), N-bromosuccinimide, N-chlorosuccinimide, chloramine-T,
hypochlorite tert-butyl, iodobenzene diacetate, and
bromine-1,4-diazabicyclo[2,2,2]octane addition complex. The amount
of the oxidant used is 1-10 equivalent weight with respect to the
compound represented by Formula (m1), preferably 1-3 equivalent
weight. A solvent to be used when it is necessary is not
particularly limited, as long as it is inert. Examples of the
solvent to be used include halogenated hydrocarbons such as
methylene chloride and chloroform. The reaction temperature is
-78.degree. C. to a solvent reflux temperature, preferably
0.degree.-40.degree. C. The reaction time is generally a period of
30 minutes to 24 hours, but it depends on the reaction temperature
and starting compound.
[0413] In the present invention, a compound having A represented by
--CH.sub.2-- can be synthesized by the method shown in Scheme
3.
[0414] The compound represented by Formula (o) can be obtained by
allowing the compound represented by Formula (a) to react with the
compound represented by Formula (n) (R.sup.2 is as defined above)
in a solvent or in the absence of a solvent. The amount of the
compound represented by Formula (n) to be used is 1-10 equivalent
weight with respect to the compound represented by Formula (a),
preferably 1-1.2 equivalent weight. A solvent to be used when it is
necessary is not particularly limited, as long as it is inert.
Examples of the solvent to be used include alcohols such as
methanol and ethanol. The reaction temperature is generally a room
temperature to a solvent reflux temperature, preferably a room
temperature to 50.degree. C. The reaction time is generally a
period of 12-24 hours, but it depends on the reaction temperature
and starting compound.
[0415] The compound represented by Formula (p) can be obtained by
allowing the compound represented by Formula (o) to react with a
Lawesson's reagent in a solvent or in the absence of a solvent. The
amount of the Lawesson's reagent used is 1-5 equivalent weight with
respect to the compound represented by Formula (o), preferably
1-1.2 equivalent weight. The reaction solvent to be used includes
ethers such as dioxane and THF, and mixed solvents thereof. The
reaction temperature is a room temperature to a solvent reflux
temperature, preferably a room temperature to 50.degree. C. The
reaction time is generally 1-12 hours, but it depends on the
reaction temperature and starting compounds.
[0416] The compound represented by Formula (r) can be obtained by
allowing the compound represented by Formula (p) to react with the
compound represented by Formula (q) in the presence of a mercury
compound. The amount of the compound represented by Formula (q) to
be used is 1-10 equivalent weight with respect to the compound
represented by Formula (p), preferably 1-1.2 equivalent weight.
Examples of the mercury compound include HgCl.sub.2 and
Hg(OAc).sub.2. The amount of the mercury compound used is 1-10
equivalent weight with respect to the compound represented by
Formula (p), preferably 1-1.2 equivalent weight. The solvent to be
used includes acetonitrile, THF, dioxane, and the like. The
reaction temperature is a room temperature to a solvent reflux
temperature, preferably a room temperature to 50.degree. C. The
reaction time is generally a period of 12-48 hours, but it depends
on the reaction temperature and starting compound.
[0417] The compound represented by Formula (k1) or a salt of the
compound can be obtained by subjecting the compound represented by
Formula (r) to deprotection of an amino group in a solvent under a
conventional condition, e.g., allowing it to react with an acid.
Examples of the acid include inorganic acids (e.g., hydrochloric
acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric
acid) and organic acids (e.g., trifluoroacetic acid,
p-toluenesulfonic acid, methanesulfonic acid). The amount of the
acid used is 1-50 equivalent weight with respect to the compound
represented by Formula (r). The reaction temperature is 0.degree.
C. to a solvent reflux temperature, preferably a room temperature
to 40.degree. C. A solvent to be used when it is necessary is not
particularly limited, as long as it is inert. Examples of the
solvent to be used include halogenated hydrocarbons such as
methylene chloride and chloroform. The reaction time is generally a
period of 30 minutes to 24 hours, but it depends on the reaction
temperature and starting compound.
[0418] The compound represented by Formula (m4) or a
pharmaceutically acceptable salt of the compound can be obtained by
allowing, in a solvent or in the absence of a solvent, the compound
represented by Formula (k1) to react with the compound represented
by Formula (l) in the presence of a base and, when necessary,
forming a salt. The amount of the compound represented by Formula
(l) to be used is 1-5 equivalent weight with respect to the
compound represented by Formula (k1), preferably 1-1.2 equivalent
weight. The base to be used includes alkali metal hydroxides, such
as NaOH and KOH, alkali metal salts, such as NaHCO.sub.3 and
K.sub.2CO.sub.3, and amines, such as triethylamine,
diisopropylethylamine, and diisopropylamine. The amount of the base
is 1-10 equivalent weight, preferably 1.0-3.0 equivalent weight.
The reaction temperature is 0.degree. C. to a solvent reflux
temperature, preferably 0.degree. C. to a room temperature. A
solvent to be used when it is necessary is not particularly
limited, as long as it is inert. Examples of the solvent to be used
include halogenated hydrocarbons such as methylene chloride and
chloroform, ethers such as dioxane and THF, and mixed solvents
thereof. The reaction time is generally a period of 30 minutes to
24 hours, but it depends on the reaction temperature and starting
compound.
[0419] The compound represented by Formula (u) or a
pharmaceutically acceptable salt of the compound can be obtained by
allowing, in a solvent or in the absence of a solvent, the compound
represented by Formula (m5) to react with the compound represented
by Formula (s) in the presence of a base and, when necessary,
forming a salt. The amount of the compound represented by Formula
(s) to be used is generally 1-10 equivalent weight with respect to
the compound represented by Formula (m5), preferably 1.1-1.5
equivalent weight. The base to be used includes alkali metal
hydroxides, such as NaOH and KOH, alkali metal salts, such as
NaHCO.sub.3 and K.sub.2CO.sub.3, and amines, such as triethylamine,
diisopropylethylamine, and diisopropylamine. The amount of the base
used is 1-10 equivalent weight with respect to the compound
represented by Formula (m5), preferably 1.0-3.0 equivalent weight.
The reaction temperature is 0.degree. C. to a solvent reflux
temperature, preferably 0.degree. C. to a room temperature. A
solvent to be used when it is necessary is not particularly
limited, as long as it is inert. Examples of the solvent to be used
include water, ethers such as dioxane and THF, dimethylformamide
(DMF), N,N'-dimethylacetamide (DMA), N,N'-dimethylpropyleneurea
(DMPU), hexamethylphosphoramide (HMPA), and mixed solvents thereof.
The reaction time is generally a period of 30 minutes to 24 hours,
but it depends on the reaction temperature and starting
compound.
[0420] Further, a functional group can be introduced to R.sup.3 by
carrying out protection, deprotection, functional group
transformation in the process described above.
[0421] For use as pharmaceutical preparations, the compounds of the
present invention may be supplemented with commonly used
excipients, extenders, pH regulators, solubilizers and so on, and
then formulated using standard techniques into tablets, granules,
pills, capsules, powders, solutions, suspensions, injections, etc.
The pharmaceutical preparations thus obtained can be administered
as oral or parenteral formulations.
[0422] The compound of the present invention can be administered to
an adult patient at a dose of 1-1000 mg per day in several
separated doses. This dosage can be increased or reduced according
to a type of a disease, an age, a weight, and a symptom of a
patient, or the like.
Advantageous Effect of the Invention
[0423] As the Test Example described below shows, it is found that
the compounds of the present invention are strong Edg-1 (S1P.sub.1)
ligands.
BEST MODE FOR CARRYING OUT THE INVENTION
[0424] The following describes the present invention in more
detail, with reference to Examples and the Test Example.
Example 1
3,4-Dichloro-N--{(R)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]-triazol-3-y-
l]ethyl}benzenesulfonamide (Compound 12)
##STR00009##
[0425] (R)-(1-Hydrazinocarbonyl-2-ethyl)carbamic acid t-butyl
ester
##STR00010##
[0426] (1) Hydrazine monohydrate (30 ml) was added to a solution of
N-(t-butoxycarbonyl)-D-alanine methyl ester (41.8 g) in methanol
(180 ml), and the mixture was stirred at room temperature for 12
hours. The reaction solution was concentrated, and the resulting
crude crystal was washed with a mixed solvent of hexane and ethyl
acetate (1:1, 300 ml) and then dried to give the titled compound as
a colorless powder (32.6 g).
[0427] .sup.1H NMR (300 MHz, DMDO-d.sub.6) .delta. ppm: 1.14 (d,
J=7.2 Hz, 3H), 1.37 (s, 9H), 3.30-4.09 (m, 3H), 6.70-6.90 (m, 1H),
8.96 (br s, 1H)
(R)-2-(N-(t-Butoxycarbonyl)amino)propionyl)-N-ethylhydrazinecarbothioamide
##STR00011##
[0428] (2) Ethyl isothiocyanate (14.6 ml) was added to a solution
of the compound (30.8 g) of Example 1-(1) in ethanol (152 ml), and
the mixture was heated under reflux for two hours. Then, the
mixture was cooled to room temperature, and the resulting crystal
was filtered. The filtrate was concentrated, and the resulting
residue was purified by silica-gel chromatography with a mixed
solvent of ethyl acetate and chloroform to give the titled compound
as a colorless amorphous substance (43.2 g).
[0429] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm: 0.98-1.28
(m, 6H), 1.40 (s, 9H), 3.25-3.65 (m, 2H), 3.77-3.95 (m, 1H),
7.20-7.39 (m, 1H), 7.45-7.60 (m, 1H), 9.25 (s, 1H), 10.00 (s,
1H)
[(R)-1-(4-Ethyl-5-mercapto-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic
acid t-butyl ester
##STR00012##
[0430] (3) One mol/l aqueous sodium hydroxide (218 ml) was added to
a mixed solution of the compound (42.1 g) of Example 1-(2) in
methanol (120 ml) and dioxane (240 ml), and the mixture was heated
under reflux for three hours. The reaction solution was
concentrated, and an aqueous hydrochloric acid (2N, 100 ml) was
added. The mixture was extracted with a mixed solution of ethyl
acetate, chloroform, and methanol (10:10:1, 500 ml). The organic
layer was dried over anhydrous magnesium sulfate and evaporated
under reduced pressure to remove the solvent. The resulting residue
was washed with a mixed solvent of hexane and ethyl acetate (1:1,
300 ml) and then dried to give the titled compound as a white solid
(29.22 g).
[0431] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm: 1.21 (t,
J=7.1 Hz, 3H), 1.30-1.50 (m, 3H), 1.39 (s, 9H), 3.82-4.05 (m, 2H),
4.72-4.88 (m, 1H), 7.58 (d, J=8.5 Hz, 1H), 13.60 (br s, 1H
[(R)-1-(4-Ethyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic
acid t-butyl ester
##STR00013##
[0432] (4) Diisopropylamine (17.4 ml) and MeI (7.7 ml) were added
to a solution of the compound (28.12 g) of Example 1-(3) in THF
(200 ml), and the mixture was stirred at room temperature for one
hour. Thereafter, the resulting crystal was filtered. The filtrate
was concentrated, and the resulting crude crystal was washed with a
mixed solvent of hexane and ethyl acetate (3:1, 200 ml) and then
dried to give the titled compound as a white powder (29.5 g).
[0433] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm: 1.21 (t,
J=7.0 Hz, 3H), 1.38 (s, 9H), 1.45 (t, J=7.0 Hz, 3H), 2.62 (s, 3H),
3.80-4.00 (m, 2H), 4.85-4.92 (m, 1H), 7.52 (d, J=8.5 Hz, 1H)
[(R)-1-(4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic
acid t-butyl ester
##STR00014##
[0434] (5) With ice cooling, m-chloroperbenzoic acid (43.0 g) was
added in four portions to a solution of the compound (21.0 g) of
Example 1-(4) in chloroform (293 ml), and the mixture was stirred
at room temperature for three hours and thereafter at 40.degree. C.
for one hour. Na.sub.2S.sub.2O.sub.3 (12.9 g) and 1 mol/l aqueous
sodium hydroxide (300 ml) were added to the reaction solution to
separate the organic layer, and the organic layer was washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate, and evaporated under reduced pressure to remove the
solvent. The resulting residue was purified by silica-gel flush
column chromatography with a mixed solvent of hexane and ethyl
acetate, and then recrystallized with hexane and chloroform to give
the titled compound as a white powder (17.2 g).
[0435] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm: 1.44 (s, 9H),
1.49 (t, J=7.1 Hz, 3H), 1.67 (t, J=6.8 Hz, 3H), 3.53 (s, 3H),
4.25-4.59 (m, 2H), 4.92-5.20 (m, 2H)
(R)-1-(4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethylamine
trifluoroacetic acid salts
##STR00015##
[0436] (6) Trifluoroacetic acid (121 ml) was added to the compound
(100.0 g) obtained in Example 1-(5), and the mixture was stirred at
room temperature for two hours. The reaction solution was
concentrated under reduced pressure to give the titled compound as
a white powder (103.8 g).
[0437] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm: 1.37 (t,
J=7.2 Hz, 3H), 1.59 (d, J=6.8 Hz, 3H), 3.65 (s, 3H), 4.21-4.50 (m,
2H), 4.72-4.90 (m, 1H), 8.69 (br s, 3H)
(1R)-1-(4-Ethyl-5(4-fluorophenoxy)-4H-[1,2,4]-triazol-3-yl)ethylamine
##STR00016##
[0438] (7) In a pressure-resistant screw cap test tube, [0439]
N,N'-dimethylpropyleneurea (DMPU) (5 mL), 4-fluorophenol (1.01 g)
and cesium carbonate (2.94 g) were added to the compound (1.00 g)
obtained in Example 1-(6), and the mixture was stirred at
200.degree. C. for one hour. The mixture was brought to room
temperature, and saturated aqueous sodium chloride was added. The
mixture was extracted with ethyl acetate (100 ml.times.5). The
organic layer was dried over anhydrous sodium sulfate, filtered,
and evaporated under reduced pressure to remove the solvent. The
resulting crude product was purified by column chromatography (NH
SiO.sub.2, hexane/ethyl acetate=50/50 to 20/80,
chloroform/methanol=30/1) to give the titled compound (brown oil
compound, 0.586 g).
[0440] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 1.41 (t,
J=7.3 Hz, 3H), 1.58 (d, J=6.4 Hz, 3H), 3.95-4.23 (m, 3H), 6.90-7.15
(m, 2H), 7.30-7.44 (m, 2H)
3,4-Dichloro-N-{(R)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]-triazol-3-yl-
]ethyl}benzenesulfonamide (Compound 12)
##STR00017##
[0441] (8) Triethylamine (0.93 mL, 6.64 mmol) and
3,4-dichlorobenzenesulfonyl chloride (0.45 mL, 2.88 mmol) were
added at room temperature to a solution of the compound (0.554 g)
of Example 1-(7) in THF (10 mL), and the mixture was stirred at
room temperature for 2.5 hours. Then, ethyl acetate was added. The
organic layer was washed with 1N aqueous hydrochloric acid and
thereafter with saturated aqueous sodium chloride, dried over
anhydrous magnesium sulfate, filtered, and evaporated under reduced
pressure to remove the solvent. The resulting crude product was
purified by column chromatography (acidic OH SiO.sub.2,
hexane/ethyl acetate=50/50 to 10/90) and then recrystallized (ethyl
acetate-hexane) to give 0.447 g of the titled compound (Compound
12) as a colorless powder.
[0442] Melting point: 190.0.degree. C. to 192.0.degree. C.
Example 2
N-[(1R)-1-(4-Ethyl-5(4-methylphenylamino)-4H-[1,2,4]triazol-3-yl)ethyl]3,4-
-dichlorobenzenesulfonamide (Compound 61)
##STR00018##
[0443]
(R)-1-(4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethylamine
##STR00019##
[0444] (1) To the compound (4.30 g) obtained in Example 1-(6),
n-BuNH.sub.2 (20 ml) was added, and the mixture was stirred at room
temperature for one hour. The reaction solution was concentrated,
and the resulting crude product was purified by NH silica-gel
chromatography with a mixed solvent of methanol and chloroform
(methanol/chloroform=10%) to give the titled compound as a
colorless crystal (2.737 g).
[0445] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. ppm: 1.53 (t,
J=7.3 Hz, 3H), 1.65 (d, J=6.8 Hz, 3H), 3.53 (s, 3H), 4.14-4.58 (m,
3H)
[5-((R)-1-Aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-4-methylphenylamine
##STR00020##
[0446] (2) The compound (437 mg) obtained in Example 2-(1), DMPU
(2.0 mL), 4-toluidine (257 mg), and NaH (240 mg, 60-72 wt % oily)
were put in a pressure-resistant screw cap test tube. The mixture
was stirred at 200.degree. C. for 1.0 hour and then brought to room
temperature, and 10% methanol/chloroform was added to the reaction
solution. The reaction solution was filtered through NH silica gel
and then concentrated, and the resulting brown oily substance was
purified by column chromatography (NH SiO.sub.2, ethyl
acetate/hexane=50-99%, methanol/chloroform=5%) to give the titled
compound (brown oil compound, 224 mg).
[0447] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. ppm: 1.31 (t,
J=7.3 Hz, 3H), 1.60 (d, J=6.6 Hz, 3H), 2.28 (s, 3H), 3.60-4.30 (m,
3H), 6.96-7.02 (m, 4H)
N-[(1R)-1-(4-Ethyl-5(4-methylphenylamino)-4H-[1,2,4]triazol-3-yl)ethyl]3,4-
-dichlorobenzenesulfonamide (Compound 61)
##STR00021##
[0449] A solution of 3,4-dichlorobenzenesulfonyl chloride (154
.mu.l) in THF (2.0 ml) was added at room temperature to a solution
of the compound (220 mg) of Example 2-(2) and triethylamine (0.249
ml) in THF (9.0 ml), and the mixture was stirred at room
temperature for five hours. The insoluble matter was filtered off,
and the resulting residue was concentrated. The resulting crude
product was purified by OH silica-gel column chromatography
(elution solvent: ethyl acetate/hexane=50-99%) and then
recrystallized (ethyl acetate-hexane) to give 160 mg of the titled
compound (Compound 61) as a pale yellow powder.
[0450] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.18 (t,
J=7.1 Hz, 3H), 1.30 (d, J=6.9 Hz, 3H), 2.23 (s, 3H), 3.87-4.03 (m,
2H), 4.63-4.72 (m, 1H), 7.00-7.12 (m, 2H), 7.35-7.45 (m, 2H), 7.74
(dd, J=8.6, 1.9 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.96 (d, J=1.9 Hz,
1H), 8.27 (s, 1H), 8.57-8.66 (m, 1H)
[0451] Melting point: 93.0.degree. C. to 99.0.degree. C.
Example 3
3,4-Dichloro-N--[(R)-1-(4-ethyl-5(4-methylbenzenesulfenyl)-4H-[1,2,4]triaz-
ol-3-yl)-ethyl]-benzenesulfonamide (Compound 55)
##STR00022##
[0452]
(R)-1-(4-Ethyl-5(4-methylphenylsulfanyl)-4H-[1,2,4]triazol-3-yl)-et-
hylamine
##STR00023##
[0453] (1) The compound (5.00 g, 15.1 mmol) obtained in Example
1-(6), DMF (50 mL), 4-methylbenzenethiol (3.74 g, 30.1 mmol), and
cesium carbonate (14.7 g, 45.1 mmol) were put in a
pressure-resistant screw cap test tube. The mixture was stirred at
150.degree. C. for four hours and thereafter brought back to room
temperature, and a mixed solvent of chloroform/methanol (10/1) was
added. The insoluble matter was filtered off. The filtrate was
removed by evaporation under reduced pressure, and the resulting
crude product was purified by column chromatography (NH SiO.sub.2,
hexane/ethyl acetate=50/50 to 10/90, chloroform/methanol=40/1) to
give 3.01 g of the titled compound (colorless oily compound).
[0454] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm 1.21 (t, J=7.3
Hz, 3H), 1.59 (d, J=6.4 Hz, 3H), 2.31 (s, 3H), 4.00-4.18 (m, 3H),
7.06-7.14 (m, 2H), 7.26-7.30 (m, 2H)
3,4-Dichloro-N--[(R)-1-(4-ethyl-5(4-methylbenzenesulfanyl)-4H-[1,2,4]triaz-
ol-3-yl)-ethyl]-benzenesulfonamide (Compound 55)
##STR00024##
[0455] (2) Starting from the compound obtained in Example 3-(1),
the same procedure as used in Example 1-(8) was repeated to give
the titled compound.
[0456] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 1.08 (t,
J=7.3 Hz, 3H), 1.32 (d, J=6.9 Hz, 3H), 2.28 (s, 3H), 3.90-4.11 (m,
2H), 4.78 (q, J=6.9 Hz, 1H), 7.17-7.23 (m, 4H), 7.67-7.74 (m, 1H),
7.81-7.88 (m, 1H), 7.92-7.94 (m, 1H), 8.77 (s, 1H)
[0457] Yield: 46%, Melting point: 141.0.degree. C. to 143.0.degree.
C.
Example 4
3,4-Dichloro-N--[(R)-1-[4-ethyl-5(4-methylbenzenesulfonyl)-4H-[1,2,4]triaz-
ol-3-yl]-ethyl]-benzenesulfonamide (Compound 57)
##STR00025##
[0459] To a solution of the compound (0.300 g) of Example 3-(2) in
chloroform (6 mL), m-chloroperbenzoic acid (0.329 g) was added, and
the mixture was stirred at room temperature for one hour. Then, a
further portion of m-chloroperbenzoic acid (0.329 g) was added, and
the mixture was stirred at room temperature for 15 hours.
Thereafter, a further portion of m-chloroperbenzoic acid (0.329 g)
was added, and the mixture was stirred at room temperature for two
hours. Then, ethyl acetate was added, and the organic layer was
washed with 5% aqueous Na.sub.2S.sub.2O.sub.3 solution and
thereafter with saturated aqueous sodium bicarbonate, dried over
anhydrous magnesium sulfate, filtered, and evaporated under reduced
pressure to remove the solvent. The resulting residue was purified
by column chromatography (acidic OH SiO.sub.2, hexane/ethyl
acetate=70/30 to 40/60) and then recrystallized (ethyl
acetate-hexane) to give 0.196 g of the titled compound (Compound
57) (colorless powdered compound). .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. ppm 1.25-1.35 (m, 6H), 2.45 (s, 3H),
4.23-4.40 (m, 2H), 4.78-4.86 (m, 1H), 7.52-7.56 (m, 2H), 7.62-7.67
(m, 1H), 7.78-7.82 (m, 1H), 7.86-7.94 (m, 3H)
[0460] Melting point: 164.0.degree. C. to 165.0.degree. C.
Example 5
3,4-Dichloro-N--[(R)-1-[4-ethyl-5(4-methylbenzyl)-4H-[1,2,4]triazol-3-yl]--
ethyl]-benzenesulfonamide (Compound 56)
##STR00026##
[0461] ((R)-1-Ethylcarbamoyl-ethyl)-carbamic acid t-butyl ester
##STR00027##
[0462] (1) EtNH.sub.2 (10 ml, 70% aqueous solution) was added to
N-(t-butoxycarbonyl)-D-alanine methyl ester (4.76 g) in methanol
(20 ml), and the mixture was stirred at room temperature for 19
hours. The reaction solution was concentrated, and the resulting
crude product was purified by column chromatography (acidic OH
SiO.sub.2, chloroform/ethyl acetate=10-50%) to give 3.96 g of the
titled compound (colorless amorphous substance).
