U.S. patent application number 12/338698 was filed with the patent office on 2009-04-30 for thienopyrimidine and thienopyridine derivatives substituted with cyclic amino group.
This patent application is currently assigned to TAISHO PHARMACEUTICAL CO., LTD.. Invention is credited to Ludo E.J. Kennis, Atsuro Nakazato, Dai Nozawa, Taketoshi Okubo, Tomoko Tamita.
Application Number | 20090111835 12/338698 |
Document ID | / |
Family ID | 34746976 |
Filed Date | 2009-04-30 |
United States Patent
Application |
20090111835 |
Kind Code |
A1 |
Nakazato; Atsuro ; et
al. |
April 30, 2009 |
THIENOPYRIMIDINE AND THIENOPYRIDINE DERIVATIVES SUBSTITUTED WITH
CYCLIC AMINO GROUP
Abstract
An object of the present invention is to provide an antagonist
against CRF receptors which is effective as a therapeutic or
prophylactic agent for diseases in which CRF is considered to be
involved, such as depression, anxiety, Alzheimer's disease,
Parkinson's disease, Huntington's chorea, eating disorder,
hypertension, gastral diseases, drug dependence, epilepsy, cerebral
infarction, cerebral ischemia, cerebral edema, cephalic external
wound, inflammation, immunity-related diseases, alpecia, irritable
bowel syndrome, sleep disorders, dermatitides, schizophrenia, pain,
etc. A thienopyrimidine or thienopyridine derivative substituted
with a cyclic amino group represented by the following formula [I]:
has a high affinity for CRF receptors and is effective against
diseases in which CRF is considered to be involved.
##STR00001##
Inventors: |
Nakazato; Atsuro; (Tokyo,
JP) ; Okubo; Taketoshi; (Tokyo, JP) ; Nozawa;
Dai; (Tokyo, JP) ; Tamita; Tomoko; (Tokyo,
JP) ; Kennis; Ludo E.J.; (Beerse, BE) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W., SUITE 800
WASHINGTON
DC
20037
US
|
Assignee: |
TAISHO PHARMACEUTICAL CO.,
LTD.
Tokyo
JP
|
Family ID: |
34746976 |
Appl. No.: |
12/338698 |
Filed: |
December 18, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10584951 |
Sep 13, 2006 |
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PCT/JP2005/000318 |
Jan 6, 2005 |
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12338698 |
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Current U.S.
Class: |
514/260.1 ;
514/301; 544/278; 546/114 |
Current CPC
Class: |
A61P 17/00 20180101;
A61P 25/20 20180101; A61P 25/22 20180101; A61P 1/04 20180101; A61P
9/10 20180101; A61P 17/14 20180101; C07D 495/04 20130101; A61P
25/36 20180101; A61P 25/14 20180101; A61P 37/00 20180101; A61P
25/28 20180101; A61P 25/02 20180101; A61P 1/00 20180101; A61P 29/00
20180101; A61P 25/08 20180101; A61P 25/18 20180101; A61P 5/40
20180101; A61P 25/24 20180101; A61P 25/16 20180101 |
Class at
Publication: |
514/260.1 ;
544/278; 514/301; 546/114 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 495/04 20060101 C07D495/04; A61K 31/4365 20060101
A61K031/4365 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 6, 2004 |
JP |
2004-001310 |
Claims
1. A thienopyridine compound substituted with the cyclic amino
group represented by the following formula [IV]: ##STR00098##
(wherein the cyclic amino group is represented by the following
formula [II]: ##STR00099## in which the cyclic amino group is a 3-
to 8-membered saturated cyclic amine or a 3- to 8-membered
saturated cyclic amine bridged with C.sub.1-5alkylene or
C.sub.1-4alkylene-O--C.sub.1-4alkylene between any different two
carbon atoms of the cyclic amine, which cyclic amine is substituted
with a group represented by
--(CR.sup.1R.sup.2).sub.m--(CHR.sup.3).sub.n--X, R.sup.4 and
R.sup.5 independently on the same or different carbon atoms of the
cyclic amine; wherein X is cyano, hydroxy, --CO.sub.2R.sup.8 or
--CONR.sup.9R.sup.10; R.sup.1 is hydrogen, hydroxy, C.sub.1-5alkyl,
C.sub.1-5alkoxy-C.sub.1-5alkyl or hydroxy-C.sub.1-5alkyl; R.sup.2
is hydrogen or C.sub.1-5alkyl; R.sup.3 is hydrogen, cyano,
C.sub.1-5alkyl, C.sub.1-5alkoxy-C.sub.1-5alkyl or
hydroxy-C.sub.1-5alkyl; m is an integer selected from 0, 1, 2, 3, 4
and 5; n is 0 or 1; R.sup.4 is hydrogen, hydroxy,
hydroxy-C.sub.1-5alkyl, cyano, cyano-C.sub.1-5alkyl or
C.sub.1-5alkyl; R.sup.5 is hydrogen or C.sub.1-5alkyl; R.sup.6 is
hydrogen, C.sub.1-5alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8
cycloalkyl-C.sub.1-5alkyl, hydroxy, C.sub.1-5alkoxy, C.sub.3-8
cycloalkyloxy, halogen, C.sub.1-5alkylthio or
--N(R.sup.12)R.sup.13; R.sup.7 is hydrogen, halogen,
C.sub.1-5alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8
cycloalkyl-C.sub.1-5alkyl, hydroxy, C.sub.1-5 alkoxy, C.sub.3-8
cycloalkyloxy, --N(R.sup.14)R.sup.15, --CO.sub.2R.sup.16,
--CON(R.sup.17)R.sup.18, cyano, nitro, C.sub.1-5alkylthio,
trifluoromethyl or trifluoromethoxy; Ar is aryl or heteroaryl which
aryl or heteroaryl is unsubstituted or substituted with 1 or more
substituents, which are the same or different, selected from the
group consisting of halogen, C.sub.1-5alkyl, C.sub.3-8 cycloalkyl,
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-5alkoxy,
C.sub.1-5alkylthio, C.sub.1-5 alkylsulfinyl,
C.sub.1-5alkylsulfonyl, cyano, nitro, hydroxy, --CO.sub.2R.sup.19,
--C(.dbd.O)R.sup.20, --CONR.sup.21R.sup.22, --OC(.dbd.O)R.sup.23,
--NR.sup.24CO.sub.2R.sup.25, --S(.dbd.O).sub.rNR.sup.26R.sup.27,
trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy,
methylenedioxy, ethylenedioxy and --N(R.sup.28)R.sup.29; R.sup.8 is
hydrogen, C.sub.1-10 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8
cycloalkyl-C.sub.1-5alkyl, aryl or aryl-C.sub.1-5 alkyl; R.sup.9
and R.sup.10 are the same or different, and independently are
hydrogen, C.sub.1-5alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8
cycloalkyl-C.sub.1-5alkyl, aryl or aryl-C.sub.1-5alkyl; or R.sup.9
and R.sup.10 form a ring selected from saturated 3 to 8 membered
ring with the attached nitrogen atom, wherein one of the carbon
atoms of such saturated 3 to 8 membered ring is optionally replaced
by an oxygen or sulfur atom or by N-Z wherein Z is hydrogen, benzyl
or C.sub.1-5alkyl; R.sup.11 is hydrogen, halogen or C.sub.1-5alkyl;
R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are the same or
different, and independently are hydrogen or C.sub.1-5 alkyl;
R.sup.16, R.sup.19 and R.sup.25 are the same or different, and
independently are hydrogen or C.sub.1-5alkyl, C.sub.3-8 cycloalkyl,
C.sub.3-8 cycloalkyl-C.sub.1-5alkyl, aryl or aryl-C.sub.1-5alkyl;
R.sup.17, R.sup.18, R.sup.20, R.sup.21, R.sup.22, R.sup.23,
R.sup.24, R.sup.26, R.sup.27, R.sup.28 and R.sup.29 are the same or
different, and independently are hydrogen, C.sub.1-5alkyl or
C.sub.3-8 cycloalkyl; r is 1 or 2), individual isomers thereof or
racemic or non-racemic mixtures of isomers thereof,
pharmaceutically acceptable prodrugs thereof or pharmaceutically
acceptable salts and hydrates thereof.
2. The thienopyridine compound substituted with the cyclic amino
group according to claim 1 represented by formula [IV], wherein X
is cyano; the cyclic amino group is a 4- to 7-membered saturated
cyclic amine; n is 0; m is an integer selected from 1, 2 and 3;
R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are hydrogen; R.sup.6 is
C.sub.1-5alkyl; R.sup.7 is hydrogen or C.sub.1-5alkyl; R.sup.11 is
hydrogen or C.sub.1-5alkyl; and Ar is phenyl which phenyl is
substituted with two or three substituents, which are the same or
different, selected from the group consisting of halogen, C.sub.1-3
alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, trifluoromethyl,
trifluoromethoxy and --N(R.sup.28)R.sup.29 (wherein R.sup.28 and
R.sup.29 are the same or different, and independently are hydrogen
or C.sub.1-3 alkyl), individual isomers thereof or racemic or
non-racemic mixtures of isomers thereof, or pharmaceutically
acceptable salts and hydrates thereof.
