Corticotropin releasing factor antagonists

Details Corticotropin releasing factor antagonists Corticotropin releasing factor antagonists

2001-01-17

2004-12-21

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S336000, C514S337000, C514S338000, C514S339000, C514S340000, C514S341000, C514S342000, C514S343000, C514S344000, C514S345000, C514S349000, C514S350000, C514S351000, C514S352000, C514S353000, C514S354000, C514S355000, C514S356000, C514S357000, C546S153000, C546S155000, C546S156000, C546S157000, C546S158000, C546S159000, C546S167000, C546S255000, C546S256000, C546S261000, C546S262000, C546S263000, C546S264000, C546S265000, C546S266000, C546S267000, C546S278400, C546S296000, C546S297000, C546S307000, C544S

Reexamination Certificate

active

06833378

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to pyridines, pyrimidines, purinones, pyrrolopyrimidinones and pyrrolopyridinones, processes for preparing them, pharmaceutical compositions containing them, and methods of using them to treat certain central nervous system (CNS) and other disorders.
CRF antagonists are mentioned in U.S. Pat. No. 4,605,642, issued Aug. 12, 1986, and U.S. Pat. No. 5,063,245, issued Nov. 5, 1991, referring to peptides and pyrazolinones, respectively. CRF antagonists are also described in U.S. Pat. No. 5,962,479, issued Oct. 5, 1999. 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. Based on the research described in these two and other references, CRF antagonists are 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, infertility, head trauma, stroke, and stress-induced infections in humans and animals. The use of CRF antagonists for treatment of Syndrome X has also been described in U.S. patent application Ser. No. 09/696,822, filed Oct. 26, 2000, and European Patent Application No. 00309441.4, filed Oct. 26, 2000, which are also incorporated in their entireties herein by reference. Methods for using CRF antagonists to treat congestive heart failure are described in U.S. Ser. No. 09/248,073, filed Feb. 10, 1999, now U.S. Pat. No. 6,043,260 (issued Mar. 28, 2000) which is also incorporated herein in its entirety by reference.
SUMMARY OF THE INVENTION
The present invention provides compounds of the formula
and pharmaceutically acceptable salts thereof, wherein
the dashed lines represent optional double bonds, with the proviso that when the dashed line in C
---
G represent a double bond, then the dashed line in N(R
6
)
---
C does not represent a double bond; and with the proviso that when the dashed line in N(R
6
)
---
C represents a double bond, R
6
is absent in formula III and the dashed line in C
---
G does not represent a double bond;
A is —CR
7
or N;
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
1
R
2
, —CHR
2
OR
1
, —CHR
1
OR
2
, —CHR
2
SR
1
, —C(S)R
2
, —C(O)R
2
, —CHR
2
NR
1
R
2
, —CHR
1
NHR
2
, —CHR
1
N(CH
3
)R
2
, or —NR
12
NR
1
R
2
;
when the dashed line in C
---
G represents a double bond, then G is hydrogen, oxygen, sulfur, NH, or N(C
1
-C
4
alkyl);
when the dashed line in C
---
G does not represent a double bond, then C
---
G is —C(H)(NH
2
), CH
2
, —C(H)(methoxy), —C(H)(ethoxy), —C(H)(O(C
3
-C
4
alkyl)), —C(H)(halo), —C(H)(trifluoromethoxy), —C(H)(methyl), —C(H)(ethyl), —C(H)(C
3
-C
4
alkyl), —C(H)(S(C
1
-C
4
alkyl)), —C(C
1
-C
4
alkyl)(C
1
-C
4
alkyl), cyclopropyl, —C(H)(cyclopropyl), thiomethoxy, —C(H)(NH
2
), —C(H)(NHCH
3
), —C(H)(N(CH
3
)
2
), or —C(H)(trifluoromethyl);
wherein said cyclopropyl, methoxy, ethoxy, C
3
-C
4
alkyl, and C
1
-C
4
alkyl groups of C
---
G may optionally be substituted by one OH, methoxy, or trifluoromethoxy, or may optionally be substituted by from one to six fluoro atoms;
Y is CH or N;
Z is NH, O, S, —N(C
1
-C
2
alkyl), —NC(O)CF
3
, or —C(R
13
R
14
), wherein R
13
and R
14
are each, independently, hydrogen, trifluoromethyl or methyl, or one of R
13
and R
14
is cyano and the other is hydrogen or methyl, or —C(R
13
R
14
) is a cyclopropyl group, or Z is nitrogen or CH and forms; a five or six membered heterocyclic ring fused with R
5
