U.S. patent application number 09/735841 was filed with the patent office on 2001-04-19 for new uses for corticotropin releasing factor antagonists.
Invention is credited to Chen, Yuhpyng L., Fossa, Anthony A..
Application Number | 20010000340 09/735841 |
Document ID | / |
Family ID | 21720388 |
Filed Date | 2001-04-19 |
United States Patent
Application |
20010000340 |
Kind Code |
A1 |
Chen, Yuhpyng L. ; et
al. |
April 19, 2001 |
New uses for corticotropin releasing factor antagonists
Abstract
A method of treating, preventing or inhibiting a disorder
selected from the group consisting of cardiovascular or heart
related diseases such as stroke, hypertension, tachycardia, and
congestive heart failure, osteoporosis, premature birth,
psychosocial dwarfism, stress-induced fever, ulcer, diarrhea,
post-operative ileus, and colonic hypersensitivity associated with
psychopathological disturbance and stress, comprising administering
to a mammal, including a human, in need of such treatment a
therapeutically effective amount of a compound of the formula 1 or
pharmaceutically acceptable salt thereof, wherein A, B, D, E, Y, Z,
R.sub.3, R.sub.4, and R.sub.5 are as defined herein.
Inventors: |
Chen, Yuhpyng L.;
(Waterford, CT) ; Fossa, Anthony A.; (Mystic,
CT) |
Correspondence
Address: |
Paul H. Ginsburg
Pfizer Inc
20th Floor
235 East 42nd Street
New York
NY
10017-5755
US
|
Family ID: |
21720388 |
Appl. No.: |
09/735841 |
Filed: |
December 13, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09735841 |
Dec 13, 2000 |
|
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08741066 |
Oct 30, 1996 |
|
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60006333 |
Nov 8, 1995 |
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Current U.S.
Class: |
514/269 ;
514/272; 514/275; 514/381; 514/415 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 31/506 20130101; A61K 31/519 20130101; A61K 31/437 20130101;
A61K 31/52 20130101; A61K 31/505 20130101; A61K 31/435
20130101 |
Class at
Publication: |
514/269 ; 514;
514/272; 514/275; 514/381; 514/415 |
International
Class: |
A61K 031/505; A61K
031/41; A61K 031/40 |
Claims
What is claimed is:
1. A method of treating a disorder selected from the group
consisting of cardiovascular or heart related diseases including
hypertension, tachycardia, and congestive heart failure,
osteoporosis, premature birth, psychosocial dwarfism,
stress-induced fever, ulcer, diarrhea, post-operative ileus, and
colonic hypersensitivity associated with psychopathological
disturbance and stress, comprising administering to a mammal in
need of such treatment a therapeutically effective amount of a
compound of the formula 3or a pharmaceutically acceptable salt
thereof, wherein the dashed line represents an optional double
bond; A is --CR.sub.7 or N; B is --NR.sub.1R.sub.2,
--CR.sub.1R.sub.2R.sub.1, --C(.dbd.CR.sub.1, R.sub.12)R.sub.2,
--NHCR.sub.11R.sub.1R.sub.2, --OCR.sub.11R.sub.1R.sub.2,
--SCR.sub.11R.sub.1R.sub.2, --CR.sub.11R.sub.2OR.sub.1,
--CR.sub.11R.sub.2SR.sub.1, --C(S)R.sub.2, --NHNR.sub.1R.sub.2,
--CR.sub.2R.sub.11NHR.sub.1 or --C(O)R.sub.2; D is: (i) N or
--CR.sub.10 when a double bond connects E and D and E is
--CR.sub.4; (ii) --CR.sub.10 when a double bond connects E and D
and E is N; or (iii) --CR.sub.8R.sub.9, --CHR.sub.10, --C.dbd.O,
--C.dbd.S, --C.dbd.NH, or --C.dbd.NCH.sub.3 when a single bond
connects E and D; E is --CR.sub.4or N when a double bond connects E
and D, and E is --CR.sub.4R.sub.6 or --NR.sub.6 when a single bond
connects E and D; Y is N or --CH; Z is NH, O, S,
--N(C.sub.1-C.sub.2 alkyl) or --CR.sub.12R.sub.13, wherein R.sub.12
and R.sub.13 are each, independently, hydrogen, trifluoromethyl or
methyl, or one of R.sub.12 and R.sub.13 is cyano and the other is
hydrogen or methyl; R.sub.1 is hydrogen or C.sub.1-C.sub.6 alkyl
which is optionally substituted with one or two substituents
independently selected from hydroxy, cyano, nitro, fluoro, chloro,
bromo, iodo, CF.sub.3, C.sub.1-C.sub.4 alkoxy,
--O--CO--(C.sub.1-C.sub.4 alkyl), --O--CO--NH(C.sub.1-C.sub.4
alkyl), --O--CO--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
--NH(C.sub.1-C.sub.4 alkyl), --N(C.sub.1-C.sub.2
alkyl)(C.sub.1-C.sub.4 alkyl), --S(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4alkyl)CO(C.sub.1-C- .sub.4 alkyl),
--NHCO(C.sub.1-C.sub.4 alkyl), --CO.sub.2(C.sub.1-C.sub.4 alkyl),
--CONH(C.sub.1-C.sub.4 alkyl), --CON(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), (C.sub.1-C.sub.4 alkyl)sulfinyl,
(C.sub.1-C.sub.4 alkyl)sulfonyl, and (C.sub.1-C.sub.4
alkyl)sulfanyl, and wherein said C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy and the C.sub.1-C.sub.4 alkyl moieties in
the foregoing R.sub.1 groups optionally contain one double or
triple bond; R.sub.2 is C.sub.1-C.sub.6 alkyl, heteroaryl, aryl
(heteroaryl)C.sub.1-C.sub.4 alkyl or (aryl)C.sub.1-C.sub.4 alkyl
wherein said aryl and the aryl moiety of said (aryl)C.sub.1-C.sub.4
alkyl are selected from the group consisting of phenyl and
naphthyl, and said heteroaryl and the heteroaryl moiety of said
(heteroaryl)C.sub.1-C.sub.4 alkyl is selected from the group
consisting of thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl,
pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl,
benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl,
benzimidazolyl, indolyl, and benzoxazolyl; or R.sup.2 is
C.sub.3-C.sub.8 cycloalkyl or (C.sub.3-C.sub.8
cycloalkyl)C.sub.1-C.sub.6 alkyl, wherein one or two of the ring
carbons of said cycloalkyl having at least 4 ring members and the
cycloalkyl moiety of said (C.sub.3-C.sub.8
cycloalkyl)C.sub.1-C.sub.6 alkyl having at least 4 ring members is
optionally replaced by an oxygen or sulfur atom or by --NR.sub.14
wherein R.sub.14 is hydrogen or C.sub.1-C.sub.4 alkyl; and wherein
each of the foregoing R.sub.2 groups is optionally substituted by
from one to three substituents independently selected from chloro,
fluoro and C.sub.1-C.sub.4 alkyl, or by one substituent selected
from bromo, iodo, cyano, nitro, C.sub.1-C.sub.6 alkoxy,
--O--CO--(C.sub.1-C.sub.4alkyl), --O--CO--N(C.sub.1-C.sub.4alkyl)-
(C.sub.1-C.sub.2 alkyl), --CO.sub.2(C.sub.1-C.sub.4 alkyl),
(C.sub.1-C.sub.4 alkyl)sulfanyl, (C.sub.1-C.sub.4 alkyl)sulfinyl,
and (C.sub.1-C.sub.4 alkyl)sulfonyl, and wherein said
C.sub.1-C.sub.6 alkyl and the C.sub.1-C.sub.4 alkyl and
C.sub.1-C.sub.6 alkyl moieties of the foregoing R.sub.2 groups
optionally contain one carbon-carbon double or triple bond; or
R.sup.1 and R.sup.2 of said --NR.sub.1R.sub.2 and said
--CR.sub.1R.sub.2R.sub.11 are taken together to form a saturated 5
to 8 member ring, wherein said ring optionally contains one or two
carbon-carbon double bonds, and wherein one or two of the ring
carbons is optionally replaced by a heteroatom selected from O, S
and N; R.sub.3 is hydrogen, C.sub.1-C.sub.6 alkyl, fluoro, chloro,
bromo, iodo, hydroxy, amino, SH, --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl), --CH.sub.2OH,