3. The thienopyridine compound substituted with the cyclic amino
group according to claim 2 represented by formula [IV], wherein X
is cyano; the cyclic amino group is a 6-membered saturated cyclic
amine; n is 0; m is 0 or 1; R.sup.1, R.sup.2, R.sup.4 and R.sup.5
are hydrogen; R.sup.6 is C.sub.1-5alkyl; R.sup.7 is hydrogen or
C.sub.1-5alkyl; R.sup.11 is hydrogen; and Ar is phenyl which phenyl
is substituted with two or three substituents, which are the same
or different, selected from the group consisting of halogen and
C.sub.1-3 alkyl, individual isomers thereof or racemic or
non-racemic mixtures of isomers thereof, or pharmaceutically
acceptable salts and hydrates thereof.
4. The thienopyridine compound substituted with the cyclic amino
group according to claim 1 represented by formula [IV], wherein X
is hydroxy; the cyclic amino group is a 4- to 7-membered saturated
cyclic amine; n is 0; m is an integer selected from 1, 2 and 3;
R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are hydrogen; R.sup.6 is
C.sub.1-5alkyl; R.sup.7 is hydrogen or C.sub.1-5alkyl; R.sup.11 is
hydrogen or C.sub.1-5alkyl; and Ar is phenyl which phenyl is
substituted with two or three substituents, which are the same or
different, selected from the group consisting of halogen, C.sub.1-3
alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, trifluoromethyl,
trifluoromethoxy and --N(R.sup.28)R.sup.29 (wherein R.sup.28 and
R.sup.29 are the same or different, and independently are hydrogen
or C.sub.1-3 alkyl), individual isomers thereof or racemic or
non-racemic mixtures of isomers thereof, or pharmaceutically
acceptable salts and hydrates thereof.
5. The thienopyridine compound substituted with the cyclic amino
group according to claim 1 represented by formula [IV], wherein X
is hydroxy; the cyclic amino group is a 6-membered saturated cyclic
amine; n is 0; m is an integer selected from 1, 2 and 3; R.sup.1,
R.sup.2, R.sup.4 and R.sup.5 are hydrogen; R.sup.6 is
C.sub.1-5alkyl; R.sup.7 is hydrogen or C.sub.1-5alkyl; R.sup.11 is
hydrogen; and Ar is phenyl which phenyl is substituted with two or
three substituents, which are the same or different, selected from
the group consisting of halogen and C.sub.1-3 alkyl, individual
isomers thereof or racemic or non-racemic mixtures of isomers
thereof, or pharmaceutically acceptable salts and hydrates
thereof.
6. The thienopyridine compound substituted with the cyclic amino
group according to claim 1 represented by formula [IV], wherein X
is --CO.sub.2R.sup.8 or --CONR.sup.9R.sup.10; the cyclic amino
group is a 4- to 7-membered saturated cyclic amine; n is 0; m is an
integer selected from 0, 1, 2 and 3; R.sup.1, R.sup.2, R.sup.4 and
R.sup.5 are hydrogen; R.sup.6 is C.sub.1-5alkyl; R.sup.7 is
hydrogen or C.sub.1-5alkyl; R.sup.8 is hydrogen or C.sub.1-10
alkyl; R.sup.9 and R.sup.10 are the same or different, and
independently are hydrogen or C.sub.1-5alkyl; R.sup.11 is hydrogen
or C.sub.1-5alkyl; and Ar is phenyl which phenyl is substituted
with two or three substituents, which are the same or different,
selected from the group consisting of halogen, C.sub.1-3 alkyl,
C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, trifluoromethyl,
trifluoromethoxy and --N(R.sup.28)R.sup.29 (wherein R.sup.28 and
R.sup.29 are the same or different, and independently are hydrogen
or C.sub.1-3 alkyl), individual isomers thereof or racemic or
non-racemic mixtures of isomers thereof, or pharmaceutically
acceptable salts and hydrates thereof.
7. The thienopyridine compound substituted with the cyclic amino
group according to claim 1 represented by formula [IV], wherein X
is --CO.sub.2R.sup.8 or --CONR.sup.9R.sup.10; the cyclic amino
group is a 6-membered saturated cyclic amine; n is 0; m is an
integer selected from 0, 1, 2 and 3; R.sup.1, R.sup.2, R.sup.4 and
R.sup.5 are hydrogen; R.sup.6 is C.sub.1-5alkyl; R.sup.7 is
hydrogen or C.sub.1-5alkyl; R.sup.8 is hydrogen or C.sub.1-10
alkyl; R.sup.9 and R.sup.10 are the same or different, and
independently are hydrogen or C.sub.1-5alkyl; R.sup.11 is hydrogen;
and Ar is phenyl which phenyl is substituted with two or three
substituents, which are the same or different, selected from the
group consisting of halogen and C.sub.1-3 alkyl, individual isomers
thereof or racemic or non-racemic mixtures of isomers thereof, or
pharmaceutically acceptable salts and hydrates thereof.
8. Compounds represented by formula [IV] according to claim 1,
which compounds are selected from the group consisting of
{1-[3-(2,4-dichloro-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidin-
-4-yl}-methanol,
{1-[5-methyl-3-(2,4,6-trimethyl-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperi-
din-4-yl}-methanol,
{1-[3-(4-bromo-2,6-dimethyl-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-p-
iperidin-4-yl}-methanol,
{1-[3-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-thieno[3,2-b]pyridin-7-y-
l]-piperidin-4-yl}-methanol,
{1-[3-(2,4-dibromo-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidin--
4-yl}-methanol,
{1-[5-methyl-3-(2,4,6-trichloro-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperi-
din-4-yl}-methanol,
2-{1-[3-(4-bromo-2,6-dimethyl-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-
-piperidin-4-yl}-ethanol,
2-{1-[3-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-thieno[3,2-b]pyridin-7-
-yl]-piperidin-4-yl}-ethanol,
2-{1-[3-(2,4-dibromo-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidi-
n-4-yl}-ethanol,
2-{1-[5-methyl-3-(2,4,6-trichloro-phenyl)-thieno[3,2-b]pyridin-7-yl]-pipe-
ridin-4-yl}-ethanol,
1-[5-methyl-3-(2,4,6-trimethyl-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperid-
ine-3-carbonitrile,
{1-[3-(4-bromo-2,6-dimethyl-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-p-
iperidin-4-yl}-acetonitrile,
{1-[3-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-thieno[3,2-b]pyridin-7-y-
l]-piperidin-4-yl}-acetonitrile,
{1-[3-(2,4-dibromo-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidin--
4-yl}-acetonitrile and
{1-[5-methyl-3-(2,4,6-trichloro-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperi-
din-4-yl}-acetonitrile.
9. A composition comprising a thienopyrimidine compound substituted
with a cyclic amino group, a pharmaceutically acceptable salt
thereof or its hydrate according to claim 1, and a pharmaceutically
acceptable carrier.
11. Use of a thienopyrimidine compound substituted with a cyclic
amino group, a pharmaceutically acceptable salt thereof or its
hydrate according to claim 1, for the manufacture of a therapeutic
agent as an antagonist for CRF receptors.
Description
DETAILED DESCRIPTION OF THE INVENTION
[0001] 1. Technical Field
[0002] The present invention relates to a therapeutic agent for
diseases in which corticotropin releasing factor (CRF) is
considered to be involved, such as depression, anxiety, Alzheimer's
disease, Parkinson's disease, Huntington's chorea, eating disorder,
hypertension, gastral diseases, drug dependence, cerebral
infarction, cerebral ischemia, cerebral edema, cephalic external
wound, inflammation, immunity-related diseases, alpecia, irritable
bowel syndrome, sleep disorders, epilepsy, dermatitides,
schizophrenia, pain, etc.