[0463] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. ppm: 1.12 (t,
J=7.2 Hz, 3H), 1.35 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 3.18-3.37 (m,
2H), 4.00-4.20 (m, 1H), 4.90-5.10 (m, 1H), 6.04-6.22 (m, 1H)
((R)-1-Ethylthiocarbamoyl-ethyl)-carbamic acid t-butyl ester
##STR00028##
[0464] (2) A Lawesson's reagent (8.89 g) was added to a solution of
the compound (3.96 g) of Example 5-(1) in THF (92 ml), and the
mixture was stirred at room temperature for one hour and thereafter
at 50.degree. C. for 30 minutes. The reaction solution was cooled
to room temperature, and the insoluble matter was filtered off.
Then, the resulting residue was concentrated. The resulting crude
product was purified by column chromatography (acidic OH SiO.sub.2,
chloroform/ethyl acetate=10-50%) and thereafter by NH silica-gel
column chromatography (ethyl acetate/hexane=50%) to give the titled
compound (3.75 g) as a colorless powder.
[0465] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. ppm: 1.26 (t,
J=7.2 Hz, 3H), 1.38-1.52 (m, 3H), 1.45 (s, 9H), 3.60-3.77 (m, 2H),
4.36-4.53 (m, 1H), 5.10-5.32 (m, 1H), 7.99-8.24 (m, 1H)
[(R)-1-[4-Ethyl-5(4-methylbenzyl)-4H-[1,2,4]triazol-3-yl]-ethyl]-carbamic
acid t-butyl ester
##STR00029##
[0466] (3) Hg (OAc).sub.2 (2.43 g) was added to a solution of the
compound (1.61 g) obtained in Example 5-(2) and
4-methylphenylacetic acid hydrazide (1.25 g) in CH.sub.3CN (30 mL),
and the mixture was stirred at room temperature for 42 hours. Ethyl
acetate was added to the reaction solution, and the insoluble
matter was filtered off through celite. The filtrate was washed
with 1N aqueous KHSO.sub.4 solution and thereafter with saturated
aqueous sodium chloride, dried over anhydrous magnesium sulfate,
filtered, and evaporated under reduced pressure to remove the
solvent. The resulting crude product was purified by column
chromatography (acidic OH SiO.sub.2, ethyl acetate/hexane=50-100%,
methanol/chloroform=1/1) (neutral OH SiO.sub.2,
methanol/chloroform=1/10) to give 0.530 g of the titled compound
(colorless amorphous substance).
[0467] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 1.04 (t,
J=7.3 Hz, 3H), 1.41 (s, 9H), 1.61 (d, J=6.9 Hz, 3H), 2.30 (s, 3H),
3.73-3.90 (m, 2H), 4.06-4.20 (m, 2H), 4.85-4.94 (m, 1H), 5.11-5.17
(m, 1H), 7.09 (s, 4H)
(R)-1-[4-Ethyl-5-(4-methylbenzyl)-4H-[1,2,4]triazol-3-yl]-ethylamine
##STR00030##
[0468] (4) Trifluoroacetic acid (5 mL) was added to a solution of
the compound (0.496 g) of Example 5-(3) in chloroform (5 mL), and
the mixture was stirred at room temperature for 18 hours. Aqueous
sodium hydroxide (1.0N) was added, and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
aqueous sodium chloride, dried over anhydrous sodium sulfate,
filtered, and evaporated under reduced pressure to remove the
solvent, whereby 0.148 g of the titled compound was obtained as a
colorless oily compound.
[0469] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 1.09 (t,
J=7.3 Hz, 3H), 1.57 (d, J=6.9 Hz, 3H), 2.30 (s, 3H), 3.74-3.94 (m,
2H), 4.01-4.20 (m, 3H), 7.10 (s, 4H)
3,4-Dichloro-N--[(R)-1-[4-ethyl-5(4-methylbenzyl)-4H-[1,2,4]triazol-3-yl]--
ethyl]-benzenesulfonamide (Compound 56)
##STR00031##
[0470] (5) Triethylamine (0.25 mL) and 3,4-dichlorobenzenesulfonyl
chloride (0.707 mL) were added to a solution of the compound (0.144
g) of Example 5-(4) in THF (3 mL), and the mixture was stirred at
room temperature for 3.5 hours. Then, 2N aqueous hydrochloric acid
was added, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated aqueous sodium chloride,
dried over anhydrous magnesium sulfate, filtered, and evaporated
under reduced pressure to remove the solvent. The resulting residue
was purified by column chromatography (acidic OH SiO.sub.2,
chloroform/methanol=50/1 to 10/1) and then recrystallized (ethyl
acetate-hexane) to give 0.100 g of the titled compound (Compound
56) as a colorless powdered compound.
[0471] .sup.1H NMR (600 MHz, DMSO-D6) .delta. ppm: 0.91 (t, J=7.1
Hz, 3H), 1.26 (d, J=6.9 Hz, 3H), 2.23 (s, 3H), 3.77-3.92 (m, 2H),
4.00 (s, 2H), 4.60-4.70 (m, 1H), 7.03-7.12 (m, 4H), 7.64-7.68 (m,
1H), 7.79-7.82 (m, 1H), 7.89-7.91 (m, 1H), 8.64 (s, 1H)
[0472] Melting point: 189.0.degree. C. to 191.0.degree. C.
Example 6
3,4-Dichloro-N--[(R)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl-
]-ethyl]-N-methyl-benzenesulfonamide (Compound 115)
##STR00032##
[0474] K.sub.2CO.sub.3 (78 mg) and MeI (0.022 ml) were added at
room temperature to a solution of Compound 12 (150 mg) of Example 1
in dimethylformamide (2.0 ml), and the mixture was stirred at room
temperature for three hours. Water was added to the reaction
solution, and the mixture was extracted with a mixed solution of
methanol/chloroform (methanol/chloroform=1/4). The resulting
organic layer was washed with saturated aqueous sodium chloride,
dried (MgSO.sub.4), filtered, and evaporated under reduced pressure
to remove the solvent. After eluting the residue with a mixed
solvent of ethyl acetate and hexane, the resulting elute was
purified by column chromatography (acidic OH SiO.sub.2, ethyl
acetate/hexane=50-99%, methanol/chloroform=0-10%) and then
recrystallized (ethyl acetate-hexane) to give 111 mg of the titled
compound as a colorless powdered compound.
[0475] Melting point: 125.5.degree. C. to 126.5.degree. C.
Example 7
3,4-Dichloro-N--((R)-1-[5-[3-(1,4-dioxa-8-aza-spiro[4.5]decan-8-yl)-phenox-
y]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide
(Compound 87)
##STR00033##
[0476] 3-(1,4-Dioxa-8-aza-spiro[4.5]decen-8-yl)-phenol
##STR00034##
[0477] (1) In a pressure-resistant screw cap test tube,
3-bromophenol (1.50 g), 1,4-dioxa-8-azaspiro[4,5]decan (1.49 g),
Pd.sub.2(dba).sub.3 (0.079 g),
(2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0.082 g),
and LiN(TMS).sub.2 (20% in THF, 18 mL) were put, and the mixture
was stirred at 65.degree. C. for 7.5 hours. Ethyl acetate was
added, and the organic layer was washed with 1N aqueous
hydrochloric acid and thereafter with saturated aqueous sodium
bicarbonate, dried over anhydrous sodium sulfate, filtered, and
evaporated under reduced pressure to remove the solvent. The
resulting residue was purified by column chromatography (acidic OH
SiO.sub.2, hexane/ethyl acetate=70/30 to 60/40) to give 1.96 g of
the titled compound (brown oil).
[0478] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 1.79-1.83 (m,
4H), 3.27-3.35 (m, 4H), 3.98 (s, 4H), 4.86 (s, 1H), 6.28 (dd,
J=8.0, 2.5 Hz, 1H), 6.41 (t, J=2.3 Hz, 1H), 6.51 (dd, J=8.5, 2.5
Hz, 1H), 7.08 (t, J=8.3 Hz, 1H)
(R)-1-[5-[3-(1,4-Dioxa-8-aza-spiro[4.5]decan-8-yl)-phenoxy]-4-ethyl-4H-[1,-
2,4]triazol-3-yl]-ethylamine
##STR00035##
[0479] (2) Starting from the compound obtained in Example 7-(1) in
place of 4-fluorophenol, the same procedure as used in Example
1-(7) was repeated to give the titled compound (brown oily
substance, yield 58%).
[0480] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 1.38 (t,
J=7.3 Hz, 3H), 1.57 (d, J=6.9 Hz, 3H), 1.77-1.83 (m, 4H), 3.27-3.36
(m, 4H), 3.95-4.06 (m, 6H), 4.14 (q, J=6.9 Hz, 1H), 6.70-6.75 (m,
2H), 6.97 (t, J=2.3 Hz, 1H), 7.20 (t, J=8.3 Hz, 1H)
3,4-Dichloro-N--((R)-1-[5-[3-(1,4-dioxa-8-aza-spiro[4.5]decan-8-yl)-phenox-
y]-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide
(Compound 87)
##STR00036##
[0481] (3) Starting from the compound obtained in Example 7-(2),
the same procedure as used in Example 1-(8) was repeated to give
the titled compound (colorless powder, yield 64%).
[0482] Melting point: 174.0.degree. C. to 179.0.degree. C.
Example 8
3,4-Dichloro-N--((R)-1-[4-ethyl-5-[3-(4-oxo-piperidin-1-yl)-phenoxy]-4H-[1-
,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 88)
##STR00037##
[0484] To a solution of the compound (0.981 g) of Example 7 in THF
(10 mL), 2N aqueous hydrochloric acid (8.4 mL) was added, and the
mixture was stirred at room temperature for one hour. Concentrated
hydrochloric acid (2 mL) was added, and the mixture was stirred at
50.degree. C. for six hours. Saturated aqueous sodium bicarbonate
was added for neutralization, and the mixture was extracted with
ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate, filtered,
and then evaporated under reduced pressure to remove the solvent.
The resulting residue was purified by column chromatography (acidic
OH SiO.sub.2, ethyl acetate) and then recrystallized
(chloroform-hexane) to give the titled compound (0.572 g, colorless
powder).
[0485] Melting point: 188.5.degree. C. to 190.5.degree. C.
Example 9
3,4-Dichloro-N--((R)-1-[4-ethyl-5-[3-(4-hydroxy-piperidin-1-yl)-phenoxy]-4-
H-[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 93)
##STR00038##
[0487] NaBH.sub.4 (0.021 g) was added at 0.degree. C. to a solution
of the compound (0.150 g) of Example 8 in methanol (3.0 ml), and
the mixture was stirred at room temperature for 16 hours. Water was
added, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated aqueous sodium chloride,
dried over MgSO.sub.4, filtered, and evaporated under reduced
pressure to remove the solvent. The resulting crude product was
purified by column chromatography (neutral OH SiO.sub.2,
methanol/chloroform=1/50 to 1/10) and then recrystallized (ethyl
acetate-hexane) to give 0.113 g of the titled compound (Compound
93) as a colorless powder.
[0488] Melting point: 167.5.degree. C. to 169.5.degree. C.
Example 10
N--[(R)-1-[5-(3-Amino-phenoxy)-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl]-3,4--
dichlorobenzenesulfonamide (Compound 82)
##STR00039##
[0489]
3-[5-((R)-1-Amino-ethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenyl
amine
##STR00040##
[0490] (1) Starting from 3-aminophenol in place of 4-fluorophenol,
the same procedure as used in Example 1-(7) was repeated to give
the titled compound (brown oily substance, yield 99%). .sup.1H NMR
(600 MHz, CDCl.sub.3) .delta. ppm: 1.37 (t, J=7.1 Hz, 3H), 1.58 (d,
J=6.9 Hz, 3H), 3.96-4.05 (m, 2H), 4.15 (q, J=6.7 Hz, 1H), 6.45-6.50
(m, 1H), 6.62-6.67 (m, 1H), 6.71-6.75 (m, 1H), 7.11 (t, J=8.0 Hz,
1H)
N--[(R)-1-[5-(3-Amino-phenoxy)-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethyl]-3,4--
dichlorobenzenesulfonamide (Compound 82)
##STR00041##
[0491] (2) Triethylamine (4.16 ml) and 3,4-dichlorobenzenesulfonyl
chloride (3.73 g) were added to a solution of the compound (3.69 g)
of Example 10-(1) in THF (15 ml), and the mixture was stirred at
room temperature overnight. The reaction solution was concentrated,
and the resulting crude product was purified by column
chromatography (NH SiO.sub.2, methanol/chloroform) and
recrystallized (ethyl acetate/hexane) to give 3.60 g of the titled
compound (Compound 82) (colorless powdered compound).
[0492] Melting point: 142.0.degree. C. to 145.0.degree. C.
Example 11
3,4-Dichloro-N--[(R)-1-[4-ethyl-5-(3-pyrrol-1-yl-phenoxy)-4H-[1,2,4]triazo-
l-3-yl]-ethyl]-benzenesulfonamide (Compound 86)
##STR00042##
[0494] To a solution of the compound (700 mg) of Example 10 in AcOH
(4.6 ml), 2,5-dimethoxy-tetrahydrofuran (375 .mu.l) was added, and
the mixture was stirred at 130.degree. C. for 30 minutes. The
reaction solution was cooled to room temperature and concentrated
under reduced pressure. Thereafter, water was added, and the
mixture was extracted with methanol/chloroform (1/4). Then, the
organic layer was washed with saturated aqueous sodium chloride,
dried over MgSO.sub.4, filtered, and evaporated under reduced
pressure to remove the solvent. The resulting residue was purified
by column chromatography (acidic OH SiO.sub.2, ethyl
acetate/hexane=33-100%, methanol/chloroform=5%) and then
recrystallized (ethyl acetate-hexane) to give the titled compound
(Compound 86) (173 mg, colorless powdered compound).
[0495] Melting point: 176.0.degree. C. to 177.0.degree. C.
Example 12
3,4-Dichloro-N--[(R)-1-[4-ethyl-5-(3-formylamino-phenoxy)-4H-[1,2,4]triazo-
l-3-yl]-ethyl]-benzenesulfonamide (Compound 90)
##STR00043##
[0497] A mixture of the compound (300 mg) obtained in Example
10-(2) and ethyl formate (1.1 ml) was stirred at 105.degree. C. for
24 hours. The reaction solution was cooled to room temperature and
concentrated under reduced pressure. The resulting crude product
was purified by column chromatography (acidic OH SiO.sub.2, ethyl
acetate/hexane=50-100%, methanol/chloroform=5%) and then
recrystallized (ethyl acetate-hexane) to give the titled compound
(Compound 90) (81 mg, colorless powder).
[0498] Melting point: 168.0.degree. C. to 170.0.degree. C.
Example 13
3,4-Dichloro-N--[(R)-1-[4-ethyl-5-(3-ureido-phenoxy)-4H-[1,2,4]triazol-3-y-
l]-ethyl]-benzenesulfonamide (Compound 91)
##STR00044##
[0500] A mixture of the compound (300 mg) obtained in Example
10-(2), potassium cyanate (65 mg), AcOH (1.0 ml), and water (0.5
ml) was stirred at room temperature for one hour. Water was added,
and the mixture was extracted with methanol/chloroform (1/4). The
organic layer was dried over MgSO.sub.4, filtered, and evaporated
to remove the solvent. The resulting crude product was purified by
column chromatography (acidic OH SiO.sub.2, ethyl
acetate/hexane=50-99%, methanol/chloroform=0-3%) and then
recrystallized (ethyl acetate-hexane) to give the titled compound
(Compound 91) (273 mg, colorless powder).
[0501] Melting point: 137.0.degree. C. to 138.0.degree. C.
Example 14
3,4-Dichloro-N--((R)-1-[5-[3-(3,3-dimethylureido)-phenoxy]-4-ethyl-4H-[1,2-
,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 97)
##STR00045##
[0503] Dimethylcarbamyl chloride (146 .mu.l) was added to a
solution of the compound (300 mg) of Example 10-(2) and
triethylamine (368 .mu.l) in chloroform (1.1 ml), and the mixture
was stirred at room temperature for three hours. The reaction
solution was concentrated, and the resulting crude product was
purified by column chromatography (neutral OH SiO.sub.2, ethyl
acetate/hexane=50-99%, methanol/chloroform=0-3%) and then
recrystallized (ethyl acetate-hexane) to give the titled compound
(Compound 97) (93 mg, colorless powder).
[0504] Melting point: 158.0.degree. C. to 159.0.degree. C.
Example 15
3,4-Dichloro-N--((R)-1-[4-ethyl-5-[3-(3-ethylureido)-phenoxy]4H-[1,2,4]tri-
azol-3-yl]-ethyl)-benzenesulfonamide (Compound 92)
##STR00046##
[0506] Ethyl isocyanate (63 .mu.l) was added to a solution of the
compound (300 mg) of Example 10-(2) in chloroform (1.1 ml), and the
mixture was stirred at room temperature for one hour. The reaction
solution was concentrated, and the resulting crude product was
purified by column chromatography (neutral OH SiO.sub.2, ethyl
acetate/hexane=50-99%, methanol/chloroform=0-3%) and then
recrystallized (ethyl acetate-hexane) to give the titled compound
(Compound 92) (228 mg, colorless powder).
[0507] Melting point: 118.0.degree. C. to 120.0.degree. C.
Example 16
3,4-Dichloro-N--[(R)-1-[4-ethyl-5-(3-methanesulfonylamino-phenoxy)-4H-[1,2-
,4]triazol-3-yl]-ethyl]-benzenesulfonamide (Compound 102)
##STR00047##
[0509] Methanesulfonyl chloride (114 mg) was added to a solution of
the compound (300 mg) of Example 10-(2) in pyridine (1.32 ml), and
the mixture was stirred at room temperature for three hours.
Hydrochloric acid (1.0 N) was added, and the mixture was extracted
with methanol/chloroform (1/4). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated, and the resulting
crude product was purified by column chromatography (neutral OH
SiO.sub.2, ethyl acetate/hexane=50-99%, methanol/chloroform=0-5%)
and then recrystallized (ethyl acetate-hexane) to give the titled
compound (Compound 102) (281 mg, colorless powder).
[0510] Melting point: 117.0.degree. C. to 118.0.degree. C.
Example 17
3,4-Dichloro-N--[(R)-1-[4-ethyl-5-(3-hydroxyphenoxy)-4H-[1,2,4]triazol-3-y-
l]-ethyl]-benzenesulfonamide (Compound 114)
##STR00048##
[0511]
(R)-1-[5-(3-Benzyloxy-phenoxy)-4-ethyl-4H-[1,2,4]triazol-3-yl]-ethy-
lamine
##STR00049##
[0512] (1) Starting from 3-benzyloxyphenol in place of
4-fluorophenol, the same procedure as used in Example 1-(7) was
repeated to give the titled compound (brown oily substance, yield
84%).
[0513] .sup.1H NMR (600 MHz, CDCl.sub.3), .delta. ppm: 1.39 (t,
J=7.3 Hz, 3H), 1.60 (d, J=6.4 Hz, 3H), 3.96-4.09 (m, 2H), 4.17 (q,
J=6.9 Hz, 1H), 5.06 (s, 2H), 6.79-6.84 (m, 1H), 6.91-6.96 (m, 1H),
7.04-7.08 (m, 1H), 7.22-7.46 (m, 6H)
3-[5-((R)-1-Aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenol
##STR00050##
[0515] (2) A suspension of the compound (1.5 g) of Example 17-(1)
and Pd(OH).sub.2/C (150 mg, Pd 20 wt %) in methanol (4.0 ml) was
stirred at room temperature for a day under a hydrogen atmosphere
(approximately 1 atmospheric pressure). The reaction mixture was
filtered through celite and evaporated to remove the solvent. The
resulting crude product was purified by column chromatography (NH
SiO.sub.2, methanol/chloroform=0-25%) to give the titled compound
(gray amorphous substance, 323 mg).
[0516] .sup.1H NMR (600 MHz, DMSO-d.sub.6), 8 ppm: 1.23 (t, J=7.3
Hz, 3H), 1.54 (d, J=6.9 Hz, 3H), 3.82-4.09 (m, 2H), 4.60 (q, J=6.0
Hz, 1H), 6.61-6.69 (m, 2H), 6.70-6.77 (m, 1H), 7.14-7.21 (m, 1H),
8.28-9.11 (m, 2H), 9.43-10.55 (m, 1H)
3,4-Dichloro-N--[(R)-1-[4-ethyl-5-(3-hydroxyphenoxy)-4H-[1,2,4]triazol-3-y-
l]-ethyl]-benzenesulfonamide (Compound 114)
##STR00051##
[0517] (3) Triethylamine (0.225 ml) and 3,4-dichlorobenzenesulfonyl
chloride (198 mg) were added at room temperature to a solution of
the compound (200 mg) of Example 17-(2) in THF (2.0 ml), and the
mixture was stirred at room temperature for 12 hours. The mixture
was evaporated to remove the solvent, and KOH (104 mg), ethanol
(4.0 ml), and water (4.0 ml) were added to the resulting crude
product. The mixture was stirred at 120.degree. C. for 40 minutes,
and then cooled to room temperature. HCl (1.0 N) was added, and the
mixture was extracted with a mixed solution of methanol/chloroform
(methanol/chloroform=1/4), dried (MgSO.sub.4), filtered, and
evaporated under reduced pressure to remove the solvent. The
resulting crude product was purified by column chromatography
(acidic OH SiO.sub.2, ethyl acetate/hexane=30-70%) and then
recrystallized (methanol/chloroform/hexane) to give 37 mg of the
titled compound (Compound 114) as a colorless powder.
[0518] Melting point: 185.0.degree. C. to 186.0.degree. C.
Example 18
3-[5-[(R)-1-(3,4-Dichlorobenzenesulfonylamino)-ethyl]-4-ethyl-4H-[1,2,4]tr-
iazol-3-yloxy]benzoic acid t-butyl ester (Compound 118)
##STR00052##
[0519]
3-[(5-((R)-1-Aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-benzoic
acid t-butyl ester
##STR00053##
[0520] (1) Starting from 3-hydroxybenzoic acid t-butyl ester in
place of 4-fluorophenol, the same procedure as used in Example
1-(7) was repeated to give the titled compound (colorless and oily,
yield 24%).
[0521] .sup.1H NMR (600 MHz, CDCl.sub.3), 8 ppm: 1.43 (t, J=7.1 Hz,
3H), 1.58-1.62 (m, 12H), 4.01-4.13 (m, 2H), 4.18 (q, J=6.6 Hz, 1H),
7.42-7.46 (m, 1H), 7.61-7.65 (m, 1H), 7.82-7.85 (m, 1H), 7.87-7.91
(m, 1H)
3-[5-[(R)-1-(3,4-Dichlorobenzenesulfonylamino)-ethyl]-4-ethyl-4H-[1,2,4]tr-
iazol-3-yloxy]benzoic acid t-butyl ester (Compound 118)
##STR00054##
[0522] (2) Starting from the compound obtained in Example 18-(1),
the same procedure as used in Example 1-(8) was repeated to give
the titled compound (colorless powder, yield 68%).
