Bicyclic compounds

Details Bicyclic compounds Bicyclic compounds

1999-03-11

2001-06-19

Huang, Evelyn Mei (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S252100, C514S256000, C514S275000, C544S333000, C544S405000, C546S119000, C546S120000

Reexamination Certificate

active

06248753

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to pyrazolopyridines and pyrrolopyridines, pharmaceutical compositions containing them, and methods of administering them to subjects in need of their corticotropin-releasing factor (CRF) antagonist activity.
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 referred to 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. Based on the research described in these and other references, CRF antagonists are believed to be effective in the treatment of a wide range of stress-related illnesses, such as depression, anxiety, headache, irritable bowel syndrome, inflammatory diseases, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction and infertility.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula
and the pharmaceutically acceptable acid addition salts thereof, wherein
A is N or —CR
6
;
B is —NR
1
R
2
, —CR
1
R
2
R
11
, —C(═CR
2
R
12
)R
1
, —NHCHR
1
R
2
, —OCHR
1
R
2
, —SCHR,R
2
, —CHR
2
OR
12
, —CHR
2
SR
12
, —C(S)R, or —C(O)R
1
;
R
1
is C
1
-C
6
alkyl which may optionally be substituted with one or two substituents independently selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, C
1
-C
4
alkoxy, —O—CO—(C
1
-C
4
alkyl), —O—CO—NH(C
1
-C
4
alkyl), —O—CO—N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), —NH(C
1
-C
4
alkyl), —N(C
1
-C
2
alkyl)(C
1
-C
4
alkyl), —S(C
1
-C
4
alkyl), —N(C
1
-C
4
alkyl)CO(C
1
-C
4
alkyl), —NHCO(C
1
-C
4
alkyl), —COO(C
1
-C
4
alkyl), —CONH(C
1
-C
4
alkyl), —CON(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), CN, NO
2
, —SO(C
1
-C
4
alkyl), —SO
2
(C
1
-C
4
alkyl), and wherein any of the foregoing C
1
-C
4
alkyl and C
1
-C
6
alkyl groups may optionally contain one carbon-carbon double or triple bond;
R
2
is C
1
-C
12
alkyl, aryl, —(C
1
-C
4
alkylene)aryl wherein said aryl is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, oxazolyl, or benzoxazolyl; or 3- to 8-membered cycloalkyl or —(C
1
-C
6
alkylene)cycloalkyl, wherein one or two of the ring carbons of said cycloalkyl having at least 4 ring members and the cycloalkyl moiety of said —(C
1
-C
6
alkylene)cycloalkyl having at least 4 ring members may optionally be replaced by an oxygen or sulfur atom or by N—Z wherein Z is hydrogen; or C
1
-C
4
alkyl, and wherein each of said groups R
2
may optionally be substituted with from one to three substituents independently selected from chloro, fluoro, and C
1
-C
4
alkyl, or by one substituent selected from bromo, iodo, C
1
-C
6
alkoxy, —O—CO—(C
1
-C
6
alkyl), —S(C
1
-C
6
alkyl), —COO(C
1
-C
4
alkyl), CN, NO
2
, —SO(C
1
-C
4
alkyl), and —SO
2
(C
1
-C
4
alkyl), and wherein said C
1
-C
12
alkyl and the C
1
-C
4
alkylene moiety of said —(C
1
-C
4
alkylene)aryl may optionally contain one carbon-carbon double or triple bond;
or —NR
1
R
2
may form a saturated 5- to 8-membered heterocyclic ring, or —CHR
1
R
2
may form a saturated 5- to 8-membered carbocyclic ring, wherein each of these rings may optionally contain one or two carbon-carbon double bonds and wherein one or two of the carbon atoms of each of these rings may optionally be replaced with a sulfur or oxygen atom;
R
3
is C
1
-C
4
alkyl, fluoro, chloro, bromo, iodo, —CH
2
OH, —CH
2
OCH
3
, —O(C
1
-C
3
alkyl), —S(C
1
-C
3
alkyl), or —SO
2
(C
1
-C
3
alkyl), wherein said C
1
-C
3
alkyl may optionally contain one carbon-carbon double or triple bond;
R
4
is hydrogen, C
1
-C
6
alkyl, fluoro, chloro, bromo, iodo, C
1
-C
4
alkoxy, amino, —NHCH
3
, —N(CH
3
)
2
, —CH
2
OH, —CH
2
OCH
3
, or —SO
n
(C
1
-C
4
alkyl), wherein n is 0, 1 or 2, cyano hydroxy, —CO(C