[0003] 2. Description of the Prior Art
[0004] CRF is a hormone comprising 41 amino acids (Science, 213,
1394-1397, 1981; and J. Neurosci., 7, 88-100, 1987), and it is
suggested that CRF plays a core role in biological reactions
against stresses (Cell. Mol. Neurobiol., 14, 579-588, 1994;
Endocrinol., 132, 723-728, 1994; and Neuroendocrinol. 61, 445-452,
1995). For CRF, there are the following toro paths: a path by which
CRF acts on peripheral immune system or sympathetic nervous system
through hypothalamus-pituitary-adrenal system, and a path by which
CRF functions as a neurotransmitter in central nervous system (in
Corticotropin Releasing Factor: Basic and Clinical Studies of a
Neuropeptide, pp. 29-52, 1990). Intraventricular administration of
CRF to hypophysectomized rats and normal rats causes an
anxiety-like symptom in both types of rats (Pharmacol. Rev., 43,
425-473, 1991; and Brain Res. Rev., 15, 71-100, 1990). That is,
there are suggested the participation of CRF in
hypothalamus-pituitary-adrenal system and the pathway by which CRF
functions as a neurotransmitter in central nervous system.
[0005] The review by Owens and Nemeroff in 1991 summarizes diseases
in wliicl CRF is involved (Pharmacol. Rev., 43, 425-474, 1991).
That is, CRF is involved in depression, anxiety, Alzheimer's
disease, Parkinson's disease, Huntington's chorea, eating disorder,
hypertension, gastrointestinal diseases, drug dependence,
inflammation, immunity-related diseases, etc. It has recently been
reported that CRF is involved also in epilepsy, cerebral
infarction, cerebral ischemia, cerebral edema, and cephalic
external wound (Brain Res. 545, 339-342, 1991; Ann. Neurol. 31,
48-498, 1992; Dev. Brain Res. 91, 245-251, 1996; and Brain Res.
744, 166-170, 1997). Accordingly, antagonists against CRF receptors
are useful as therapeutic agents for the diseases described
above.
[0006] WO021002549, WO97129110 and WO98/47903 disclose
thienopyridine and thienopyrimidine derivatives respectively as CRF
receptor antagonists. However, none disclose the compounds provided
in the present invention.
PROBLEM(S) TO BE SOLVED BY INVENTION
[0007] An object of the present invention is to provide an
antagonist against CRF receptors which is effective as a
therapeutic or prophylactic agent for diseases in which CRF is
considered to be involved, such as depression, anxiety, Alzheimer's
disease, Parkinson's disease, Huntington's chorea, eating disorder,
hypertension, gastral diseases, drug dependence, epilepsy, cerebral
infarction, cerebral ischemia, cerebral edema, cephalic external
wound, inflammation, immunity-related diseases, alpecia, irritable
bowel syndrome, sleep disorders, dermatitides, schizophrenia, pain,
etc.
MEANS FOR SOLVING PROBLEM
[0008] The present inventors earnestly investigated
thienopyrimidine or thienopyridine derivatives substituted with a
cyclic amino group that have a high affinity for CRF receptors,
whereby the present invention has been accomplished.
[0009] The present invention is thienopyrimidine or thienopyridine
derivatives substituted with a cyclic amino group explained
below.
[0010] A thienopyrimidine or thienopyridine derivative substituted
with a cyclic amino group represented by the following formula
[I]):
##STR00002##
(wherein the cyclic amino group is represented by the following
formula [II]:
##STR00003##
[0011] in which the cyclic amino group is a 3- to 8-membered
saturated cyclic amine or a 3- to 8-membered saturated cyclic amine
bridged with C.sub.1-5alkylene or
C.sub.1-4alkylene-O--C.sub.1-4alkylene between any different two
carbon atoms of the cyclic amine, which cyclic amine is substituted
with a group represented by
--(CR.sup.1R.sup.2).sub.m--(CHR.sup.3).sub.n--X, R.sup.4 and
R.sup.5 independently on the same or different carbon atoms of the
cyclic amine;
[0012] X is cyano, hydroxy, --CO.sub.2R.sup.8 or
--CONR.sup.9R.sup.10;
[0013] Y is N or CR.sup.11;
[0014] R.sup.1 is hydrogen, hydroxy, C.sub.1-5alkyl,
C.sub.1-5alkoxy-C.sub.1-5alkyl or hydroxy-C.sub.1-5alkyl;
[0015] R.sup.2 is hydrogen or C.sub.1-5alkyl;
[0016] R.sup.3 is hydrogen, cyano, C.sub.1-5alkyl,
C.sub.1-5alkoxy-C.sub.1-5alkyl or hydroxy-C.sub.1-5 alkyl;
[0017] m is an integer selected from 0, 1, 2, 3, 4 and 5;
[0018] n is 0 or 1;
[0019] R.sup.4 is hydrogen, hydroxy, hydroxy-C.sub.1-5alkyl, cyano,
cyano-C.sub.1-5alkyl or C.sub.1-5 alkyl;
[0020] R.sup.5 is hydrogen or C.sub.1-5alkyl;
[0021] R.sup.6 is hydrogen, C.sub.1-5alkyl, C.sub.3-8 cycloalkyl,
C.sub.3-8 cycloalkyl-C.sub.1-5alkyl, hydroxy, C.sub.1-5alkoxy,
C.sub.3-8 cycloalkyloxy, halogen, C.sub.1-5alkylthio or
--N(R.sup.12)R.sup.13;
[0022] R.sup.7 is hydrogen, halogen, C.sub.1-5alkyl, C.sub.3-8
cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-5 alkyl, hydroxy,
C.sub.1-5alkoxy, C.sub.3-8-cycloalkyloxy, --N(R.sup.14)R.sup.15,
--CO.sub.2R.sup.16, --CON(R.sup.17)R.sup.18, cyano, nitro,
C-.sub.1-5alkylthio, trifluoromethyl or trifluoromethoxy;
[0023] Ar is aryl or heteroaryl which aryl or heteroaryl is
unsubstituted or substituted with 1 or more substituents, which are
the same or different, selected from the group consisting of
halogen, C.sub.1-5alkyl, C.sub.3-8 cycloalkyl, C.sub.2-5alkenyl,
C.sub.2-5 alkynyl, C.sub.1-5alkoxy, C.sub.1-5alkylthio,
C.sub.1-5alkylsulfinyl, C.sub.1-5alkylsulfonyl, cyano, nitro,
hydroxy, --CO.sub.2R.sup.19, --C(.dbd.O)R.sup.20,
--CONR.sup.21R.sup.22, --OC(.dbd.O)R.sup.23,
--NR.sup.24CO.sub.2R.sup.25, --S(.dbd.O).sub.rNR.sup.26R.sup.27,
trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy,
methylenedioxy, ethylenedioxy and --N(R.sup.28)R.sup.29;
[0024] R.sup.8 is hydrogen, C.sub.1-10 alkyl, C.sub.3-8 cycloalkyl,
C.sub.3-8 cycloalkyl-C.sub.1-5alkyl, aryl or
aryl-C.sub.1-5alkyl;
[0025] R.sup.9 and R.sup.10 are the same or different, and
independently are hydrogen, C.sub.1-5 alkyl, C.sub.3-8 cycloalkyl,
C.sub.3-8 cycloalkyl-C.sub.1-5alkyl, aryl or aryl-C.sub.1-5alkyl;
or R.sup.9 and R.sup.10 form a ring selected from saturated 3 to 8
membered ring with the attached nitrogen atom, wherein one of the
carbon atoms of such saturated 3 to 8 membered ring is optionally
replaced by an oxygen or sulfur atom or by N-Z wherein Z is
hydrogen, benzyl or C.sub.1-5alkyl;
[0026] R.sup.11 is hydrogen, halogen or C.sub.1-5alkyl;
[0027] R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are the same or
different, and independently are hydrogen or C.sub.1-5alkyl;
[0028] R.sup.16, R.sup.19 and R.sup.25 are the same or different,
and independently are hydrogen or C.sub.1-5alkyl, C.sub.3-8
cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-5alkyl, aryl or
aryl-C.sub.1-5alkyl;
[0029] R.sup.17, R.sup.18,R.sup.20, R.sup.21, R.sup.22, R.sup.23,
R.sup.24, R.sup.26, R.sup.27, R.sup.28 and R.sup.29 are the same or
different, and independently are hydrogen, C.sub.1-5alkyl or
C.sub.3-8 cycloalkyl;
[0030] r is 1 or 2)
[0031] ,individual isomers thereof or racemic or non-racemic
mixtures of isomers thereof, pharmaceutically acceptable prodrugs
thereof or pharmaceutically acceptable salts and hydrates
thereof.
[0032] The terms used in the present specification have the
following meanings.
[0033] The term "a 3- to 8-membered saturated cyclic amine" means
aziridine, azetidine, pyrrolidine, piperidine, azepane or
azocane.
[0034] The term "C.sub.1-5alkylene" means a straight or branched
chain alkylene of 1 to 5 carbon atoms, such as methylene, ethylene,
propylene, trimethylene, tetramethylene, pentamethylene or the
like.