--CH.sub.2OCH.sub.3, --O(C.sub.1-C.sub.4 alkyl), (C.sub.1-C.sub.4
alkyl)sulfanyl, (C.sub.1-C.sub.4 alkyl)sulfonyl, or
(C.sub.1-C.sub.4 alkyl)sulfinyl, wherein said C.sub.1-C.sub.6 alkyl
and the C.sub.1-C.sub.4 alkyl moieties of the foregoing R.sub.3
groups optionally contain one double or triple bond and are
optionally substituted by from one to three substituents
independently selected from hydroxy, amino, C.sub.1-C.sub.3 alkoxy,
--NH(C.sub.1-C.sub.2 alkyl), --N(C.sub.1-C.sub.2).sub.2,
--NHCOCH.sub.3, fluoro, chloro and C.sub.1-C.sub.3 thioalkyl;
R.sub.4 is hydrogen, C.sub.1-C.sub.6 alkyl, fluoro, chloro, bromo,
iodo, C.sub.1-C.sub.6 alkoxy, formyl, trifluoromethoxy,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2CF.sub.3, CF.sub.3, amino,
nitro, --NH(C.sub.1-C.sub.4 alkyl), --N(CH.sub.3).sub.2,
--NHCOCH.sub.3, --NHCONHCH.sub.3, (C.sub.1-C.sub.4 alkyl)sulfanyl,
(C.sub.1-C.sub.4 alkyl)sulfinyl, (C.sub.1-C.sub.4alkyl)su- lfonyl,
cyano, hydroxy, --CO(C.sub.1-C.sub.4alkyl), --CHO, or
--CO.sub.2(C.sub.1-C.sub.4 alkyl), wherein said C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy and the C.sub.1-C.sub.4 alkyl
moieties of the foregoing R.sub.4 groups optionally contain one
double or triple bond and are optionally substituted with one
substituent selected from hydroxy, amino, --NHCOCH.sub.3,
--NH(C.sub.1-C.sub.2 alkyl), --N(C.sub.1-C.sub.2 alkyl).sub.2,
--CO.sub.2(C.sub.1-C.sub.4 alkyl), --CO(C.sub.1-C.sub.4 alkyl),
C.sub.1-C.sub.3 alkoxy, (C.sub.1-C.sub.3 alkyl)sulfanyl, fluoro,
chloro, cyano and nitro; R.sub.5 is phenyl, naphthyl, thienyl,
benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl,
imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl,
benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl,
benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl,
azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl,
morpholinyl, pyridinyl, tetrazolyl, or 3- to 8-membered cycloalkyl
or 9- to 12-membered bicycloalkyl, wherein said cycloalkyl and
bicycloalkyl optionally contain one or two of O, S or --N--G
wherein G is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkanoyl, phenyl or benzyl, wherein each of the above R.sub.5
groups is optionally substituted by from one to three substituents
independently selected from fluoro, chloro, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy and trifluoromethyl, or one substituent
selected from bromo, iodo, cyano, nitro, amino,
--NH(C.sub.1-C.sub.4 alkyl), --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), --CO.sub.2(C.sub.1-C.sub.4 alkyl),
--CO(C.sub.1-C.sub.4 alkyl), --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
--SO.sub.2NH.sub.2, --NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
--S(C.sub.1-C.sub.4 alkyl), and --SO.sub.2(C.sub.1-C.sub.4 alkyl),
wherein said C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.6 alkyl
moieties of the foregoing R.sub.5 groups optionally contain one
double or triple bond and are optionally substituted by one or two
substituents independently selected from fluoro, chloro, hydroxy,
amino, methylamino, dimethylamino and acetyl; R.sub.6 is hydrogen
or C.sub.1-C.sub.6 alkyl, wherein said C.sub.1-C.sub.6 alkyl is
optionally substituted by a single hydroxy, methoxy, ethoxy or
fluoro group; R.sub.7 is hydrogen, C.sub.1-C.sub.4 alkyl, fluoro,
chloro, bromo, iodo, cyano, hydroxy, C.sub.1-C.sub.4 alkoxy,
--CO(C.sub.1-C.sub.4 alkyl), --CO.sub.2(C.sub.1-C.sub.4 alkyl),
--OCF.sub.3, CF.sub.3, --CH.sub.2OH, --CH.sub.2OCH.sub.3 or
--CH.sub.2OCH.sub.2CH.sub.3; R.sub.8 and R.sub.9 are each,
independently, hydrogen, hydroxy, methyl, ethyl, methoxy, or
ethoxy; or R.sub.8 and R.sub.9 together form an oxo (.dbd.O) group;
R.sub.10 is hydrogen, C.sub.1-C.sub.6 alkyl, fluoro, chloro, bromo,
iodo, C.sub.1-C.sub.6 alkoxy, formyl, amino, --NH(C.sub.1-C.sub.4
alkyl), --N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
--SO.sub.n(C.sub.1-C.sub.4 alkyl), wherein n is 0, 1 or 2, cyano,
carboxy, or amido, wherein said C.sub.1-C.sub.6 alkyl and the
C.sub.1-C.sub.4 alkyl moieties of the foregoing R.sub.10 groups are
optionally substituted by one of hydroxy, trifluoromethyl, amino,
carboxy, amido, --NHCO(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4
alkyl), --N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
--CO.sub.2(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 thioalkyl, fluoro, bromo, chloro, iodo, cyano or
nitro; and, R.sub.11 is hydrogen, hydroxy, fluoro, or methoxy.
2. The method of claim 1 wherein B is --NR.sub.1R.sub.2,
--NHCHR.sub.1R.sub.2, --CR.sub.1R.sub.2R.sub.11,
--SCHR.sub.1R.sub.2 or --OCHR.sub.1R.sub.2; R.sub.1 is
C.sub.1-C.sub.6 alkyl which is optionally substituted with a single
hydroxy, fluoro or C.sub.1-C.sub.2 alkoxy group and optionally
contains one carbon-carbon double or triple bond; R.sub.2 is benzyl
or C.sub.1-C.sub.6 alkyl which optionally contains one
carbon-carbon double or triple bond, wherein said C.sub.1-C.sub.6
alkyl and the phenyl moiety of said benzyl are optionally
substituted with fluoro, C.sub.1-C.sub.2 alkyl, or C.sub.1-C.sub.2
alkoxy; and R.sub.11 is hydrogen or fluoro.
3. The method of claim 1 wherein R.sub.2 is (aryl)C.sub.1-C.sub.4
alkyl or (heteroaryl)C.sub.1-C.sub.4 alkyl in which said aryl or
heteroaryl moiety is phenyl, thienyl, benzofuranyl, furanyl,
benzothienyl, thiazolyl, pyridyl or benzothiazolyl.
4. The method of claim 1 wherein B is NR.sub.1R.sub.2 or
CHR.sub.1R.sub.2 in which R.sub.1 and R.sub.2 are taken together
with N or CH to form a 5- or 6-membered ring optionally having
sulfur, oxygen, or, where B is NR.sub.1R.sub.2, one more nitrogen
in said ring.
5. The method of claim 1 wherein B is --NHCHR.sub.1R.sub.2 or
--OCHR.sub.1R.sub.2, wherein the CHR.sub.1R.sub.2 moiety is a 5- or
6-membered ring which optionally contains one oxygen or sulfur.
6. The method of claim 5 wherein B is tetrahydrofuranyl,
tetrahydrothiafuranyl or cyclopentanyl.
7. The method of claim 5 wherein B is tetrahydrofuranyl,
tetrahydrothienyl or thiazolidinyl.
8. The method of claim 1 wherein R.sub.3 is methyl, chloro, or
methoxy; R.sub.4 is methyl, --CH.sub.2OH, cyano, trifluoromethoxy,
methoxy, trifluoromethyl, chloro, --CO.sub.2CH.sub.3,
--CH.sub.2OCH.sub.3, --CH.sub.2Cl, --CH.sub.2F, amino or nitro;
R.sub.6 is hydrogen, methylsulfinyl, methylsulfanyl,
methylsulfonyl, or ethyl; and R.sub.5 is phenyl or pyridyl wherein
said phenyl or pyridyl is substituted by one substituent
independently selected from fluoro, chloro, bromo, iodo,
C.sub.1-C.sub.4 alkoxy, trifluoromethyl, C.sub.1-C.sub.3
hydroxyalkyl, --CO.sub.2(C.sub.1-C.sub.2 alkyl),
(amino)C.sub.1-C.sub.2 alkyl, --CO(C.sub.1-C.sub.4 alkyl), and
C.sub.1-C.sub.6 alkyl, wherein said C.sub.1-C.sub.6 alkyl and said
C.sub.1-C.sub.4 alkyl are optionally substituted by a single
hydroxy, or fluoro group and optionally contains one carbon-carbon
double or triple bond.
