Pyrrolopyrimidines as CRF antagonists

Details Pyrrolopyrimidines as CRF antagonists Pyrrolopyrimidines as CRF antagonists

1995-06-14

2004-07-20

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...

C544S280000

Reexamination Certificate

active

06765008

ABSTRACT:

This invention relates to pyrrolopyrimidines, pharmaceutical compositions containing them, and their use in the treatment of stress-related and other diseases. The compounds have 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 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 considered effective in the treatment of a wide range of diseases including stress-related illnesses, such as stress-induced depression, anxiety, and headache; irritable bowel syndrome; inflammatory diseases; immune suppression; human immunodeficiency virus (HIV) infections; Alzheimer's disease; gastrointestinal diseases; anorexia nervosa; hemorrhagic stress; drug and alcohol withdrawal symptoms; drug addiction, and fertility problems.
The present invention relates to a compound of the formula
and the acid addition salts thereof, wherein
B is XA wherein X is (CH
2
)
n
in which n is 0, 1 or 2, NH, O, S, or N(C
1
-C
4
alkyl);
A is NR
1
R
2
, CR
1
R
2
R
11
, or C(═CR
2
R
12
)R
1
;
R
1
is hydrogen, or mono or divalent C
1
-C
6
aliphatic hydrocarbon which may be substituted by one or two substituents R
7
independently selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, C
1
-C
8
alkoxy, O—C(═O)—(C
1
-C
6
alkyl), O—C(═O)—NH(C
1
-C
4
alkyl), O—C(═O)—N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), amino, NH(C
1
-C
4
alkyl), N(C
1
-C
2
alkyl)(C
1
-C
4
alkyl), S(C
1
-C
6
alkyl), N(C
1
-C
4
alkyl)(C
1
-C
4
alkyl), NH(C
1
-C
4
alkyl), COOH, O(C
1
-C
4
alkyl), NH(C
1
-C
4
alkyl), N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), SH, CN, NO
2
, SO(C
1
-C
4
alkyl), SO
2
(C
1
-C
4
alkyl SO
2
NH(C
1
-C
4
alkyl), SO
2
N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), and said mono or divalent C
1
-C
6
aliphatic hydrocarbon may contain one or two double or triple bonds;
R
2
is monovalent C
1
-C
12
aliphatic hydrocarbon, aryl or (divalent C
1
-C
10
aliphatic hydrocarbon)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, pyrrolopyridyl, oxazolyl, or benzoxazolyl; 3- to 8-membered cycloalkyl or (C
1
-C
6
alkylene) cycloalkyl, wherein one or two methylene groups of said cycloalkyl may be independently replaced by one or two O, S or N—Z radicals wherein Z is hydrogen, C
1
-C
4
alkyl, benzyl or C
1
-C
4
alkanoyl, wherein R
2
may be substituted independently by from one to three of chloro, fluoro, or C
1
-C
4
alkyl, or one of hydroxy, bromo, iodo, C
1
-C
6
alkoxy, O—C(═O)—(C
1
-C
6
alkyl), O—C—N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), S(C
1
-C
6
alkyl), NH
2
, NH(C
1
-C
2
alkyl), N(C
1
-C
2
alkyl) (C
1
-C
4
alkyl), N(C
1
-C
4
alkyl)—C(═O)—(C
1
-C
4
alkyl), NHC(═O)(C
1
-C
4
alkyl), COOH, C(═O)—O(C
1
-C
4
alkyl), C(═O)NH(C
1
-C
4
alkyl), C(═O)N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), SH, CN, NO
2
, SO(C
1
-C
4
alkyl), SO
2
(C
1
-C
4
alkyl), SO
2
NH(C
1
-C
4
alkyl), SO
2
N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), and wherein said monovalent C
1
-C
12
aliphatic hydrocarbon or said divalent C
1
-C
10
aliphatic hydrocarbon may contain one to three double or triple bonds; or
when A is NR
1
R
2
or CR
1
R
2
R
11
, the R
1
and R
2
may be taken together with the atom to which they are attached to form a saturated 4- to 8-membered ring optionally containing one or two double bonds or one or two O, S or N—Z radicals wherein Z is hydrogen, C
1
-C
4
alkyl, or C
1
-C
4
alkanoyl;
R
3
is hydrogen, monovalent C
1
-C
6