[0035] The term "a 3- to 8-membered saturated cyclic amine bridged
with C.sub.1-5 alkylene or C.sub.1-4alkylene-O--C.sub.1-4alkylene
between any different two carbon atoms of the cyclic amine"
includes, for example, 8-azabicyclo[3.2.1]oct-8-yl,
9-azabicyclo[3.3.1]non-9-yl, 7-azabicyclo[2.2.1]hept-7-yl,
3-oxa-7-azabicyclo[3.3.1]non-7-yl and
3-oxa-9-azabicyclo[3.3.1]non-9-yl.
[0036] The term "C.sub.1-5alkyl" means a straight chain or branched
chain alkyl group of 1 to 5 carbon atoms, such as methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, t-butyl, sec-butyl, pentyl,
isopentyl or the like.
[0037] The term "C.sub.1-5alkoxy" means a straight chain or
branched chain alkoxy group of 1 to 5 carbon atoms, such as
methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy,
pentyloxy, isopentyloxy or the like.
[0038] The term "C.sub.1-5alkoxy-C.sub.1-5alkyl" means a
substituted C.sub.1-5alkyl group having the above-mentioned
C.sub.1-5alkoxy group as the substituent, such as methoxymethyl,
2-methoxyethyl, 2-ethoxyethyl or the like.
[0039] The term "hydroxy-C.sub.1-5alkyl" means a substituted
C.sub.1-5alkyl group having hydroxy group, such as hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl,
3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl or the like.
[0040] The term "cyano-C.sub.1-5alkyl" means a substituted
C.sub.1-5alkyl group having cyano group, such as cyanomethyl,
1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl,
5-cyanopentyl or the like.
[0041] The term "C.sub.3-8 cycloalkyl" means a cyclic alkyl group
of 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or the like.
[0042] The term "C.sub.3-8 cycloalkyl-C.sub.1-5alkyl" means a
substituted C.sub.1-5alkyl group having the above-mentioned
C.sub.3-8 cycloalkyl as the substituent, such as cyclopropylmethyl,
2-cyclopropylethyl, 2-cyclopentylethyl or the like.
[0043] The term "C.sub.3-8 cycloalkyloxy" means a cyclic alkoxy
group of 3 to 8 carbon atoms, such as cyclopropyloxy,
cyclobutyloxy, cyclopentyloxy or the like.
[0044] The term "halogen" means fluorine, chlorine, bromine or
iodine atom.
[0045] The term "C.sub.1-5alkylthio" means a straight chain or
branched chain alkylthio group of 1 to 5 carbon atoms, such as
methylthio, ethylthio, propylthio or the like.
[0046] The term "C.sub.1-5alkylsulfinyl" means a straight chain or
branched chain alkylsulfinyl group of 1 to 5 carbon atoms, such as
methylsulfinyl, ethylsulfinyl, propylsulfinyl or the like.
[0047] The term "C.sub.1-5alkylsulfonyl" means a straight chain or
branched chain alkylsulfonyl group of 1 to 5 carbon atoms, such as
metlhylsulfonyl, ethylsulfonyl, propylsulfonyl or the like.
[0048] The term "aryl" means a monocyclic or bicyclic group of 6 to
12 ring carbon atoms having at least one aromatic ring, such as
phenyl, naphthyl, or the like.
[0049] The term "heteroaryl" means a monocyclic or bicyclic group
of 5 to 12 ring atoms having at least one aromatic ring having in
its ring 1 to 4 atoms which may be the same or different and are
selected from nitrogen, oxygen and sulfur, such as pyridyl,
pyrimidinyl, imidazolyl, quinolyl, indolyl, benzofuranyl,
quinoxalinyl, benzo[1,2,5]thiadiazolyl, benzo[1,2,5]oxadiazolyl or
the like.
[0050] The term "ary-C.sub.1-5alkyl" means a substituted
C.sub.1-5alkyl group having the above-mentioned aryl as the
substituent, such as benzyl, phenethyl or the like.
[0051] The term "C.sub.2-5alkenyl" means a straight chain or
branched chain alkenyl group of 2 to 5 carbon atoms, such as vinyl,
isopropenyl, allyl or the like.
[0052] The term "C.sub.2-5alkynyl" means a straight chain or
branched chain alkynyl group of 2 to 5 carbon atoms, such as
ethynyl, prop-1-ynyl, prop-2-ynyl or the like.
[0053] The phrase "aryl or heteroaryl which aryl or heteroaryl is
unsubstituted or substituted with 1 or more substituents, which are
the same or different, selected from the group consisting of
halogen, C.sub.1-5alkyl, C.sub.3-8 cycloalkyl, C.sub.2-5alkenyl,
C.sub.2-5 alkynyl, C.sub.1-5alkoxy, C.sub.1-5alkylthio,
C.sub.1-5alkylsulfinyl, C.sub.1-5alkylsulfonyl, cyano, nitro,
hydroxy, --CO.sub.2R.sup.19, --C(.dbd.O)R.sup.20,
--CONR.sup.21R.sup.22, --OC(.dbd.O)R.sup.23,
--NR.sup.24CO.sub.2R.sup.25, S(.dbd.O).sub.rNR.sup.26R.sup.27,
trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy,
methylenedioxy, ethylenedioxy and --N(R.sup.28)R.sup.29" includes,
for example, 2,4-dimethylphenyl, 2,6-dimethylphenyl,
2,4-dibromophenyl, 2-bromo-4-isoproylphenyl, 2,4-dichlorophenyl,
2,6-dichlorophenyl, 2-chloro-4-trifluoromethylphenyl,
4-methoxy-2-methylphenyl, 2-chloro-4-trifluoromethoxyphenyl,
4-isopropyl-2-methylthiophenyl, 2,4,6-trimethylphenyl,
4-bromo-2,6-dimethylphenyl, 4-bromo-2,6-diethylphenyl,
4-chloro-2,6-dimethylphenyl, 2,4,6-tribromophenyl,
2,4,5-tribromophenyl, 2,4,6-trichlorophenyl, 2,4,5-trichlorophenyl,
4-bromo-2,6-dichlorophenyl, 6-chloro-2,4-dibromophenyl,
2,4-dibromo-6-fluorophenyl, 2,4-dibromo-6-methylphenyl,
2,4-dibromo-6-methoxyphenyl, 2,4-dibromo-6-methylthiophenyl,
2,6-dibromo-4-isopropylphenyl, 2,6-dibromo-4-trifluoromethylphenyl,
2-bromo-4-trifluoromethylphenyl, 4-bromo-2-chlorophenyl,
2-bromo4-chlorophenyl, 4-bromo-2-methylphenyl,
4-chloro-2-methylphenyl, 2,4-dimethoxyphenyl,
2,6-dimethyl-4-methoxyphenyl, 4-chloro-2,6-dibromophenyl,
4-bromo-2,6-difluorophenyl, 2,6-dichloro-4-trifluoromethylphenyl,
2,6-dichloro-4-trifluoromethoxyphenyl,
2,6-dibromo-4-trifluoromethoxyphenyl, 2-chloro-4,6-dimethylphenyl,
2-bromo4,6-dimethoxyphenyl, 2-bromo4-isopropyl-6-methoxyphenyl,
2,4-dimethoxy-6-methylphenyl, 6-diietlylamino-4-methylpyridin-3-yl,
2-chloro-6-trifluoromethylpyridin-3-yl,
2-chloro-6-trifluoromethoxypyridin-3-yl,
2-chloro-6-methoxypyridin-3-yl,
6-methoxy-2-trifluoromethylpyridin-3-yl,
2-chloro-6-difluoromethylpyridin-3-yl,
6-methoxy-2-methylpyridin-3-yl, 2,6-dimethoxypyridin-3-yl,
4,6-dimethyl-2-trifluoromethylpyrimidin-5-yl or
2-dimethylamino-6-methylpyridin-3-yl.
[0054] The "pharmaceutically acceptable salts" in the present
invention include, for example, salts with an inorganic acid such
as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric
acid, nitric acid or the like; salts with an organic acid such as
acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid,
maleic acid, citric acid, benzenesulfonic acid, methanesulfonic
acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid,
ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic
acid, glycolic acid, malic acid, malonic acid, mandelic acid,
galactaric acid, naphthalene-2-sulfonic acid or the like; salts
with one or more metal ions such as lithium ion, sodium ion,
potassium ion, calcium ion, magnesium ion, zinc ion, aluminium ion
or the like; salts with amines such as ammonia, arginine, lysine,
piperazine, choline, diethylamine, 4-phenylcyclohexylamine,
2-aminoethanol, benzathine or the like.
[0055] Prodrugs are also included in this invention. The term
"prodrug" means a compound which is converted within the body, e.g.
by hydrolysis in the blood, into its active form that has medical
effects. The "pharmaceutically acceptable prodrugs" are described
in, for example, Advanced Drug Delivery Reviews (1996) 19 (2)
115-130 and Tetrahedron Letter (2002) 43 1161-1164. The
"pharmaceutically acceptable prodrugs thereof" in the present
invention include, for example, esters such as methyl esters, ethyl
esters, and the like when X is carboxylic acid.