9. The method of claim 1 wherein the compound of formula I or II is
selected from the group consisting of:
4-(1-ethyl-propoxy)-2,5-dimethyl-6-
-(2,4,6-trimethyl-benzyl)-pyrimidine;
2-(4-bromo-2,6-dimethyl-phenoxy)-4-(-
1-ethyl-propoxy)-3,6-dimethyl-pyridine;
2-(4-ethyl-2,6-dimethyl-phenoxy)-4-
-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;
3-ethyl-4-(1-ethyl-propoxy)-6-me-
thyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;
2-(2,6-dimethyl-4-propyl-phenox-
y)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;
4-(1-ethyl-propoxy)-2-(4-met-
hoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine;
2-(4-ethoxy-2,6-dimethyl-
-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridi-
ne; 4-(1-methoxymethyl-propoxy)-3,6-dimethyl-pyridine;
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine;
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propyl-amin-
e;
[2,5-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl]-(1-ethyl-prop-
yl)-amine;
butyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-e-
thyl-amine;
4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulf-
anyl)-pyridine;
butyl-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyri-
din-4-yl]-ethyl-amine;
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-
-phenoxy)-nicotinic acid methyl ester;
[3,6-dimethyl-2-(2,4,6-trimethyl-ph-
enylsulfanyl)-pyridin-4-yl]-ethyl-propyl-amine;
[4-(1-ethyl-propylamino)-6-
-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-methanol;
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-propy-
l-amine;
1-(ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-py-
ridin-4-yl]-amine;
4-(1-ethyl-propyl)-6-methyl-3-nitro-2-(2,4,6-trimethyl--
phenyl)-pyridine-2,4-diamine;
4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimeth-
yl-phenoxy)-pyridine-3,4-diamine;
4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-tri-
methyl-phenyl)-pyridine-2,3,4-triamine;
[3,6-dimethyl-2-(2,4,6-trimethyl-p-
henoxy)-pyridin-4-yl]-ethyl-(2,2,2-trifluoro-ethyl)-amine;
[3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)pyridin-4-yl]-(1-ethy-
l-propyl)-amine;
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(-
1-ethyl-propyl)-amine;
(1-ethyl-propyl)-[2-methyl-5-nitro-6-(2,4,6-trimeth-
yl-pyridin-3-yloxy)-pyrimidin-4-yl]-amine;
(1-ethyl-propyl)-[3-methoxymeth-
yl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;
-(1-ethyl-propyl)-2-methyl-5-nitro-'-(2,4,6-trimethyl-pyridin-3-yl)-pyrim-
idine-4,6-diamine;
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-
-4-yl]-diethyl-amine;
4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethylp-
henoxy)-pyridine;
butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydr- o-5H
-pyrrolo[2,3-d]pyrimidin-4-yl]-ethyl-amine;
4-(butyl-ethylamino)-2,5--
dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-o-
ne;
4-(1-ethylpropoxy)-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidine;
-butyl-N-ethyl-2,5-dimethyl-'-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diam-
ine;
(1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5--
b]pyridin-7-yl]-amine;
[2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo-
[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;
4-(1-ethyl-propyl)-6,3-dimeth-
yl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;
4-(1-ethyl-propyl)-6,3,3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-
,4-diamine;
6-(1-ethyl-propoxy)-2-methyl-4-(2,4,6-trimethyl-phenyl)-pyrimi-
dine-4,5-diamine;
[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-t-
rimethylphenyl)-amine;
6-(ethyl-propyl-amino)-2,7-dimethyl-9-(2,4,6-trimet-
hylphenyl)-7,9-dihydro-purin-8-one, and pharmaceutically acceptable
salts of the foregoing compounds.
10. The method of claim 1 wherein said compound is a compound of
formula II in which E and D are connected by a double bond, E is
--CR.sub.4, D is --CR.sub.10 or N, Y is N, and A is --CR.sub.7.
11. The method of claim 10 wherein said compound is selected from
the group consisting of:
butyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyr-
azolo[3,4-b]pyridin-4-yl]-ethylamine;
3,6-dimethyl-4-(tetrahydrofuran-3-yl-
oxy)-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridine
[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4,b]pyridin-4-yl]-(-
1-methoxymethylpropyl)-amine;
4-(1-methoxymethylpropoxy)-3,6-dimethyl-1-(2-
,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridine;
(1-ethylpropyl)-[3,5,6-t-
rimethyl-1-(2,4,6trimethylphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-amine;
4-(1-ethylpropoxy)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3--
b]pyridine;
4-(1-ethylpropoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7-
H-pyrrolo[2,3-b]pyridine;
4-(1-ethylpropoxy)-2,5-dimethyl-7-(2,6-dimethyl--
4-bromophenyl)-7H-pyrrolo[2,3-b]pyridine, and pharmaceutically
acceptable salts of the foregoing compounds.
12. The method of claim 1 wherein said compound is a compound of
formula II in which E and D are connected by a double bond, E is
--CR.sub.4, and D, Y and A are N.
13. The method of claim 12 wherein said compound is selected from
the group consisting of:
3-{(4-methyl-benzyl)-[3,6-dimethyl-1-(2,4,6-trimethy-
lphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-propan-1-ol;
diethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[-
3,4-d]pyrimidin-4-yl]-amine; 2-{butyl-[6-methyl-3-methylsulfanyl
-1-(2,4,6-trichlorophenyl)-1H-pyrazolo
[3,4-d]pyrimidin-4-yl]-amino}-etha- nol;
dibutyl-{6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yl}-amine;
butyl-ethyl-[6-methyl-3-methylsulfanyl-1--
(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
butyl-ethyl-[6-methyl-3-methylsulfonyl-1-(2,4,6-trichlorophenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yl]-amine;
butyl-cyclopropylmethyl-[6-methyl-3-methy-
lsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amin-
e;
di-1-propyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyr-
azolo[3,4-d]pyrimidin-4-yl]-amine;
diallyl-[6-methyl-3-methylsulfanyl-1-(2-
,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
butyl-ethyl-[6-chloro-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yl]-amine;
butyl-ethyl-[6-methoxy-3-methylsulfanyl-1-
-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
propyl-ethyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]py-
rimidin-4-yl]-amine;
4-(1-ethyl-propyl)-6-methyl-3-methylsulfanyl-1-(2,4,6-
-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine;
2-[3,6-dimethyl-1-(2,4,6-t-
rimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine]-butan-1-ol;
[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo-[3,4-d]pyrimidin-4-yl-
]-(1-methylpropyl)amine;
4-(1-methoxymethylpropoxy)-3,6-dimethyl-1-(2,4,6--
trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine, and pharmaceutically
acceptable salts of the foregoing compounds.
14. The method of claim 1 wherein said compound is a compound of
formula II in which E and D are connected by a double bond, E is
--CR.sub.4, D is --CR.sub.10, and Y and A are N.
15. The method of claim 14 wherein said compound is selected from
the group consisting of:
n-butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl-
)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;
di-n-propyl-[2,5-dimethyl-7-(2,4,-
6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;
ethyl-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]p-
yrimidin-4-yl]amine;
diethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyr-
rolo[2,3-d]pyrimidin-4-yl]amine;
n-butyl-ethyl-[2,5,6-trimethyl-7-(2,4,6-t-
rimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;
2-{N-n-butyl-N-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]p-
yrimidin-4-yl]amino}-ethanol;
4-(1-ethyl-propyl)-2,5,6-trimethyl-7-(2,4,6--
trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;
n-butyl-ethyl-[2,5-dimethyl--
7-(2,4-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;
2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidyl-4-yl]-(-
1-ethyl-propyl)amine;
2-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-py-
rrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;
2-(S)-[7-(4-bromo-2,6-dimethy-
lphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;
4-(1-ethyl-propoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[-
2,3-d]pyrimidine;
4-(1-methoxymethyl-propoxy)-2,5,6-trimethyl-7-(2,4,6-tri-
methylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;
4-(1-ethyl-butyl)-2,5,6-trimeth-
yl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo-[2,3-d]pyrimidine;
[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin--
4-yl]-(1-methoxymethyl-propyl)-amine;
2-[7-(2-bromo-4,6-dimethyl-phenyl)-2-
,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;
2-[7-(4-ethyl-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-butan-1-ol;
2-[7-(2-ethyl-4,6-dimethylphenyl)-2,5-dimethyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;
2-[7-(2-fluoromethyl-4,6-d-
imethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1--
ol, and pharmaceutically acceptable salts of the foregoing
compounds.