aliphatic hydrocarbon, fluoro, chloro, bromo, iodo, hydroxy, amino, O(monovalent C
1
-C
6
aliphatic hydrocarbon), NH(monovalent C
1
-C
4
aliphatic hydrocarbon), N(monovalent C
1
-C
4
aliphatic hydrocarbon)(C
1
-C
2
alkyl), SH, S(monovalent C
1
-C
4
aliphatic hydrocarbon), SO(monovalent C
1
-C
4
aliphatic hydrocarbon), or SO
2
(monovalent C
1
-C
4
aliphatic hydrocarbon), wherein said monovalent C
1
-C
4
aliphatic hydrocarbon and said monovalent C
1
-C
6
aliphatic hydrocarbon may contain one or two double or triple bonds and may be substituted by one to three substituents R
8
independently selected from the group consisting of hydroxy, amino, C
1
-C
3
alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NHC(═O)CH
3
, fluoro, chloro and C
1
-C
3
alkylthio;
R
4
and R
6
are each independently hydrogen, C
1
-C
6
alkyl, fluoro, chloro, bromo, iodo, C
1
-C
6
alkoxy, amino, NH(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)(C
1
-C
2
alkyl), SO
n
(C
1
-C
6
alkyl) wherein n is 0, 1 or 2, cyano, hydroxy, carboxy, or amido, wherein said C
1
-C
6
alkyls may be substituted by one to three of hydroxy, amino, carboxy, amido, NHC(═O)(C
1
-C
4
alkyl), NH(C
1
-C
4
alkyl), N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), C(═O)O(C
1
-C
4
alkyl), C
1
-C
3
alkoxy, C
1
-C
3
alkylthio, fluoro, bromo, chloro, iodo, cyano or nitro;
R
5
is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, piperidinyl, piperazinyl, tetrazolyl, or 3- to 8-membered cycloalkyl or 9- to 12-membered bicycloalkyl, optionally containing one to three O, S or N—Z radicals wherein Z is hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkanoyl, phenyl or phenylmethyl, wherein each one of the above groups may be substituted independently by from one to four of fluoro, chloro, monovalent C
1
-C
6
aliphatic hydrocarbon, C
1
-C
6
alkoxy or trifluoromethyl, or one of bromo, iodo, cyano, nitro, amino, NH(monovalent C
1
-C
4
aliphatic hydrocarbon), N(monovalent C
1
-C
4
aliphatic hydrocarbon)(C
1
-C
2
alkyl), COO(monovalent C
1
-C
4
aliphatic hydrocarbon), CO(monovalent C
1
-C
4
aliphatic hydrocarbon), SO
2
NH(monovalent C
1
-C
4
aliphatic hydrocarbon), SO
2
N(monovalent C
1
-C
4
aliphatic hydrocarbon)(C
1
-C
2
alkyl), SO
2
NH
2
, NHSO
2
(monovalent C
1
-C
4
aliphatic hydrocarbon), S(monovalent C
1
-C
6
aliphatic hydrocarbon), SO
2
(monovalent C
1
-C
6
aliphatic hydrocarbon), wherein said monovalent C
1
-C
4
aliphatic hydrocarbon and said monovalent C
1
-C
6
aliphatic hydrocarbon may be substituted by one or two of fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or acetyl;
R
11
is hydrogen, hydroxy, fluoro, chloro, COO(C
1
-C
2
alkyl), cyano, or CO(C
1
-C
2
alkyl); and
R
12
is hydrogen or monovalent C
1
-C
4
aliphatic hydrocarbon; with the proviso that (1) when R
5
is pbromophenyl, and at least two of R
3
, R
4
and R
6
are methyl, then B is not ethyl, ethoxy, S-ethyl, methylamino, dimethylamino, or hydroxyethylamino; and (2) when R
5
is unsubstituted phenyl or unsubstitued cycloalkyl, then at least one of R
3
and R
4
is methyl, and B is not benzylamino, furfuryl (furanylmethyl)amino, or anilino (phenylamino).
Preferred compounds of the formula I of the invention are those wherein R
1
is monovalent C
1
-C
6
aliphatic hydrocarbon, which may be substituted by one or two of substituents R
7
independently selected from the group consisting of hydroxy, fluoro, chloro, C
1
-C
2
alkoxy, and OC—O—(C
1
-C
2
alkyl); those wherein R
2
is monovalent C
2
-C
6
aliphatic hydrocarbon or ethylenephenyl; those wherein R
3
is hydrogen, methyl, ethyl, fluoro, chloro or methoxy; those wherein R
4
and R
6
are independently hydrogen, methyl, or ethyl; and those

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