Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-06-14
1998-01-27
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5483664, 5483667, 5483671, 5483687, 5483691, 5483694, C07D23144
Patent
active
057123039
DESCRIPTION:
BRIEF SUMMARY
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.dbd.O, R.sub.1 is amino, R.sub.2 is methylthio, R.sub.3 is 2-chlorophenyl, and R.sub.4 is 2,4,6-trichlorophenyl is a commercial compound of no known utility.
The present invention relates to a compound of the formula ##STR2## and the acid addition salts thereof, wherein
A is C.dbd.O or SO.sub.2, or A and R.sub.1 together with the carbons to which they are attached form pyrimidinyl or 5-pyridyl which may be substituted by R.sub.5 which is hydrogen, C.sub.1 -C.sub.6 alkyl, fluoro, chloro, bromo, hydroxy, amino, O(C.sub.1 -C.sub.6 alkyl), NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), SH, S(O).sub.n (C.sub.1 -C.sub.6 alkyl) wherein n=0, 1 or 2, wherein said C.sub.1 -C.sub.6 alkyl may be substituted by from 1 to 3 substituents R.sub.6 which is hydroxy, amino, C.sub.1 -C.sub.3 alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NH(C.dbd.O)CH.sub.3, fluoro, chloro, bromo or C.sub.1 -C.sub.3 thioalkyl;
R.sub.1 is hydrogen, C.sub.1 -C.sub.6 alkyl, amino, O(C.sub.1 -C.sub.6 alkyl), NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), wherein said C.sub.1 -C.sub.6 alkyl may be substituted by from 1 to 3 substituents R.sub.6 as defined above;
R.sub.2 is hydrogen, C.sub.1 -C.sub.6 alkyl, hydroxy, amino, O(C.sub.1 -C.sub.6 alkyl), NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), SH, S(O).sub.n (C.sub.1 -C.sub.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.dbd.O)(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), (C.dbd.O)O(C.sub.1 -C.sub.6 alkyl), C.sub.1 -C.sub.3 alkoxy, C.sub.1 -C.sub.3 thioalkyl, fluoro, bromo, chloro, iodo, cyano or nitro;
R.sub.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.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.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.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or trifluoromethyl, or one of cyano, nitro, amino, NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.2 alkyl), COO(C.sub.1 -C.sub.4 alkyl), CO(C.sub.1 -C.sub.4 alkyl), SO.sub.2 NH(C.sub.1 -C.sub.4 alkyl), SO.sub.2 N(C.sub.1 -C.sub.4 alkyl)(C.sub.1 -C.sub.2 alkyl), SO.sub.2 NH.sub.2
REFERENCES:
patent: 3778443 (1973-12-01), Arya et al.
patent: 4337263 (1982-06-01), Techer et al.
patent: 4804675 (1989-02-01), Jensen-Korte et al.
patent: 4945165 (1990-07-01), Jensen-Korte et al.
patent: 5063245 (1991-11-01), Abreu et al.
Chemical Abstracts 106:50185s (1987).
Chemical Abstracts 99:88106s (1983).
Chemical Abstracts 95:43095p (1981).
Chemical Abstracts 89:215295y (1978).
T. Nishiwaki et al., "Synthesis of 4-Aroyl-1-arylpyrazoles from alpha-Aroyl-beta-anilinoacrylonitriles and Photochemistry of 4-Carbonyl-substituted Pyrazoles," J. Chem. Soc., Perkin Transactions, No. 15, pp. 1871-1875, 1974.
M. J. Owens et al., "Physiology and Pharmacology of Corticotropin-releasing Factor" Pharmacological Reviews, v. 43, pp. 425-473 (1991).
Faraci William Stephen
Welch, Jr. Willard McKowan
Ginsburg Paul H.
Koller Alan L.
Morris Patricia L.
Pfizer Inc.
Richardson Peter C.
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