16. A method of treating stroke comprising administering to a
mammal in need of such treatment a therapeutically effective amount
of a compound of the formula 4or a pharmaceutically acceptable salt
thereof, wherein B is --NR.sub.1R.sub.2, --CR.sub.1R.sub.2R.sub.11,
--C(.dbd.CR.sub.1R.sub.1- 2)R.sub.2, --NHCR.sub.11R.sub.1R.sub.2,
--OCR.sub.11R.sub.1R.sub.2, --SCR.sub.11R.sub.1R.sub.2,
--CR.sub.11R.sub.2OR.sub.1, --CR.sub.11R.sub.2SR.sub.1,
--C(S)R.sub.2, --NHNR.sub.1R.sub.2, --CR.sub.2R.sub.11NHR, or
--C(O)R.sub.2; D is N or --CR.sub.10; R.sub.1 is hydrogen or
C.sub.1-C.sub.6 alkyl which is optionally substituted with one or
two substituents independently selected from hydroxy, cyano, nitro,
fluoro, chloro, bromo, iodo, CF.sub.3, C.sub.1-C.sub.4 alkoxy,
--O--CO--(C.sub.1-C.sub.4 alkyl), --O--CO--NH(C.sub.1-C.sub.4
alkyl), --O--CO--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
--NH(C.sub.1-C.sub.4 alkyl), --N(C.sub.1-C.sub.2
alkyl)(C.sub.1-C.sub.4 alkyl), --S(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4alkyl)CO(C.sub.1-C- .sub.4 alkyl),
--NHCO(C.sub.1-C.sub.4 alkyl), --CO.sub.2(C.sub.1-C.sub.4 alkyl),
--CONH(C.sub.1-C.sub.4 alkyl), --CON(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), (C.sub.1-C.sub.4 alkyl)sulfinyl,
(C.sub.1-C.sub.4 alkyl)sulfonyl, and (C.sub.1-C.sub.4
alkyl)sulfanyl, and wherein said C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy and the C.sub.1-C.sub.4 alkyl moieties in
the foregoing R.sub.1 groups optionally contain one double or
triple bond; R.sub.2 is C.sub.1-C.sub.6 alkyl, heteroaryl, aryl,
(heteroaryl)C.sub.1-C.sub.4 alkyl or (aryl)C.sub.1-C.sub.4 alkyl
wherein said aryl and the aryl moiety of said (aryl)C.sub.1-C.sub.4
alkyl are selected from the group consisting of phenyl and
naphthyl, and said heteroaryl and the heteroaryl moiety of said
(heteroaryl)C.sub.1-C.sub.4 alkyl is selected from thienyl,
benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl,
furanyl, benzofuranyl, benzothiazolyl, isothiazolyl,
benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, and
benzoxazolyl; or R.sup.2 is C.sub.3-C.sub.8 cycloalkyl or
(C.sub.3-C.sub.8 cycloalkyl)C.sub.1-C.sub.6 alkyl, wherein one or
two of the ring carbons of said cycloalkyl having at least 4 ring
members and the cycloalkyl moiety of said (C.sub.3-C.sub.8
cycloalkyl)C.sub.1-C.sub.6 alkyl having at least 4 ring members is
optionally replaced by an oxygen or sulfur atom or by --NR.sub.14
wherein R.sub.14 is hydrogen or C.sub.1-C.sub.4 alkyl; and wherein
each of the foregoing R.sub.2 groups is optionally substituted by
from one to three substituents independently selected from chloro,
fluoro and C.sub.1-C.sub.4 alkyl, or by one substituent selected
from bromo, iodo, cyano, nitro, C.sub.1-C.sub.6 alkoxy,
--O--CO--(C.sub.1-C.sub.4alky- l), --O--CO--N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), --CO.sub.2(C.sub.1-C.sub.4 alkyl),
(C.sub.1-C.sub.4 alkyl)sulfanyl, (C.sub.1-C.sub.4 alkyl)sulfinyl,
and (C.sub.1-C.sub.4 alkyl)sulfonyl, and wherein said
C.sub.1-C.sub.6 alkyl and the C.sub.1-C.sub.4 alkyl and
C.sub.1-C.sub.6 alkyl moieties of the foregoing R.sub.2 groups
optionally contain one carbon-carbon double or triple bond; or
R.sup.1 and R.sup.2 of said --NR.sub.1R.sub.2 and said
--CR.sub.1R.sub.2R.sub.11 are taken together to form a saturated 5
to 8 member ring, wherein said ring optionally contains one or two
carbon-carbon double bonds, and wherein one or two of the ring
carbons is optionally replaced by a heteroatom selected from O, S
and N; R.sub.3 is hydrogen, C.sub.1-C.sub.6 alkyl, fluoro, chloro,
bromo, iodo, hydroxy, amino, SH, --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl), --CH.sub.2OH,
--CH.sub.2OCH.sub.3, --O(C.sub.1-C.sub.4 alkyl), (C.sub.1-C.sub.4
alkyl)sulfanyl, (C.sub.1-C.sub.4 alkyl)sulfonyl, or
(C.sub.1-C.sub.4 alkyl)sulfinyl, wherein said C.sub.1-C.sub.6 alkyl
and the C.sub.1-C.sub.4 alkyl moieties of the foregoing R.sub.3
groups optionally contain one double or triple bond and are
optionally substituted by from one to three substituents
independently selected from hydroxy, amino, C.sub.1-C.sub.3 alkoxy,
--NH(C.sub.1-C.sub.2 alkyl), --N(C.sub.1-C.sub.2).sub.2,
--NHCOCH.sub.3, fluoro, chloro and C.sub.1-C.sub.3 thioalkyl;
R.sub.4 is hydrogen, C.sub.1-C.sub.6 alkyl, fluoro, chloro, bromo,
iodo, C.sub.1-C.sub.6 alkoxy, formyl, trifluoromethoxy,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2CF.sub.3, CF.sub.3, amino,
nitro, --NH(C.sub.1-C.sub.4 alkyl), --N(CH.sub.3).sub.2,
--NHCOCH.sub.3, --NHCONHCH.sub.3, (C.sub.1-C.sub.4 alkyl)sulfanyl,
(C.sub.1-C.sub.4 alkyl)sulfinyl, (C.sub.1-C.sub.4alkyl)sulfonyl,
cyano, hydroxy, --CO(C.sub.1-C.sub.4alkyl), --CHO, or
--CO.sub.2(C.sub.1-C.sub.4 alkyl), wherein said C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy and the C.sub.1-C.sub.4 alkyl
moieties of the foregoing R.sub.4 groups optionally contain one
double or triple bond and are optionally substituted with one
substituent selected from hydroxy, amino, --NHCOCH.sub.3,
--NH(C.sub.1-C.sub.2 alkyl), --N(C.sub.1-C.sub.2 alkyl).sub.2,
--CO.sub.2(C.sub.1-C.sub.4 alkyl), --CO(C.sub.1-C.sub.4 alkyl),
C.sub.1-C.sub.3 alkoxy, (C.sub.1-C.sub.3 alkyl)sulfanyl, fluoro,
chloro, cyano and nitro; R.sub.5 is phenyl, naphthyl, thienyl,
benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl,
imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl,
benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl,
benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl,
azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl,
morpholinyl, pyridinyl, tetrazolyl, or 3- to 8-membered cycloalkyl
or 9- to 12-membered bicycloalkyl, wherein said cycloalkyl and
bicycloalkyl optionally contain one or two of O, S or --N--G
wherein G is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkanoyl, phenyl or benzyl, wherein each of the above R.sub.5
groups is optionally substituted by from one to three substituents
independently selected from fluoro, chloro, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy and trifluoromethyl, or one substituent
selected from bromo, iodo, cyano, nitro, amino,
--NH(C.sub.1-C.sub.4 alkyl), --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), --CO.sub.2(C.sub.1-C.sub.4 alkyl),
--CO(C.sub.1-C.sub.4 alkyl), --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
--SO.sub.2NH.sub.2, --NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
--S(C.sub.1-C.sub.4 alkyl), and --SO.sub.2(C.sub.1-C.sub.4alkyl),
wherein said C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.6 alkyl
moieties of the foregoing R.sub.5 groups optionally contain one
double or triple bond and are optionally substituted by one or two
substituents independently selected from fluoro, chloro, hydroxy,
amino, methylamino, dimethylamino and acetyl; R.sub.10 is hydrogen,
C.sub.1-C.sub.6 alkyl, fluoro, chloro, bromo, iodo, C.sub.1-C.sub.6
alkoxy, formyl, amino, --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl), --SO
(C.sub.1-C.sub.4 alkyl), wherein n is 0, 1 or 2, cyano, carboxy, or
amido, wherein said C.sub.1-C.sub.6 alkyl and the C.sub.1-C.sub.4
alkyl moieties of the foregoing R.sub.10 groups are optionally
substituted by one of hydroxy, trifluoromethyl, amino, carboxy,
amido, --NHCO(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
--CO.sub.2(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 thioalkyl, fluoro, bromo, chloro, iodo, cyano or
nitro; and, R.sub.11 is hydrogen, hydroxy, fluoro, or methoxy.