[0056] A compound of the present invention includes any isomers
such as diastereomers, enantiomers, geometricisomers and tautomeric
forms. In a compound represented by formula [I], if the cyclic
amino group has one or more chiral carbons and/or if there is an
axial chirality between Ar and thienopyrimidine (or thienopyridine)
ring, several stereoisomers (diastereomers or enantiomers) can
exist. The compound of the present invention includes the
individual isomers and the racemic and non-racemic mixtures of the
isomers.
[0057] Preferable examples of the compound of the present invention
are as follows.
##STR00004##
[0058] That is preferable are compounds of the formula [III] in
which X, m, n, the cyclic amino group, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and Ar are as defined in above
formula [I]. More preferable are compounds of the formula [III] in
which X is cyano; the cyclic amino group is a 4- to 7-membered
saturated cyclic amine; n is 0; m is 0, 1, 2 and 3; R.sup.1,
R.sup.2, R.sup.4 and R.sup.5 are hydrogen; R.sup.6 is
C.sub.1-5alkyl; R.sup.7 is hydrogen or C.sub.1-5alkyl; and Ar is
phenyl which phenyl is substituted with two or three substituents,
which are the same or different, selected from the group consisting
of halogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio,
trifluoromethyl, trifluoromethoxy and --N(R.sup.28)R.sup.29
(wherein R.sup.28 and R.sup.29 are the same or different, and
independently are hydrogen or C.sub.1-3 alkyl). More preferable are
compounds of the formula [III] in which X is cyano; the cyclic
amino group is a 6-membered saturated cyclic amine; n is 0; m is 0
or 1; R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are hydrogen; R.sup.6
is C.sub.1-5alkyl; R.sup.7 is hydrogen or C.sub.1-5alkyl; and Ar is
phenyl which phenyl is substituted with two or three substituents,
which are the same or different, selected from the group consisting
of halogen and C.sub.1-3 alkyl.
[0059] Other preferable are compounds of the formula [III] in which
X is hydroxy; the cyclic amino group is a 4- to 7-membered
saturated cyclic amine; n is 0; m is an integer selected from 1, 2
and 3; R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are hydrogen; R.sup.6
is C.sub.1-5alkyl; R.sup.7 is hydrogen or C.sub.1-5alkyl; and Ar is
phenyl which phenyl is substituted with two or three substituents,
which are the same or different, selected from the group consisting
of halogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio,
trifluoromethyl, trifluoromethoxy and --N(R.sup.28)R.sup.29
(wherein R.sup.28 and R.sup.29 are the same or different, and
independently are hydrogen or C.sub.1-3 alkyl). More preferable are
compounds of the formula [III] in which X is hydroxy; the cyclic
amino group is a 6-membered saturated cyclic amine; n is 0; m is an
integer selected from 1, 2 and 3; R.sup.1, R.sup.2, R.sup.4 and
R.sup.5 are hydrogen; R.sup.6 is C.sub.1-5alkyl; R.sup.7 is
hydrogen or C.sub.1-5alkyl; and Ar is phenyl which phenyl is
substituted with two or three substituents, which are the same or
different, selected from the group consisting of halogen and
C.sub.1-3 alkyl.
##STR00005##
[0060] Other preferable are compounds of the formula [IV] in which
X, m, n, the cyclic amino group, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.11 and Ar are as defined
in above formula [I]. More preferable are compounds of the formula
[IV] in which X is cyano; the cyclic amino group is a 4- to
7-membered saturated cyclic amine; n is 0; m is 0 or 1; R.sup.1,
R.sup.2, R.sup.4 and R.sup.5 are hydrogen; R.sup.6 is
C.sub.1-5alkyl; R.sup.7 is hydrogen or C.sub.1-5 alkyl; R.sup.11 is
hydrogen or C.sub.1-5alkyl; and Ar is phenyl which phenyl is
substituted with two or three substituents, which are the same or
different, selected from the group consisting of halogen, C.sub.1-3
alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, trifluoromethyl,
trifluoromethoxy and --N(R.sup.28)R.sup.29 (wherein R.sup.28 and
R.sup.29 are the same or different, and independently are hydrogen
or C.sub.1-3 alkyl). More preferable are compounds of the formula
[IV] in which X is cyano; the cyclic amino group is a 6-membered
saturated cyclic amine; n is 0; m is 0 or 1; R.sup.1, R.sup.2,
R.sup.4 and R.sup.5 are hydrogen; R.sup.6 is C.sub.1-5 alkyl;
R.sup.7 is hydrogen or C.sub.1-5alkyl; R.sup.11 is hydrogen; and Ar
is phenyl which phenyl is substituted with two or three
substituents, which are the same or different, selected from the
group consisting of halogen and C.sub.1-3 alkyl.
[0061] Other preferable are compounds of the formula [IV] in which
X is hydroxy; the cyclic amino group is a 4- to 7-membered
saturated cyclic amine; n is 0; m is an integer selected from 1, 2
and 3; R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are hydrogen; R.sup.6
is C.sub.1-5 alkyl; R.sup.7 is hydrogen or C.sub.1-5 alkyl;
R.sup.11 is hydrogen or C.sub.1-5alkyl; and Ar is phenyl which
phenyl is substituted with two or three substituents, which are the
same or different, selected from the group consisting of halogen,
C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio,
trifluoromethyl, trifluoromethoxy and --N(.sup.28)R.sup.29 (wherein
R.sup.28 and R.sup.29 are the same or different, and independently
are hydrogen or C.sub.1-3 alkyl). More preferable are compounds of
the formula [IV] in which X is hydroxy; the cyclic amino group is a
6-membered saturated cyclic amine; n is 0; m is an integer selected
from 1, 2 and 3; R.sup.1, R.sup.2, R.sup.4and R.sup.5 are hydrogen;
R.sup.6 is C.sub.1-5alkyl; R.sup.7 is hydrogen or C.sub.1-5alkyl;
R.sup.11 is hydrogen; and Ar is phenyl which phenyl is substituted
with two or three substituents, which are the same or different,
selected from the group consisting of halogen and C.sub.1-3
alkyl.
[0062] The preferable cyclic amino group is a 6-membered saturated
cyclic amine.
[0063] The preferable R.sup.1 is hydrogen.
[0064] The preferable R.sup.2 is hydrogen.
[0065] The preferable R.sup.3 is hydrogen.
[0066] The preferable R.sup.4 is hydrogen.
[0067] The preferable R.sup.5 is hydrogen.
[0068] The preferable R.sup.6 is C.sub.1-3 alkyl. The more
preferable R.sup.6 is methyl.
[0069] The preferable R.sup.7 is hydrogen or C.sub.1-3 alkyl.
[0070] The preferable R.sup.11 is hydrogen.
[0071] The preferable Ar is phenyl which phenyl is substituted with
two or three substituents, which are the same or different,
selected from the group consisting of halogen, C.sub.1-3 alkyl,
C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, trifluoromethyl,
trifluoromethoxy and --N(R.sup.28)R.sup.29 (wherein R.sup.28 and
R.sup.29 are the same or different, and independently are hydrogen
or C.sub.1-3 alkyl). The more preferable Ar is phenyl which phenyl
is substituted with two or three substituents, which are the same
or different, selected from the group consisting of halogen and
C.sub.1-3 alkyl.