[0523] .sup.1H NMR (600 MHz, CDCl.sub.3), 8 ppm: 1.38 (t, J=7.3 Hz,
3H), 1.51 (d, J=6.9 Hz, 3H), 1.58 (s, 9H), 3.93-4.01 (m, 2H),
4.29-4.35 (m, 1H), 7.43-7.48 (m, 1H), 7.50-7.60 (m, 3H), 7.64-7.69
(m, 1H), 7.81-7.89 (m, 2H), 7.90-7.94 (m, 1H)
Example 19
3-[5-[(R)-1-(3,4-Dichlorobenzenesulfonylamino)-ethyl]-4-ethyl-4H-[1,2,4]tr-
iazol-3-yloxy]-benzoic acid (Compound 113)
##STR00055##
[0525] Trifluoroacetic acid (0.12 ml) was added to a solution of
the compound (260 mg) of Example 18 in chloroform (12.0 ml), and
the mixture was stirred at room temperature for five days. The
mixture was evaporated to remove the solvent, and the resulting
crude product was purified by column chromatography (neutral OH
SiO.sub.2, ethyl acetate/hexane=50-99%, methanol/chloroform=0-20%)
and then recrystallized (methanol/chloroform/hexane) to give the
titled compound (Compound 113) (101 mg, colorless powder).
[0526] Melting point: 183.0.degree. C. to 185.0.degree. C.
N--[(R)-1-[4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-ethyl]-4-me-
thoxybenzenesulfonamide (Compound 175)
##STR00056##
[0528] To a solution of the compound (12.5 mg) of Example 1-(7) in
THF (0.3 ml), triethylamine (25 .mu.l) was added, and then a
solution of 4-methoxybenzenesulfonylchloride (15.5 mg) in THF (0.3
ml) was added. The mixture was stirred at room temperature for two
hours. PSA (product name: VARIAN Inc. polymer supported amine, 1.4
meq/g) (75 .mu.l) was added to the reaction mixture, and the
mixture was stirred at room temperature for 12 hours. The insoluble
matter was filtered off, and the resulting residue was evaporated
to remove the solvent. The resulting crude product was purified by
silica-gel column chromatography (acidic OH SiO.sub.2, ethyl
acetate/hexane=50-100%, methanol/chloroform=10%) to give 10.7 mg of
the titled compound (Compound 175) as a colorless powder.
[0529] APCI MS (M-H)-: 419, APCI MS (M+H)+: 421
Example 21
3,4-Dichloro-N-((R)-1-[4-ethyl-5-[3-(4-methyl-piperazin-1-yl)-phenoxy]-4H--
[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 45)
##STR00057##
[0530] (1) The following compound was obtained by the same
procedure as used in Example 1-(7) (the procedure will be
specifically described below).
(R)-1-[4-Ethyl-5-[3-(4-methyl-piperazin-1-yl)-phenoxy]-4H-[1,2,4]triazol-3-
-yl]-ethylamine
##STR00058##
[0532] In a pressure-resistant screw cap test tube,
N,N'-dimethylpropyleneurea (DMPU) (4.0 ml),
3-(4-methyl-piperazin-1-yl)-phenol (500 mg), and cesium carbonate
(2.21 g) were added to the compound (750 mg) obtained in Example
1-(6), and the mixture was stirred at 160.degree. C. for three
hours. The mixture was brought to room temperature, and saturated
aqueous sodium chloride was added. The mixture was extracted with
ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate, filtered, and evaporated under reduced pressure to remove
the solvent. The resulting crude product was purified by column
chromatography (NH SiO.sub.2, chloroform/methanol=50/1-30/1) to
give the titled compound (yellow oily compound, 427 mg).
[0533] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 1.40 (t,
J=7.3 Hz, 3H), 1.59 (d, J=6.9 Hz, 3H), 2.35 (s, 3H), 2.52-2.61 (m,
4H), 3.22-3.27 (m, 4H), 3.97-4.08 (m, 2H), 4.15 (q, J=6.9 Hz, 1H),
6.71-6.80 (m, 2H), 6.99-7.03 (m, 1H), 7.20-7.25 (m, 1H)
(2) The following compound was obtained by the same procedure as
used in Example 1-(8) (the procedure will be specifically described
below).
3,4-Dichloro-N-((R)-1-[4-ethyl-5-[3-(4-methyl-piperazin-1-yl)-phenoxy]-4H--
[1,2,4]triazol-3-yl]-ethyl)-benzenesulfonamide (Compound 45)
##STR00059##
[0535] Triethylamine (0.41 mL) and 3,4-dichlorobenzenesulfonyl
chloride (0.232 mL) were added at room temperature to a solution of
the compound (427 mg) of Example 21-(1) in THF (8.0 mL), and the
mixture was stirred at room temperature overnight. The reaction
mixture was concentrated, and the resulting residue was purified by
column chromatography (NH SiO.sub.2, chloroform/methanol=50/1-30/1)
and then recrystallized (ethyl acetate-hexane) to give 280 mg of
the titled compound (Compound 45) as a colorless powder.
[0536] Melting point: 194.0.degree. C. to 196.0.degree. C.
Example 22
3,4-Dichloro-N--[(R)-1-[4-ethyl-5-(1H-indol-6-yloxy)-4H-1,2,4]triazol-3-yl-
]-ethyl]-benzenesulfonamide (Compound 64)
##STR00060##
[0537] (1) The following compound was obtained by the same
procedure as used in Example 1-(7) (the procedure will be
specifically described below).
(R)-1-[4-Ethyl-5-(1H-indol-6-yloxy)-4H-[1,2,4]triazol-3-yl]-ethylamine
##STR00061##
[0539] In a pressure-resistant screw cap test tube,
N,N''-dimethylpropyleneurea (DMPU) (5.0 ml), 1H-indol-6-ol (601
mg), and cesium carbonate (2.94 g) were added to the compound (1.00
g) obtained in Example 1-(6), and the mixture was stirred at
200.degree. C. for one hour and then brought to room temperature.
Saturated aqueous sodium chloride was added, and the mixture was
extracted with ethyl acetate. The organic layer was dried
(MgSO.sub.4), filtered, and evaporated under reduced pressure to
remove the solvent. Then, the resulting crude product was purified
by column chromatography (NH SiO.sub.2,
chloroform/methanol=50/1-30/1) to give the titled compound (yellow
oily compound, 750 mg).
[0540] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 1.42 (t,
J=7.1 Hz, 3H), 1.58 (d, J=6.4 Hz, 3H), 3.98-4.10 (m, 2H), 4.15 (q,
J=6.7 Hz, 1H), 6.30-6.39 (m, 1H), 6.87-7.00 (m, 2H), 7.39-7.52 (m,
2H), 9.55 (s, 1H)
(2) The following compound was obtained by the same procedure as
used in Example 1-(8) (the procedure will be specifically described
below).
3,4-Dichloro-N--[(R)-1-[4-ethyl-5-(1H-indol-6-yloxy)-4H-1,2,4]triazol-3-yl-
]-ethyl]-benzenesulfonamide (Compound 64)
##STR00062##
[0542] Triethylamine (0.77 mL) and 3,4-dichlorobenzenesulfonyl
chloride (1.02 g) were added at room temperature to the compound
(748 mg) of Example 22-(1) in THF (10.0 mL), and the mixture was
stirred at room temperature overnight. The reaction mixture was
concentrated, and the resulting residue was purified by column
chromatography (NH SiO.sub.2,chloroform/methanol=30/1) and then
recrystallized (CHCl.sub.3/MeOH/hexane) to give 815 mg of the
titled compound (Compound 64) as a colorless powder.
[0543] Melting point: 223.0.degree. C. to 224.0.degree. C.
Example 23
N--[(S)-2-Benzyloxy-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-
-ethyl]-3,4-dichlorobenzenesulfonamide (Compound 695)
##STR00063##
[0545] Starting from (R)-2-amino-3-benzyloxy-propionic acid methyl
ester in place of N-(t-butoxycarbonyl)-D-alanine methyl ester used
in Example 1-(1), the same procedure as used in Example 1 was
repeated to give the titled compound (Compound 695) as a colorless
powder.
[0546] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. ppm: 1.31 (t,
J=7.3 Hz, 3H), 3.65-4.03 (m, 4H), 4.35 (s, 2H), 4.67 (q, J=7.9 Hz,
1H), 7.03-7.39 (m, 10H), 7.68 (dd, J=8.8, 2.2 Hz, 1H), 7.93 (d,
J=2.2 Hz, 1H)
Example 24
3,4-Dichloro-N--[(S)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl-
]-2-hydroxyethyl]-benzenesulfonamide (Compound 696)
##STR00064##
[0548] AlCl.sub.3 (49 mg) and PhNMe.sub.2 (148 mg) were added to a
solution of the compound (69 mg) of Example 23 in CH.sub.2Cl.sub.2
(2.0 ml), and the mixture was stirred at room temperature for one
hour. Then, AcOEt was added, and the mixture was washed with 1N
hydrochloric acid and thereafter with saturated aqueous sodium
chloride. The organic layer was dried (Na.sub.2SO.sub.4), filtered,
and evaporated under reduced pressure to remove the solvent. Then,
the resulting crude product was purified by column chromatography
(OH SiO.sub.2, AcOEt/hexane=2/1) to give 54 mg of the titled
compound (Compound 696) as a colorless powder.
[0549] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. ppm: 1.41 (t,
J=7.5 Hz, 3H), 3.62 (dd, J=4.8, 11.8 Hz, 1H), 3.88 (dd, J=4.8, 11.8
Hz, 1H), 4.05 (q, J=7.5 Hz, 2H), 4.51-4.60 (m, 1H), 7.04-7.13 (m,
2H), 7.23-7.31 (m, 3H), 7.53 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.8,
2.2 Hz, 1H), 7.93 (d, J=2.2 Hz, 1H)
Example 25
3,4-Dichloro-N--[(S)-1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl-
]-2-fluoroethyl]-benzenesulfonamide (Compound 689)
##STR00065##
[0551] A solution of diethylaminosulfurtrifluoride (DAST) (16 mg)
in CH.sub.2Cl.sub.2 (1.0 ml) was added at 0.degree. C. to a
solution of the compound (45 mg) of Example 24 in CH.sub.2Cl.sub.2
(2.0 ml), and the mixture was stirred at the same temperature for
one hour. The reaction solution was added to saturated aqueous
sodium bicarbonate, and the mixture was extracted with AcOEt. The
organic layer was dried (Na.sub.2SO.sub.4) and filtered evaporated
under reduced pressure to remove the solvent. The resulting crude
product was purified by column chromatography (OH SiO.sub.2,
AcOEt/hexane=30-50%) to give 6 mg of the titled compound (Compound
696) as a pale yellow powder.
[0552] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. ppm 1.39 (t, J=7.5
Hz, 3H), 4.01 (q, J=7.5 Hz, 2H), 4.45-4.86 (m, 3H), 6.98 (br, 1H),
7.05-7.36 (m, 4H), 7.48 (d, J=8.5 Hz, 1H), 7.69 (dd, J=8.5, 2.2 Hz,
1H), 7.93 (d, J=2.2 Hz, 1H)
Example 26
3,4-Dichloro-N-[1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]-triazol-3-yl]-2,-
2,2-trifluoroethyl]-benzenesulfonamide (Compound 687)
##STR00066##
[0553] 4-Ethyl-5-mercapto-4H-[1,2,4]triazol-3-carboxylic acid ethyl
ester
##STR00067##
[0554] (1) To a solution of diethyl formate (48.64 g) in MeOH (100
ml), a solution of hydrazine monohydrate (16.33 g) in MeOH (100 ml)
was added dropwise at -5.degree. C. over 1.5 hours, and
ethylisothiocyanate (29.00 g) was added at the same temperature.
The mixture was warmed to room temperature and stirred overnight.
The insoluble matter was filtered off, and the resulting residue
was evaporated to remove the solvent. The resulting solid was
washed with a mixed solution of hexane/AcOEt (1/1) and dried, and
the resulting white powder (55.30 g) was added to an aqueous
solution (228 ml) of NaOH (913 mg). The mixture was stirred at
70.degree. C. for four hours, at room temperature overnight, and
then at 100.degree. C. for seven hours. The reaction mixture was
concentrated to approximately 1/3, and then a saturated aqueous
NH.sub.4Cl solution (300 ml) was added. The resulting white
precipitate was filtered and dried to give the titled compound
(15.06 g) as a colorless powder.
[0555] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. ppm 1.38 (t, J=6.6
Hz, 3H), 1.45 (t, J=6.5 Hz, 3H), 4.40-4.57 (m, 4H), 11.58-11.84 (m,
1H)
4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-carboxylic acid ethyl
ester
##STR00068##
[0556] (2) Starting from the compound obtained in Example 26-(1),
the same procedure as used in Example 1-(4) was repeated to give
the titled compound as a light yellow solid (yield 84%).
[0557] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. ppm 1.31-1.50 (m,
6H), 2.80 (s, 3H), 4.31 (q, J=7.2 Hz, 2H), 4.47 (q, J=7.1 Hz,
2H)
4-Ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-carboxylic acid ethyl
ester
##STR00069##
[0558] (3) Starting from the compound obtained in Example 26-(2),
the same procedure as used in Example 1-(5) was repeated to give
the titled compound as a light yellow solid (yield 84%).
[0559] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. ppm 1.48 (t, J=7.1
Hz, 3H), 1.53 (t, J=7.2 Hz, 3H), 3.60 (s, 3H), 4.53 (q, J=7.1 Hz,
2H), 4.75 (q, J=7.2 Hz, 2H)
4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-carboxylic acid
ethyl ester
##STR00070##
[0560] (4) To a suspension of NaH (1.236 g, oil free) in THF (68
ml), 4-fluorophenol (4.62 g) was added at 0.degree. C., and the
mixture was warmed to room temperature and stirred for 30 minutes.
The reaction mixture was cooled to 0.degree. C., and a solution of
the compound (8.49 g) of Example 26-(3) in THF (20 ml) was added.
The mixture was stirred at room temperature for 30 minutes and
thereafter at 70.degree. C. for 1.5 hours. The temperature was
cooled to room temperature, and then the reaction mixture was added
to a saturated aqueous NH.sub.4Cl solution (500 ml). The mixture
was extracted with AcOEt (500 ml) and washed with saturated aqueous
sodium chloride. The organic layer was dried (MgSO.sub.4),
filtered, and concentrated, and the resulting crude product was
purified by column chromatography (OH acid SiO.sub.2,
AcOEt/hexane=10-99%) to give the titled compound (5.144 g, light
yellow solid).
[0561] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. ppm 1.35-1.52 (m,
6H), 4.36 (q, J=7.2 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 7.02-7.18 (m,
2H), 7.28-7.48 (m, 2H)
4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-carbaldehyde
##STR00071##
[0562] (5) DiBAl--H (0.99 M, toluene solution, 36.1 ml) was added
at -5.degree. C. to a solution of the compound (5.00 g) of Example
26-(4) in THF (50 ml), and the mixture was stirred at the same
temperature for three hours. Then, 1N-hydrochloric acid was added
to the reaction solution, and the mixture was extracted with AcOEt.
The organic layer was washed with saturated aqueous sodium
chloride, dried (MgSO.sub.4), filtered, and concentrated, and the
resulting crude product was purified by column chromatography
(neutral OH SiO.sub.2, AcOEt/hexane=5-40%) to give the titled
compound (2.22 g, colorless and oily).
[0563] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm ppm 1.44 (t,
J=7.3 Hz, 3H), 4.37 (J=7.3 Hz, 2H), 7.10-7.17 (m, 2H), 7.36-7.40
(m, 2H)
4-Methylbenzene sulfonic acid
4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-ylmethyleneamide
##STR00072##
[0564] (6) A solution of the compound (1.00 g) obtained in Example
26-(5), 4-methylbenzene sulfonic acid amide (660 mg), and cesium
carbonate (1.39 g) in chloroform (21 ml) was stirred at 45.degree.
C. for nine hours. The reaction solution was filtered through
celite, and the filtrate was concentrated. The resulting residue
was purified by silica-gel chromatography (neutral OH silica gel,
elution solvent: AcOEt/hexane 0-30%) to give the titled compound
(630 mg) as a pale yellow solid.
[0565] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm 1.30 (t, J=7.1
Hz, 3H), 2.42 (s, 3H), 4.27-4.43 (m, 2H), 7.07-7.15 (m, 2H),
7.31-7.39 (m, 4H), 7.57-7.62 (m, 2H), 8.85 (s, 1H)
N-[1-[4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]2,2,2-trifluoroet-
hyl]-4-methylbenzamide
##STR00073##
[0566] (7) Under an argon atmosphere, a solution of
(trifluoromethyl)trimethyl silane (120 .mu.l) in THF (5.0 ml) was
added at -35.degree. C. to a suspension of the compound (200 mg) of
Example 26-(6) and tetramethylfluoride (60 mg) in THF (5.0 ml), and
the mixture was stirred at the same temperature for an hour and a
half. A further portion of tetramethylfluoride (60 mg) and
thereafter a further portion of (trifluoromethyl)trimethyl silane
(60 mg) were added to the reaction solution at the same
temperature, and the mixture was stirred at the same temperature
for two hours and warmed to -10.degree. C., and a saturated aqueous
ammonium chloride solution was added, and the aqueous layer was
extracted with ethyl acetate. The organic layer was dried over
magnesium sulfate and filtered, and the filtrate was concentrated.
The resulting residue was purified by silica-gel column
chromatography (neutral --OH silica gel, AcOEt/hexane 0-40%) to
give the titled compound (219 mg) as a pale yellow oily
substance.
[0567] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm 1.32 (t, J=7.3
Hz, 3H), 2.40 (s, 3H), 3.80-3.87 (m, 2H), 4.86-4.92 (m, 1H), 5.59
(d, J=8.3 Hz, 1H), 7.06-7.13 (m, 2H), 7.27-7.31 (m, 2H), 7.32-7.37
(m, 2H), 7.53-7.59 (m, 2H)
1-[4-Ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-2,2,2,-trifluoroeth-
ylamine
##STR00074##
[0568] (8) HCl (4N, dioxane solution, 1.25 ml) was added at room
temperature to a solution of the compound (215 mg) of Example
26-(7) in methanol (5.0 ml), and the mixture was stirred at
85.degree. C. for two hours. The reaction solution was
concentrated, and the resulting residue was purified by silica-gel
column chromatography (NH SiO.sub.2, AcOEt/hexane 0-50%) to give
the titled compound (82 mg) as a colorless oily substance.
[0569] (600 MHz, CDCl.sub.3) .delta. ppm: 1.43 (t, J=7.3 Hz, 3H),
3.97-4.11 (m, 2H), 4.47-4.54 (m, 1H), 7.06-7.12 (m, 2H), 7.35-7.40
(m, 2H)
3,4-Dichloro-N-[1-[4-ethyl-5-(4-fluorophenoxy)-4H-[1,2,4]triazol-3-yl]-2,2-
,2-trifluoroethyl]-benzenesulfonamide (Compound 687)
##STR00075##
[0570] (9) Starting from the compound (79 mg) obtained in Example
26-(8), the same procedure as used in Example 1-(8) was repeated to
give the titled compound (3 mg) as a light yellow oily
substance.
[0571] (600 MHz, CDCl.sub.3) .delta. ppm: 1.43 (t, J=7.1 Hz, 3H),
3.91-4.07 (m, 2H), 5.06-5.13 (m, 1H), 7.07-7.16 (m, 2H), 7.29-7.35
(m, 2H), 7.50-7.57 (m, 1H), 7.67-7.74 (m, 1H), 7.90 (s, 1H)
Example 27
N--((R)-1-[5-[3-(4-Acetylpiperazin-1-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazo-
l-3-yl]-ethyl)-3,4-dichlorobenzenesulfonamide (Compound 697)
##STR00076##
[0572]
(R)-1-[4-Ethyl-5-(3-piperazin-1-yl-phenoxy)-4H-[1,2,4]triazol-3-yl]-
-ethylamine
##STR00077##
[0573] (1) In a pressure-resistant screw cap test tube, DMPU (10
ml), 3-piperazinylphenol (1.34 g), and Cs.sub.2CO.sub.3 (6.13 g)
were added to the compound (2.08 g) obtained in Example 1-(6), and
the mixture was stirred at 200.degree. C. for 40 minutes. It was
cooled to room temperature and then concentrated under reduced
pressure, and the resulting crude product was purified by column
chromatography (NH SiO.sub.2, AcOEt to MeOH/CHCl.sub.2=1/50) to
give the titled compound (yellow oily compound, 1.17 g).
[0574] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 1.40 (t,
J=7.1 Hz, 3H), 1.59 (d, J=6.9 Hz, 3H), 2.98-3.04 (m, 4H), 3.14-3.19
(m, 4H), 3.97-4.09 (m, 2H), 4.13-4.18 (m, 1H), 6.70-6.80 (m, 2H),
6.97-7.03 (m, 1H), 7.21-7.26 (m, 1H)
1-(4-[3-[5-((R)-1-Aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenyl]-p-
iperazin-1-yl)-ethanone
##STR00078##
[0575] (2) AcCl (0.24 ml) was added at -30.degree. C. to a solution
of the compound (1.06 g) of Example 27-(1) and Et.sub.3N (1.4 ml)
in THF (20 ml), and the mixture was stirred at the same temperature
for two hours. Then, the mixture was warmed to room temperature and
then stirred for another five hours. The reaction mixture was
concentrated, and the resulting crude product was purified by
column chromatography (neutral OH SiO.sub.2, MeOH/CHCl.sub.3=1/5)
to give a mixture (315 mg, colorless solid) of the titled compound
and triethylamine hydrochloride.
[0576] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 1.35 (t,
J=7.3 Hz, 3H), 1.72 (d, J=6.4 Hz, 3H), 2.12 (s, 3H), 3.14-3.23 (m,
4H), 3.57-3.64 (m, 2H), 3.71-3.77 (m, 2H), 3.87-4.10 (m, 2H),
4.57-4.66 (m, 1H), 6.70-6.81 (m, 2H), 6.95-6.99 (m, 1H), 7.21-7.26
(m, 1H)
N--((R)-1-[5-[3-(4-Acetylpiperazin-1-yl)-phenoxy]-4-ethyl-4H-[1,2,4]triazo-
l-3-yl]-ethyl)-3,4-dichlorobenzenesulfonamide (Compound 697)
##STR00079##
[0577] (3) Water was added to a mixture (307 mg) of
1-(4-[3-[5-((R)-1-aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenyl]--
piperazin-1-yl)-ethanone obtained in Example 27-(2) and
triethylamine hydrochloride, 3,4-dichlorobenzenesulfonyl chloride
(0.13 ml), and K.sub.2CO.sub.3 (355 mg). The mixture was stirred at
room temperature for 15 hours. The precipitated solid was filtered
and purified by column chromatography (NH SiO.sub.2,
MeOH/CHCl.sub.3=1/50) to give the titled compound (Compound 697)
(117 mg, colorless syrup).
