Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-01-31
1997-11-18
Gupta, Yogendra N.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514212, 514326, 540605, 544330, 544332, 546209, A61K 31445, C07D21114
Patent
active
056888040
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to novel substituted derivatives of nitrogen containing heterocycles, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention of inflammatory and central nervous system disorders, as well as several other disorders. The pharmaceutically active compounds of this invention are substance P receptor antagonists.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals (having originally been isolated from gut) and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in U.S. Pat. No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has recently been shown to be involved in the transmission of pain or migraine (see B. E. B. Sandberg et al., Journal of Medicinal Chemistry, 25, 1009 (1982)), as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, in rheumatic diseases such as fibrositis, and in gastrointestinal disorders and diseases of the GI tract such as ulcerative colitis and Crohn's disease, etc. (see D. Regoli in "Trends in Cluster Headache," edited by F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, pp. 85-95 (1987)).
Quinuclidine derivatives and related compounds that exhibit activity as substance P receptor antagonists are referred to in PCT Patent Application PCT/US 89/05338, filed Nov. 20, 1989 and U.S. patent application Ser. No. 557,442, filed Jul. 23, 1990. Similar compounds are referred to in the PCT Application PCT/US91/02853, filed on Apr. 25, 1991 and PCT Application PCT/US91/03369, filed on May 14, 1991.
Monocyclic piperidine compounds are referred to in European Patent Publication 0,436,334 published on Jul. 10, 1990.
Piperidine derivatives and related heterocyclic nitrogen containing compounds that are useful as substance P antagonists are referred to in U.S. patent application Ser. No. 619,361, filed Nov. 28, 1990, U.S. patent application Ser. No. 590,423, filed Sep. 28, 1990, U.S. patent application Ser. No. 717,943 filed Jun. 20, 1991, U.S. patent application Ser. No. 719,884 filed on Jun. 21, 1991, and U.S. patent application Ser. No. 724,268 filed Jul. 1, 1991.
Compounds containing a sulfur or an oxygen group at the 3 position of a nitrogen containing ring are referred to in European Patent Publications 520,555A1 published on Dec. 12, 1992, 499,313A1 published on Aug. 19, 1992, and 528,495A1 published on Feb. 24, 1993.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula ##STR2## wherein m is an integer from 1 to 8, any one of the carbon--carbon single bonds of (CH.sub.2).sub.m may optionally be replaced by a carbon--carbon double bond or a carbon--carbon triple bond, and any one of the carbon atoms of said (CH.sub.2).sub.m may optionally be substituted with R.sup.11 ;
w is an integer from zero to four;
x is an integer from zero to four;
y is an integer from zero to four;
z is an integer from zero to six and wherein the ring containing (CH.sub.2).sub.z may contain from zero to three double bonds, and one of the carbons of (CH.sub.2).sub.z may optionally be replaced by oxygen, sulfur or nitrogen;
R.sup.1 is hydrogen or (C.sub.1 -C.sub.8) alkyl optionally substituted with hydroxy, alkoxy or fluoro;
R.sup.3 is aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from benzothienyl, benzofuryl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, and quinolyl; or cycloalkyl having from three to seven carbon atoms, wherein one of said carbon atoms may optionall
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Creagan B. Timothy
Ginsburg Paul H.
Gupta Yogendra N.
Pfizer Inc.
Richardson Peter C.
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