Pyrazoles and pyrazolopyrimidines having CRF antagonistic...

Details Pyrazoles and pyrazolopyrimidines having CRF antagonistic... Pyrazoles and pyrazolopyrimidines having CRF antagonistic...

1999-08-19

2002-09-10

Krass, Frederick (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S307000, C514S311000, C514S314000, C514S406000, C514S407000

Reexamination Certificate

active

06448265

ABSTRACT:

This invention relates to pyrazoles and pyrazolopyrimidines, 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 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 diseases including stress-related illnesses, such as stress-induced depression, anxiety, and headache; abdominal 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 compound of formula I below wherein A is C═O, R
1
is amino, R
2
is methylthio, R
3
is 2-chlorophenyl, and R
4
is 2,4,6-trichlorophenyl is a commercial compound of no known utility.
The present invention relates to a compound of the formula
and the acid addition salts thereof, wherein
A is C═O or SO
2
, or A and R
1
together with the carbons to which they are attached form pyrimidinyl or 5-pyridyl which may be substituted by R
5
which is hydrogen, C
1
-C
6
alkyl, fluoro, chloro, bromo, hydroxy, amino, O(C
1
-C
6
alkyl), NH(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)(C
1
-C
6
alkyl), SH, S(O)
n
(C
1
-C
6
alkyl) wherein n=0, 1 or 2, wherein said C
1
-C
6
alkyl may be substituted by from 1 to 3 substituents R
6
which is hydroxy, amino, C
1
-C
3
alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NH(C═O)CH
3
, fluoro, chloro, bromo or C
1
-C
3
thioalkyl;
R
1
is hydrogen, C
1
-C
6
alkyl, amino, O(C
1
-C
6
alkyl), NH(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)(C
1
-C
6
alkyl), wherein said C
1
-C
6
alkyl may be substituted by from 1 to 3 substituents R
6
as defined above;
R
2
is hydrogen, C
1
-C
6
alkyl, hydroxy, amino, O(C
1
-C
6
alkyl), NH(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)(C
1
-C
6
alkyl), SH, S(O)
n
(C
1
-C
6
alkyl) wherein n=0, 1, or 2, cyano, hydroxy, carboxy, or amido, wherein said alkyls may be substituted by one to three of hydroxy, amino, carboxy, amido, NH(C═O)(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)(C
1
-C
6
alkyl), (C═O)O(C
1
-C
6
alkyl), C
1
-C
3
alkoxy, C
1
-C
3
thioalkyl, fluoro, bromo, chloro, iodo, cyano or nitro;
R
3
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 9 to 12 membered bicycloalkyl, optionally containing one to three of O, S or N—Z 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 three of fluoro, chloro, bromo, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or trifluoromethyl, or one of cyano, nitro, amino, NH(C
1
-C
6
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 be substituted by one or two of fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or acetyl; and
R
4
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, optionally containing one to three of O, S or N—Z wherein Z is hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkanoyl, phenyl or phenylmethyl, wherein each of the above groups may be substituted independently by from one to three of fluoro, chloro, bromo, trifluoromethyl, C
1
-C
6
alkyl or C
1
-C
6
alkoxy, or one of cyano, nitro, amino, NH(C
1
-C
6
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
, NH
2
SO
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 be substituted by one or two of fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or acetyl; provided that (1) R
4
is not unsubstituted phenyl; (2) when R
1
is amino, R
2
is methylthio, R
4
is 2,4,6-trichlorophenyl, and A is C═O, then R
3
is not 2-chlorophenyl; and (3) R
1
and R
2
are not both hydrogen.
More specific compounds of the formula I include those wherein R
3
is phenyl substituted independently with one or two of fluoro, chloro, bromo, methyl, trifluoromethyl, nitro, C
1
-C
6
alkyl, C
1
-C
6
alkyloxy, SO
2
NH
2
, SO
2
NH(C
1
-C
6
alkyl), SO
2
N(C
1
-C
6
alkyl)
2
, or R
3
is primary, secondary or tertiary alkyl of from 4-9 carbon atoms wherein said C
4
-C
9
alkyl may contain from one to two double or triple bonds and may be substituted by from 1 to 3 substituents R
6
which is hydroxy, amino, C
1
-C
3
alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NH(C═O)CH
3
, fluoro, chloro, bromo, or C
1
-C
3
thioalkyl.
More specific compounds of the formula I are those wherein A is C═O, those wherein R
1
is amino, methylamino or dimethylamino; those wherein R
2
is ethyl or methylthio and those wherein R
4
is 2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl, 2,6-dichloro-4-trifluoromethylphenyl or 4-bromo-2,6-dimethylphenyl.
More specific compounds of formula I further include those wherein R
3
is phenyl which may be substituted at positions 2 or 5 with one or two of methyl, C
2
-C
6
straight-chain or branched alkyl, trifluoromethyl, fluoro, chloro, bromo or nitro, those wherein A and R
1
together form a pyrimidine ring, such that the bicyclic structure formed is pyrazolo[3,4-d]pyrimidine, and R
5
is substituted at the 6 position; and those wherein R
3
is phenyl substituted independently with one or two of fluoro, chloro, bromo, methyl, trifluoromethyl, nitro, C
1
-C
6
alkyl, C
1
-C
6
alkyloxy, SO
2
NH
2
, SO
2
NH(C
1
-C
6
alkyl), or SO
2
N(C
1
-C
6
alkyl)
2
, R
4
is 2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl, 2,6-dichloro-4-trifluoromethylphenyl or 4-bromo-2,6-dimethylphenyl, and R
2
is methylthio, methyl or ethyl.
More specific compounds of formula I also include those wherein R
3
is phenyl substituted independently with one or two of fluoro, chloro, bromo, methyl, trifluoromethyl, nitro, C
1
-C
6
alkyl, C
1
-C
6
alkyloxy, SO
2
NH
2
, SO
2
NH(C
1
-C
6
alkyl), SO
2
N(C
1
-C
6
alkyl)
2
, or R
3
is primary, secondary or tertiary alkyl of from 4-9 carbon atoms wherein said C
4
-C
9
alkyl may contain from one to two double or triple bonds and may be substituted by from 1 to 3 substituents R
6
which is hydroxy, amino, C
1
-C
3
alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NH(C═O)CH
3
, fluoro, chloro, bromo or C
1
-C
3
thioalkyl; R
4
is 2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl, 2,6-dichloro-4-trifluoromethylphenyl or 4-bromo-2,6-dimethylphenyl; R
1
is amino, methylamino or dimethylamino; and R
2
is methylthio or ethyl.
The most preferred compounds of the invention are
[5-amino-1-(2,6-dichloro-4-triflu

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