[0578] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 1.38 (t,
J=7.3 Hz, 3H), 1.52 (d, J=6.9 Hz, 3H), 2.14 (s, 3H), 3.14-3.27 (m,
4H), 3.56-3.64 (m, 2H), 3.72-3.80 (m, 2H), 3.88-4.01 (m, 2H),
4.58-4.68 (m, 1H), 5.98-6.06 (m, 1H), 6.72-6.82 (m, 2H), 6.95-7.01
(m, 1H), 7.25-7.30 (m, 1H), 7.51-7.57 (m, 1H), 7.65-7.73 (m, 1H),
7.89-7.97 (m, 1H)
Example 28
3,4-Dichloro-N--[(R)-1-[4-ethyl-5-(3-piperazin-1-yl-phenoxy)-4H-[1,2,4]tri-
azol-3-yl]-ethyl]-benzenesulfonamide (Compound 683),
##STR00080##
[0580] A mixture of the compound (107 mg) obtained in Example
27-(3), NaOH (105 mg), water (2.0 ml), and EtOH (4.0 ml) was
stirred at 80.degree. C. for one hour and then stirred at
100.degree. C. for 18 hours. The mixture was cooled to room
temperature and then extracted with AcOEt. The organic layer was
washed with saturated aqueous sodium chloride, dried (MgSO.sub.4),
filtered, and concentrated. The resulting crude product was
purified by column chromatography (NH SiO.sub.2,
MeOH/CHCl.sub.2=1/30) and then recrystallized (AcOEt/hexane) to
give the titled compound (Compound 683) (55 mg, colorless
powder).
[0581] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm: 1.24 (t,
J=7.3 Hz, 3H), 1.31 (d, J=6.9 Hz, 3H), 2.77-2.86 (m, 4H), 3.03-3.10
(m, 4H), 3.81-3.99 (m, 2H), 4.67-4.75 (m, 1H), 6.56-6.62 (m, 1H),
6.76-6.85 (m, 2H), 7.19-7.27 (m, 1H), 7.69-7.77 (m, 1H), 7.88 (d,
J=8.7 Hz, 1H), 7.93-7.97 (m, 1H)
[0582] Melting point: 175.0.degree. C. to 178.0.degree. C.
[0583] The compounds shown in Table 1 were obtained using the
corresponding starting compounds and the procedures shown in
Examples 1 to 28.
[0584] The compounds obtained in the Examples above are also shown
in Table 1 together with the other compounds.
Test Example 1
(S1P.sub.1 Binding Assay
[0585] Using a human Edg-1 (S1P.sub.1) gene transferred HEK-293
cell strain membrane fraction, the Edg-1 (S1P.sub.1) binding
inhibiting action of the compounds of the present invention was
determined in accordance with the method described in the
literature (Science. 2002, 296: 346) (showing a binding of Kd=0.15
nM, Bmax=2.5 fmol/.mu.g to [.sup.33P]-S1P). The membrane fraction
was obtained by treating the cells with a solubilizing buffer (1 mM
Tris/HCl, pH 7.2) for 10 minutes on ice, centrifuging at
1000.times.g for 5 minutes to remove insoluble fractions, and then
centrifuging at 40000.times.g for 30 minutes at 4.degree. C. The
resulting membrane fraction was dissolved in a binding buffer (20
mM Tris-HCl, pH 7.4, 100 mM NaCl, 15 mM NaF, 2 mM deoxypyridoxine,
4 mg/mL fatty acid-free BSA), and then [.sup.33P]-S1P (manufactured
by ARC, final concentration 0.1 nM) and a DMSO solution (final
concentration of the compound 10.sup.-5M, final concentration of
DMSO 0.1%) of the test compound were added. Thereafter, the mixture
was stirred and then treated for one hour at 30.degree. C. Using a
harvester, the membrane fraction was harvested onto unifilter-96
GF/C filter (manufactured by Perkin Elmer), washing was carried out
four times with the binding buffer, and the filter was dried.
Twenty five .mu.L Microscint 0 (manufactured by Perkin Elmer) was
added, and radioactivity was measured using Top Count NXT
(manufactured by Packard) to calculate the amount (A) of
[.sup.33P]-S1P bound to the membrane fraction at the time when the
compound was added.
[0586] The same procedure was carried out in the absence of the
test compound, and the amount (B) of [.sup.33P]-S1P bound was
calculated. Further, the same procedure was carried out in the
absence of the test compound by use of HEK-293 cells to which no
Edg-1 (S1P.sub.1) gene was introduced, and the background amount
(C) of [.sup.33P]-S1P bound was calculated.
[0587] The Edg-1 (S1P.sub.1) binding inhibition rates of the
compound calculated using the following equation are shown in Table
1.
Inhibition rate(%)=[1-(A-C)/(B-C)].times.100
[0588] Further, concentrations (IC.sub.50) at the time when binding
in the absence of the test compound was inhibited by 50% were
calculated. The membrane system binding assay was carried out in
the presence of test compounds with various concentrations, and the
Edg-1 (S1P.sub.1) binding inhibition rates were calculated using
the equation above. Then, IC.sub.50 values were calculated using
Origin (Lightstone Corp.), a software for data analysis.
[0589] The compounds below each had an IC.sub.50 value of 35 nM or
lower and showed particularly strong activity.
[0590] Compounds 5, 13, 16, 18, 21, 23, 25, 26, 32, 35, 37, 43, 46,
64, 69, 76, 101, 102, 109, 122, 123, 125, 131, 134, 141, 142, 145,
665.
[0591] The following compounds had an IC.sub.50 value of 10 nM or
below, and showed even stronger activity.
[0592] Compounds 24, 39, 40, 70, 75, 87, 93, 94, 107, 111, 112,
121, 132, 133, 137, 138, 139, 140, 147, 151, 663, 666, 667, 669,
671, 681, 683, 690.
[0593] Specific IC.sub.50 values of the individual compounds are as
follows (unit: nM).
[0594] Compound 3: 4.2. Compound 7: 35.5. Compound 8: 18.5.
Compound 10: 17.5. Compound 11: 8.9. Compound 12: 20.0. Compound
14: 6.4. Compound 15: 32.5. Compound 22: 14.0. Compound 28: 3.1.
Compound 34: 2.0. Compound 36: 17.5. Compound 38: 11.7. Compound
42: 22.0. Compound 45: 4.2. Compound 46: 28.5. Compound 49: 6.0.
Compound 61: 39.0. Compound 73: 2.2. Compound 74: 15.0. Compound
83: 8.1. Compound 88: 5.4. Compound 99: 25.0. Compound 100: 18.5.
Compound 105: 2.9. Compound 108: 18.0. Compound 120:1.7. Compound
129: 20.0. Compound 130: 2.9. Compound 136: 8.1. Compound 143: 7.3.
Compound 144: 7.9. Compound 146: 12.0. Compound 148: 1.9. Compound
149: 7.8. Compound 670: 5.2. Compound 678: 10.2. Compound 680:1.4.
Compound 688: 1.5. Compound 691: 2.6. Compound 692: 5.1. Compound
694: 2.9. Compound 698: 2.3.
TABLE-US-00001 TABLE 1 Binding assay (membrane) Compound Melting %
inhibition number Chemical structure point (.degree. C.) (10 .mu.M)
Compound 1 ##STR00081## 182.0-184.0 100.8 Compound 2 ##STR00082##
134.0-138.0 97.8 Compound 3 ##STR00083## 183.5-187.5 98.7 Compound
4 ##STR00084## 198.5-200.5 95.7 Compound 5 ##STR00085## 160.0-161.0
97.3 Compound 6 ##STR00086## 180.0-190.0 98.2 Compound 7
##STR00087## 159.5-161.5 99.4 Compound 8 ##STR00088## 179.0-179.5
100.1 Compound 9 ##STR00089## 145.0-148.0 100.3 Compound 10
##STR00090## 182.5-184.5 99.8 Compound 11 ##STR00091## 155.0-160.0
98.5 Compound 12 ##STR00092## 190.0-192.0 99.2 Compound 13
##STR00093## 152.0-156.0 102.0 Compound 14 ##STR00094## 161.0-162.5
99.5 Compound 15 ##STR00095## 200.0-205.0 102.7 Compound 16
##STR00096## 125.0-127.0 101.3 Compound 17 ##STR00097## 129.5-131.5
95.4 Compound 18 ##STR00098## 189.0-194.0 102.1 Compound 19
##STR00099## 145.0-150.0 97.9 Compound 20 ##STR00100## 118.0-120.0
97.4 Compound 21 ##STR00101## 146.5-149.5 96.7 Compound 22
##STR00102## 163.0-167.5 95.4 Compound 23 ##STR00103## 173.0-176.0
96.7 Compound 24 ##STR00104## 172.5-173.0 101.0 Compound 25
##STR00105## 155.0-156.0 97.5 Compound 26 ##STR00106## 159.0-164.0
97.9 Compound 27 ##STR00107## 163.0-168.0 100.1 Compound 28
##STR00108## 165.0-170.0 104.4 Compound 29 ##STR00109## 177.0-178.5
101.4 Compound 30 ##STR00110## 212.0-216.0 100.4 Compound 31
##STR00111## 143.0-146.0 101.2 Compound 32 ##STR00112## 147.0-148.0
104.1 Compound 33 ##STR00113## 173.5-174.5 100.8 Compound 34
##STR00114## 192.5-195.5 106.1 Compound 35 ##STR00115## 156.0-159.0
100.4 Compound 36 ##STR00116## 125.0-130.0 102.2 Compound 37
##STR00117## 145.0-147.0 100.3 Compound 38 ##STR00118## 148.5-150.0
104.8 Compound 39 ##STR00119## 176.0-178.0 98.5 Compound 40
##STR00120## 155.5-156.5 105.6 Compound 41 ##STR00121## 166.0-170.0
92.0 Compound 42 ##STR00122## 176.5-179.5 102.4 Compound 43
##STR00123## 182.5-185.0 99.8 Compound 44 ##STR00124## 140.0-145.5
100.1 Compound 45 ##STR00125## 194.0-196.0 106.0 Compound 46
##STR00126## 247.0-250.0 94.6 Compound 47 ##STR00127## 191.0-192.0
102.3 Compound 48 ##STR00128## 195.5-196.5 96.7 Compound 49
##STR00129## 198.0-199.0 102.5 Compound 50 ##STR00130## 129.0-130.0
92.9 Compound 51 ##STR00131## 148.5-150.5 99.9 Compound 52
##STR00132## 203.0-205.0 100.2 Compound 53 ##STR00133## 172.0-173.0
86.8 Compound 54 ##STR00134## 192.0-193.0 104.1 Compound 55
##STR00135## 141.0-143.0 80.6 Compound 56 ##STR00136## 189.0-191.0
88.3 Compound 57 ##STR00137## 164.0-165.0 Compound 58 ##STR00138##
181.0-183.0 99.7 Compound 59 ##STR00139## 169.5-170.5 94.3 Compound
60 ##STR00140## 192.5-195.0 98.9 Compound 61 ##STR00141## 93.0-99.0
102.2 Compound 62 ##STR00142## 186.0-188.5 83.5 Compound 63
##STR00143## 216.5-217.5 104.7 Compound 64 ##STR00144## 223.0-224.0
100.8 Compound 65 ##STR00145## 201.0-202.0 105.3 Compound 66
##STR00146## 183.0-190.0 93.4 Compound 67 ##STR00147## 182.0-188.0
95.5 Compound 68 ##STR00148## 212.0-223.0 100.9 Compound 69
##STR00149## 119.0-120.5 103.2 Compound 70 ##STR00150## 144.0-146.0
96.5 Compound 71 ##STR00151## 126.0-135.0 99.3 Compound 72
##STR00152## 198.0-200.5 99.0 Compound 73 ##STR00153## 185.0-187.0
103.3 Compound 74 ##STR00154## 218.5-227.0 104.9 Compound 75
##STR00155## 177.0-179.0 95.0 Compound 76 ##STR00156## 151.5-153.5
99.2 Compound 77 ##STR00157## 123.0-127.0 99.7 Compound 78
##STR00158## 178.0-179.0 90.7 Compound 79 ##STR00159## 190.0-195.0
103.7 Compound 80 ##STR00160## 164.0-165.0 87.6 Compound 81
##STR00161## 160.0-165.0 93.2 Compound 82 ##STR00162## 142.0-145.0
100.8 Compound 83 ##STR00163## 170.0-173.0 100.7 Compound 84
##STR00164## 160.0-165.0 100.5 Compound 85 ##STR00165## 133.0-134.0
100.0 Compound 86 ##STR00166## 176.0-177.0 106.7 Compound 87
##STR00167## 174.0-179.0 99.9 Compound 88 ##STR00168## 188.5-190.5
99.5 Compound 89 ##STR00169## 101.0-103.0 90.3 Compound 90
##STR00170## 168.0-170.0 99.0 Compound 91 ##STR00171## 137.0-138.0
90.6 Compound 92 ##STR00172## 118.0-120.0 92.1 Compound 93
##STR00173## 167.5-169.5 99.9 Compound 94 ##STR00174## 190.0-192.0
106.4 Compound 95 ##STR00175## 205.0-208.5 92.4 Compound 96
##STR00176## 191.0-194.0 78.7 Compound 97 ##STR00177## 158.0-159.0
93.0 Compound 98 ##STR00178## 143.0-144.0 100.4 Compound 99
##STR00179## 103.0-105.5 102.4 Compound 100 ##STR00180## 109.9
Compound 101 ##STR00181## 142.0-143.0 100.9 Compound 102
##STR00182## 117.0-118.0 104.2 Compound 103 ##STR00183##
146.5-147.5 91.2 Compound 104 ##STR00184## 187.0-187.5 95.2
Compound 105 ##STR00185## 121.0-123.0 104.4 Compound 106
##STR00186## 132.0-134.0 110.2 Compound 107 ##STR00187##
159.0-162.0 103.8 Compound 108 ##STR00188## 175.0-180.0 101.3
Compound 109 ##STR00189## 152.0-153.0 103.5 Compound 110
##STR00190## 187.5-188.5 103.6 Compound 111 ##STR00191##
204.0-205.0 108.7 Compound 112 ##STR00192## 171.0-173.0 99.2
Compound 113 ##STR00193## 183.0-185.0 74.2 Compound 114
##STR00194## 185.0-186.0 94.5 Compound 115 ##STR00195## 125.5-126.5
81.8 Compound 116 ##STR00196## 192.0-195.0 83.1 Compound 117
##STR00197## 153.5-155.5 87.1 Compound 118 ##STR00198## Compound
119 ##STR00199## Compound 120 ##STR00200## 211.5-216.5 93.03
Compound 121 ##STR00201## 195.5-198.5 103.45 Compound 122
##STR00202## 167.0-170.0 81.93
Compound 123 ##STR00203## 162.0-165.0 97.12 Compound 124
##STR00204## 178.5-180.0 97.44 Compound 125 ##STR00205##
253.5-254.5 94.28 Compound 126 ##STR00206## 176.5-178.0 91.80
Compound 127 ##STR00207## 94.44 Compound 128 ##STR00208##
182.5-183.5 90.70 Compound 129 ##STR00209## 96.0-104.0 96.79
Compound 130 ##STR00210## 107.0-114.0 98.87 Compound 131
##STR00211## 102.0-110.5 97.35 Compound 132 ##STR00212## 95.0-104.0
99.52 Compound 133 ##STR00213## 164.0-169.5 101.11 Compound 134
##STR00214## 108.5-114.5 101.47 Compound 135 ##STR00215##
188.5-192.0 100.63 Compound 136 ##STR00216## 100.0-106.0 96.51
Compound 137 ##STR00217## 173.5-177.0 101.74 Compound 138
##STR00218## 167.5-169.0 99.58 Compound 139 ##STR00219##
174.0-177.0 101.46 Compound 140 ##STR00220## 110.0-119.0 101.57
Compound 141 ##STR00221## 169.0-173.0 104.70 Compound 142
##STR00222## 183.0-184.0 98.11 Compound 143 ##STR00223##
144.0-145.0 99.89 Compound 144 ##STR00224## 187.0-188.0 99.38
Compound 145 ##STR00225## 150.0-152.0 101.30 Compound 146
##STR00226## 121.0-122.0 101.65 Compound 147 ##STR00227##
141.0-143.0 102.74 Compound 148 ##STR00228## 154.5-155.5 102.47
Compound 149 ##STR00229## 212.0-214.5 100.70 Compound 1
##STR00230## 191.5-196.0 93.40 Compound 2 ##STR00231## 252.0-255.0
102.84 Binding assay APCI APCI (membrane) Compound MS MS %
inhibition number Chemical Structure (M - H).sup.- (M + H).sup.+
(10 .mu.M) Compound 152 ##STR00232## 467 469 Compound 153
##STR00233## 446 448 Compound 154 ##STR00234## 431 433 92.3
Compound 155 ##STR00235## 389 391 59.9 Compound 156 ##STR00236##
467, 469 469, 471 106.6 Compound 157 ##STR00237## 445 447 74.6
Compound 158 ##STR00238## 467, 469 469, 471 Compound 159
##STR00239## 461 463 Compound 160 ##STR00240## 467, 469 469, 471
96.9 Compound 161 ##STR00241## 551, 553 553, 554 Compound 162
##STR00242## 423 425 109.3 Compound 163 ##STR00243## 414 416
Compound 164 ##STR00244## 465 467 Compound 165 ##STR00245## 414 416
72.9 Compound 166 ##STR00246## 493 495 Compound 167 ##STR00247##
451 453 113.3 Compound 168 ##STR00248## 457 459 68.4 Compound 169
##STR00249## 457 459 Compound 170 ##STR00250## 449 451 76.0
Compound 171 ##STR00251## 341 343 Compound 172 ##STR00252## 417 419
92.0 Compound 173 ##STR00253## 407 409 97.2 Compound 174
##STR00254## 431 433 52.5 Compound 175 ##STR00255## 419 421 102.7
Compound 176 ##STR00256## 327 329 Compound 177 ##STR00257## 467 469
55.3 Compound 178 ##STR00258## 467 469 Compound 179 ##STR00259##
439 441 83.0 Compound 180 ##STR00260## 467 469 94.6 Compound 181
##STR00261## 479 481 50.4 Compound 182 ##STR00262## 514 517 109.3
Compound 183 ##STR00263## 415 417 92.8 Compound 184 ##STR00264##
491, 493 493, 495 97.3 Compound 185 ##STR00265## 515 517 Compound
186 ##STR00266## 403 405 86.8 Compound 187 ##STR00267## 403 405
Compound 188 ##STR00268## 457 459 106.6 Compound 189 ##STR00269##
403 405 99.7 Compound 190 ##STR00270## 473 475 87.9 Compound 191
##STR00271## 415 417 96.9 Compound 192 ##STR00272## 403 405 95.2
Compound 193 ##STR00273## 530 532 Compound 194 ##STR00274## 540 542
80.7 Compound 195 ##STR00275## 417 419 90.1 Compound 196
##STR00276## 479 481 65.6 Compound 197 ##STR00277## 535 537
Compound 198 ##STR00278## 441 443 Compound 199 ##STR00279## 408 410
Compound 200 ##STR00280## 465 467 Compound 201 ##STR00281## 450 452
84.3 Compound 202 ##STR00282## 421 423 Compound 203 ##STR00283##
447 449 Compound 204 ##STR00284## 457 459 Compound 205 ##STR00285##
465 467 Compound 206 ##STR00286## 431 433 85.4 Compound 207
##STR00287## 491, 493 493, 495 107.7 Compound 208 ##STR00288## 445
447 80.2 Compound 209 ##STR00289## 457 459 91.4 Compound 210
##STR00290## 437 439 Compound 211 ##STR00291## 423 425 Compound 212
##STR00292## 525 527 69.7 Compound 213 ##STR00293## 457 459 101.9
Compound 214 ##STR00294## 437 439 102.1 Compound 215 ##STR00295##
419 421 91.4 Compound 216 ##STR00296## 503, 505 505, 507 88.9
Compound 217 ##STR00297## 461 463 57.5 Compound 218 ##STR00298##
497, 499 499, 501 74.7 Compound 219 ##STR00299## 421 423 70.8
Compound 220 ##STR00300## 459 461 93.7 Compound 221 ##STR00301##
433 435 69.2 Compound 222 ##STR00302## 473 475 Compound 223
##STR00303## 414 416 90.8 Compound 224 ##STR00304## 481 483
Compound 225 ##STR00305## 491, 493 493, 495 Compound 226
##STR00306## 457 459 80.4 Compound 227 ##STR00307## 425 427 51.4
Compound 228 ##STR00308## 449 451 53.9 Compound 229 ##STR00309##
441 443 Compound 230 ##STR00310## 407 409 Compound 231 ##STR00311##
423 425 65.1 Compound 232 ##STR00312## 431 433 68.7 Compound 233
##STR00313## 455 457 87.1 Compound 234 ##STR00314## 495, 497 497,
499 50.6 Compound 235 ##STR00315## 481, 483 483, 485 82.9 Compound
236 ##STR00316## 448 450 Compound 237 ##STR00317## 443 445 64.8
Compound 238 ##STR00318## 425 427 Compound 239 ##STR00319## 525 527
Compound 240 ##STR00320## 459 461 82.5 Compound 241 ##STR00321##
425 427 95.8 Compound 242 ##STR00322## 485, 487 487, 489 85.9
Compound 243 ##STR00323## 459 461 90.0 Compound 244 ##STR00324##
503, 505 505, 507 94.6 Compound 245 ##STR00325## 459 461 89.3
Compound 246 ##STR00326## 471 473 Compound 247 ##STR00327## 493 495
Compound 248 ##STR00328## 471 473 104.9 Compound 249 ##STR00329##
581, 583 583, 585 Compound 250 ##STR00330## 425 427 Compound 251
##STR00331## 491 493 59.0 Compound 252 ##STR00332## 407 409 82.8
Compound 253 ##STR00333## 480 482 Compound 254 ##STR00334## 453 455
75.1 Compound 255 ##STR00335## 471 473 86.4 Compound 256
##STR00336## 443 445 85.2 Compound 257 ##STR00337## 545, 547 547,
549 78.2 Compound 258 ##STR00338## 462 464 67.9 Compound 259
##STR00339## 437 439 Compound 260 ##STR00340## 545, 547 547, 549
74.1 Compound 261 ##STR00341## 432 434 73.6 Compound 262
##STR00342## 417 419 79.6 Compound 263 ##STR00343## 455 457 82.6
Compound 264 ##STR00344## 455 457 95.9 Compound 265 ##STR00345##
503, 505 505, 507 59.1 Compound 266 ##STR00346## 425 427 99.0
Compound 267 ##STR00347## 441 443 89.6 Compound 268 ##STR00348##
443 445 99.9 Compound 269 ##STR00349## 485, 487 487, 489 91.5
Compound 270 ##STR00350## 535, 537 537, 539 73.0 Compound 271
##STR00351## 535, 537 537, 539 57.1 Compound 272 ##STR00352## 421
423 104.3 Compound 273 ##STR00353## 421 423 71.6 Compound 274
##STR00354## 441 443 53.5 Compound 275 ##STR00355## 485, 487 487,
489 107.1 Compound 276 ##STR00356## 501, 503 503, 505 94.4 Compound
277 ##STR00357## 535, 537 537, 539 Compound 278 ##STR00358## 477