Description
BACKGROUND OF THE INVENTION
1. The present invention relates to the treatment of certain
conditions using a compound of formula I or II, or a
pharmaceutically acceptable salt thereof, as defined below.
Specifically, the compounds of formulas I and II, and their
pharmaceutically acceptable salts, as defined below, exhibit
corticotropin-releasing factor (CRF) antagonist activity and are
useful in the treatment of cardiovascular or heart related diseases
such as hypertension, tachycardia, and congestive heart failure,
stroke, osteoporosis, premature birth, psychosocial dwarfism,
stress-induced fever, ulcer, diarrhea, post-operative ileus, and
colonic hypersensitivity associated with psychopathological
disturbance and stress.
2. The compounds of formulas I and II, their pharmaceutically
acceptable salts, and methods of preparing such compounds and salts
are referred to in copending PCT international patent application
numbers PCT/IB95/00373 (filed May 18, 1995) and PCT/IB95/00439
(filed Jun. 6, 1995), both of which designate the United States,
and in copending U.S. patent applications Ser. Nos. 08/448,539
(filed Jun. 14, 1995) and 08/481,413 (filed Jun. 15, 1995). PCT
international patent application numbers PCT/IB95/00373 and
PCT/IB95/00439, and U.S. patent application Ser. Nos. 08/448,539
and 08/481,413, referred to above, are incorporated herein by
reference in their entirety.
3. The foregoing PCT international patent applications and United
States patent applications refer to the use of the compounds of
formulas I and II in the treatment of illnesses induced or
facilitated by corticotropin releasing factor and in the treatment
of anxiety, depression, fatigue syndrome, gastrointestinal
diseases, headache, pain, cancer, immune dysfunction, hemorrhagic
stress, drug addiction, drug and alcohol withdrawal symptoms,
fertility problems, stress-induced psychotic episodes,
neurodegenerative diseases such as Alzheimer's disease; irritable
bowel syndrome including Crohn's disease, spastic colon and
irritable colon; eating disorders such as anorexia nervosa; and
inflammatory disorders such as arthritis, asthma and allergies.
4. Other CRF antagonists that can be used to treat the disorders
recited in the method of this invention are referred to in
copending PCT international patent application number
PCT/IB95/00318(filed May 4, 1995), which designates the United
States, and in copending U.S. patent applications Ser. Nos.
08/448,534 (filed Jun. 14, 1995) and 08/448,529 (filed Jun. 14,
1995). PCT international patent application number PCT/IB95/00318,
and U.S. patent application Ser. Nos. 08/448,534 and 08/448,529,
referred to above, are incorporated herein by reference in their
entirety.
5. CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and
5,063,245 referring to peptides and pyrazolinones, respectively.
The importance of CRF antagonists is set out in the literature,
e.g., as discussed in U.S. Pat. No. 5,063,245, which is
incorporated herein by reference. A recent outline of the different
activities possessed by CRF antagonists is found in M. J. Owens et
al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991), also
incorporated herein by reference.
SUMMARY OF THE INVENTION
6. This invention relates to a method of treating a disorder
selected from cardiovascular or heart related diseases such as
hypertension, tachycardia, and congestive heart failure,
osteoporosis, premature birth, psychosocial dwarfism,
stress-induced fever, ulcer, diarrhea, post-operative ileus, and
colonic hypersensitivity associated with psychopathological
disturbance and stress, by administering to a mammal, including a
human, in need of such treatment a therapeutically effective amount
of a compound of the formula 2
7. or a pharmaceutically acceptable salt thereof, wherein
8. the dashed line represents an optional double bond;
9. A is --CR.sub.7 or N;
10. B is --NR.sub.1R.sub.2, --CR.sub.1R.sub.2R.sub.11,
--C(.dbd.CR.sub.1R.sub.12)R.sub.2,
--NHCR.sub.1R.sub.11R.sub.1R.sub.2, --OCR.sub.11R.sub.1R.sub.2,
--SCR.sub.11R.sub.1R.sub.2, --CR.sub.11R.sub.2OR.sub.1,
--CR.sub.11R.sub.2SR.sub.1, --C(S)R.sub.2, --NHNR.sub.1R.sub.2,
--CR.sub.2R.sub.11NHR.sub.1 or --C(O)R.sub.2;
11. D is: (i) N or --CR.sub.10 when a double bond connects E and D
and E is --CR.sub.4; (ii) --CR.sub.10 when a double bond connects E
and D and E is N; (iii) --CR.sub.8R.sub.9, --CHR.sub.10, --C.dbd.O,
--C.dbd.S, --C.dbd.NH, or --C.dbd.NCH.sub.3 when a single bond
connects E and D;
12. E is --CR.sub.4or N when a double bond connects E and D, and E
is --CR.sub.4R.sub.6or --NR.sub.6 when a single bond connects E and
D;
13. Y is N or --CH;
14. Z is NH, O, S, --N(C.sub.1-C.sub.2 alkyl) or
--CR.sub.12R.sub.13, wherein R.sub.12 and R.sub.13 are each,
independently, hydrogen, trifluoromethyl or methyl, or one of
R.sub.12 and R.sub.13 is cyano and the other is hydrogen or
methyl;
15. R.sub.1 is hydrogen or C.sub.1-C.sub.6 alkyl which is
optionally substituted with one or two substituents independently
selected from hydroxy, cyano, nitro, fluoro, chloro, bromo, iodo,
CF.sub.3, C.sub.1-C.sub.4 alkoxy, --O--CO--(C.sub.1-C.sub.4 alkyl),
--O--CO--NH(C.sub.1-C.sub.4 alkyl), --O--CO--N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.2 alkyl)(C.sub.1-C.sub.4 alkyl),
--S(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4alkyl)CO(C.sub.1-C.sub.4 alkyl),
--NHCO(C.sub.1-C.sub.4 alkyl), --CO.sub.2(C.sub.1-C.sub.4 alkyl),
--CONH(C.sub.1-C.sub.4 alkyl), --CON(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), (C.sub.1-C.sub.4 alkyl)sulfinyl,
(C.sub.1-C.sub.4 alkyl)sulfonyl, and (C.sub.1-C.sub.4
alkyl)sulfanyl, and wherein said C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy and the C.sub.1-C.sub.4 alkyl moieties in
the foregoing R.sub.1 groups optionally contain one double or
triple bond;
16. R.sub.2 is C.sub.1-C.sub.6 alkyl, heteroaryl, aryl,
(heteroaryl)C.sub.1-C.sub.4 alkyl or (aryl)C.sub.1-C.sub.4 alkyl
wherein said aryl and the aryl moiety of said (aryl)C.sub.1-C.sub.4
alkyl are selected from the group consisting of phenyl and
naphthyl, and said heteroaryl and the heteroaryl moiety of said
(heteroaryl)C.sub.1-C.sub.4 alkyl is selected from the group
consisting of thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl,
pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl,
isothiazolyl, thiazolyl, benzisothiazolyl, benzisoxazolyl,
benzimidazolyl, indolyl, and benzoxazolyl; or R.sup.2 is
C.sub.3-C.sub.8 cycloalkyl or (C.sub.3-C.sub.8
cycloalkyl)C.sub.1-C.sub.6 alkyl, wherein one or two of the ring
carbons of said cycloalkyl having at least 4 ring members and the
cycloalkyl moiety of said (C.sub.3-C.sub.8
cycloalkyl)C.sub.1-C.sub.6 alkyl having at least 4 ring members is
optionally replaced by an oxygen or sulfur atom or by --NR.sub.14
wherein R.sub.14 is hydrogen or C.sub.1-C.sub.4 alkyl; and wherein
each of the foregoing R.sub.2 groups is optionally substituted by
from one to three substituents independently selected from chloro,
fluoro and C.sub.1-C.sub.4 alkyl, or by one substituent selected
from bromo, iodo, cyano, nitro, C.sub.1-C.sub.6 alkoxy,
--O--CO--(C.sub.1-C.sub.4 alkyl), --O--CO--N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), --CO.sub.2(C.sub.1-C.sub.4 alkyl),
(C.sub.1-C.sub.4 alkyl)sulfanyl, (C.sub.1-C.sub.4 alkyl)sulfinyl,
