Amino-substituted pyrazoles having CRF antagonistic activity

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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514311, 514314, 514406, 514407, 546148, 546167, 5483641, 5483651, 5483677, 5483714, 5483741, C07D40306, C07D40106, A61K 3147, A61K 31415

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056681453

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BRIEF SUMMARY
This is a national stage application, filed pursuant to 35 U.S.C. .sctn.371, of PCT international application number PCT/US93/10716, filed Nov. 12, 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 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 ##STR2## and the pharmaceutically acceptable acid addition salts thereof, wherein linear C.sub.1 -C.sub.6 alkyl, or branched C.sub.3 -C.sub.8 alkyl; alkyl, branched C.sub.3 -C.sub.8 alkyl, C.sub.3 -C.sub.8 alkenyl wherein the double bond is not adjacent to the N or X.sub.1 when X.sub.1 is oxygen or sulfur, or C.sub.3 -C.sub.7 cycloalkyl (CH.sub.2).sub.n wherein n is 0, 1, 2, 3 or 4; or R.sub.1 and R.sub.2 when taken together with the nitrogen form a saturated four, five or six membered ring optionally condensed with benzo; and R.sub.3 may also be (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, or C.sub.3 -C.sub.6 cycloalkyl (CH.sub.2).sub.n wherein n is 0 to 4; 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 ##STR3## wherein the B ring is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazilyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thienyl, or indolyl, each of which may be substituted by methyl methoxy, 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.o --X.sub.2 --(CH.sub.2).sub.r --Q.sub.2 --R.sub.6 ; -C.sub.8 alkyl, or C.sub.3 -C.sub.8 alkenyl; alkyl), or one of X.sub.2 and Q.sub.2 may be a covalent bond; ##STR4## wherein R.sub.4 and R.sub.5 are as defined above, and t and u are each independently 1 or 2; hydrogen, C.sub.1 -C.sub.6 linear alkyl, branched C.sub.3 -C.sub.8 alkyl, C.sub.3 -C.sub.8 alkenyl, (CH.sub.2).sub.v CH.sub.2 OH, (CH.sub.2).sub.v NR.sub.9 R.sub.10, wherein v is 0 to 3, and R.sub.9 and R.sub.10 are each independently hydrogen, or linear C.sub.1 -C.sub.6 alkyl; C.sub.1 -C.sub.12 cycloalkyl, (C.sub.3 -C.sub.12 cycloalkyl) (CH.sub.2).sub.n, (C.sub.6 -C.sub.10 bicycloalkyl) (CH.sub.2).sub.n, wherein n is 0 to 4, benzofused C.sub.3 -C.sub.6 cycloalkyl, C.sub.1 -C.sub.6 hydroxyalkyl, phenyl, phenyl (C.sub.

REFERENCES:
patent: 4605642 (1986-08-01), Rivier et al.
patent: 5063245 (1991-11-01), Abren et al.
Sandstrom, Antiviral Therapy in Aids, vol. 34, 1987, pp. 373-390.
M. J. Owens et al., Pharm. Rev., 43(4), 425-473 (1991).
L. K. Altman, "At AIDS Meeting, Experts Find An Uneasy Mix of Hope and Fear," The N.Y. Times, Jul. 9, 1996.
"A Solution for AIDS?", The Economist, Jun. 29, 1996.
M. Waldholz, "Precious Pills," The Wall Street Journal, Jul. 3, 1996.
D. E. Grigoriadis et al., Peptides 10, 179-188 (1989).
E. B. DeSouza, j. Neuroscience 7(1), 88-100 (1987).
M. J. Owens et al., Pharm. Rev. 43(4), 425-473 (1991).

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