479 Compound 279 ##STR00359## 421 423 79.6 Compound 280
##STR00360## 441 443 87.3 Compound 281 ##STR00361## 475 477
Compound 282 ##STR00362## 495 497 Compound 283 ##STR00363## 482 484
Compound 284 ##STR00364## 404 406 Compound 285 ##STR00365## 419 421
Compound 286 ##STR00366## 409 411 60.6 Compound 287 ##STR00367##
456 455 Compound 288 ##STR00368## 394 396 Compound 289 ##STR00369##
447 449 105.6 Compound 290 ##STR00370## 424 426 Compound 291
##STR00371## 447 449 Compound 292 ##STR00372## 447 449 106.9
Compound 293 ##STR00373## 431 433 Compound 294 ##STR00374## 395 397
50.8 Compound 295 ##STR00375## 462 464 Compound 296 ##STR00376##
469 471 Compound 297 ##STR00377## 478 480 Compound 298 ##STR00378##
543 545 Compound 299 ##STR00379## 519 521 Compound 300 ##STR00380##
423 425 82.1 Compound 301 ##STR00381## 449 451 78.8 Compound 302
##STR00382## 538 540 Compound 303 ##STR00383## 491 493 77.4
Compound 304 ##STR00384## 517 519 Compound 305 ##STR00385## 561 563
Compound 306 ##STR00386## 431 433 60.2 Compound 307 ##STR00387##
457 459 94.4 Compound 308 ##STR00388## 490 492 Compound 309
##STR00389## 490 492 Compound 310 ##STR00390## 494 496 Compound 311
##STR00391## 447 449 76.5 Compound 312 ##STR00392## 461 463
Compound 313 ##STR00393## 437 439 Compound 314 ##STR00394## 502 504
52.2 Compound 315 ##STR00395## 440 442 Compound 316 ##STR00396##
525 527 Compound 317 ##STR00397## 535, 537 537, 539 Compound 318
##STR00398## 535, 537 537, 539 78.9 Compound 319 ##STR00399## 535,
537 537, 539 61.7 Compound 320 ##STR00400## 390 392 Compound 321
##STR00401## 475 477 Compound 322 ##STR00402## 539 541 Compound 323
##STR00403## 445 447 77.9 Compound 324 ##STR00404## 445 447 81.8
Compound 325 ##STR00405## 488 490 Compound 326 ##STR00406## 487 469
Compound 327 ##STR00407## 452 454 92.3 Compound 328 ##STR00408##
410 412 85.2 Compound 329 ##STR00409## 488, 490 490, 492 100.8
Compound 330 ##STR00410## 466 468 81.6 Compound 331 ##STR00411##
488, 490 490, 492 59.8 Compound 332 ##STR00412## 482 484 Compound
333 ##STR00413## 488, 490 490, 492 102.2 Compound 334 ##STR00414##
572, 574 574, 576 Compound 335 ##STR00415## 444 446 106.1 Compound
336 ##STR00416## 435 437 56.8 Compound 337 ##STR00417## 486 488
Compound 338 ##STR00418## 435 437 69.2 Compound 339 ##STR00419##
514 516 62.8 Compound 340 ##STR00420## 472 474 100.0 Compound 341
##STR00421## 478 480 92.8 Compound 342 ##STR00422## 478 480 53.6
Compound 343 ##STR00423## 470 472 86.5 Compound 344 ##STR00424##
362 364 Compound 345 ##STR00425## 438 440 90.4 Compound 346
##STR00426## 428 430 89.2 Compound 347 ##STR00427## 452 454 50.1
Compound 348 ##STR00428## 440 442 109.1 Compound 349 ##STR00429##
348 350 Compound 350 ##STR00430## 488 490 75.0 Compound 351
##STR00431## 488 490 Compound 352 ##STR00432## 460 462 88.5
Compound 353 ##STR00433## 488 490 92.3 Compound 354 ##STR00434##
500 502 Compound 355 ##STR00435## 536 538 98.8 Compound 356
##STR00436## 436 438 95.6 Compound 357 ##STR00437## 512, 514 514,
516 106.1 Compound 358 ##STR00438## 536 538 Compound 359
##STR00439## 424 426 95.7 Compound 360 ##STR00440## 424 426
Compound 361 ##STR00441## 424 426 96.9 Compound 362 ##STR00442##
494 496 95.1 Compound 363 ##STR00443## 436 438 96.2 Compound 364
##STR00444## 424 426 87.5 Compound 365 ##STR00445## 551 553
Compound 366 ##STR00446## 561 563 63.2 Compound 367 ##STR00447##
438 440 94.3 Compound 368 ##STR00448## 500 502 60.5 Compound 369
##STR00449## 556 558 Compound 370 ##STR00450## 462 464
Compound 371 ##STR00451## 429 431 Compound 372 ##STR00452## 471 473
106.3 Compound 373 ##STR00453## 442 444 Compound 374 ##STR00454##
468 470 Compound 375 ##STR00455## 478 480 Compound 376 ##STR00456##
486 488 Compound 377 ##STR00457## 452 454 73.9 Compound 378
##STR00458## 466 468 71.6 Compound 379 ##STR00459## 478 480 89.2
Compound 380 ##STR00460## 458 460 Compound 381 ##STR00461## 444 446
Compound 382 ##STR00462## 546 548 66.9 Compound 383 ##STR00463##
478 480 83.6 Compound 384 ##STR00464## 458 460 88.1 Compound 385
##STR00465## 462 464 98.0 Compound 386 ##STR00466## 440 442 84.0
Compound 387 ##STR00467## 524, 526 526, 528 63.5 Compound 388
##STR00468## 482 484 65.8 Compound 389 ##STR00469## 518, 520 520,
522 88.0 Compound 390 ##STR00470## 442 444 65.9 Compound 391
##STR00471## 480 482 80.4 Compound 392 ##STR00472## 566, 568 568,
570 73.6 Compound 393 ##STR00473## 454 456 79.7 Compound 394
##STR00474## 494 496 Compound 395 ##STR00475## 435 437 79.1
Compound 396 ##STR00476## 502 504 Compound 397 ##STR00477## 512,
514 514, 516 Compound 398 ##STR00478## 478 480 84.7 Compound 399
##STR00479## 446 448 Compound 400 ##STR00480## 470 472 75.3
Compound 401 ##STR00481## 462 464 Compound 402 ##STR00482## 428 430
Compound 403 ##STR00483## 444 446 72.5 Compound 404 ##STR00484##
452 454 60.2 Compound 405 ##STR00485## 476 478 61.4 Compound 406
##STR00486## 516, 518 518, 520 56.3 Compound 407 ##STR00487## 502,
504 504, 506 68.2 Compound 408 ##STR00488## 469 471 Compound 409
##STR00489## 464 466 74.7 Compound 410 ##STR00490## 446 448
Compound 411 ##STR00491## 546 548 Compound 412 ##STR00492## 480 482
82.5 Compound 413 ##STR00493## 446 448 95.3 Compound 414
##STR00494## 506, 508 508, 510 92.5 Compound 415 ##STR00495## 480
482 91.5 Compound 416 ##STR00496## 524, 526 526, 528 83.2 Compound
417 ##STR00497## 480 482 90.8 Compound 418 ##STR00498## 492 494
Compound 419 ##STR00499## 514 516 Compound 420 ##STR00500## 602,
604 604, 606 61.0 Compound 421 ##STR00501## 446 448 Compound 422
##STR00502## 512 514 83.1 Compound 423 ##STR00503## 428 430 87.8
Compound 424 ##STR00504## 501 503 Compound 425 ##STR00505## 474 476
90.1 Compound 426 ##STR00506## 492 494 92.3 Compound 427
##STR00507## 464 466 86.5 Compound 428 ##STR00508## 566, 568 568,
570 81.4 Compound 429 ##STR00509## 483 485 71.1 Compound 430
##STR00510## 458 460 50.0 Compound 431 ##STR00511## 566, 568 568,
570 80.5 Compound 432 ##STR00512## 453 455 84.2 Compound 433
##STR00513## 438 440 93.8 Compound 434 ##STR00514## 476 478 79.5
Compound 435 ##STR00515## 476 478 94.6 Compound 436 ##STR00516##
524, 526 526, 528 67.5 Compound 437 ##STR00517## 446 448 97.3
Compound 438 ##STR00518## 462 464 71.6 Compound 439 ##STR00519##
464 466 98.1 Compound 440 ##STR00520## 502, 504 504, 506 88.4
Compound 441 ##STR00521## 506, 508 508, 510 63.0 Compound 442
##STR00522## 556, 558 558, 560 70.1 Compound 443 ##STR00523## 556,
558 558, 560 55.7 Compound 444 ##STR00524## 442 444 100.2 Compound
445 ##STR00525## 442 444 55.6 Compound 446 ##STR00526## 462 464
75.8 Compound 447 ##STR00527## 506, 508 508, 510 95.5 Compound 448
##STR00528## 522, 524 524, 526 81.1 Compound 449 ##STR00529## 556,
558 558, 560 Compound 450 ##STR00530## 498 500 Compound 451
##STR00531## 442 444 76.8 Compound 452 ##STR00532## 462 464 68.9
Compound 453 ##STR00533## 496 498 Compound 454 ##STR00534## 516 518
Compound 455 ##STR00535## 503 505 Compound 456 ##STR00536## 425 427
Compound 457 ##STR00537## 440 442 Compound 458 ##STR00538## 430 432
83.8 Compound 459 ##STR00539## 474 476 Compound 460 ##STR00540##
482 484 53.2 Compound 461 ##STR00541## 468 470 99.7 Compound 462
##STR00542## 445 447 Compound 463 ##STR00543## 468 470 Compound 464
##STR00544## 468 470 87.9 Compound 465 ##STR00545## 452 454
Compound 466 ##STR00546## 416 418 51.1 Compound 467 ##STR00547##
483 485 59.9 Compound 468 ##STR00548## 490 492 56.2 Compound 469
##STR00549## 499 501 Compound 470 ##STR00550## 564 566 Compound 471
##STR00551## 540 542 Compound 472 ##STR00552## 444 446 55.3
Compound 473 ##STR00553## 470 472 74.5 Compound 474 ##STR00554##
559 561 Compound 475 ##STR00555## 512 514 51.8 Compound 476
##STR00556## 482 484 Compound 477 ##STR00557## 452 454 58.1
Compound 478 ##STR00558## 478 480 87.0 Compound 479 ##STR00559##
511 513 Compound 480 ##STR00560## 511 513 Compound 481 ##STR00561##
515 517 Compound 482 ##STR00562## 468 470 87.4 Compound 483
##STR00563## 482 484 Compound 484 ##STR00564## 523 525 65.3
Compound 485 ##STR00565## 461 463 Compound 486 ##STR00566## 546 548
Compound 487 ##STR00567## 556, 558 558, 560 Compound 488
##STR00568## 556, 558 558, 560 62.5 Compound 489 ##STR00569## 556,
558 558, 560 Compound 490 ##STR00570## 411 413 Compound 491
##STR00571## 496 498 Compound 492 ##STR00572## 560 562 Compound 493
##STR00573## 466 468 83.1 Compound 494 ##STR00574## 466 468 66.0
Compound 495 ##STR00575## 547 549 Compound 496 ##STR00576## 526
528
Compound 497 ##STR00577## 511 513 103.6 Compound 498 ##STR00578##
469 471 84.0 Compound 499 ##STR00579## 547, 549 549, 551 108.9
Compound 500 ##STR00580## 525 527 90.2 Compound 501 ##STR00581##
547, 549 549, 551 61.7 Compound 502 ##STR00582## 541 543 75.5
Compound 503 ##STR00583## 547, 549 549, 551 116.0 Compound 504
##STR00584## 631, 633 633, 635 53.5 Compound 505 ##STR00585## 503
505 108.0 Compound 506 ##STR00586## 494 496 83.2 Compound 507
##STR00587## 545 547 84.8 Compound 508 ##STR00588## 494 496
Compound 509 ##STR00589## 573 575 87.0 Compound 510 ##STR00590##
531 533 113.5 Compound 511 ##STR00591## 537 539 98.6 Compound 512
##STR00592## 537 539 60.7 Compound 513 ##STR00593## 529 531 96.6
Compound 514 ##STR00594## 421 423 Compound 515 ##STR00595## 497 499
108.9 Compound 516 ##STR00596## 487 489 106.7 Compound 517
##STR00597## 511 513 69.6 Compound 518 ##STR00598## 499 501 110.8
Compound 519 ##STR00599## 407 409 Compound 520 ##STR00600## 547 549
69.9 Compound 521 ##STR00601## 547 549 Compound 522 ##STR00602##
519 521 98.4 Compound 523 ##STR00603## 547 549 113.5 Compound 524
##STR00604## 559 561 83.0 Compound 525 ##STR00605## 595 597 110.9
Compound 526 ##STR00606## 571, 573 573, 575 111.8 Compound 527
##STR00607## 595 597 52.1 Compound 528 ##STR00608## 483 485 106.2
Compound 529 ##STR00609## 483 485 Compound 530 ##STR00610## 537 539
114.7 Compound 531 ##STR00611## 483 485 100.1 Compound 532
##STR00612## 553 555 99.2 Compound 533 ##STR00613## 495 497
Compound 534 ##STR00614## 483 485 100.8 Compound 535 ##STR00615##
610 612 Compound 536 ##STR00616## 620 622 50.3 Compound 537
##STR00617## 497 499 96.7 Compound 538 ##STR00618## 559 561 97.1
Compound 539 ##STR00619## 615 617 Compound 540 ##STR00620## 521 523
64.3 Compound 541 ##STR00621## 488 490 65.5 Compound 542
##STR00622## 545 547 50.1 Compound 543 ##STR00623## 530 532 111.8
Compound 544 ##STR00624## 501 503 53.9 Compound 545 ##STR00625##
527 529 50.7 Compound 546 ##STR00626## 537 539 55.8 Compound 547
##STR00627## 545 547 Compound 548 ##STR00628## 511 513 96.7
Compound 549 ##STR00629## 525 527 89.2 Compound 550 ##STR00630##
537 539 103.6 Compound 551 ##STR00631## 517 519 76.1 Compound 552
##STR00632## 503 505 67.2 Compound 553 ##STR00633## 605 607 106.6
Compound 554 ##STR00634## 537 539 116.5 Compound 555 ##STR00635##
517 519 102.0 Compound 556 ##STR00636## 499 501 104.8 Compound 557
##STR00637## 583, 585 585, 587 107.3 Compound 558 ##STR00638## 541
543 64.8 Compound 559 ##STR00639## 577, 579 579, 581 79.3 Compound
560 ##STR00640## 501 503 74.4 Compound 561 ##STR00641## 539 541
92.4 Compound 562 ##STR00642## 513 515 93.3 Compound 563
##STR00643## 553 555 64.1 Compound 564 ##STR00644## 494 496 105.4
Compound 565 ##STR00645## 561 563 Compound 566 ##STR00646## 571,
573 573, 575 88.7 Compound 567 ##STR00647## 537 539 101.6 Compound
568 ##STR00648## 505 507 71.1 Compound 569 ##STR00649## 529 531
75.0 Compound 570 ##STR00650## 521 523 77.4 Compound 571
##STR00651## 487 489 55.7 Compound 572 ##STR00652## 503 505 96.5
Compound 573 ##STR00653## 511 513 86.3 Compound 574 ##STR00654##
575, 577 577, 579 86.9 Compound 575 ##STR00655## 561, 563 563, 565
103.7 Compound 576 ##STR00656## 528 530 81.4 Compound 577
##STR00657## 523 525 92.4 Compound 578 ##STR00658## 505 507
Compound 579 ##STR00659## 605 607 87.6 Compound 580 ##STR00660##
539 541 89.2 Compound 581 ##STR00661## 505 507 99.9 Compound 582
##STR00662## 565, 567 567, 569 106.0 Compound 583 ##STR00663## 539
541 108.9 Compound 584 ##STR00664## 583, 585 585, 587 96.2 Compound
585 ##STR00665## 539 541 103.0 Compound 586 ##STR00666## 551 553
87.9 Compound 587 ##STR00667## 573 575 60.0 Compound 588
##STR00668## 551 553 109.3 Compound 589 ##STR00669## 661, 663 663,
665 80.2 Compound 590 ##STR00670## 505 507 62.3 Compound 591
##STR00671## 571 573 77.5 Compound 592 ##STR00672## 487 489 95.8
Compound 593 ##STR00673## 560 562 65.9 Compound 594 ##STR00674##
533 535 84.0 Compound 595 ##STR00675## 551 553 93.7 Compound 596
##STR00676## 523 525 100.3 Compound 597 ##STR00677## 625, 627 627,
629 97.3 Compound 598 ##STR00678## 542 544 89.5 Compound 599
##STR00679## 517 519 80.6 Compound 600 ##STR00680## 625, 627 627,
629 100.5 Compound 601 ##STR00681## 512 514 100.4 Compound 602
##STR00682## 497 499 106.7 Compound 603 ##STR00683## 535 537 106.8
Compound 604 ##STR00684## 535 537 109.4 Compound 605 ##STR00685##
583, 585 535, 587 83.4 Compound 606 ##STR00686## 505 507 107.8
Compound 607 ##STR00687## 521 523 Compound 608 ##STR00688## 523 525
108.6 Compound 609 ##STR00689## 565, 567 567, 569 93.1 Compound 610
##STR00690## 615, 617 617, 619 91.2 Compound 611 ##STR00691## 615,
617 617, 619 63.9 Compound 612 ##STR00692## 501 503 114.0 Compound
613 ##STR00693## 501 503 90.9 Compound 614 ##STR00694## 521 523
77.8 Compound 615 ##STR00695## 565, 567 567, 569 110.3 Compound 616
##STR00696## 581, 583 583, 585 99.9 Compound 617 ##STR00697## 615,
617 617, 619 77.5 Compound 618 ##STR00698## 557 559 65.4 Compound
619 ##STR00699## 497 499 114.2 Compound 620 ##STR00700## 501 503
88.4 Compound 621 ##STR00701## 521 523 95.4
Compound 622 ##STR00702## 555 557 58.9 Compound 623 ##STR00703##
575 577 Compound 624 ##STR00704## 562 564 Compound 625 ##STR00705##
484 486 Compound 626 ##STR00706## 499 501 61.1 Compound 627
##STR00707## 489 491 90.0 Compound 628 ##STR00708## 533 535 64.4
Compound 629 ##STR00709## 541 543 101.1 Compound 630 ##STR00710##
527 529 107.4 Compound 631 ##STR00711## 504 506 95.2 Compound 632
##STR00712## 527 529 59.9 Compound 633 ##STR00713## 527 529 111.2
Compound 634 ##STR00714## 511 513 51.0 Compound 635 ##STR00715##
475 477 68.7 Compound 636 ##STR00716## 542 544 85.7 Compound 637
##STR00717## 549 551 50.6 Compound 638 ##STR00718## 558 560
Compound 639 ##STR00719## 623 625 Compound 640 ##STR00720## 599 601
59.5 Compound 641 ##STR00721## 503 505 85.2 Compound 642
##STR00722## 529 531 85.5 Compound 643 ##STR00723## 618 620
Compound 644 ##STR00724## 571 573 93.0 Compound 645 ##STR00725##
597 599 Compound 646 ##STR00726## 641 643 Compound 647 ##STR00727##
511 513 99.0 Compound 648 ##STR00728## 537 539 107.8 Compound 649
##STR00729## 570 572 64.7 Compound 650 ##STR00730## 570 572
Compound 651 ##STR00731## 574 576 Compound 652 ##STR00732## 527 529
91.9 Compound 653 ##STR00733## 541 543 Compound 654 ##STR00734##
582 584 71.7 Compound 655 ##STR00735## 605 607 Compound 656
##STR00736## 615, 617 617, 619 Compound 657 ##STR00737## 615, 617
617, 619 94.9 Compound 658 ##STR00738## 615, 617 617, 619 80.4
Compound 659 ##STR00739## 470 472 Compound 660 ##STR00740## 555 557
Compound 661 ##STR00741## 619 621 Compound 662 ##STR00742## 525 527
95.4 Binding assay (membrane) Compound Melting % inhibition number
Chemical structure point (.degree. C.) (10 .mu.M) Compound 663
##STR00743## 210.0-217.0 99.5 Compound 664 ##STR00744## 218.0-221.5
85.4 Compound 665 ##STR00745## 197.0-201.0 100.3 Compound 666
##STR00746## 143.5-144.5 97.9 Compound 667 ##STR00747## 207.0-208.0
99.2 Compound 668 ##STR00748## 98.6 Compound 669 ##STR00749##
131.5-132.5 100.3 Compound 670 ##STR00750## 214.5-218.0 100.8
Compound 671 ##STR00751## 100.6 Compound 672 ##STR00752## 102.7
Compound 673 ##STR00753## 62.0 Compound 674 ##STR00754## 97.0
Compound 675 ##STR00755## 96.6 Compound 676 ##STR00756## 92.6
Compound 677 ##STR00757## 60.8 Compound 678 ##STR00758## 97.4
Compound 679 ##STR00759## 104.0 Compound 680 ##STR00760##
169.5-170.5 100.1 Compound 681 ##STR00761## 189.0-189.5 100.2
Compound 682 ##STR00762## 228.0-228.5 76.6 Compound 683
##STR00763## 175.0-178.0 100.5 Compound 684 ##STR00764##
169.5-171.5 Compound 685 ##STR00765## 255.0-260.0 65.1 Compound 686
##STR00766## 220.5-221.0 92.7 Compound 687 ##STR00767## 80.1
Compound 688 ##STR00768## 192.0-193.0 100.5 Compound 689
##STR00769## 92.7 Compound 690 ##STR00770## 198.0-200.0 102.2
Compound 691 ##STR00771## 180.0-182.0 98.5 Compound 692
##STR00772## 227.0-229.0 98.5 Compound 693 ##STR00773## 158.0-161.0
97.7 Compound 694 ##STR00774## 189.0-191.0 106.0 Compound 695
##STR00775## Compound 696 ##STR00776## Compound 697 ##STR00777##
Compound 698 ##STR00778## 99.8
[0595] In Table 1, some of the compounds have two data on APCI MS
(M-H)- and APCI MS (M+H)+, because two peaks were detected due to
isotopes of a chlorine atom or a bromine atom.
[0596] For the compounds listed below, .sup.1H-NMR data is
shown.
[0597] Compound 100: (600 MHz, DMSO-d.sub.6) .delta. ppm: 1.21 (t,
J=7.1 Hz, 3H) 1.27 (d, J=6.9 Hz, 3H) 3.22 (s, 6H) 3.40-3.50 (m, 8H)
3.77-3.93 (m, 2H) 4.68 (q, J=6.9 Hz, 1H) 6.34 (dd, J=7.3, 2.29 Hz,
1H) 6.52 (dd, J=8.3, 2.29 Hz, 1H) 6.56 (t, J=2.3 Hz, 1H) 7.12 (t,
J=8.3 Hz, 1H) 7.70 (dd, J=8.3, 2.3 Hz, 1H) 7.85 (d, J=8.3 Hz, 1H)
7.92 (d, J=1.8 Hz, 1H) 8.66 (s, 1H).
[0598] Compound 119: (600 MHz, CDCl.sub.3) .delta. ppm: 1.34 (t,
J=7.3 Hz, 3H), 1.50 (d, J=7.3 Hz, 3H), 3.89-3.98 (m, 2H), 4.59-4.65
(m, 1H), 5.06 (s, 2H) 6.37-6.42 (m, 1H), 6.80-6.95 (m, 2H),
7.01-7.04 (m, 1H), 7.24-7.36 (m, 2H), 7.36-7.44 (m, 4H), 7.49-7.53
(m, 1H), 7.67-7.73 (m, 1H), 7.93-7.96 (m, 1H).
