Pyrazolopyrimidines as CRF antagonists

Details Pyrazolopyrimidines as CRF antagonists Pyrazolopyrimidines as CRF antagonists

1998-09-04

2001-04-17

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S262000

Reexamination Certificate

active

06218397

ABSTRACT:

This invention relates to pyrazolopyrimidines, 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. No. 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; abdominal bowel syndrome; inflammatory diseases; immune suppression; Alzheimer's disease; gastronintestinal diseases; anorexia nervosa; hemorrhagic stress; drug and alcohol withdrawal symptoms; drug addition, and fertility problems.
Certain substituted pyrazolopyrimidines have been described in the past. For instance, European Patent Publication 496,617 refers to adenosine kinase inhibitors among which are 1-ribofuranosylpyrazolopyrimidines and 1-(substituted ribofuranosyl)pyrazolopyrimidines. U.S. Pat. No. 4,904,666 refers to pyrazolopyrimidines having 1-tetrahydrofuranyl or 1-tetrahydropyranyl substituents. Senga et al, J. Heterocyclic Chem., 19, 1565 (1982) refers to certain pyrazolopyrimidines having xanthine oxidase inhibitory acitivity. Other pyrazolopyrimidines are mentioned in U.S. Pat. Nos. 2,965,643 and 3,600,389.
The present invention relates to a pyrazolopyrimidine compound of the formula
and the pharmaceutically acceptable acid addition salts thereof, wherein
A is NR
1
R
2
, CR
1
R
2
R
11
, C(═CR
2
R
12
)R
1
, NHCR
1
R
2
R
11
, OCR
1
R
2
R
11
, SCR
1
R
2
R
11
, NHNR
1
R
2
, CR
2
R
11
NHR
1
, CR
2
R
11
OR
1
, CR
2
R
11
SR
1
or C(O)R
2
;
R
1
is hydrogen, or C
1
-C
6
alkyl which may contain one or two double or triple bonds or which may be substituted by one or two substitutents R
6
independently selected form the group consisting of hydroxy, fluoro, chloro, bromo, iodo, C
1
-C
5
alkoxy,
NH(C
1
-C
4
alkyl), amino, N(C
1
-C
2
alkyl) (C
1
-C
4
alkyl), S(C
1
-C
6
alkyl),
SO
2
(C
1
-C
4
alkyl), SH, CN, NO
2
, SO(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), wherein said (C
1
-C
6
) alkyl may have one or two double or triple bonds;
R
2
is C
1
-C
12
alkyl, aryl or (C
1
-C
10
alkylene)aryl wherein said aryl is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, oxazolyl, or benzoxazolyl; 3- to 8-membered cycloalkyl or (C
1
-C
6
alkylene) cycloalkyl, wherein said cycloalkyl may have one or two or O, S or N—Z wherein Z is hydrogen, C
1
-C
4
alkyl, benzyl, or C
1
-C
4
alkanoyl, wherein each one of the above groups may be substituted independently by from one to three of chloro, fluroro, or (C
1
-C
4
)alkyl, or one of hydroxy, bromo, iodo, C
1
-C
6
alkoxy,
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)
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 C
1
-C
12
alkyl or C
1
-C
10
alkylene may have one to three double or triple bonds; or
NR
2
R
2
or CR
1
R
2
R
11
may form a saturated 4- to 8-membered ring optionally having one or two or O, S or N—Z wherein Z is hydrogen, C
1
-C
4
alkyl, benzyl or C
1
-C
4
alkanoyl;
R
3
is hydrogen, C
1
-C
6
alkyl, fluoro, chloro, bromo, iodo, hydroxy, amino, O(C
1
-C
6
alkyl), NH((C
1
-C
6
alkyl), N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), SH, S(C
1
-C
4
alkyl), SO(C
1
-C
4
alkyl), or SO
2
(C
1
-C
4
alkyl), wherein said C
1
-C
4
alkyl and C
1
-C
6