1
-C
4
alkyl), —CHO, or —COO(C
1
-C
4
alkyl) wherein the C
1
-C
4
alkyl moieties in the foregoing R
4
groups may optionally contain one carbon-carbon double or triple bond;
R
5
is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, pyrimidyl, benzofuranyl, pyrazinyl or benzothiazolyl, wherein each one of said groups R
5
may optionally be substituted with from one to three substituents independently selected from fluoro, chloro, C
1
-C
6
alkyl and C
1
-C
6
alkoxy, or by one substituent selected from iodo, hydroxy, bromo, formyl, cyano, nitro, amino, trifluoromethyl, —NH(C
1
-C
4
alkyl), —N(C
1
-C
6
)(C
1
-C
2
alkyl), —COO(C
1
-C
4
alkyl), —CO(C
1
-C
4
alkyl), —COOH, —SO
2
NH(C
1
-C
4
alkyl), —SO
2
N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), —SO
2
NH
2
, —NHSO
2
(C
1
-C
4
alkyl), —S(C
1
-C
6
alkyl) and —SO
2
(C
1
-C
6
alkyl), wherein each of said C
1
-C
4
alkyl and C
1
-C
6
alkyl moieties in the foregoing R
5
groups may optionally be substituted with one to three fluorine atoms;
R
6
is hydrogen, C
1
-C
4
alkyl, fluoro, chloro, bromo, iodo, —CH
2
OH, —CH
2
OCH
3
, or C
1
-C
4
alkoxy;
R
7
is hydrogen, C
1
-C
4
alkyl, fluoro, chloro, bromo, iodo, —O(C
1
-C
4
alkyl), cyano, —CH
2
OH, —CH
2
O(C
1
-C
2
alkyl), —CO(C
1
-C
2
alkyl), or —COO(C
1
-C
2
alkyl);
R
11
is hydrogen, hydroxy, fluoro, or methoxy; and
R
12
is hydrogen or C
1
-C
4
alkyl;
with the proviso that when A is N, then: (a) B is not unsubstituted alkyl; (b) R
5
is not unsubstituted phenyl; and (c) R
3
is not unsubstituted alkyl.
More specific embodiments of this invention relate to compounds of the formula I wherein B is —NR
1
R
2
, —NHCHR
1
R
2
, —CR
1
R
2
R
11
, —SCHR
1
R
2
or —OCHR
1
R
2
; R
1
is C
1
-C
4
alkyl, which may optionally be substituted with one hydroxy, fluoro or C
1
-C
2
alkoxy group and may optionally contain one carbon-carbon double or triple bond; R
2
is benzyl or C
1
-C
6
alkyl which may optionally contain one carbon-carbon double or triple bond, wherein said C
1
-C
6
alkyl or the phenyl moiety of said benzyl may optionally be substituted with fluoro, C
1
-C
2
alkyl, or C
1
-C
2
alkoxy; and R
11
is hydrogen or fluoro.
Other more specific embodiments of this invention relate to compounds of the formula I wherein B is tetrahydrofuranyl, tetrahydrothienyl or thiazolidinyl.
Other more specific embodiments of this invention relate to compounds of the formula I wherein: (a) R
1
and R
2
are each, independently, C
1
-C
4
alkyl which may optionally be substituted with fluoro, C
1
-C
2
alkyl or C
1
-C
2
alkoxy and which may optionally contain one carbon-carbon double or triple bond; or (b) R
1
is C
1
-C
4
alkyl substituted with hydroxy.
Other more specific embodiments of this invention relate to compounds of the formula I wherein: (a) R
3
is methyl, chloro, or methoxy; (b) R
4
and R
6
are each, independently, hydrogen, methyl, ethyl, or chloro, and R
4
and R
6
are not both hydrogen: and (c) R
5
is phenyl substituted by two or three substituents independently selected from fluoro, chloro, bromo, iodo, C
1
-C
4
alkoxy, trifluoromethyl, C
1
-C
6
alkyl which may optionally be substituted by one of hydroxy, C
1
-C
4
alkoxy and fluoro and may optionally have one double or triple bond, —(C
1
-C
4
alkylene)O(C
1
-C
2
alkyl), C
1
-C
3
hydroxyalkyl, hydroxy, formyl, —COO(C
1
-C
2
alkyl), and —(C(O)(C
1
-C
4
alkyl).
Other more specific embodiments of this invention relate to compounds of the formula I wherein R
3
is methyl, ethyl halo, methoxy or thiomethyl, R
4
is hydrogen, C
1
-C
3
alkyl, halo, thiomethyl, sulfanylmethyl, sulfonylmethyl or methoxy and R
5
is substituted phenyl, substituted pyridyl or substituted pyrimidyl.
Examples of specific compounds of this invention are:
butyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]py

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