[0599] Compound 127: (600 MHz, CDCl.sub.3) .delta. ppm: 1.38 (t,
J=7.1 Hz, 3H), 1.49 (d, J=6.9 Hz, 3H), 2.41 (s, 3H), 3.93-4.02 (m,
2H), 4.59-4.65 (m, 1H), 5.47 (d, J=9.6 Hz, 1H), 7.05-7.10 (m, 2H),
7.31-7.37 (m, 3H), 7.61-7.64 (m, 1H), 7.80-7.82 (m, 1H).
[0600] Compound 129: (600 MHz, DMSO-d.sub.6) .delta. ppm: 1.21-1.29
(m, 6H), 2.29 (s, 6H), 3.83-4.01 (m, 2H), 4.61 (q, J=6.4 Hz, 1H),
6.43-6.47 (m, 1H), 6.89-6.93 (m, 1H), 7.34-7.40 (m, 3H), 7.52-7.60
(m, 3H), 8.24 (s, 1H), 11.18 (s, 1H).
[0601] Compound 130: (600 MHz, DMSO-d.sub.6) .delta. ppm: 1.22 (d,
J=6.8 Hz, 3H), 1.26 (t, J=7.1 Hz, 3H), 3.87-4.02 (m, 2H), 4.70 (q,
J=6.8 Hz, 1H), 6.43-6.45 (m, 1H), 6.77-6.80 (m, 1H), 7.28-7.30 (m,
1H), 7.36-7.38 (m, 1H), 7.50-7.53 (m, 1H), 7.67-7.75 (m, 2H),
7.83-7.86 (m, 1H), 8.04-8.07 (m, 1H), 8.12-8.19 (m, 2H), 8.45-8.47
(m, 1H), 8.52 (s, 1H), 11.16 (s, 1H).
[0602] Compound 131: (600 MHz, DMSO-d.sub.6) .delta. ppm: 1.28 (t,
J=7.1 Hz, 3H), 1.35 (d, J=6.9 Hz, 3H), 2.36 (s, 3H), 3.89-4.03 (m,
2H), 4.64-4.72 (m, 1H), 6.44-6.46 (m, 1H), 6.87-6.90 (m, 1H),
7.36-7.38 (m, 2H), 7.53-7.57 (m, 1H), 7.82-7.84 (m, 1H), 7.88-7.91
(m, 1H), 8.77 (s, 1H), 11.18 (s, 1H).
[0603] Compound 132: (600 MHz, DMSO-d.sub.6) .delta. ppm: 1.23-1.31
(m, 6H), 2.39 (s, 3H), 3.85-4.02 (m, 2H), 4.69 (q, J=6.9 Hz, 1H),
6.43-6.47 (m, 1H), 6.88-6.92 (m, 1H), 7.36-7.39 (m, 2H), 7.53-7.60
(m, 2H), 7.64-7.68 (m, 1H), 7.77-7.80 (m, 1H), 8.51 (s, 1H), 11.18
(s, 1H).
[0604] Compound 134: (600 MHz, DMSO-d.sub.6) .delta. ppm: 1.29 (t,
J=7.3 Hz, 3H), 1.36 (d, J=6.9 Hz, 3H), 3.89-4.05 (m, 2H), 4.67-4.73
(m, 1H), 6.44-6.46 (m, 1H), 6.86-6.90 (m, 1H), 7.35-7.39 (m, 2H),
7.54-7.57 (m, 1H), 7.83-7.88 (m, 1H), 7.91-7.94 (m, 1H), 9.01 (s,
1H), 11.17 (s, 1H).
[0605] Compound 136: (600 MHz, DMSO-d.sub.6) .delta. ppm: 1.23-1.31
(m, 6H), 3.85-4.02 (m, 2H), 4.72 (q, J=6.9 Hz, 1H), 6.44-6.47 (m,
1H), 6.87-6.91 (m, 1H), 7.34-7.39 (m, 2H), 7.52-7.57 (m, 1H),
7.97-8.05 (m, 4H), 8.74 (s, 1H), 11.17 (s, 1H).
[0606] Compound 150: (200 MHz, CDCl.sub.3) .delta. ppm: 0.94 (d,
J=6.4 Hz, 3H), 0.97 (d, J=6.4 Hz, 3H), 1.30 (t, J=7.3 Hz, 3H),
2.00-2.20 (m, 1H), 2.37 (s, 3H), 3.70-3.88 (m, 2H), 4.10 (dd,
J=6.9, 9.4 Hz, 1H), 6.71 (d, J=9.4 Hz, 2H), 7.12-7.22 (m, 4H), 7.40
(d, J=8.4 Hz, 1H), 7.65 (dd, J=2.2, 8.4 Hz, 1H), 7.84 (d, J=2.2 Hz,
1H).
[0607] Compound 668: (600 MHz, DMSO-d.sub.6) ppm: 1.19-1.25 (m,
6H), 2.22 (s, 3H), 2.41-2.46 (m, 4H), 2.49-2.54 (m, 3H), 3.11-3.17
(m, 4H), 3.83-3.99 (m, 2H), 4.65-4.71 (m, 1H), 6.47-6.51 (m, 1H),
6.77-6.82 (m, 2H), 7.17-7.22 (m, 1H), 7.51-7.55 (m, 1H), 7.77-7.84
(m, 2H), 8.01-8.10 (m, 2H), 8.38-8.51 (m, 2H).
[0608] Compound 671: (200 MHz, CDCl.sub.3) .delta. ppm: 0.89 (t,
J=7.5 Hz, 3H), 1.23 (t, J=7.3 Hz, 3H), 1.70-2.06 (m, 2H), 2.42 (s,
3H), 2.66 (bs, 4H), 3.29 (t, J=5.1 Hz, 4H), 3.68-3.92 (m, 2H), 4.38
(dd, J=7.0, 15.4 Hz, 1H), 6.50 (bs, 1H), 6.56 (dd, J=2.0, 8.1 Hz,
1H), 6.72 (dd, J=2.0, 8.4 Hz, 1H), 6.89 (t, J=2.0 Hz, 1H), 7.20 (t,
J=8.4 Hz, 1H), 7.46 (t, J=8.1 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.80
(d, J=8.0 Hz, 1H), 7.94 (d, J=2.0, 9.0 Hz, 1H), 8.28 (d, J=9.0 Hz,
1H), 8.4 (d, J=2.0 Hz, 1H).
[0609] Compound 672: (200 MHz, CDCl.sub.3) .delta. ppm: 1.33 (t,
J=7.3 Hz, 3H), 1.49 (d, J=6.8 Hz, 3H), 2.41 (s, 3H), 2.57-2.70 (m,
4H), 3.16-3.33 (m, 6H), 3.91 (q, J=7.3 Hz, 2H), 4.52-4.69 (m, 3H),
5.08 (d, J=9.0 Hz, 1H), 6.73 (dd, J=2.2, 8.6 Hz, 2H), 6.81 (d,
J=9.0 Hz, 1H), 6.97 (t, J=2.2 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H),
7.62-7.68 (m, 2H).
[0610] Compound 673: (200 MHz, CDCl.sub.3) .delta. ppm: 1.31 (t,
J=7.0 Hz, 3H), 1.33 (s, 6H), 1.49 (d, J=7.0 Hz, 3H), 1.80 (t, J=6.6
Hz, 2H), 2.39 (s, 3H), 2.59 (t, J=5.0 Hz, 4H), 2.79 (t, J=7.0 Hz,
2H), 3.25 (t, J=5.0 Hz, 4H), 3.90 (q, J=7.0 Hz, 2H), 4.48-4.65 (m,
1H), 5.07 (d, J=9.5 Hz, 1H), 6.73 (dd, J=2.4, 8.1 Hz, 2H), 6.82 (d,
J=9.2 Hz, 1H), 6.97 (t, J=2.4 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H),
7.51-7.57 (m, 2H).
[0611] Compound 674: (200 MHz, CDCl.sub.3) .delta. ppm: 1.34 (t,
J=7.3 Hz, 3H), 1.49 (d, J=6.8 Hz, 3H), 2.21 (quint, J=6.0 Hz, 2H),
2.37 (s, 3H), 2.59 (t, J=4.6 Hz, 4H), 3.25 (t, J=4.6 Hz, 4H), 3.93
(q, J=7.3 Hz, 2H), 4.27 (dd, J=6.0, 11.6 Hz, 4H) 4.51-4.66 (m, 1H),
5.15 (d, J=9.5 Hz, 1H), 6.74 (dd, J=2.2, 8.4 Hz, 1H), 7.07-7.13 (m,
2H), 7.23 (t, J=8.1 Hz, 1H), 7.38 (dd, J=2.4, 8.1 Hz, 1H), 7.43 (d,
J=2.0 Hz, 1H).
[0612] Compound 675: (200 MHz, CDCl.sub.3) .delta. ppm: 1.36 (t,
J=7.3 Hz, 3H), 1.49 (d, J=6.8 Hz, 3H), 2.39 (s, 3H), 2.59 (t, J=5.0
Hz, 4H), 3.26 (t, J=5.0 Hz, 4H), 3.95 (q, J=7.3 Hz, 2H), 4.50-4.68
(m, 1H), 5.18 (d, J=9.5 Hz, 1H), 6.05 (s, 2H), 6.74 (dd, J=2.4, 8.1
Hz, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.98 (t, J=2.4 Hz, 1H), 7.19-7.27
(m, 2H), 7.42 (dd, J=1.8, 8.1 Hz, 1H).
[0613] Compound 676: (200 MHz, CDCl.sub.3) .delta. ppm: 1.27-1.33
(m, 15H), 1.47 (d, J=6.8 Hz, 3H), 2.43 (s, 3H), 2.61-2.72 (m, 4H),
3.25-3.33 (m, 4H), 3.90 (q, J=7.5 Hz, 2H), 4.57 (dd, J=6.8, 9.2 Hz,
1H), 5.13 (d, J=9.2 Hz, 1H), 6.70-6.79 (m, 2H), 6.99 (t, J=2.2 Hz,
1H), 7.22 (t, J=8.1 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.57 (dd,
J=2.0, 8.1 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H).
[0614] Compound 677: (200 MHz, CDCl.sub.3) .delta. ppm: 1.32 (t,
J=7.3 Hz, 3H), 1.49 (d, J=6.8 Hz, 3H), 2.22 (s, 3H), 2.38 (s, 3H),
2.56-2.63 (m, 4H), 3.14-3.30 (m, 6H), 3.84-4.10 (m, 4H), 4.53-4.64
(m, 1H), 5.25 (d, J=9.5 Hz, 1H), 6.71-6.79 (m, 2H), 7.01 (t, J=2.4
Hz, 1H), 7.22 (t, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.69 (dd, J=2.0, 8.4
Hz, 1H), 8.27 (d, J=8.4 Hz, 1H).
[0615] Compound 678: (200 MHz, CDCl.sub.3) .delta. ppm: 1.32 (t,
J=7.3 Hz, 3H), 1.46 (d, J=6.8 Hz, 3H), 2.11 (quint, J=7.5 Hz, 2H),
2.36 (s, 3H), 2.58 (t, J=5.0 Hz, 4H), 2.94 (t, J=7.5 Hz, 4H), 3.25
(t, J=5.0 Hz, 4H), 3.92 (q, J=7.3 Hz, 2H), 4.52-4.67 (m, 1H), 5.15
(d, J=10.0 Hz, 1H), 6.73 (dd, J=2.2, 8.1 Hz, 2H), 6.98 (t, J=2.2
Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.62 (dd,
J=2.2, 7.9 Hz, 1H), 7.67 (s, 1H).
[0616] Compound 679: (600 MHz, DMSO-d.sub.6) .delta. ppm: 1.24 (t,
J=7.1 Hz, 3H), 1.29 (d, J=6.9 Hz, 3H), 2.22 (s, 3H), 2.40-2.46 (m,
4H), 3.12-3.16 (m, 4H), 3.81-3.97 (m, 2H), 4.64-4.72 (m, 1H),
6.53-6.58 (m, 1H), 6.60-6.65 (m, 1H), 6.77-6.82 (m, 2H), 7.20 (t,
J=8.3 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.94-7.99 (m, 1H), 8.17-8.23
(m, 2H), 8.54-8.61 (m, 1H).
[0617] Compound 698: (600 MHz, CDCl.sub.3) .delta. ppm: 1.33 (t,
J=7.1 Hz, 3H), 1.43 (d, J=6.9 Hz, 3H), 2.11 (s, 3H), 3.10-3.20 (m,
4H), 3.53-3.59 (m, 2H), 3.67-3.74 (m, 2H), 3.89-4.00 (m, 2H), 4.67
(q, J=7.1 Hz, 1H), 6.65-6.75 (m, 2H), 6.94-6.97 (m, 1H), 7.21-7.25
(m, 1H), 7.46-7.50 (m, 1H), 7.69-7.73 (m, 1H), 7.80-7.84 (m, 1H),
7.95-7.99 (m, 1H), 8.29-8.34 (m, 1H), 8.45-8.47 (m, 1H).
[0618] The following describes exemplary methods of preparing
starting materials used to produce the compounds of the present
application.
Reference Examples 1-3
[0619] Starting from the corresponding amine in place of
1,4-dioxa-8-azaspiro[4,5]decane used in Example 7-(1), the same
procedure as used in Example 7-(1) was repeated to give the titled
compounds.
Reference Example 1
3-((2R,6S)-2,6-Dimethylmorpholine-4-yl)-phenol
##STR00779##
[0621] Brown oily substance, yield 71%
[0622] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 1.24 (d,
J=6.0 Hz, 6H), 2.36-2.45 (m, 2H), 3.37-3.46 (m, 2H), 3.73-3.83 (m,
2H), 5.01 (s, 1H), 6.28-6.33 (m, 1H), 6.36-6.38 (m, 1H), 6.46-6.51
(m, 1H), 7.10 (t, J=8.0 Hz, 1H)
Reference Example 2
3-[4-(2-Dimethylaminoethyl)-piperazin-1-yl]-phenol
##STR00780##
[0624] Yellow oily substance, yield 12%
[0625] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 2.29 (s, 6H),
2.48-2.57 (m, 4H), 2.57-2.64 (m, 4H), 3.11-3.16 (m, 4H), 6.24-6.30
(m, 1H), 6.32-6.37 (m, 1H), 6.42-6.49 (m, 1H), 7.04-7.09 (m,
1H)
Reference Example 3
3-[(2-Dimethylaminoethyl)-methyl-amino]-phenol
##STR00781##
[0627] Brown oily substance, yield 42%
[0628] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 2.27 (s, 6H),
2.44-2.50 (m, 2H), 2.87 (s, 3H), 3.37-3.44 (m, 2H), 6.09-6.16 (m,
2H), 6.19-6.24 (m, 1H), 7.01 (t, J=8.0 Hz, 1H)
Reference Example 4
3-(4-Isopropyl-piperazin-1-yl)-phenol
##STR00782##
[0630] Acetone (1.95 g) and NaBH(OAc).sub.3 (7.12 g) were added to
a solution of 3-piperazin-1-yl-phenol (2.00 g) in THF (40 ml), and
the mixture was stirred at room temperature for 18 hours. Saturated
aqueous sodium bicarbonate was added to the reaction solution, and
the mixture was extracted with ethyl acetate. The organic layer was
dried (MgSO.sub.4) and filtered to give the titled compound (1.48
g, colorless powder).
[0631] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 1.11 (d,
J=6.4 Hz, 6H), 2.68-2.72 (m, 4H), 2.71-2.78 (m, 1H), 3.15-3.23 (m,
4H), 6.28-6.32 (m, 1H), 6.36 (t, J=2.3 Hz, 1H), 6.50 (dd, J=8.3,
2.3 Hz, 1H), 7.09 (t, J=8.3 Hz, 1H)
Reference Example 5
3-(1-Isopropylpiperidin-4-yl)-phenol
##STR00783##
[0633] Starting from 3-piperidin-4-yl-phenol in place of
3-piperazin-1-yl-phenol used in Reference Example 4, the same
procedure as used in Reference Example 4 was repeated to give the
titled compound (yield 31%, colorless powder).
[0634] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 1.16 (d,
J=6.4 Hz, 6H), 1.76-1.86 (m, 2H), 1.91-2.01 (m, 2H), 2.31-2.50 (m,
3H), 2.92-3.02 (m, 1H), 3.08-3.19 (m, 2H), 6.66-6.72 (m, 2H),
6.74-6.79 (m, 1H), 7.11 (t, J=7.8 Hz, 1H)
Reference Example 6
4-Fluoro-3-(4-methyl-piperazin-1-yl)-phenol
##STR00784##
[0635] 4-Benzyloxy-2-chloro-1-fluorobenzene
##STR00785##
[0636] (1) A suspension of 3-chloro-4-fluorophenol (2.00 g), benzyl
chloride (1.88 ml), and potassium carbonate (2.82 g) in
dimethylformamide (10 ml) was stirred at room temperature for three
hours. Water was added to the reaction mixture, and the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride, dried (MgSO.sub.4), filtered,
and concentrated, and the resulting residue was purified by
silica-gel column chromatography (OH SiO.sub.2, AcOEt/hexane=0-10%)
to give the titled compound (2.00 g) as a light yellow oily
substance.
[0637] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 5.01 (s, 2H),
6.77-6.86 (m, 1H), 6.96-7.09 (m, 2H), 7.30-7.46 (m, 5H) [0638]
1-(5-Benzyloxy-2-fluorophenyl)-4-methyl-piperazine
##STR00786##
[0638] (2) Under an argon atmosphere at room temperature, the
compound (7.5 g) obtained in Reference Example 6-(1) and thereafter
a solution of 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-1
phosphino-bicyclo[3,3,3]-undecane (1.1 g) in toluene (320 ml) were
added to tris dibenzylidenedipalladium (1.45 g) and t-butoxysodium
(4.26 g). Then, a solution of N-methylpiperazine (1.02 g) in
toluene (20 ml) was added at room temperature, and the mixture was
stirred at 100.degree. C. for 60 hours. The reaction mixture was
concentrated, and the resulting residue was purified by silica-gel
column chromatography (NH SiO.sub.2, AcOEt/hexane=0-30%) to give
the titled compound (2.27 g) as a yellow oily substance.
[0639] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. ppm: 2.35 (s, 3H),
2.55-2.63 (m, 4H), 3.06-3.15 (m, 4H), 5.00 (s, 2H), 6.46-6.51 (m,
1H), 6.56-6.59 (m, 1H), 6.89-6.95 (m, 1H), 7.29-7.45 (m, 5H) [0640]
4-Fluoro-3-(4-methylpiperazin-1-yl)-phenol
##STR00787##
[0640] (3) A suspension of the compound (2.48 g) obtained in
Reference Example 6-(2) and palladium hydroxide (10%, 250 mg) in
methanol (30 ml) was stirred under a hydrogen atmosphere at
65.degree. C. for two hours and a half and thereafter at room
temperature for overnight. The reaction solution was filtered
through celite, and the filtrate was concentrated. The resulting
residue was purified by silica-gel column chromatography (NH
SiO.sub.2, AcOEt/hexane=0-99%, methanol/chloroform=0-10%).
Thereafter, the resulting compound was purified again by silica-gel
column chromatography (OH SiO.sub.2, methanol/chloroform=0-10%) to
give the titled compound (877 mg) as an ocher solid.
[0641] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm: 2.21 (s,
3H), 2.39-2.48 (m, 4H), 2.89-2.99 (m, 4H), 6.26-6.31 (m, 1H),
6.35-6.39 (m, 1H), 6.84-6.91 (m, 1H), 9.20 (s, 1H)
[0642] The following describes an exemplary method of producing an
intermediate represented by Formula (II) of the present
application.
[0643] Starting from the corresponding starting materials, the same
procedures as shown in Examples 1-(1) to 1-(7), Examples 2-(1) and
2-(2), Examples 7-(1) and 7-(2), Examples 17-(1) and 17-(2),
Example 18-(1), Example 21-(1), Example 22-(1), Example 23-(1), and
Examples 26-(1) to 26-(8) were repeated, followed by salt formation
as needed to obtain compounds or salts of the compounds which are
intermediates useful in producing the compound of Formula (I) of
the present application. The resulting intermediates are shown in
Table 2 together with the intermediates obtained in the Examples
above.