[0072] Especially preferable compounds of the present invention
are:
[0073]
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-thieno[3,2-d]pyrimidin-
-4-yl]-piperidin-4-yl}-methanol
##STR00006##
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-4-
-yl]-piperidin4-yl}-methanol
##STR00007##
2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-
-4-yl]-piperidin-4-yl}-ethanol
##STR00008##
{1-[7(4-bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-4--
yl]-piperidin-4-yl}-acetonitrile
##STR00009##
{1-[3-(2,4-dichloro-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidin-
-4-yl}-methanol
##STR00010##
{1-[5-methyl-3-(2,4,6-trimethyl-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperi-
din-4-yl}-methanol
##STR00011##
{1-[3-(4-bromo-2,6-dimethyl-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-p-
iperidin-4-yl}-methanol
##STR00012##
{1-[3-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-thieno[3,2-b]pyridin-7-y-
l]-piperidin-4-yl}-methanol
##STR00013##
{1-[3-(2,4-dibromo-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidin--
4-yl}-methanol
##STR00014##
{1-[5-methyl-3-(2,4,6-trichloro-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperi-
din-4-yl}-methanol
##STR00015##
2-{1-[3-(4-bromo-2,6-dimethyl-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-
-piperidin-4-yl}-ethanol
##STR00016##
2-{1-[3-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-thieno[3,2-b]pyridin-7-
-yl]-piperidin-4-yl}-ethanol
##STR00017##
2-{1-[3-(2,4-dibromo-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidi-
n4-yl}-ethanol
##STR00018##
2-{1-[5-methyl-3-(2,4,6-trichloro-phenyl)-thieno[3,2-b]pyridin-7-yl]-pipe-
ridin-4-yl}-ethanol
##STR00019##
1-[5-methyl-3-(2,4,6-trimethyl-phenyl)-thieno[3,2-b]pyridin-7-yl]-piperid-
ine-3-carbonitrile
##STR00020##
{1-[3-(4-bromo-2,6-dimethyl-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-p-
iperidin-4-yl}-acetonitrile
##STR00021##
{1-[3-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-thieno[3,2-b]pyridin-7-y-
l]-piperidin-4-yl}-acetonitrile
##STR00022##
{1-[3-(2,4-dibromo-phenyl)-5-methyl-thieno[3,2-b]pyridin-7-yl]-piperidin--
4-yl}-acetonitrile
##STR00023##
and
{1-[5-methyl-3-(2,4,6-trichloro-phenyl)-thieno[3,2-b]pyridin-7-yl]-pi-
peridin-4-yl}-acetonitrile.
##STR00024##
[0074] The compound of the formula [I] can be produced, for
example, by the process shown in the following reaction scheme 1
(in the following reaction scheme, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, m, n, X, Y
and Ar are as defined above, LG is chloro, bromo, iodo,
methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy or
trifluoromethanesulfonyloxy, X.sup.a is carboxy, carbamoyl or
--CO.sub.2(C.sub.1-5alkyl), X.sup.b is CO.sub.2(C.sub.1-5alkyl) or
CONR.sup.9R.sup.10).
##STR00025##
Step 1
[0075] Compound (3), a compound of the present invention, can be
obtained by reacting Compound (1) with Compound (2) in an inert
solvent in the presence or absence of a base. Herein, the base
includes, for example, amines such as triethylamine,
N,N-diisopropylethylamine, pyridine and the like; inorganic bases
such as sodium carbonate, potassium carbonate, sodium
hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide,
potassium hydroxide, barium hydroxide, sodium hydride and the like;
metal alcoholates such as sodium methoxide, sodium ethoxide,
potassium tert-butoxide and the like; metal amides such as sodium
amide, lithium diisopropylamide and the like; and Grignard reagents
such as methylmagnesium bromide and the like. The inert solvent
includes, for example, alcohols such as methanol, ethanol,
isopropyl alcohol, ethylene glycol and the like; ethers such as
diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyetlhane
and the like; hydrocarbons such as benzene, toluene, xylene and the
like; amides such as N,N-dimethylformamide, N-methylpyrrolidone,
N,N-dimethylacetamide and the like; acetonitrile; dimethyl
sulfoxide; pyridine; water; and mixtures of solvents selected from
these inert solvents.
[0076] The compound of the present invention can be converted to a
salt in an inert solvent with an inorganic acid such as sulfuric
acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric
acid or the like, with an organic acid such as acetic acid, oxalic
acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric
acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic
acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid,
glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid,
malic acid, malonic acid, mandelic acid, galactaric acid,
naphthalene-2-sulfonic acid or the like, with an inorganic base
such as lithium hydroxide, sodium hydroxide, potassium hydroxide,
calcium hydroxide, magnesium hydroxide, zinc hydroxide, aluminium
hydroxide or the like or with an organic base such as ammonia,
arginine, lysine, piperazine, choline, diethylamine,
4-phenylcyclohexylamine, 2-aminoethanol, benzathine or the like.
The inert solvent includes, for example, alcohols such as methanol,
ethanol, isopropyl alcohol, ethylene glycol and the like; ethers
such as diethyl ether, tetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane and the like; esters such as ethyl acetate,
ethyl formate and the like; ketones such as acetone,
methylethylketone and the like; hydrocarbons such as benzene,
toluene and the like; amides such as N,N-dimethylformamide,
N-methylpyrrolidone, N,N-dimethylacetamide and the like;
acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide;
pyridine; water; and mixtures of solvents selected from these inert
solvents.
##STR00026##
Step 2
[0077] The cyano group in compound (4), which was synthesized by
the similar method described in step 1, can be converted to the
carboxyl group, a C.sub.1-5 alkoxycarbonyl group or the carbamoyl
group by using an acid or a base in an inert solvent or without any
solvent. An oxidizing agent and/or a crown ether may be used as an
additive in this reaction. Herein, the acid includes, for example,
organic acids such as formic acid, acetic acid, trifluoroacetic
acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic
acid, benzoic acid, trifluoromethanesulfonic acid and the like;
inorganic acids such as sulfuric acid, hydrochloric acid,
hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric
acid, boron trifluoride or the like. The base includes, for
example, inorganic bases such as sodium carbonate, potassium
carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate,
sodium hydroxide, potassium hydroxide, lithium hydroxide, barium
hydroxide and the like; metal alcoholates such as sodium methoxide,
sodium ethoxide, potassium tert-butoxide and the like. The
oxidizing agent includes, for example, hydrogen peroxide, oxygen
gas, manganese oxide and the like. The crown ether includes, for
example, 18-crown-6, 15-crown-5 and the like. The inert solvent
includes, for example, alcohols such as methanol, ethanol,
isopropyl alcohol, ethylene glycol, tert-butanol and the like;
ethers such as diethyl ether, tetrahydrofuran, 1,4dioxane,
1,2-dimethoxyethane and the like; hydrocarbons such as benzene,
toluene, xylene and the like; esters such as ethyl acetate, ethyl
formate and the like; amides such as N,N-dimethylformamide,
N-methylpyrrolidone, N,N-dimethylacetamide and the like;
acetonitrile; dimethyl sulfoxide; pyridine; chloroform;
dichloromethane; water; and mixtures of solvents selected from
these inert solvents.
##STR00027##
Step 3
[0078] Compound (7), a compound of the present invention, can be
synthesized from Compound (6) by conventional methods for amidating
a carboxyl group, esterification of a carboxyl group in the
presence or absence of an acid or a base or alkylation of a
carboxyl group with an alkylating reagent in an inert solvent.
Herein, conventional methods for amidating a carboxyl group or
esterification of a carboxyl group are: for example, the reaction
via a mixed acid anhydride obtained by the reaction of Compound (6)
with haloformic acid ester (e.g., ethyl chloroformate or isobutyl
chloroformate) or an acid chloride (e.g., benzoyl chloride or
pivaloyl chloride); the reaction in the presence of a condensing
agent such as N,N'-dicyclohexylcarbodiimide (DCC),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl),
carbonyldiimidazole (CDI), diphenylphosphorylazide (DPPA), diethyl
cyanophosphate or the like, optionally an additive such as
1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide,
4-dimethylaminopyridine or the like; or the reaction via an acid
halide obtained by the reaction of Compound (6) with a halogenating
reagent such as thionyl chloride, oxalyl chloride, or the like. The
alkylating reagent is, for example, alkyl halide such as
iodomethane, iodoethane, bromomethane, bromoethane and the like.
The base includes amines such as triethylamine,
N,N-diisopropylethylamine, pyridine,
1,8-diazabicyclo[5.4.0]undec-7-ene, 4-(dimethylamino)pyridine and
the like; inorganic bases such as sodium carbonate, potassium
carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate
and the like. The acid includes, for example, organic acids such as
formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic
acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid,
trifluoromethanesulfonic acid and the like; inorganic acids such as
sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric
acid, polyphosphoric acid, nitric acid or the like. The inert
solvent includes, for example, alcohols such as methanol, ethanol,
isopropyl alcohol, ethylene glycol and the like; ethers such as
diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane
and the like; esters such as ethyl acetate, ethyl formate and the
like; hydrocarbons such as benzene, toluene and the like; amides
such as N,N-dimethylformamide, N-methylpyrrolidone,
N,N-dimethylacetamide and the like; acetonitrile; dimethyl
sulfoxide; pyridine; chloroform; dichloromethane; water; and
mixtures of solvents selected from these inert solvents.
[0079] The compound of the present invention is useful as a
therapeutic or prophylactic agent for diseases in which CRF is
considered to be involved. For this purpose, the compound of the
present invention can be formulated into tablets, pills, capsules,
granules, powders, solutions, emulsions, suspensions, injections
and the like by a conventional preparation technique by adding
conventional fillers, binders, disintegrators, pH-adjusting agents,
solvents, etc.