, which ring optionally comprises two or three further hetero members selected independently from oxygen, nitrogen, NR
12
, and S(O)
m
, and optionally comprises from one to three double bonds, and is optionally substituted with halo, C
1
-C
4
alkyl, —O(C
1
-C
4
alkyl), NH
2
, NHCH
3
, N(CH
3
)
2
, CF
3
, or OCF
3
, with the proviso that said ring does not contain any —S—S—, —S—O—, —N—S—, or —O—O— bonds, and does not comprise more than two oxygen or S(O)
m
heterologous members;
R
1
is —C(O)H, —C(O)(C
1
-C
6
alkyl), —C(O)(C
1
-C
6
alkylene)(C
3
-C
8
cycloalkyl), —C(O)(C
3
-C
8
cycloalkylene)(C
3
-C
8
cycloalkyl), —C(O)(C
1
-C
6
alkylene)(C
4
-C
8
heterocycloalkyl), —C(O)(C
3
-C
8
cycloalkylene)(C
4
-C
8
heterocycloalkyl), —C
1
-C
6
alkyl, —C
3
-C
8
cycloalkyl, —C
4
-C
8
heterocycloalkyl, —(C
1
-C
6
alkylene)(C
3
-C
8
cycloalkyl), —(C
3
-C
8
cycloalkylene)(C
3
-C
8
cycloalkyl), —(C
1
-C
6
alkylene)(C
4
-C
8
heterocycloalkyl), —(C
3
-C
8
cycloalkylene)(C
4
-C
8
heterocycloalkyl), or —O-aryl, or —O—(C
1
-C
6
alkylene)-aryl; wherein said aryl, C
4
-C
8
heterocycloalkyl, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkylene, and C
1
-C
6
alkylene groups may each independently be optionally substituted with from one to six fluoro and may each independently be optionally substituted with one or two substituents R
8
independently selected from the group consisting of C
1
-C
4
alkyl, —C
3
-C
8
cycloalkyl, hydroxy, fluoro, chloro, bromo, iodo, CF
3
, —O—(C
1
-C
6
alkyl), —O—(C
3
-C
5
cycloalkyl), —O—CO—(C
1
-C
4
alkyl), —O—CO—NH(C
1
-C
4
alkyl), —O—CO—N(R
24
)(R
25
), —N(R
24
)(R
25
), —S(C
1
-C
4
alkyl), —S(C
3
-C
5
cycloalkyl), —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
, —OSO
2
(C
1
-C
4
alkyl), S
+
(C
1
-C
6
alkyl)(C
1
-C
2
alkyl), —SO(C
1
-C
4
alkyl) and —SO
2
(C
1
-C
4
alkyl); and wherein the C
1
-C
6
alkyl, C
1
-C
6
alkylene, C
5
-C
8
cycloalkyl, C
5
-C
8
cycloalkylene, and C
5
-C
8
heterocycloalkyl moieties of R
1
may optionally independently contain from one to three double or triple bonds; and wherein the C
1
-C
4
alkyl moieties and the C
1
-C
6
alkyl moieties of R
8
can optionally independently be substituted with hydroxy, C
1
-C
4
alkyl, amino, aryl, —CH
2
-aryl, —C
3
-C
5
cycloalkyl, or —O—(C
1
-C
4
alkyl), and can optionally independently be substituted with from one to five fluoro, and can optionally contain one or two double or triple bonds; and wherein each heterocycloalkyl group of R contains from one to three heteromoieties selected from oxygen, S(O)
m
, nitrogen, and NR
12
;
R
2
is hydrogen, C
1
-C
12
alkyl, C
3
-C
8
cycloalkyl, C
4
-C
8
heterocycloalkyl, —(C
1
-C
6
alkylene)(C
3
-C
8
cycloalkyl), —(C
3
-C
8
cycloalkylene)(C
3
-C
8
cycloalkyl), —(C
1
-C
6
alkylene)(C
4
-C
8
heterocycloalkyl), —(C
3
-C
8
cycloalkylene)(C
4
-C
8
heterocycloalkyl), aryl, —(C
1
-C
6
alkylene)aryl, or —(C
3
-C
8
cycloalkylene)(aryl); wherein each of the foregoing R
2
groups may optionally be substituted with from one three substituents independently selected from chloro, fluoro, and C
1
-C
6
alkyl, wherein one of said one to three substituents can further be selected from bromo, iodo, C
1
-C
6
alkoxy, —OH, —O—CO—(C
1
-C
6
alkyl), —O—CO—N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), —S(C
1
-C
6
alkyl), —S(O)(C
1
-C
6
alkyl), —S(O)
2
(C
1
-C
6
alkyl), S
+
(C
1
-C
6
alkyl)(C
1
-C
2
alkyl), CN, and NO
2
; and wherein the C
1
-C
12
alkyl, —(C
1
-C
6
alkylene), —(C
5
-C
8
cycloalkyl), —(C
5
-C
8
cycloalkylene), and —(C
5
-C
8
heterocycloalkyl) moieties of R
2
may optionally independently contain from one to three double or triple bonds; and wherein each heterocycloalkyl group of R
2
contains from one to three heteromoieties selected from oxygen, S(O)
m
, nitrogen, and NR
12
;
or where R
1
and R
2
are as in —NHCHR
1
R
2
, —OCHR
1
R
2
, —SCHR
1
R
2
, —CHR
1
R
2
or —NR
1
R
2
, R
1
and R
2
of B may form a saturated 5- to 8-membered ring which may optionally contain one or two double bonds and in which one or two of the ring carbons may optionally be replaced by an

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