TABLE-US-00002 TABLE 2 Compound number Chemical structure .sup.1H
NMR Intermediate 1 ##STR00788## (200 MHz, CDCl.sub.3) .delta. ppm:
1.25 (t, J = 7.3 Hz, 3H), 3.12 (dd, J = 13.3, 8.6 Hz, 1H), 3.38
(dd, J = 13.3, 6.1 Hz, 1H), 3.60-4.30 (m, 3H), 7.10-7.46 (m, 10H)
Intermediate 2 ##STR00789## (600 MHz, DMSO-d6) .delta. ppm: 1.29
(t, J = 7.3 Hz, 3H), 1.41 (d, J = 6.9 Hz, 3H), 2.30 (s, 3H), 3.96-
4.09 (m, 3H), 7.15-7.30 (m, 4H) Intermediate 3 ##STR00790## (600
MHz, DMSO-d6) .delta. ppm: 1.33 (t, J = 7.1 Hz, 3H), 1.42 (d, J =
6.4 Hz, 3H), 2.23 (s, 3H), 4.00- 4.12 (m, 3H), 7.10-7.40 (m, 4H)
Intermediate 4 ##STR00791## (600 MHz, DMSO-d6) .delta. ppm:
1.22-1.30 (m, 3H), 1.41-1.48 (m, 3H), 2.33 (s, 3H), 3.83-4.10 (m,
3H), 7.04-7.14 (m, 3H), 7.26-7.37 (m, 1H) Intermediate 5
##STR00792## (600 MHz, CDCl.sub.3) .delta. ppm: 1.46 (t, J = 7.1
Hz, 3H), 1.57 (d, J = 6.9 Hz, 3H), 4.05-4.25 (m, 3H), 6.81- 7.32
(m, 4H) Intermediate 6 ##STR00793## (200 MHz, CDCl.sub.3) .delta.
ppm: 1.41 (t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.6 Hz, 3H), 3.87-4.26
(m, 3H), 7.14- 7.26 (m, 1H), 7.30-7.45 (m, 4H) Intermediate 7
##STR00794## (600 MHz, CDCl.sub.3) .delta. ppm: 1.35-1.45 (m, 3H),
1.53- 1.62 (m, 3H), 3.95-4.20 (m, 3H), 7.27-7.40 (m, 4H)
Intermediate 8 ##STR00795## (600 MHz, CDCl.sub.3) .delta. ppm: 1.41
(t, J = 7.1 Hz, 3H), 1.60(d, J = 6.9 Hz, 3H). 3.90-4.25 (m, 3H),
7.15-7.50 (m, 4H) Intermediate 9 ##STR00796## (600 MHz, DMSO-d6)
.delta. ppm: 1.14 (t, J = 7.3 Hz, 3H), 2.30 (s, 3H), 3.00 (dd, J =
13.3, 7.3 Hz, 1H), 3.19 (dd, J = 13.3, 6.9 Hz, 1H), 3.77-3.98 (m,
2H), 4.11 (t, J = 7.1 Hz, 1H), 7.13-7.139 (m, 9H) Intermediate 10
##STR00797## (600 MHz, CDCl.sub.3) .delta. ppm: 1.41 (t, J = 7.4
Hz, 3H). 1.57 (d, J = 6.8 Hz, 3H), 3.80 (s, 3H), 3.95-4.20 (m, 3H),
6.82-6.97 (m, 2H), 7.21-7.34 (m, 2H) Intermediate 11 ##STR00798##
(600 MHz, CDCl.sub.3) .delta. ppm: 1.41 (t, J = 7.3 Hz, 3H), 1.58
(d, J = 6.4 Hz, 3H), 3.95-4.23 (m, 3H), 6.90-7.15 (m, 2H),
7.30-7.44 (m, 2H) Intermediate 12 ##STR00799## (600 MHz,
CDCl.sub.3) .delta. ppm: 1.41 (t, J = 7.4 Hz, 3H), 1.60 (d, J = 6.8
Hz, 3H), 3.98-4.21 (m, 3H), 7.26-7.65 (m, 3H) Intermediate 13
##STR00800## (600 MHz, CDCl.sub.3) .delta. ppm: 1.40 (t, J = 7.1
Hz, 3H), 1.58 (d, J = 6.9 Hz, 3H), 2.24 (s, 3H), 2.25 (s, 3H),
3.95- 4.23 (m, 3H), 7.00-7.19 (m, 3H) Intermediate 14 ##STR00801##
(200 MHz, CDCl.sub.3) .delta. ppm: 1.05-2.03 (m, 16 H), 2.32- 2.65
(m, 1 H), 3.87-4.29 (m, 3 H), 700-7.46 (m, 4 H) Intermediate 15
##STR00802## (200 MHz, CDCl.sub.3) .delta. ppm: 1.43 (t, J = 7.3
Hz, 3 H), 1.59 (d, J = 7.0 Hz, 3 H), 3.87 (s, 6 H), 3.96-4.27 (m, 3
H), 6.82-6.88 (m, 2 H), 6.97 (d, J = 2.6 Hz, 1 H) Intermediate 16
##STR00803## (600 MHz, CDCl.sub.3) .delta. ppm: 1.42 (t, J = 7.3
Hz, 3 H), 1.59 (d, J = 6.4 Hz, 3 H), 3.80 (s, 3 H), 3.82 (s, 6 H),
3.99-4.12 (m, 2 H), 4.13-4.19 (m, 1 H), 6.63 (s, 2 H) Intermediate
17 ##STR00804## (600 MHz, CDCl.sub.3) .delta. ppm: 1.39 (t, J = 7.3
Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.12 (s, 3 H), 2.26 (s, 6 H),
3.96-4.07 (m, 2 H), 4.14 (q, J = 6.6 Hz, 1 H), 6.97 (s, 2 H)
Intermediate 18 ##STR00805## (600 MHz, CDCl.sub.3) .delta. ppm:
1.38 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.30 (s, 6
H), 3.94-4.08 (m, 2 H) 4.15 (q, J = 6.9 Hz, 1 H), 6.81 (s, 1 H),
6.95 (s, 2 H) Intermediate 19 ##STR00806## (600 MHz, CDCl.sub.3)
.delta. ppm: 1.43 (t, J = 7 .3 Hz, 3 H), 1.63 (d, J = 6.9 Hz, 3 H),
3.81 (s, 6 H), 4.00-4.12 (m, 2 H), 4.20 (q, J = 6.7 Hz, 1 H), 6.33
(s, 1 H), 6.59 (s, 2 H) Intermediate 20 ##STR00807## (600 MHz,
CDCl.sub.3) .delta. ppm: 0.96-0.98 (m, 3 H), 1.40 (t, J = 7.3 Hz, 3
H), 1.43-1.52 (m, 2 H), 1.56 (d, J = 6.9 Hz, 3 H), 1.71-1.78 (m,
2H), 3.93 (t, J = 6.4 Hz, 2 H), 3.97-4.08 (m, 2 H), 4.15 (q, J =
6.6 Hz, 1 H), 6.85- 6.89 (m, 2 H) 7.23-7.28 (m, 2 H) Intermediate
21 ##STR00808## (600 MHz, CDCl.sub.3) .delta. ppm: 1.42 (t, J = 7.3
Hz, 3H), 1.59 (d, J = 6.9 Hz, 3H), 3.99-4.13 (m, 2H), 4.17 (q, J =
6.9 Hz, 1H), 6.98-7.05 (m, 4H), 7.07-7.13 (m, 1H), 7.29-7.39 (m,
4H) Intermediate 22 ##STR00809## (600 MHz, CDCl.sub.3) .delta. ppm:
1.41 (t, J = 7 .1 Hz, 3H), 1.58 (d, J = 6.9 Hz, 3H), 3.99-4.10 (m,
2H), 4.16 (q, J =6.9 Hz, 1H), 5.05 (s, 2H). 6.94-7.00 (m, 2H).
7.25- 7.31 (m, 2H), 7.31-7.35 (m, 1H), 7.36-7.41 (m, 2H), 7.41-7.44
(m, 2H) Intermediate 23 ##STR00810## (600 MHz, CDCl.sub.3), .delta.
ppm: 1.23 (t, J = 7.6 Hz, 3 H), 1.40 (t, J = 7.3 Hz, 3 H), 1.58 (d,
J = 6.4 Hz, 3 H), 2.64 (q, J = 7.5 Hz, 2 H), 3.98-4.11 (m, 2H),
4.16 (q, J = 6.9 Hz, 1 H), 7.16-7.31 (m, 4 H) Intermediate 24
##STR00811## (600 MHz, CDCl.sub.3), .delta. ppm: 0.94 (t, J =7.3
Hz, 3 H), 1.40 (t, J = 7.3 Hz, 3 H), 1.54-1.67 (m, 5 H), 2.53- 2.61
(m, 2 H), 3.94-4.10 (m, 2 H), 4.17 (q, J = 6.4 Hz, 1 H), 7.12-7.31
(m, 4 H) Intermediate 25 ##STR00812## (600 MHz, , CDCl.sub.3)
.delta. ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H),
2.35 (s, 3 H), 3.96-4.09 (m, 2 H), 4.14 (q, J = 6.6 Hz, 1 H), 7.14
(dd, J = 8.7, 3.7 Hz, 1 H), 7.27 (d, J = 3.2 Hz, 1 H), 7.31 (d, J =
8.7 Hz, 1 H) Intermediate 26 ##STR00813## (600 MHz, , CDCl.sub.3)
.delta. ppm: 1.40 (t, J = 7.3 Hz, 3 H), 1.56 (d, J = 6.9 Hz, 3 H),
3.99-4.10 (m, 2 H), 4.14 (q, J = 6.7 Hz, 1 H), 6.30-6.33 (m, 2 H),
6.99-7.03 (m, 2 H), 7.34-7.38 (m, 2 H), 7.41-7.44 (m, 2 H)
Intermediate 27 ##STR00814## (600 MHz, , CDCl.sub.3) .delta. ppm:
1.38 (t, J = 7.1 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.94 (s, 6
H), 3.95-4.07 (m, 2 H), 4.14 (q, J = 6.9 Hz, 1 H), 6.52 (dd, J =
8.7, 2.8 Hz, 1 H), 6.60 (dd, J = 8.7, 2.3 Hz, 1 H), 6.72 (t, J =
2.3 Hz, 1 H), 7.18 (t, J = 8.3 Hz, 1 H) Intermediate 28
##STR00815## (600 MHz, CDCl.sub.3) .delta. ppm 1..43 (t, J = 7.1
Hz, 3H), 1.60 (d, J = 6.9 Hz, 3H), 4.02-4.13 (m, 2H), 4.19 (q, J =
6.9 Hz, 1H), 7.32-7.37 (m, 1H), 7.40-7.48 (m, 4H), 7.55-7.62 (m,
4H) Intermediate 29 ##STR00816## (600 MHz, CDCl.sub.3) .delta. ppm:
1.40 (t, J = 7.3 Hz, 3H), 1.61 (d, J = 6.9 Hz, 3H), 4.00-4.12 (m,
2H), 4.17-4.23 (m, 1H), 7.19-7.23 (m, 1H), 7.37-7.42 (m, 2H)
Intermediate 30 ##STR00817## (600 MHz, CDCl.sub.3) .delta. ppm:
1.42 (t, J = 7.1 Hz, 3H), 1.60 (d, J = 6.4 Hz, 3H), 4.01-4.13 (m,
2H), 4.17(q, J = 6.4 Hz, 1H), 7.13-7.18 (m, 1H), 7.30-7.34 (m, 1H),
7.51-7.54 (m, 1H) Intermediate 31 ##STR00818## (600 MHz,
CDCl.sub.3), .delta. ppm: 0.92 (t, J = 7.6 Hz, 3 H), 1.30-1.44 (m,
5 H), 1.54-1.63 (m, 5 H), 2.55-2.64 (m, 2 H), 3.97-4.10 (m, 2 H),
4.17 (q, J = 6.6 Hz, 1 H), 7.15-7.29 (m, 4 H) Intermediate 32
##STR00819## (600 MHz, CDCl.sub.3), .delta. ppm: 1.42 (t, J = 7.3
Hz, 3 H), 1.60 (d, J = 6.9 Hz, 3 H), 4.00-4.15 (m, 2 H), 4.18 (q, J
= 6.9 Hz, 1 H), 7.19-7.28 (m, 2 H), 7.39-7.47 (m, 2 H) Intermediate
33 ##STR00820## (600 MHz, , CDCl.sub.3) .delta. ppm: 1.39 (t, J =
7.3 Hz, 3 H), 1.58 (d, J = 6 .4 Hz, 3 H), 3.12-3.19 (m, 4 H), 3.79-
3.86 (m, 4 H), 3.95-4.09 (m, 2 H), 4.14 (q, J = 6.7 Hz, 1 H), 6.71
(dd, J = 8.0, 2.1 Hz, 1 H), 6.79 (dd, J = 8.3, 2.3 Hz, 1 H)
7.00-7.03 (m, 1 H), 7.21-7.25 (m, 1 H) Intermediate 34 ##STR00821##
(600 MHz, CDCl.sub.3) .delta. ppm: 1.39 (t, J = 7.1 Hz, 3 H), 1.56
(d, J = 6.9 Hz, 3 H), 2.33 (s, 6 H), 2.67-2.76 (m, 2 H), 3.95-4.08
(m, 4 H), 4.14 (q, J = 6.6 Hz, 1 H), 6.84- 6.93 (m, 2 H), 7.19-7.31
(m, 2 H) Intermediate 35 ##STR00822## (600 MHz, CDCl.sub.3) .delta.
ppm: 1.40 (t, J = 7.1 Hz, 3 H), 1.56 (d, J = 6.9 Hz, 3 H),
2.54-2.59 (m, 4 H), 2.78 (t, J = 5.7 Hz, 2 H), 3.71-3.75 (m, 4 H),
3.98-4.06 (m, 2 H), 4.08 (t, J = 5.7 Hz, 2 H), 4.14 (q, J = 6.6 Hz,
1 H), 6.86-6.90 (m, 2 H), 7.24-7.28 (m, 2 H) Intermediate 36
##STR00823## (600 MHz, CDCl.sub.3), .delta. ppm: 1.41 (t, J = 7.3
Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.27 (d, J = 1.8 Hz, 3 H),
3.98-4.11 (m, 2 H), 4.17 (q, J = 6.9 Hz, 1 H), 6.95- 7.03 (m, 1 H),
7.11-7.16 (m, 1 H), 7.21-7.24 (m, 1 H) Intermediate 37 ##STR00824##
(200 MHz, CDCl.sub.3) .delta. ppm: 1.00-1.20 (m, 4H), 1.58 (d, J =
6.6 Hz, 3H), 2.90-3.06 (m, 1H), 3.80 (s, 3H), 4.05- 4.32 (m, 1H),
6.38-6.95 (m, 2H), 7.20-7.30 (m, 2H) Intermediate 38 ##STR00825##
(600 MHz, , CDCl.sub.3) .delta. ppm: 1.23 (d, J = 7.3 Hz, 6 H),
1.39 (t, J = 7.1 Hz, 3 H), 1.57 (d, J = 6.9 Hz, 3 H), 2.86- 2.93
(m, 1 H), 3.97-4.09 (m, 2 H), 4.15 (q, J = 6.6 Hz, 1 H), 7.19-7.23
(m, 2 H) 7.24-7.27 (m, 2 H) Intermediate 39 ##STR00826## (600 MHz,
CDCl.sub.3), .delta. ppm: 1.25 (d, J = 6.9 Hz, 6 H), 1.41 (t, J =
7.3 Hz, 3 H), 1.59 (d, J = 6.4 Hz, 3 H), 2.85-2.97 (m, 1 H),
3.99-4.10 (m, 2 H), 4.16 (q, J = 6.7 Hz, 1 H), 7.06-7.10 (m, 1 H),
7.13-7.18 (m, H), 7.20-7.24 (m, 1 H), 7.26-7.32 (m, 1 H)
Intermediate 40 ##STR00827## (600 MHz, CDCl.sub.3) .delta. ppm:
1.48 (t, J = 7.3 Hz, 3 H), 1.61 (d, J = 6.9 Hz, 3 H), 4.09-4.24 (m,
3 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.51-7.56 (m, 2 H), 7.61 (d, J =
6.9 Hz, 1 H), 7.68 (d, J = 8.3 Hz, 1 H), 7.85-7.90 (m, 1 H), 8.11-
8.16 (m,1 H) Intermediate 41 ##STR00828## (600 MHz, CDCl.sub.3)
.delta. ppm: 1.43 (t, J = 7.3 Hz, 3 H), 1.60 (d, J = 6.4 Hz, 3 H),
4.02-4.13 (m, 2 H), 4.18 (q, J = 6.6 Hz, 1 H), 7.41-7.51 (m, 3 H),
7.76-7.92 (m, 4 H) Intermediate 42 ##STR00829## (600 MHz,
CDCl.sub.3), .delta. ppm: 1.41 (t, J = 7.1 Hz, 3 H), 1.57 (d, J =
6.9 Hz, 3 H), 2.93 (s, 6 H), 3.96-4.09 (m, 2 H), 4.15 (q, J = 6.9
Hz, 1 H), 6.66-6.76 (m, 2 H), 7.17-7.25 (m, 2 H) Intermediate 43
##STR00830## (600 MHz, CDCl.sub.3) .delta. ppm 1.38-1.61 (m, 6 H),
4.00-4.19 (m, 3 H), 6.69-7.37 (m, 3 H) Intermediate 44 ##STR00831##
(600 MHz, CDCl.sub.3) .delta. ppm: 1.40 (t, J = 7.3 Hz, 3H), 1.59
(d, J = 6.9 Hz, 3H), 2.35 (s, 3H), 2.52-2.61 (m, 4H), 3.22-3.27 (m,
4H), 3.97-4.08 (m, 2H), 4.15 (q, J = 6.9 Hz, 1H), 6.71-6.80 (m,
2H), 6.99- 7.03 (m, 1H) , 7.20-7.25 (m, 1H) Intermediate 45
##STR00832## (600 MHz, CDCl.sub.3) .delta. ppm: 1.43 (t, J = 7.1
Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.82 (s, 3 H), 4.02-4.14 (m, 2
H), 4.18 (q, J = 6.7 Hz, 1 H), 7.42 (dd, J = 8.7, 2.8 Hz, 1 H),
7.77 (d, J = 8.7 Hz, 1 H), 7.85 (d, J = 2.3 Hz, 1 H) Intermediate
46 ##STR00833## (200 MHz, CDCl.sub.3), .delta. ppm: 1.33-1.47 (m, 3
H), 1.57 (d, J = 7.0 Hz, 3 H), 3.03-3.19 (m, 4 H), 3.78-3.92 (m, 4
H), 3.95-4.25 (m, 3 H), 6.81-7.00 (m, 2 H), 7.18-7.33 (m, 2 H)
Intermediate 47 ##STR00834## (200 MHz, CDCl.sub.3), .delta. ppm:
1.34-1.46 (m, 3 H), 1.48-1.82 (m, 9 H), 3.02-3.18 (m, 4 H),
3.89-4.27 (m, 3 H), 6.88-7.00 (m, 2 H), 7.16-7.29 (m, 2 H)
Intermediate 48 ##STR00835## (600 MHz, CDCl.sub.3), .delta. ppm:
1.41 (t, J = 7.1 Hz, 3 H), 1.57 (d, J = 6.4 Hz, 3 H), 1.96-2.03 (m,
4 H), 3.23- 3.30 (m, 4 H), 3.96-4.09 (m, 2 H), 4.16 (q, J = 6.6 Hz,
1 H), 6.47-6.56 (m, 2 H), 7.15-7.22 (m, 2 H) Intermediate 49
##STR00836## (600 MHz, CDCl.sub.3), .delta. ppm: 1.41 (t, J = 7.1
Hz, 3 H), 1.57 (d, J = 6.4 Hz, 3 H), 1.96-2.03 (m, 4 H), 3.23- 3.30
(m, 4 H), 3.96-4.09 (m, 2 H), 4.16 (q, J = 6.6 Hz, 1 H), 6.47-6.56
(m, 2 H), 7.15-7.22 (m, 2 H) Intermediate 50 ##STR00837## (600 MHz,
CDCl.sub.3) .delta. ppm: 1.43 (t, J = 7.1 Hz, 3 H), 1.59 (d, J =
6.9 Hz, 3 H), 2.56 (s, 3 H), 4.03-4.14 (m, 2 H), 4.17 (q, J = 6.6
Hz, 1 H), 7.19 (d, J = 8.7 Hz, 1 H), 7.81 (dd, J = 8.7, 2.8 Hz, 1
H), 8.52 (d, J = 3.2 Hz, 1 H) Intermediate 51 ##STR00838## (600
MHz, CDCl.sub.3) .delta. ppm: 1.40(t, J = 7.3 Hz, 3H), 1.59 (d, J =
6.9 Hz, 3H), 2.35 (s, 3H), 2.52-2.61 (m, 4H), 3.22-3.27 (m, 4H),
3.97-4.08 (m, 2H), 4.15 (q, J = 6.9 Hz, 1H), 6.71-6.80 (m, 2H),
6.09-7.03 (m, 1H), 7.20- 7.25 (m, 1H) Intermediate 52 ##STR00839##
(600 MHz, CDCl3) .delta. ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.63 (d, J
= 6.9 Hz, 3 H), 3.96-4.09 (m, 2 H), 4.20 (q, J = 6.9 Hz, 1 H),
7.13-7.17 (m, 1 H), 7.30-7.34 (m, 1 H), 7.77-7.81 (m, 1 H),
8.22-8.25 (m, 1 H) Intermediate 53 ##STR00840## (600 MHz, CDCl3)
.delta. ppm 1.46 (t, J = 7.3 Hz, 3 H), 1.62 (d, J = 6.4 Hz, 3 H),
4.06-4.17 (m, 2 H), 4.20 (q, J = 6.6 Hz, 1 H), 7.64-7.68 (m, 1 H),
7.70-7.73 (m, 1 H), 7.85-7.90 (m, 1 H), 8.10-8.13 (m, 1 H),
8.52-8.54 (m, 1 H), 9.19-9.25 (m, 1 H) Intermediate 54 ##STR00841##
(600 MHz, CDCl.sub.3) .delta. ppm.: 1.57 (d, J = 6.9 Hz, 3H), 2.34
(s, 3H), 3.59 (s, 3H), 4.16-4.22(m, 1H), 7.15- 7.18 (m, 2H),
7.21-7.25 (m, 2H)
Intermediate 55 ##STR00842## (600 MHz, CDCl.sub.3) .delta. ppm:
0.99 (t, J = 7.3 Hz, 3H), 1.58 (d, J = 6.9 Hz, 3H). 1.77-1.85 (m,
2H), 2.34 (s, 3H), 3.85-3.99 (m, 2H), 4.12 (q, J = 6.9 Hz, 1H),
7.15-7.18 (m, 2H), 7.21-7.24 (m, 2H) Intermediate 56 ##STR00843##
(600 MHz, CDCl.sub.3) .delta. ppm: 1.53-1.58 (m, 9H), 2.34 (s, 3H),
4.20 (q, J = 6.9 Hz, 1H), 4.66-4.72 (m, 1H), 7.15- 7.19 (m, 2H),
7.21-7.24 (m, 2H) Intermediate 57 ##STR00844## (200 MHz,
CDCl.sub.3) .delta. ppm: 1.31 (t, J = 7.3Hz, 3H), 1.60 (d, J = 6.6
Hz, 3H), 2.28 (s, 3H), 3.60-4.30 (m, 3H), 6.96-7.02 (m, 4H)
Intermediate 58 ##STR00845## (600 MHz, CDC1.sub.3) .delta. ppm:
1.40 (t, J = 7.3 Hz, 3H), 1.58 (d, J = 6.4 Hz, 3H), 2.34 (s, 3H),
3.99-4.09 (m, 2H). 4.16 (q, J = 6.4 Hz, 1H), 7.15-7.19 (m, 2H),
7.22-7.25 (m, 2H) Intermediate 59 ##STR00846## (600 MHz,
CDCl.sub.3), .delta. ppm: 1.44 (t, J = 7.1 Hz, 3 H), 1.59 (d, J =
6.9 Hz, 3 H), 4.02-4.13 (m, 2 H), 4.17 (q, J = 6.6 Hz, 1 H),
6.44-6.47 (m, 1 H), 7.04-7.08 (m, 1 H), 7.15-7.25 (m, 2 H),
7.50-7.57 (m, 1 H), 8.72 (s, 1 H) Intermediate 60 ##STR00847## (600
MHz, CDCl.sub.3), .delta. ppm: 1.42 (t, J = 7.1 Hz, 3 H), 1.58 (d,
J = 6.4 Hz, 3 H), 3.98-4.10 (m, 2 H), 4.15 (q, J = 6.7 Hz, 1 H),
6.30-6.39 (m, 1 H), 6.87-7.00 (m, 2 H), 7.39-7.52 (m, 2 H), 9.55
(s, 1 H) Intermediate 61 ##STR00848## (600 MHz, CDCl.sub.3),
.delta. ppm: 1.43 (t, J = 7.3 Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H),
2.34 (s, 3 H), 3.99-4.12 (m, 2 H), 4.16 (q, J = 6.9 Hz, 1 H),
6.03-6.13 (m, 1 H), 6.86-7.07 (m, 2 H), 7.28-7.37 (m, 1 H), 8.76
(s, 1 H) Intermediate 62 ##STR00849## (600 MHz, CDCl.sub.3) .delta.