[0080] The compound of the present invention can be administered to
an adult patient in a dose of 0.1 to 500 mg per day in one portion
or several portions orally or parenterally. The dose can be
properly increased or decreased depending on the kind of a disease
and the age, body weight and symptom of a patient.
EMBODIMENTS OF THE INVENTION
[0081] The present invention is concretely explained with reference
to the following examples and test example, but is not limited
thereto.
EXAMPLE 1
[0082] Synthesis of
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-4-
-yl]-piperidin-4-yl}-methanol hydrochloride (compound 1-004)
##STR00028##
[0083] (1) A mixture of
7-(4-bromo-2,6-dimethyl-phenyl)-4-chloro-2,6-dimethyl-thieno[3,2-d]pyrimi-
dine (500 mg), piperidin-4-ylmethanol (226 mg),
N,N-diisopropylethylamine (253 mg) in ethanol (1.5 mL) was heated
at reflux for 1 day. The reaction mixture was cooled to room
temperature, poured into a saturated aqueous sodium
hydrogencarbonate, and then extracted with EtOAc. The organic layer
was washed with brine, dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated under reduced pressure and
purified by a silica gel column chromatography (silica gel: Wako
Gel (C200), eluent: hexane/EtOAc=3:1) to obtain
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-4-
-yl]-piperidin-4-yl}-methanol as a white solid (568 mg).
[0084] (2) To a suspension of
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-4-
-yl]-piperidin-4-yl}-methanol (568 mg) in a mixture (1:1) of EtOH
and EtOAc (2 mL) was added 4 M HCl in EtOAc (0.37 mL) under
ice-cooling. The mixture was stirred overnight to afford a white
crystal. The crystal was collected by filtration to give the title
compound (532 mg).
[0085] Table 1 lists the compound obtained in Example 1 and
compounds obtained by the similar procedure as described in Example
1.
EXAMPLE 2
[0086]
{1-[7-(4-Bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrim-
idin-4-yl]-piperidin-4-yl}-acetic acid
##STR00029##
[0087] (1) A mixture of
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-4-
-yl]-piperidin-4yl}-acetonitrile (350 mg) and KOH (492 mg) in a
mixture of EtOH (1.5 mL) and H.sub.2O (1.0 mL) in a sealed tube was
heated at 105.degree. C. for 3 hours. After concentration of the
reaction mixture under reduced pressure, 5% KHSO.sub.4 aqueous
solution was added and extracted with CHCl.sub.3. The organic layer
was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was purified by a
silica gel column chromatography (silica gel: Walco Gel (C200),
eluent: CHCl.sub.3/methanol=20:1) to obtain the title compound (164
mg).
[0088] Table 1 lists the compound obtained in Example 2 and
compounds obtained by the similar procedure as described in Example
2.
EXAMPLE 3
[0089]
2-{1-[7-(4-Bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyr-
imidin-4-yl]-piperidin-4-yl}-acetamide
##STR00030##
[0090]
{1-[7-(4-Bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrim-
idin-4yl]-piperidin-4-yl}-acetonitrile hydrochloride (30 mg) was
dissolved in c H.sub.2SO.sub.4 (0.5 mL) and the solution was
stirred at room temperature for 20 hours. After addition of ice,
the reaction mixture was made to alkaline (pH 7) with an aqueous
NaOH solution and an aqueous NaHCO.sub.3 solution. The mixture was
extracted with EtOAc and the organic layer was washed with brine,
dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was purified by a silica gel column
chromatography (silica gel: Wako Gel (C200), eluent: EtOAc) to
obtain the title compound (20 mg) as a white crystal.
EXAMPLE 4
[0091]
{1-[7-(4-Bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thienio[3,2-d]pyri-
midin-4-yl]-piperidin-4-yl}-acetic acid ethyl ester
##STR00031##
[0092] A mixture of
{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-4-
-yl]-piperidin-4-yl}-acetic acid (30 mg), iodoethane (97 mg) and
K.sub.2CO.sub.3 (17 mg) in DMF (1 mL) was stirred at room
temperature for 16 hours. To the reaction mixture were added
H.sub.2O and EtOAc and separated. The organic layer was washed
brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was purified by a silica gel column
chromatography (silica gel: Walco Gel (C200), eluent:
Hexane/EtOAc=4:1) to obtain the title compound (22 mg) as a white
crystal.
TABLE-US-00001 TABLE 1*.sup.1 ##STR00032## Com.No. Ex.No.
##STR00033## Y R.sup.6 R.sup.7 --Ar melting point(.degree.
C.)(solvent forcystrallization) 1-001 1 ##STR00034## N CH.sub.3 H
##STR00035## amorphous 1-002 1 ##STR00036## N CH.sub.3 H
##STR00037## amorphous 1-003 1 ##STR00038## N CH.sub.3 H
##STR00039## 177-180*.sup.2(EtOAc/EtOH) 1-004 1 ##STR00040## N
CH.sub.3 CH.sub.3 ##STR00041## 242-244*.sup.2(EtOAc/EtOH) 1-005 1
##STR00042## N CH.sub.3 H ##STR00043## 192-194*.sup.2(EtOH) 1-006 1
##STR00044## N CH.sub.3 CH.sub.3 ##STR00045##
192-193*.sup.2(EtOAc/EtOH) 1-007 1 ##STR00046## N CH.sub.3 H
##STR00047## amorphous 1-008 1 ##STR00048## N CH.sub.3 H
##STR00049## amorphous 1-009 1 ##STR00050## N CH.sub.3 H
##STR00051## 163-165*.sup.2(EtOAc/EtOH) 1-010 1 ##STR00052## N
CH.sub.3 CH.sub.3 ##STR00053## 202-204*.sup.2(EtOAc/EtOH) 1-011 1
##STR00054## CH CH.sub.3 H ##STR00055## amorphous 1-012 1
##STR00056## CH CH.sub.3 H ##STR00057## amorphous 1-013 1
##STR00058## CH CH.sub.3 H ##STR00059## amorphous 1-014 1
##STR00060## CH CH.sub.3 H ##STR00061## 228-230*.sup.2(EtOAc/EtOH)
1-015 1 ##STR00062## CH CH.sub.3 CH.sub.3 ##STR00063##
234-236*.sup.2(EtOAc/EtOH) 1-016 1 ##STR00064## CH CH.sub.3 H
##STR00065## 196-199*.sup.2(EtOAc/EtOH) 1-017 1 ##STR00066## CH
CH.sub.3 H ##STR00067## 231-233*.sup.2(EtOAc/EtOH) 1-018 1
##STR00068## CH CH.sub.3 H ##STR00069## 172-174*.sup.2(EtOAc) 1-019
1 ##STR00070## CH CH.sub.3 CH.sub.3 ##STR00071##
182-184*.sup.2(EtOAc/EtOH) 1-020 1 ##STR00072## CH CH.sub.3 H
##STR00073## 166-168*.sup.2(EtOAc/EtOH) 1-021 1 ##STR00074## CH
CH.sub.3 H ##STR00075## 158-160*.sup.2(EtOAc/EtOH) 1-022 1
##STR00076## CH CH.sub.3 H ##STR00077## amorphous 1-023 1
##STR00078## CH CH.sub.3 H ##STR00079## amorphous 1-024 1
##STR00080## CH CH.sub.3 H ##STR00081## amorphous 1-025 1
##STR00082## CH CH.sub.3 H ##STR00083## 186-188*.sup.2(EtOAc/IPE)
1-026 1 ##STR00084## CH CH.sub.3 CH.sub.3 ##STR00085##
135-137*.sup.2(EtOAc/EtOH) 1-027 1 ##STR00086## CH CH.sub.3 H
##STR00087## 179-182*.sup.2(EtOAc/EtOH) 1-028 1 ##STR00088## CH
CH.sub.3 H ##STR00089## 203-205*.sup.2(EtOAc) 1-029 2 ##STR00090##
N CH.sub.3 CH.sub.3 ##STR00091## 268-270(EtOAc) 1-030 2
##STR00092## N CH.sub.3 CH.sub.3 ##STR00093## 222-224(EtOAc) 1-031
3 ##STR00094## N CH.sub.3 CH.sub.3 ##STR00095## 212-124*.sup.3
1-032 4 ##STR00096## N CH.sub.3 CH.sub.3 ##STR00097##
110-112*.sup.3 *.sup.1Com. No. = compound number, Ex. No. = example
number, solvent for crystallization; EtOAc = ethyl acetate, EtOH =
ethanol, IPE = diisopropylether, Et = ethyl
Analytical data of non-crystal compounds are described below.