alkyl may have one or two double or triple bonds and may be substituted by from 1 to 3 substituents R
7
independently selected frothier group consisting of hydroxy, amino, C
1
-C
3
alkoxy, dimethylamino, diethylamino, methylamino, ethylamino,
fluoro, chloro or C
1
-C
3
thioalkyl;
R
4
is 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 hdyroxy, amino, carboxy, amido,
NH(C
1
-C
4
alkyl), N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl),
C
1
-C
3
alkoxy, C
1
-C
3
thioalkyl, fluoro, bormo, chloro, iodo, cyano or nitro;
R
5
is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, piperazinyl, piperidinyl, tetrazolyl, or 3- to 8-membered cycloalkyl or 9- to 12-membered bicycloalkyl, optionally having one or two of O, S or N—Z wherein Z is hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkanoyl, phenyl or benzyl, wherein each one of the above groups may be substituted independently by from one to three of fluoro, chloro, bromo, formyl, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or trifluoromethyl, or one of hydroxy, iodo, cyano, nitro, amino, cycloproyl, NH(C
1
-C
4
alkyl), N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), COO(C
1
-C
4
alkyl), CO(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), SO
2
NH
2
, NHSO
2
((C
1
-C
4
alkyl), S(C
1
-C
6
alkyl), SO
2
(C
1
-C
6
alkyl), wherein said C
1
-C
4
alkyl and C
1
-C
6
alkyl may have one double or triple bond and may be substituted by one or two of fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or acetyl; with the proviso that R
5
is not unsubstituted phenyl;
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 C
1
-C
5
alkyl; with the following provisos:
(a) A is not straight chain C
1
-C
12
alkyl;
(b) R
5
is not a sugar group;
(c) when R
3
and R
4
are hydrogen and R
5
is chlorophenyl, then A is not NH—CH(CH
3
)—(CH
2
)
3
—N(C
2
H
5
)
2
;
(d) when R
3
and R
4
are hydrogen and A is NR
1
R
2
wherein R
1
is C
3
-C
7
cycloalkyl, and R
2
is C
2
-C
6
alkenyl, phenyl-(C
1
-C
6
alkylene) or hetero-(C
1
-C
6
alkylene) wherein the hetero radical is furyl, thienyl or pyridinyl, and wherein said pehnyl may be substituted by fluoro, chloro, bromo or iodo, then R
5
is not tetrahydrofuranyl or tetrahydropyranyl;
(e) when R
3
is methoxy, methylthio, or methylsulfonyl, R
4
is hydrogen, and R
5
is tetrahydrofuranyl or tetrahydropyranyl, then A is not NH(C
1
-C
2
alkyl), morpholinyl, hdyrazino, or NHC
2
H
4
C
6
H
5
the phenyl of which may be substituted by one methyl or two methoxy;
(f) when R
3
is hydrogen, C
1
-C
6
alkyl, hydrazino, chloro, bromo, SH, or S (C
1
-C
4
alkyl), R
4
is hydrogen and R
5
is C
3
-C
8
cycloalkyl, then A is not hydrazino, NH(C
1
-C
2
alkyl) or N(C
1
-C
6
alkyl) (C
1
-C
12
alkyl);
(g) when R
3
and R
4
are hydrogen and A is NH(CH
2
)
m
COOH wherein m is 1-12, then R
5
is not pehnyl substituted by one of fluoro, chloro, bromo or iodo;
(h) when R
3
is hydrogen, hydroxy, methythio, chloro or NHbenzyl, R
4
is hydrogen, and R
5
is chlorophenyl or bromophenyl, then A is not NH(C
1
-C
12
alkyl), NHallyl, or N((C
1
-C
6
alkyl) (C
1
-C
12
alkyl), wherein said C
1
-C
12
alkyl may be substituted by NC
2
H
5
, or NH benzyl which may be substituted by one or two bromo, chloro, fluoro, NC
2
H
5
phenyl or morpholinopropyl;
(i) when R
3
and R
4
are hydrogen and R
5

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