and (C.sub.1-C.sub.4 alkyl)sulfonyl, and wherein said
C.sub.1-C.sub.6 alkyl and the C.sub.1-C.sub.4 alkyl and
C.sub.1-C.sub.6 alkyl moieties of the foregoing R.sub.2 groups
optionally contain one carbon-carbon double or triple bond;
17. or R.sup.1 and R.sup.2 of said --NR.sub.1R.sub.2 and said
--CR.sub.1R.sub.2R.sub.11 are taken together to form a saturated 5
to 8 member ring, wherein said ring optionally contains one or two
carbon-carbon double bonds, and wherein one or two of the ring
carbons is optionally replaced by a heteroatom selected from O, S
and N;
18. R.sub.3 is hydrogen, C.sub.1-C.sub.6 alkyl, fluoro, chloro,
bromo, iodo, hydroxy, amino, SH, --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl), --CH.sub.2OH,
--CH.sub.2OCH.sub.3, --O(C.sub.1-C.sub.4 alkyl), (C.sub.1-C.sub.4
alkyl)sulfanyl, (C.sub.1-C.sub.4 alkyl)sulfonyl, or
(C.sub.1-C.sub.4 alkyl)sulfinyl, wherein said C.sub.1-C.sub.6 alkyl
and the C.sub.1-C.sub.4 alkyl moieties of the foregoing R.sub.3
groups optionally contain one double or triple bond and are
optionally substituted by from one to three substituents
independently selected from hydroxy, amino, C.sub.1-C.sub.3 alkoxy,
--NH(C.sub.1-C.sub.2 alkyl), --N(C.sub.1-C.sub.2).sub.2,
--NHCOCH.sub.3, fluoro, chloro and C.sub.1-C.sub.3 thioalkyl;
19. R.sub.4 is hydrogen, C.sub.1-C.sub.6 alkyl, fluoro, chloro,
bromo, iodo, C.sub.1-C.sub.6 alkoxy, formyl, trifluoromethoxy,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2OCH.s- ub.3, --CH.sub.2CF.sub.3, CF.sub.3, amino,
nitro, --NH(C.sub.1-C.sub.4 alkyl), --N(CH.sub.3).sub.2,
--NHCOCH.sub.3, --NHCONHCH.sub.3, (C.sub.1-C.sub.4 alkyl)sulfanyl,
(C.sub.1-C.sub.4 alkyl)sulfinyl, (C.sub.1-C.sub.4 alkyl)sulfonyl,
cyano, hydroxy, --CO(C.sub.1-C.sub.4 alkyl), --CHO, or
--CO.sub.2(C.sub.1-C.sub.4 alkyl), wherein said C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy and the C.sub.1-C.sub.4 alkyl
moieties of the foregoing R.sub.4 groups optionally contain one
double or triple bond and are optionally substituted with one
substituent selected from hydroxy, amino, --NHCOCH.sub.3,
--NH(C.sub.1-C.sub.2 alkyl), --N(C.sub.1-C.sub.2 alkyl).sub.2,
--CO.sub.2(C.sub.1-C.sub.4 alkyl), --CO(C.sub.1-C.sub.4 alkyl),
C.sub.1-C.sub.3 alkoxy, (C.sub.1-C.sub.3 alkyl)sulfanyl, fluoro,
chloro, cyano and nitro;
20. R.sub.5 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl,
quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl,
benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl,
thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl,
pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl,
pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or
3- to 8-membered cycloalkyl or 9- to 12-membered bicycloalkyl,
wherein said cycloalkyl and bicycloalkyl optionally contain one or
two of O, S or --N--G wherein G is hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkanoyl, phenyl or benzyl, wherein each of the
above R.sub.5 groups is optionally substituted by from one to three
substituents independently selected from fluoro, chloro,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and trifluoromethyl,
or one substituent selected from bromo, iodo, cyano, nitro, amino,
--NH(C.sub.1-C.sub.4 alkyl), --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), --CO.sub.2(C.sub.1-C.sub.4 alkyl),
--CO(C.sub.1-C.sub.4 alkyl), --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
--SO.sub.2NH.sub.2, --NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
--S(C.sub.1-C.sub.4alkyl), and --SO.sub.2(C.sub.1-C.sub.4alkyl),
wherein said C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.6 alkyl
moieties of the foregoing R.sub.5 groups optionally contain one
double or triple bond and are optionally substituted by one or two
substituents independently selected from fluoro, chloro, hydroxy,
amino, methylamino, dimethylamino and acetyl;
21. R.sub.6 is hydrogen or C.sub.1-C.sub.6 alkyl, wherein said
C.sub.1-C.sub.6 alkyl is optionally substituted by a single
hydroxy, methoxy, ethoxy or fluoro group;
22. R.sub.7 is hydrogen, C.sub.1-C.sub.4 alkyl, fluoro, chloro,
bromo, iodo, cyano, hydroxy, C.sub.1-C.sub.4 alkoxy,
--CO(C.sub.1-C.sub.4 alkyl), --CO.sub.2(C.sub.1-C.sub.4 alkyl),
--OCF.sub.3, CF.sub.3, --CH.sub.2OH, --CH.sub.2OCH.sub.3 or
--CH.sub.2OCH.sub.2CH.sub.3;
23. R.sub.8 and R.sub.9 are each, independently, hydrogen, hydroxy,
methyl, ethyl, methoxy, or ethoxy;
24. or R.sub.8 and R.sub.9 together form an oxo (.dbd.O) group;
25. R.sub.10 is hydrogen, C.sub.1-C.sub.6 alkyl, fluoro, chloro,
bromo, iodo, C.sub.1-C.sub.6 alkoxy, formyl, amino,
--NH(C.sub.1-C.sub.4 alkyl), --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.2 alkyl), --SO.sub.n(C.sub.1-C.sub.4 alkyl),
wherein n is 0, 1 or 2, cyano, carboxy, or amido, wherein said
C.sub.1-C.sub.6 alkyl and the C.sub.1-C.sub.4 alkyl moieties of the
foregoing R.sub.10 groups are optionally substituted by one of
hydroxy, trifluoromethyl, amino, carboxy, amido,
--NHCO(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.2 alkyl),
--CO.sub.2(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 thioalkyl, fluoro, bromo, chloro, iodo, cyano or
nitro; and,
26. R.sub.11 is hydrogen, hydroxy, fluoro, or methoxy.
27. The term "alkyl", as used herein, unless otherwise indicated,
includes saturated monovalent hydrocarbon radicals having straight
or branched moieties or combinations thereof.
28. The term "alkoxy", as used herein, unless otherwise indicated,
includes O-alkyl groups wherein "alkyl" is defined above.
29. The term "treatment", as used herein, unless otherwise
indicated, includes the treatment, prevention, or inhibition of any
disorder enumerated within the method of the invention.
30. More specific compounds for use in the method of the invention
include compounds of formula I or II, or pharmaceutically
acceptable salts thereof, wherein: B is --NR.sub.1R.sub.2,
--NHCHR.sub.1R.sub.2, --CR.sub.1R.sub.2R.sub.11,
--SCHR.sub.1R.sub.2 or --OCHR.sub.1R.sub.2; R.sub.1 is
C.sub.1-C.sub.6 alkyl which is optionally substituted with a single
hydroxy, fluoro or C.sub.1-C.sub.2 alkoxy group and optionally
contains one carbon-carbon double or triple bond; R.sub.2 is benzyl
or C.sub.1-C.sub.6 alkyl which optionally contains one
carbon-carbon double or triple bond, wherein said C.sub.1-C.sub.6
alkyl and the phenyl moiety of said benzyl are optionally
substituted with fluoro, C.sub.1-C.sub.2 alkyl, or C.sub.1-C.sub.2
alkoxy; and R.sub.1 is hydrogen or fluoro.
31. Other more specific compounds for use in the method of the
invention include compounds of formula I or II, or pharmaceutically
acceptable salts thereof, wherein R.sub.2 is (aryl)C.sub.1-C.sub.4
alkyl or (heteroaryl)C.sub.1-C.sub.4 alkyl in which said aryl or
heteroaryl moiety is phenyl, thienyl, benzofuranyl, furanyl,
benzothienyl, thiazolyl, pyridyl or benzothiazolyl.
32. Other more specific compounds for use in the method of the
invention include compounds of formula I or II, or pharmaceutically
acceptable salts thereof, wherein B is --NR.sub.1R.sub.2 or
--CHR.sub.1R.sub.2in which R.sub.1 and R.sub.2 are taken together
with N or CH to form a 5- or 6-membered ring optionally having
sulfur, oxygen, or one more nitrogen in said ring, such as a
pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,
isoxazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrazinyl or
pyrimidyl group.