ppm: 1.38 (t, J = 7.1 Hz, 3H), 1.61 (d, J = 6.9 Hz, 3H), 2.40 (s,
3H), 3.96-4.07 (m, 2H), 4.23 (q, J = 6.9 Hz, 1H), 6.95-6.97 (m,
1H), 7.13-7.1.5 (m, 1H), 8.07-8.09 (m, 1H) Intermediate 63
##STR00850## (600 MHz, CDCl.sub.3) .delta. ppm: 1.36-1.45 (m, 3H),
1.60- 1.70 (m, 3H), 2.32 (s, 3H), 3.96-4.10 (m, 2H), 4.16- 4.27 (m,
1H), 7.22-7.27 (m, 1H), 7.56-7.66 (m, 1H). 8.02-8.10 (m, 1H)
Intermediate 64 ##STR00851## (600 MHz, CDCl.sub.3) .delta. ppm:
1.43 (t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.4 Hz, 3H), 2.59-2.63 (m,
2H). 2.92-2.99 (m, 2H), 4.00-4.11 (m, 2H), 4.18 (q, J = 6.4 Hz,
1H), 6.80-6.84 (m, 1H), 7.11-7.16 (m, 1H), 7.21-7.25 (m, 1H),
8.28-8.72 (m, 1H) Intermediate 65 ##STR00852## (600 MHz,
CDCl.sub.3) .delta. ppm: 1.35 (t, J = 7.3 Hz, 3 H), 1.54 (d, J =
6.9 Hz, 3 H), 3.76 (s, 3 H), 3.93-4.05 (m, 2 H), 4.11 (q, J = 6.4
Hz, 1 H), 6.69 (dd, J = 8.3, 2.3 Hz, 1 H), 6.87 (dd, J = 8.3, 2.3
Hz, 1 H), 6.92 (t, J = 2.3 Hz, 1 H), 7.18-7.24 (m, 1 H)
Intermediate 66 ##STR00853## (600 MHz, , CDCl.sub.3) .delta. ppm:
1.14 (t, J = 7.1 Hz, 6 H), 1.38 (t, J = 7.3 Hz, 3 H), 1.57 (d, J =
6.9 Hz, 3 H), 3.32 (q, J = 6.9 Hz, 4 H), 3.95-4.07 (m, 2 H),
4.11-4.17 (m, 1 H), 6.46 (dd, J = 8.7, 2.3 Hz, 1 H), 6.50 (dd, J =
8.0, 2.5 Hz, 1 H), 6.67 (t, J = 2.5 Hz, 1 H), 7.14 (t, J = 8.3 Hz,
1 H) Intermediate 67 ##STR00854## (600 MHz, CDCl.sub.3) .delta.
ppm: 1.39 (t, J = 7.3 Hz, 3H), 1.62 (d, J = 6.4 Hz, 3H), 2.45 (s,
3H), 3.97-4.09 (m, 2H), 4.19 (q, J = 6.4 Hz, 1H), 6.98-7.01 (m,
1H), 7.13-7.16 (m, 1H), 7.64-7.67 (m, 1H) Intermediate 68
##STR00855## (600 MHz, CDCl.sub.3) .delta. ppm: 1.45 (t, J = 7.3
Hz, 3H), 1.62 (d, J = 6.9 Hz, 3H), 4.05-4.15 (m, 2H), 4.20 (q, J =
6.9 Hz, 1H), 7.37-7.41 (m, 1H), 7.65-7.68 (m, 1H), 7.84-7.88 (m,
1H), 7.94-7.96 (m, 1H), 8.14-8.19 (m, 1H), 8.90-8.93 (m, 1H)
Intermediate 69 ##STR00856## (600 MHz, CDCl.sub.3) .delta. ppm:
1.38 (t, J = 7.1 Hz, 3 H), 1.53-1.60 (m, 5 H), 1.64-1.71 (m, 4 H),
3.95-4.07 (m, 2 H), 4.14 (q, J = 6.7 Hz, 1 H), 6.69-6.74 (m, 2 H),
6.95 (t, J = 2.5 Hz, 1 H), 7.19 (t, J = 8.3 Hz, 1 H) Intermediate
70 ##STR00857## (600 MHz, CDCl.sub.3) .delta. ppm: 1.41 (t, J = 7.1
Hz, 3H). 1.58 (d, J = 6.9 Hz, 3H), 2.57-2.61 (m, 2H), 2.89-2.93 (m,
2H), 3.99-4.11 (m, 2H), 4.17 (q, J= 6.9 Hz, 1H), 6.90-6.97 (m, 2H),
7.11-7.15 (m, 1H), 8.66 (s, 1H) Intermediate 71 ##STR00858## (600
MHz, CDCl.sub.3) .delta. ppm: 1.38 (t, J = 7.3 Hz, 3 H), 1.58 (d, J
= 6.9 Hz, 3 H), 2.30-2.39 (m, 2 H), 3.85- 3.89 (m, 4 H), 3.94-4.06
(m, 2 H), 4.15 (q, J = 6.6 Hz, 1 H), 6.22-6.25 (m, 1 H), 6.43 (t, J
= 2.3 Hz, 1 H), 6.59- 6.63 (m, 1 H), 7.15 (t, J = 8.0 Hz, 1 H)
Intermediate 72 ##STR00859## (600 MHz, CDCl.sub.3) .delta. ppm:
1.24 (d, J = 6.4 Hz, 6 H), 1.39 (t, J = 7.3 Hz, 3 H), 1.58 (d, J =
6.9 Hz, 3 H), 2.39- 2.46 (m, 2 H), 3.42-3.46 (m, 2 H), 3.73-3.81
(m, 2 H), 3.97-4.09 (m, 2 H), 4.15 (q, J = 6.9 Hz, 1 H), 6.71 (dd,
J = 8.0, 2.1 Hz, 1 H), 6.76 (dd, J = 8.5, 2.1 Hz, 1 H), 6.98 (t, J
= 2.3 Hz, 1 H), 7.22 (t, J = 8.3 Hz, 1 H) Intermediate 73
##STR00860## (600 MHz, CDCl.sub.3) .delta. ppm: 1.42 (d, J = 7.3
Hz, 3H), 1.59 (d, J = 6.9 Hz, 3H), 3.92 (s, 3H), 4.02-4.13 (m, 2H),
4.16 (q, J = 6.9 Hz, 1H); 6.90 (s, 1H) Intermediate 74 ##STR00861##
(600 MHz, CDCl3) .delta. ppm: 1.45 (t, J = 7.3 Hz, 3 H), 1.63 (d,
J= 6.4 Hz, 3 H), 4.06-4.17 (m, 2 H), 4.18- 4.23 (m, 1 H), 7.39-7.44
(m, 1 H), 7.65-7.71 (m, 1 H), 8.02-8.05 (m, 1 H), 8.11-8.16 (m, 2
H), 8.88- 8.91 (m, 1 H) Intermediate 75 ##STR00862## (600 MHz,
CDCl.sub.3) .delta. ppm: 1.38 (t, J = 7.1 Hz, 3 H), 1.67 (d, J =
6.4 Hz, 3 H), 1.94-2.02 (m, 4 H), 3.22- 3.29 (m, 4 H), 3.95-4.07
(m, 2 H), 4.10-4.19 (m, 1 H), 6.36 (dd, J = 8.2, 2.3 Hz, 1 H),
6.50-6.56 (m, 2 H), 7.16 (t, J = 8.3 Hz, 1 H) Intermediate 76
##STR00863## (600 MHz, CDCl.sub.3) .delta. ppm: 1.38 (t, J = 7.3
Hz, 3H), 1.61 (d, J = 6.9 Hz, 3H), 2.53 (s, 6H), 3.98-4.11 (m, 2H),
4.18 (q, J = 6.9 Hz, 1H), 7.05 (s, 2H) Intermediate 77 ##STR00864##
(600 MHz, CDCl.sub.3) .delta. ppm: 1.46 (t, J = 7.1 Hz, 3H), 1.63
(d, J = 6.9 Hz, 3H), 4.07-4.24 (m, 3H), 7.63-7.65 (m, 1H),
8.00-8.03(m, 1H), 8.11-8.13 (m, 1H) Intermediate 78 ##STR00865##
(600 MHz, CDCl.sub.3) .delta. ppm: 1.37 (t, J = 7.1 Hz, 3 H), 1.58
(d, J = 6.9 Hz, 3 H), 3.96-4.05 (m, 2 H), 4.15 (q, J = 6.7 Hz, 1
H), 6.45-6.50 (m, 1 H), 6.62-6.67 (m, 1 H), 6.71-6.75 (m, 1 H),
7.11 (t, J = 8.0 Hz, 1 H) Intermediate 79 ##STR00866## (600 MHz,
CDCl.sub.3) .delta. ppm: 1.38 (t, J = 7.1 Hz, 3 H), 1.58 (d, J =
6.9 Hz, 3 H), 2.27 (s, 6 H), 2.45-2.56 (m, 4 H), 2.58-2.63 (m, 4
H), 3.20-3.24 (m, 4 H), 3.95- 4.07 (m, 2 H), 4.11-4.17 (m, 1 H),
6.68-6.78 (m, 2 H), 6.95-6.98 (m, 1 H), 7.21 (t, J = 8.3 Hz, 1 H)
Intermediate 80 ##STR00867## (600 MHz, CDCl.sub.3) .delta. ppm:
1.43 (t, J = 7.1 Hz, 3 H), 1.60 (d, J = 6.9 Hz, 3 H), 4.02-4.15 (m,
2 H), 4.15- 4.22 (m, 1 H), 7.18-7.20 (m, 1 H), 7.22-7.25 (m, 1 H),
7.28-7.30 (m, 1 H), 7.38-7.41 (m, 1 H), 7.46- 7.51 (m, 1 H),
7.54-7.57 (m, 1 H), 7.85-7.89 (m, 1 H) Intermediate 81 ##STR00868##
(600 MHz, CDCl.sub.3) .delta. ppm: 1.38 (t, J = 7.3 Hz, 3 H), 1.57
(d, J = 6.9 Hz, 3 H), 1.77-1.83 (m, 4 H), 3.27- 3.36 (m, 4 H),
3.95-4.06 (m, 6 H), 4.14 (q, J = 6.9 Hz, 1 H), 6.70-6.75 (m, 2 H),
6.97 (t, J = 2.3 Hz, 1 H), 7.20 (t, J = 8.3 Hz, 1 H) Intermediate
82 ##STR00869## (600 MHz, CDCl3) .delta. ppm: 1.42-1.47 (m, 3 H)
1.62 (dd, J = 6.65, 2.06 Hz, 3 H) 4.05-4.17 (m, 2 H) 4.17-4.22 (m,
1 H) 7.24-7.28 (m, 1 H) 7.48-7.61 (m, 2 H) 7.66 (s, 1 H) 8.52 (s, 2
H) Intermediate 83 ##STR00870## (600 MHz, CDCl.sub.3) .delta. ppm:
1.07 (d, J = 6.9 Hz, 6 H), 1.38 (t, J = 7.3 Hz, 3 H), 1.57 (d, J =
6.4 Hz, 3 H), 2.62- 2.67 (m, 4 H), 2.67-2.74 (m, 1 H), 3.19-3.24
(m, 4 H), 3.96-4.08 (m, 2 H), 4.14 (q, J = 6.7 Hz, 1 H), 6.71 (dd,
J = 8.3, 2.3 Hz, 1 H), 6.75 (dd, J =8.3, 2.3 Hz, 1 H), 6.97 (t, J =
2.3 Hz, 1 H), 7.21 (t, J = 8.3 Hz, 1 H) Intermediate 84
##STR00871## (600 MHz, CDCl.sub.3) .delta. ppm: 1.38 (t, J = 7.3
Hz, 3H), 1.61 (d, J = 6.9 Hz, 3H), 2.33 (s, 3H) , 2.40 (s, 3H),
3.97- 4.09 (m, 2H), 4.18 (q, J = 6.9 Hz. 1H), 6.82-6.83 (m, 1H),
6.97-6.98 (m, 1H) Intermediate 85 ##STR00872## (600 MHz,
CDCl.sub.3) .delta. ppm: 1.30-1.76 (m, 6H), 2.56 (s, 3H), 2.68 (s,
3H), 4.08-4.19 (m, 3H), 6.59 (s, 1H), 6.73 (s, 1H) Intermediate 86
##STR00873## (600 MHz, CDCl.sub.3) .delta. ppm: 1.26 (d, J = 6.9
Hz, 6H), 1.40 (t, J = 7.3 Hz, 3H), 1.57 (d, J = 6.9 Hz, 3H),
2.87-2.94 (m, 1H), 3.72 (s, 3H), 3.99-4.11 (m, 2H), 4.14 (q, J =
6.9 Hz, 1H), 6.25 (s, 1H) Intermediate 87 ##STR00874## (600 MHz,
CDCl.sub.3) .delta. ppm: 1.39 (t, J = 7.3 Hz, 3 H), 1.57 (d, J =
6.9 Hz, 3 H), 3.34 (s, 6 H), 3.50-3.57 (m, 8 H), 3.96-4.07 (m, 2
H), 4.15 (q, J = 6.6 Hz, 1 H), 6.51 (dd, J = 8.5, 2.5 Hz, 1 H),
6.56 (dd, J = 7.8, 2.3 Hz, 1 H), 6.69 (t, J = 2.3 Hz, 1 H), 7.15
(t, J = 8.3 Hz, 1 H) Intermediate 88 ##STR00875## (600 MHz,
CDCl.sub.3) .delta. ppm: 1.36-1.41 (m, 3 H), 1.57 (d, J = 6.9 Hz, 3
H), 2.28 (s, 6 H), 2.45-2.50 (m, 2 H), 2.94 (s, 3 H), 3.39-3.48 (m,
2 H), 3.94-4.08 (m, 2 H), 4.14 (q, J = 6.9 Hz, 1 H), 6.50 (dd, J =
8.3, 2.3 Hz, 1 H), 6.58 (dd, J = 8.3, 2.3 Hz, 1 H), 6.67 (t, J =
2.5 Hz, 1 H), 7.16 (t, J = 8.3 Hz, 1 H) Intermediate 89
##STR00876## (600 MHz, CDCl.sub.3) .delta. ppm: 1.39 (t, J = 7.1
Hz; 3H), 1.59 (d, J = 6.4 Hz, 3H), 2.34 (s, 6H), 2.73 (t, J = 5.7
Hz, 2H), 3.98-4.09 (m, 1H), 4.16 (q, J = 6.4 Hz, 1H), 6.75- 6.77
(m, 1H), 6.91-6.93 (m, 1H) , 6.98-7.00 (m, 1H), 7.24-7.27 (m, 1H)
Intermediate 90 ##STR00877## (600 MHz, CDCl.sub.3) .delta. ppm:
1.25 (d, J = 6.9Hz, 12H), 1.40 (t, J = 7.1 Hz, 3H), 1.58 (d, J= 6.9
Hz, 3H), 3.76- 3.85 (m, 2H), 3.96-1.08 (m, 2H), 4.15 (q, J = 6.9
Hz, 1H), 6.57-6.70 (m, 2H), 6.88-6.93 (m, 1H), 7.10-7.17 (m, 1H)
(Intermediate 91 ##STR00878## (600 MHz, CDCl.sub.3) .delta. ppm:
1.06 (d, J = 6.42 Hz, 6 H) 1.39 (t, J = 7.3 Hz, 3 H), 1.58 (d, J =
6.9 Hz, 3 H), 1.68- 1.89 (m, 4 H), 2.17-2.25 (m, 2 H), 2.44-2.53
(m, 1 H), 2.70-2.77 (m, 1 H), 2.94-3.03 (m, 2 H) 3.96-4.08 (m, 2
H), 4.15 (q, J = 6.6 Hz, 1 H), 7.03-7.07 (m, 1 H), 7.15-7.22 (m, 2
H), 7.28 (t, J = 8.0 Hz, 1 H) Intermediate 92 ##STR00879## (600
MHz, CDCl.sub.3), .delta. ppm: 1.43 (t, J = 7.1 Hz, 3 H), 1.58-1.62
(m, 12 H), 4.01-4.13 (m, 2 H), 4.18 (q, J = 6.6 Hz, 1 H), 7.42-7.46
(m, 1 H), 7.61-7.65 (m, 1 H), 7.82-7.85 (m, 1 H), 7.87-7.91 (m, 1
H) Intermediate 93 ##STR00880## (600 MHz, DMSO-d6) .delta. ppm:
1.23 (t, J = 7.3 Hz, 3 H), 1.54 (d, J = 6.9 Hz, 3 H), 3.82-4.09 (m,
2 H), 4.60 (q, J = 6.0 Hz, 1 H), 6.61-6.69 (m, 2 H), 6.70- 6.77 (m,
1 H), 7.14-7.21 (m, 1 H), 8.28-9.11 (m, 2 H), 9.43-10.55 (m, 1 H)
Intermediate 94 ##STR00881## (600 MHz, CDCl.sub.3), .delta. ppm:
1.39 (t, J = 7.3 Hz, 3 H), 1.60 (d, J = 6.4 Hz, 3 H), 3.96-4.09 (m,
2 H), 4.17 (q, J = 6.9 Hz, 1 H), 5.06 (s, 2 H), 6.79-6.84 (m, 1 H),
6.91-6.96 (m, 1 H), 7.04-7.08 (m, 1 H), 7.22- 7.46 (m, 6 H)
Intermediate 95 ##STR00882## (200 MHz, CDCl.sub.3) .delta. ppm:
1.34 (t, J = 7.3 Hz, 3H), 1.61 (d, J = 6.8 Hz. 3H). 3.80-4.23 (m,
3H), 5.96 (br s, 1H), 6.88-7.05 (m, 2H), 7.08-7.25 (m, 2H)
Intermediate 96 ##STR00883## (600 MHz, CDCl.sub.3) .delta. ppm:
1.42-1.66 (m, 9H), 4.06- 4.20 (m, 5H), 7.01-7.05 (m, 1H), 7.24-7.26
(m, 1H), 7.62-7.69 (m, 2H) Intermediate 97 ##STR00884## (600 MHz,
CDCl3) .delta. ppm: 1.02-1.16 (m, 4 H), 1.59 (d, J = 6.9 Hz, 3 H),
2.35 (s, 3 H), 2.52-2.61 (m, 4 H), 2.92-3.01 (m, 1 H), 3.21-3.25
(m, 4 H), 4.24 (q, J = 6.6 Hz, 1 H), 6.68-6.75 (m, 2 H), 6.94-6.98
(m, 1 H), 7.19-7.25 (m, 1 H) Intermediate 98 ##STR00885## (600 MHz,
CDCL3) .delta. ppm: 1.03-1.18 (m, 4 H), 1.59 (d, J = 6.9 Hz, 2 H),
2.98-3.04 (m, 1 H), 4.25 (q, J = 6.6 Hz, 1 H), 7.04-7.10 (m, 2 H),
7.30-7.35 (m, 2 H) Intermediate 99 ##STR00886## (600 MHz, CDCl3)
.delta. ppm: 0.98-1.20 (m, 4 H), 1.59 (d, J = 6.9 Hz, 3 H),
2.93-3.05 (m, 1 H), 4.22- 4.31 (m, 1 H), 6.33-6.44 (m, 1 H),
6.90-7.05 (m, 2 H), 7.31-7.43 (m, 1 H), 7.46-7.55 (m, 1 H), 9.08-
9.32 (m, 1 H) Intermediate 100 ##STR00887## (CDCl.sub.3, 200 MHz)
.delta. 1.02 (t, J = 7.5 Hz, 3H), 1.39 (t, J = 7.3 Hz, 3H), 1.68
(bs, 2H), 1.91-2.14 (m, 2H), 2.34 (s, 3H), 3.90 (t, J = 6.4 Hz,
1H), 4.03(q, J = 7.3 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.24 (d, J
= 8.1 Hz, 2H) Intermediate 101 ##STR00888## (CDCl.sub.3, 200 MHz)
.delta. 0.96 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 1.39
(t, J = 7.8 Hz, 3H), 1.71 (bs, 2H), 2.06-2.24 (m, 1H), 2.34 (s,
3H), 3.69 (d, J = 7.5 Hz, 1H), 4.01 (q, J = 7.3 Hz, 2H), 7.16 (d, J
= 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H) Intermediate 102
##STR00889## (200 MHz, CDCl.sub.3) .delta. ppm: 1.01 (t, J = 7.3
Hz, 3H), 1.39 (t, J = 7.3 Hz, 3H), 1.70-2.11 (m, 2H), 2.35 (s, 3H),
2.56 (t, J = 5.0 Hz, 4H), 3.24 (t, J = 5.0 Hz, 4H), 3.89 (t, J =
7.3 Hz, 1H), 4.02 (q, J = 7.3 Hz, 2H), 6.74 (dt, J = 2.4, 8.4 Hz,
2H), 7.02 (t, J = 2.4 Hz, 1H), 7.22 (t, J = 8.4 Hz, 1H)
Intermediate 103 ##STR00890## (600 MHz, CDCl.sub.3) .delta. ppm:
1.41 (t, J = 7.3 Hz, 3H), 1.59 (d, J = 6.4 Hz, 3H), 2.36 (s, 3H),
2.55-2.65 (m, 4H), 3.11-3.19 (m, 4H), 3.98-4.19 (m, 3H), 6.87- 6.92
(m, 1H), 6.96-7.04 (m, 2H) Intermediate 104 ##STR00891## (600 MHz,
CDCl.sub.3) .delta. ppm: 1.42 (t, J = 6.9 Hz, 3H), 1.62 (s, 6H),
4.31 (q, J = 6.9 Hz, 2H), 7.04-7.09 (m, 2H), 7.34-7.40 (m, 2H)
Intermediate 105 ##STR00892## (600 MHz, CDCl.sub.3) .delta. ppm:
1.40 (t, J = 7.1 Hz, 3H), 1.59 (d, J = 6.9 Hz, 3H), 2.98-3.04 (m,
4H), 3.14- 3.19 (m, 4H), 3.97-4.09 (m, 2H), 4.13-4.18 (m, 1H),
6.70-6.80 (m, 2H), 6.97-7.03 (m, 1H), 7.21- 7.26 (m, 1H)
Intermediate 106 ##STR00893## (600 MHz, CDCl.sub.3) .delta. ppm:
1.35 (t, J = 7.3 Hz, 3H), 1.72 (d, J = 6.4 Hz, 3H), 2.12 (s, 3H),
3.14-3.23 (m, 4H), 3.57-3.64 (m, 2H), 3.71-3.77 (m, 2H), 3.87- 4.10
(m, 2H), 4.57-4.66 (m, 1H), 6.70-6.81 (m, 2H), 6.95-6.99 (m, 1H),
7.21-7.26 (m, 1H) Intermediate 107 ##STR00894## (200 MHz,
CDCl.sub.3) .delta. ppm: 0.94-1.08 (m, 2H), 1.22- 1.31 (m, 2H),
1.47 (t, J = 7.1 Hz, 3H), 4.18 (q, J = 7.1 Hz, 2H), 6.98-7.15 (m,
2H), 7.29- 7.42 (m, 2H) Intermediate 108 ##STR00895## (600 MHz,
CDCl.sub.3) .delta. ppm: 1.43 (t, J = 7.3 Hz, 3H), 3.97-4.11 (m,
2H), 4.47-4.54 (m, 1H), 7.06- 7.12 (m, 2H), 7.35-7.40 (m, 2H)
Intermediate 109 ##STR00896## (200 MHz, CDCl.sub.3) .delta. ppm:
1.41 (t, J = 7.5 Hz, 3H), 3.62 (dd, J = 4.8, 11.8 Hz, 1H), 3.88
(dd, J = 4.8, 11.8 Hz, 1H), 4.05 (q, J = 7.5 Hz, 2H), 4.51-4.60 (m,
1H), 7.04-7.13 (m, 2H), 7.23-7.31 (m, 3H), 7.53 (d, J = 8.8 Hz,
1H), 7.70 (dd, J = 8.8, 2.2 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H)
INDUSTRIAL APPLICABILITY
[0644] Since the compounds of the present invention are excellent
Edg-1 (S1P.sub.1) ligands, they are useful as agents for treating
or preventing autoimmune diseases, such as Crohn disease,
hypersensitivity colitis, Sjogren's syndrome, multiple sclerosis,
and systemic lupus erythematosus, and diseases such as rheumatoid
arthritis, asthma, atopic dermatitis, organ transplant rejection,
cancer, retinopathy, psoriasis, osteoarthritis, and age-related
macular degeneration.
* * * * *