1-001: MS (Pos, ES): 408 (M+1).sup.+, 410 (M+3).sup.+, 430
(M+Na).sup.+, 432 (M+Na+2).sup.+; NMR (300 MHz, CDCl.sub.3) 67
1.50-2.13 (5 H, m), 2.56 (3H, s), 3.48-3.62 (2H, m), 3.71-4.00 (3
H, m), 4.06-4.29 (2 H, m), 7.35 (1 H, dd, J=2.0, 8.4 Hz), 7.52 (1
H, d, J=2.0 Hz), 7.57 (1H, d, J=8.4 Hz), 7.84 (1 H, s) 1-002: MS
(Pos, ES): 408 (M+1).sup.+, 410 (M+3).sup.+; HPLC Retention time:
9.69 Xterra MS C18 (Waters, Milford, Mass.) 3.5 .mu.m,
4.6.times.100 mm); Flow rate 1.6 ml/min. Three mobile phases
(mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile; mobile
phase B: acetonitrile; mobile phase C: methanol) were employed to
run a gradient condition from 100% A to 50% B and 50% C in 10 min.,
to 100% B in 1 min, 100% B for 3 min. and reequilibrate with 100% A
for 2.5 min) 1-007: MS (Pos, ES): 436 (M+1).sup.+, 438 (M+3).sup.+;
HPLC Retention time: 9.97 (Xterra MS C18 (Waters, Milford, Mass.)
3.5 .mu.m, 4.6.times.100 mm); Flow rate 1.6 ml/min. Three mobile
phases (mobile phase A 95% 25 mM ammonium acetate+5% acetonitrile;
mobile phase B: acetonitrile; mobile phase C: methanol) were
employed to run a gradient condition from 100% A to 50% B and 50% C
in 10 min., to 100% B in 1 min, 100% B for 3 min. and reequilibrate
with 100% A for 2.5 min) 1-008: MS (Pos, ES): 403 (M+1).sup.+, 405
(M+3).sup.+; HPLC Retention time: 9.94 Xterra MS C18 (Waters,
Milford, Mass.) 3.5 .mu.m, 4.6.times.100 mm); Flow rate 1.6 ml/min.
Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5%
acetonitrile; mobile phase B: acetonitrile; mobile phase C:
methanol) were employed to run a gradient condition from 100% A to
50% B and 50% C in 10 min., to 100% B in 1 min, 100% B for 3 min.
and reequilibrate with 100% A for 2.5 min) 1-011: MS (Pos, ES): 407
(M+1).sup.+, 409 (M+3).sup.+, 429 (M+Na).sup.+, 431 (M+Na+2).sup.+;
NMR (300 MHz, CDCl.sub.3) .delta. 1.20-2.12 (5 H, m), 2.57 (3H, s),
2.80-3.06 (2H, m), 3.52-4.00 (5 H, m), 6.61(1 H, s), 7.33 (1 H, dd,
J=2.0, 8.4 Hz), 7.51 (1 H, d, J=2.0 Hz), 7.63 (1H, d, J=8.4 Hz),
7.73 (1 H, s) 1-012: MS (Pos, ES): 407 (M+1).sup.+, 409
(M+3).sup.+; HPLC Retention time: 10.02 (Xterra MS C18 (Waters,
Milford, Mass.) 3.5 .mu.m, 4.6.times.100 mm); Flow rate 1.6 ml/min.
Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5%
acetonitrile; mobile phase B: acetonitrile; mobile phase C:
methanol) were employed to run a gradient condition from 100% A to
50% B and 50% C in 10 min., to 100% B in 1 min, 100% B for 3 min.
and reequilibrate with 100% A for 2.5 min) 1-013: MS (Pos, ES): 381
(M+1).sup.+; HPLC Retention time: 9.22 (Xterra MS C18 (Waters,
Milford, Mass.) 3.5 .mu.m, 4.6.times.100 mm); Flow rate 1.6 ml/min.
Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5%
acetonitrile; mobile phase B: acetonitrile; mobile phase C:
methanol) were employed to run a gradient condition from 100% A to
50% B and 50% C in 10 min., to 100% B in 1 min, 100% B for 3 min.
and reequilibrate with 100% A for 2.5 min) 1-022: MS (Pos, ES): 409
(M+1).sup.+; HPLC Retention time: 9.89 Xterra MS C18 (Waters,
Milford, Mass.) 3.5 .mu.m, 4.6.times.100 mm); Flow rate 1.6 ml/min.
Three mobile phases (mobile phase A 95% 25 mM ammonium acetate+5%
acetonitrile; mobile phase B: acetonitrile; mobile phase C:
methanol) were employed to run a gradient condition from 100% A to
50% B and 50% C in 10 min., to 100% B in 1 min, 100% B for 3 min.
and reequilibrate with 100% A for 2.5 min) 1-023: MS (Pos, ES): 402
(M+1).sup.+, 404 (M+3).sup.+; HPLC Retention time: 6.40 (Xterra MS
C18 (Waters, Milford, Mass.) 3.5 .mu.m, 4.6.times.100 mm); Flow
rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM
ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile;
mobile phase C: methanol) were employed to run a gradient condition
from 100% A to 50% B and 50% C in 10 min., to 100% B in 1 min, 100%
B for 3 min. and reequilibrate with 100% A for 2.5 min) 1-024: MS
(Pos, ES): 376 (M+1).sup.+; HPLC Retention time: 6.21 (Xterra MS
C18 (Waters, Milford, Mass.) 3.5 .mu.m, 4.6.times.100 mm); Flow
rate 1.6 ml/min. Three mobile phases (mobile phase A 95% 25 mM
ammonium acetate+5% acetonitrile; mobile phase B: acetonitrile;
mobile phase C: methanol) were employed to run a gradient condition
from 100% A to 50% B and 50% C in 10 min., to 100% B in 1 min, 100%
B for 3 min. and reequilibrate with 100% A for 2.5 min)
2: HCl Salt
[0093] 3: Crystallized on standing from the compound purified
(silica gel column chromatography) and dried.
Test Example [CRF Receptor Binding Test]
[0094] Monkey amygdala membranes were used as a receptor
preparation.
[0095] .sup.125-CRF was used as .sup.125I-labeled ligand.
[0096] Binding reaction using the .sup.125I-labeled ligand was
carried out by the following method described in The Journal of
Neuroscience, 7, 88 (1987).
Preparation of Receptor Membranes
[0097] Monkey amygdala was homogenized in 50 mM Tris-HCl buffer (pH
7.0) containing 10 mM MgCl.sub.2, 2 mM EDTA and centrifuged at
48,000.times.g for 20 min, and the precipitate was washed once with
Tris-HCl buffer. The washed precipitate was suspended in 50 mM
Tris-HCl buffer (pH 7.0) containing 10 mM MgCl.sub.2, 2 mM EDTA,
0.1% bovine serum albumin and 100 kallikrein units/ml aprotinin, to
obtain a membrane preparation.
CRF Receptor Binding Test
[0098] The membrane preparation (0.3 mg protein/ml), .sup.125I-CRF
(0.2 nM) and a test drug were reacted at 25.degree. C. for 2 hours.
After completion of the reaction, the reaction mixture was filtered
by suction through a glass filter (GF/C) treated with 0.3%
polyethylene imine, and the glass filter was washed three times
with phosphate-buffered saline containing 0.01% Triton X-100. After
the washing, the radioactivity of the filter paper was measured in
a gamma counter.
[0099] The amount of .sup.125I-CRF bound when the reaction was
carried out in the presence of 1 .mu.M CRF was taken as the degree
of nonspecific binding of .sup.125I-CRF, and the difference between
the total degree of .sup.125I-CRF binding and the degree of
nonspecific .sup.125I-CRF binding was taken as the degree of
specific .sup.125I-CRF binding. An inhibition curve was obtained by
reacting a definite concentration (0.2 nM) of .sup.125I-CRF with
various concentrations of each test drug under the conditions
described above. A concentration of the test drug at which binding
of .sup.1251-CRF is inhibited by 50% (IC.sub.50) was determined
from the inhibition curve.
[0100] As a result, it was found that compounds 1-003, 1-004,
1-006, 1-010, 1-012, 1-013, 1-014, 1-015, 1-016, 1-017, 1-018,
1-019, 1-020, 1-021, 1-024, 1-025, 1-026, 1-027 and 1-028 can be
exemplified as typical compounds having an IC.sub.50 value of 100
nM or less.
EFFECT OF THE INVENTION
[0101] According to the present invention, compounds having a high
affinity for CRF receptors have been provided. These compounds are
effective against diseases in which CRF is considered to be
involved, such as depression, anxiety, Alzheimer's disease,
Parkinson's disease, Huntington's chorea, eating disorder,
hypertension, gastral diseases, drug dependence, epilepsy, cerebral
infarction, cerebral ischemia, cerebral edema, cephalic external
wound, inflammation, immunity-related diseases, alpecia, irritable
bowel syndrome, sleep disorders, dermatitides, schizophrenia, pain,
etc.
* * * * *