33. Other more specific compounds for use in the method of the
invention include compounds of formula I or II, or pharmaceutically
acceptable salts thereof, wherein B is --NHCHR.sub.1R.sub.2 or
--OCHR.sub.1R.sub.2, wherein the CHR.sub.1R.sub.2 moiety is a 5- or
6-membered ring which optionally contains one oxygen or sulfur,
such as a tetrahydrofuranyl, tetrahydrothiafuranyl or cyclopentanyl
group.
34. Other more specific compounds for use in the method of the
invention include compounds of formula I or II, or pharmaceutically
acceptable salts thereof, wherein B is tetrahydrofuranyl,
tetrahydrothienyl or thiazolidinyl.
35. Other more specific compounds for use in the method of the
invention include compounds of formula I or II, or pharmaceutically
acceptable salts thereof, wherein R.sub.3 is methyl, chloro, or
methoxy; R.sub.4 is methyl, --CH.sub.2OH, cyano, trifluoromethoxy,
methoxy, trifluoromethyl, chloro, --CO.sub.2CH.sub.3,
--CH.sub.2OCH.sub.3, --CH.sub.2Cl, --CH.sub.2F, amino, nitro,
hydrogen, methylsulfinyl, methylsulfanyl, methylsulfonyl, or ethyl;
and R.sub.5 is phenyl or pyridyl wherein said phenyl or pyridyl is
substituted by one substituent independently selected from fluoro,
chloro, bromo, iodo, C.sub.1-C.sub.4 alkoxy, trifluoromethyl,
C.sub.1-C.sub.3 hydroxyalkyl, hydroxy, formyl,
--CO.sub.2(C.sub.1-C.sub.2alkyl), (amino)C.sub.1-C.sub.2 alkyl,
--CO(C.sub.1-C.sub.4alkyl), and C.sub.1-C.sub.6alkyl, wherein said
C.sub.1-C.sub.6 alkyl and said C.sub.1-C.sub.4 alkyl are optionally
substituted by a single hydroxy, or fluoro group and optionally
contains one carbon-carbon double or triple bond.
36. For use in the method of the invention, specific compounds of
formulas I and II include:
37.
4-(1-ethyl-propoxy)-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine-
;
38.
2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyri-
dine;
39.
2-(4-ethyl-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyri-
dine;
40.
3-ethyl-4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyrid-
ine;
41.
2-(2,6-dimethyl-4-propyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyr-
idine;
42.
4-(1-ethyl-propoxy)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-py-
ridine;
43.
2-(4-ethoxy-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyr-
idine;
44.
2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyr-
idine;
45.
4-(1-methoxymethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-p-
yridine;
46.
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-diethyl-amine;
47.
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propyl-a-
mine;
48.
[2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl](1-ethyl-prop-
yl)-amine;
49.
butyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-am-
ine;
50.
4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-py-
ridine;
51.
butyl-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-et-
hyl-amine;
52.
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic
acid methyl ester;
53.
[3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-pyridin-4-yl]-ethyl-p-
ropyl-amine;
54.
[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin--
3-yl]-methanol;
55.
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-pr-
opyl-amine;
56.
1-(ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridin-
-4-yl]-amine;
57.
4-(1-ethyl-propyl)-6-methyl-3-nitro-2-(2,4,6-trimethyl-phenyl)-pyridin-
e-2,4-diamine;
58.
4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-d-
iamine;
59.
4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4--
triamine;
60.
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-(2,2,2-t-
rifluoro-ethyl)-amine;
61.
[3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)pyridin-4-yl]-(1-e-
thyl-propyl)-amine;
62.
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propy-
l)-amine;
63.
(1-ethyl-propyl)-[2-methyl-5-nitro-6-(2,4,6-trimethyl-pyridin-3-yloxy)-
-pyrimidin-4-yl]-amine;
64.
(1-ethyl-propyl)-[3-methoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-
-pyridin-4-yl]-amine;
65.
-(1-ethyl-propyl)-2-methyl-5-nitro-'-(2,4,6-trimethyl-pyridin-3-yl)-py-
rimidine-4,6-diamine;
66.
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-diethyl--
amine;
67.
4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyridine;
68.
butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2-
,3-d]pyrimidin-4-yl]-ethyl-amine;
69.
4-(butyl-ethylamino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydr-
o-pyrrolo[2,3-d]pyrimidin-6-one;
70.
4-(1-ethylpropoxy)-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidine;
71.
-butyl-N-ethyl-2,5-dimethyl-'-(2,4,6-trimethylphenyl)-pyrimidine-4,6-d-
iamine;
72.
(1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b-
]pyridin-7-yl]-amine;
73.
[2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl-
]-(1-ethyl-propyl)-amine;
74.
4-(1-ethyl-propyl)-6,3-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-
,4-diamine;
75.
4-(1-ethyl-propyl)-6,3,3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-
e-3,4-diamine;
76.
6-(1-ethyl-propoxy)-2-methyl-4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-
-diamine;
77.
[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethylphenyl-
)-amine; and
78.
6-(ethyl-propyl-amino)-2,7-dimethyl-9-(2,4,6-trimethylphenyl)-7,9-dihy-
dro-purin-8-one.
79. For use in the method of the invention, specific compounds of
formula II wherein E and D are connected by a double bond, E is
--CR.sub.4, D is --CR.sub.10 or N, Y is N, and A is --CR.sub.7,
include:
80.
butyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridi-
n-4-yl]-ethylamine;
81.
3,6-dimethyl-4-(tetrahydrofuran-3-yloxy)-1-(2,4,6-trimethylphenyl)-1H--
pyrazo[3,4-b]pyridine;
82.
[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4,b]pyridin-4-yl-
]-(1-methoxymethylpropyl)-amine;
83.
4-(1-methoxymethylpropoxy)-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-p-
yrazo[3,4-b]pyridine;
84.
(1-ethylpropyl)-[3,5,6-trimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo-
[3,4-b]pyridin-4-yl]-amine;
85.
4-(1-ethylpropoxy)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2-
,3-b]pyridine;
86.
4-(1-ethylpropoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrol-
o[2,3-b]pyridine; and
87.
4-(1-ethylpropoxy)-2,5-dimethyl-7-(2,6-dimethyl-4-bromophenyl)-7H-pyrr-
olo[2,3-b]pyridine.
88. For use in the method of the invention, specific compounds of
formula II wherein E and D are connected by a double bond, E is
--CR.sub.4, and D, Y and A are N, include:
89.
3{(4-methyl-benzyl)-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazol-
o[3,4-d]pyrimidin-4-yl]-amino}-propan-1-ol;
90.
diethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazo-
lo[3,4-d]pyrimidin-4-yl]-amine;
91.
2-{butyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yl]-amino}-ethanol;
92.
dibutyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazo-
lo[3,4-d]pyrimidin-4-yl}-amine;
93.
butyl-ethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-py-
razolo[3,4-d]pyrimidin-4-yl]-amine;
94.
butyl-ethyl-[6-methyl-3-methylsulfonyl-1-(2,4,6-trichlorophenyl)-1H-py-
razolo[3,4-d]pyrimidin-4-yl]-amine;
95.
butyl-cyclopropylmethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorop-
henyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
96.
di-1-propyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-py-
razolo[3,4-d]pyrimidin-4-yl]-amine;
97.
diallyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazo-
lo[3,4-d]pyrimidin-4-yl]-amine;
98.
butyl-ethyl-[6-chloro-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-py-
razolo[3,4-d]pyrimidin-4-yl]-amine;
99.
butyl-ethyl-[6-methoxy-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-p-
yrazolo[3,4-d]pyrimidin-4-yl]-amine;
100.
propyl-ethyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yl]-amine;
101.
4-(1-ethyl-propyl)-6-methyl-3-methylsulfanyl-1-(2,4,6-trimethylphenyl-
)-1H-pyrazolo[3,4-d]pyrimidine;
102.
2-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4d-]pyrimidin-
-4-ylamine]-butan-1-ol;
103.
[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo-[3,4-d]pyrimidin--
4-yl]-(1-methylpropyl)amine; and
104.
4-(1-methoxymethylpropoxy)-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H--
pyrazolo[3,4-d]pyrimidine.
105. For use in the method of the invention, specific compounds of
formula II wherein E and D are connected by a double bond, E is
--CR.sub.4, D is --CR.sub.10, and Y and A are N, include:
106.
n-butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3--
d]pyrimidin-4-yl]amine;
107.
di-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl]amine;
108.
ethyl-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-
-d]pyrimidin-4-yl]amine;
109.
diethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrim-
idin-4-yl]amine;
110.
n-butyl-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2-
,3-d]pyrimidin-4-yl]amine;
111.
2-{N-n-butyl-N-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-
-d]pyrimidin-4-yl]amino}-ethanol;
112.
