Substituted pyrazoles as CRF antagonists

Details Substituted pyrazoles as CRF antagonists Substituted pyrazoles as CRF antagonists

1995-06-14

1998-01-06

Richter, Johann

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546141, 546142, 546143, C07D21702

Patent

active

057056463

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/U.S.93/09170 filed Sep. 30, 1993.
This invention relates to substituted pyrazoles, 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; abdominal bowel syndrome; inflammatory diseases; immune suppression; human immunedeficiency 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 ##STR2## and the pharmaceutically acceptable acid addition salts thereof, wherein A is CH.sub.2 ; -C.sub.6 alkyl containing one or two non-adjacent double bonds; hydroxy; O(C.sub.1 -C.sub.6 alkyl); SH; S(C.sub.1 -C.sub.6 alkyl); C.sub.3 -C.sub.6 cycloalkyl; morpholinyl, piperidinyl or aryl which aryl may be substituted by one to three of fluoro, chloro, bromo, trifluoromethyl, hydroxy, O(C.sub.1 -C.sub.6 alkyl), SH, S(C.sub.1 -C.sub.6 alkyl), amino, NH(C.sub.1 -C.sub.6 alkyl), N(C.sub.1 -C.sub.6 alkyl).sub.2, or one of iodo, nitro or cyano, said aryl being selected from the group consisting of phenyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, benzimidazolyl, fumnyl, benzofuranyl, thiazolyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, isoxazolyl, benzisoxazolyl, triazolyl, pyrazolyl, pyrrolyi, indolyl, azaindolyl, oxazolyl, benzoxazolyl, pyrrolidinyl, and thiazolidinyl; C.sub.3 -C.sub.8 alkenyl wherein the double bond is not adjacent to X.sub.1 when X.sub.1 is a heteroatom, or C.sub.3 -C.sub.7 cycloalkyl(CH.sub.2).sub.n wherein n is 0 to 4, or (CH.sub.2).sub.q Q.sub.1 R.sub.19 wherein q is 0, 1 or 2, Q.sub.1 is O, S, NH, N(C.sub.1 -C.sub.6 alkyl), or a covalent bond when X.sub.1 is not a covalent bond, and R.sub.19 is hydrogen, linear C.sub.1 -C.sub.6 alkyl, branched C.sub.3 -C.sub.8, C.sub.3 -C.sub.8 alkenyl, C.sub.3 -C.sub.6 cycloalkyl or C.sub.3 -C.sub.6 cycloalkyl (CH.sub.2); linear C.sub.1 -C.sub.6 alkyl or branched C.sub.3 -C.sub.8 alkyl; pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, isoxazolyl, benzisoxazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, oxazolyl, benzoxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, or piperidinyl, each of which may be substituted by one to three of any one of fluoro, chloro, bromo, or methyl, or one of trifluoromethyl; with the proviso that Y is not unsubstituted phenyl; and
(a) ##STR3## wherein the B ring is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, or indolyl, each of which may be substituted by methyl, methoxy, trifluoromethyl, fluoro, chloro, bromo or iodo; or a saturated 5- or 6-membered carbocyclic ring or a partially unsaturated ring having one or two double bonds; hydroxy, fluoro, chloro, bromo, iodo, or trifluoromethyl; -C.sub.8 alkyl, C.sub.3 -C.sub.8 alkenyl, or (CH.sub.2).sub.0 --X.sub.2 --(CH.sub.2).sub.r --Q.sub.2 --R.sub.6 ; alkyl), or one of X.sub.2 and Q.sub.2 may be a covalent bond; -C.sub.8 alkyl or C.sub.3 -C.sub.8 alkenyl;
(b) ##STR4## wherein R.sub.4 and R.sub.5 are as defined above, and t and u are each ind

REFERENCES:
patent: 4605642 (1986-08-01), Rivier et al.
patent: 5063248 (1991-11-01), Abreu et al.
M. J. Owens et al., Pharmacological Reviews, "Physiology and Pharmacology of Corticotropin-releasing Factor", vol. 43, pp. 425-473 (1991).
Furniss et al., Vogel's Textbook of Practical Organic Chemistry, pp. 736-738 (1989).
Sandler et al., Organic Functional Group Preparations, vol. I, pp. 434-465 (1983).
Aldrich Catalog, pp. 851-852 and 1319, (Aldrich Chemical Company, Inc.) (1994).
The Merck Index, pp. ONR-10, ONR-11, ONR-34, ONR-70, ONR-71 and ONR-73 (1996).

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