4-(1-ethyl-propyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrro-
lo[2,3-d]pyrimidine;
113.
n-butyl-ethyl-[2,5-dimethyl-7-(2,4-dimethylphenyl)-7H-pyrrolo[2,3-d]p-
yrimidin-4-yl]amine;
114.
2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidyl-4-y-
l]-(1-ethyl-propyl)amine;
115.
2-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrim-
idin-4-ylamino]-butan-1-ol;
116.
2-(S)-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]p-
yrimidin-4-ylamino]-butan-1-ol;
117.
4-(1-ethyl-propoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrr-
olo[2,3-d]pyrimidine;
118.
4-(1-methoxymethyl-propoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-
-7H-pyrrolo[2,3-d]pyrimidine;
119.
4-(1-ethyl-butyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrol-
o-[2,3-d]pyrimidine;
120.
[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimi-
din-4-yl]-(1-methoxymethyl-propyl)-amine;
121.
2-[7-(2-bromo-4,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyri-
midin-4-ylamino]-butan-1-ol;
122.
2-[7-(4-ethyl-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyri-
midin-4-ylamino]-butan-1-ol;
123.
2-[7-(2-ethyl-4,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrim-
idin-4-ylamino]-butan-1-ol; and
124.
2-[7-(2-fluoromethyl-4,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3--
d]pyrimidin-4-ylamino]-butan-1-ol.
125. The method of the invention further comprises the treatment of
stroke by administering to a mammal, including a human, in need of
such treatment a therapeutically effective amount of a compound of
formula II, referred to above, or a pharmaceutically acceptable
salt thereof, wherein a double bond connects E and D, D is
--CR.sub.10 or N, E is --CR.sub.4, and Y and A are N. Compounds of
formula III, provided below, are the compounds of formula II
wherein a double bond connects E and D, D is --CR.sub.10 or N, E is
--CR.sub.4, and Y and A are N. The compounds of formula III are
provided below in the claims and are directed to the treatment of
stroke.
126. Whenever reference is made herein to 3- to 8-membered
cycloalkyl or 9- to 12-membered bicycloalkyl optionally containing
one or two of O, S, or --N--G, it is understood that the oxygen and
sulfur atoms are not adjacent to each other in the cycloalkyl or
bicycloalkyl ring system. The three membered cycloalkyl optionally
contains just one of O, S, or --N--G. An example of a six-membered
cycloalkyl having O and NH is morpholinyl.
127. Whenever R.sub.2 or R.sub.5 is a heterocyclic group, the
attachment of the group is through a carbon atom.
128. In the compounds of formulas I and II, referred to above,
certain aminal or acetal moieties may not be sufficiently stable
for use in the method of the invention. Such unstable compounds may
include, for example, a compound of formula I or II wherein B is
--NR.sub.1R.sub.2 and R.sub.1 is --CH(OH)CH.sub.3. Such unstable
compounds will be apparent to those skilled in the art and do not
form part of the invention.
129. Formulas I and II, referred to above, are intended to include
all stereoisomers (e.g., all geometric and optical isomers) as well
as racemates of all individual compounds within the depicted
genus.
DETAILED DESCRIPTION OF THE INVENTION
130. The compounds of formulas I and II, and their pharmaceutically
acceptable salts, are readily prepared. The compounds of formula II
wherein A, D and Y are N, a double bond connects E and D, and E is
--CR.sub.4, are prepared by one or more of the synthetic methods
referred to in U.S. patent application Ser. No. 08/481,13, referred
to above. The compounds of formula II wherein A and Y are N, a
double bond connects E and D, E is --CR.sub.4, and D is
--CF.sub.10, are prepared by one or more of the synthetic methods
referred to in U.S. patent application Ser. No. 08/448,539,
referred to above. The compounds of formula II wherein A is
--CR.sub.7, a double bond connects E and D, E is --CR.sub.4, D is N
or --CF.sub.10, and Y is N, are prepared by one or more of the
synthetic methods referred to in PCT international application
number PCT/IB95/00373, referred to above. The remaining compounds
of formula II and the compounds of formula I are prepared by one or
more of the synthetic methods referred to in PCT international
application number PCT/IB95/00439, referred to above.
131. Pharmaceutically acceptable salts of the compounds of formulas
I and II include salts of acidic or basic groups. For example,
pharmaceutically acceptable salts include sodium, calcium and
potassium salts of acidic groups, such as when the R.sub.10
substituent is carboxy. Such salts are generally prepared by
combining a compound of formula I or II with one molar equivalent
of NaOH or KOH in a suitable solvent. Pharmaceutically acceptable
acid addition salts of basic groups, such as amino groups, are
formed by reacting the base form of a compound of formula I or II
with an appropriate acid. Pharmaceutically acceptable salts of
basic groups include hydrochloride, hydrobromide, sulfate, hydrogen
sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate,
acetate, succinate, citrate, tartrate, lactate, mandelate,
methanesulfonate (mesylate) and p-toluenesulfonate (tosylate)
salts. When the salt is of a monobasic acid (e.g., the
hydrochloride, the hydrobromide, the p-toluenesulfonate, the
acetate), at least one molar equivalent and usually a molar excess
of the acid is employed. However, when such salts as the sulfate,
the hemisuccinate, the hydrogen phosphate or the phosphate are
desired, the appropriate and exact chemical equivalents of acid
will generally be used. The free base and the acid are usually
combined in a co-solvent from which the desired salt precipitates,
or can be otherwise isolated by concentration or addition of a
non-solvent.
132. In the method of the invention, the compounds of formulas I
and II, and their pharmaceutically acceptable salts, can be
administered alone or in combination with pharmaceutically
acceptable carriers, in either single or multiple doses. Suitable
pharmaceutical carriers include inert solid diluents or fillers,
sterile aqueous solution and various organic solvents. The
pharmaceutical compositions formed by combining the active
compounds and the pharmaceutically acceptable carriers are then
readily administered in a variety of dosage forms such as tablets,
powders, lozenges, syrups, injectable solutions and the like. These
pharmaceutical compositions can, if desired, contain additional
ingredients such as flavorings, binders, excipients and the like.
Thus, for purposes of oral administration, tablets containing
various excipients such as sodium citrate, calcium carbonate and
calcium phosphate may be employed along with various disintegrants
such as starch, alginic acid and certain complex silicates,
together with binding agents such as polyvinylpyrrolidone, sucrose,
gelatin and acacia. Additionally, lubricating agents such as
magnesium stearate, sodium lauryl sulfate and talc are often useful
for tabletting purposes. Solid compositions of a similar type can
also be employed as fillers in soft and hard filled gelatin
capsules. Preferred materials for this include lactose or milk
sugar and high molecular weight polyethylene glycols. When aqueous
suspensions or elixirs are desired for oral administration, the
essential active ingredient therein may be combined with various
sweetening or flavoring agents, coloring matter or dyes and, if
desired, emulsifying or suspending agents, together with diluents
such as water, ethanol, propylene glycol, glycerin and combinations
thereof. Oral administration is generally preferred. However, if
the patient is unable to swallow, or oral absorption is otherwise
impaired, another route of administration such as suppositories,
parenteral (i.m., i.v.), or topical administration will be
appropriate.
133. For parenteral administration, solutions of the active
compound in sesame or peanut oil, aqueous propylene glycol, or in
sterile aqueous solution can be employed. Such aqueous solutions
should be suitably buffered if necessary and the liquid diluent
first rendered isotonic with sufficient saline or glucose. These
particular aqueous solutions are especially suitable for
intravenous, intramuscular, subcutaneous and intraperitoneal
administration. The sterile aqueous media employed are all readily
available by standard techniques known to those skilled in the
art.
134. In the method of the invention, the effective dosage for the
compounds of formulas I and II, and their pharmaceutically
acceptable salts, depends on the intended route of administration
and other factors such as age and weight of the patient, as
generally known to a physician. The dosage also depends on the
illness to be treated. In general, the daily dosage will generally
range from about 0.1 to 50 mg/kg of the body weight of the patient
to be treated. The daily dosage may be given in a single dose or up
to three divided doses. In the prevention of premature birth, the
dosage should be administered daily after high levels of
corticotropin-releasing hormone have been detected early in
pregnancy and then discontinued just prior to the end of the term
for normal pregnancy.
135. The methods for testing the compounds of formulas I and II,
and their pharmaceutically acceptable salts, for CRF antagonist
activity are as described in Endocrinology, 116, 1653-1659 (1985)
and Peptides 10, 179-188 (1989) which determine the binding
affinity of a test compound for a CRF receptor. The binding
affinities for the active compounds, expressed as IC.sub.50 values,
generally range from about 0.2 nanomolar to about 10
micromolar.
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