Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-12-14
1998-06-30
Wu, Shean C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514331, 514336, 514344, 514345, 514438, 514461, 514468, 546223, A61K 31445, C07D21156
Patent
active
057734500
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This application is a 371 of PCT/US92/03571 filed May 5, 1992.
The present invention relates to novel fluoroalkoxybenzylamino 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. This invention also relates to novel intermediates used in the synthesis of such 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)).
In the recent past, some attempts have been made to provide antagonists for substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases listed above. The few such antagonists thus far described are generally peptide-like in nature and are therefore too labile from a metabolic point of view to serve as practical therapeutic agents in the treatment of disease. The non-peptidic antagonists of the present invention, on the other hand, do not possess this drawback, being far more stable from a metabolic point of view than the agents referred to above.
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, both of which are assigned in common with the present application. Similar compounds are referred to in PCT patent applications PCT/US 91/02853 and PCT/US 91/03369, filed on Apr. 25, 1991 and May 15, 1991, respectively. These applications are also assigned in common with the present application.
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 and U.S. patent application Ser. No. 590,423, filed Sep. 28, 1990, both of which are assigned in common with the present application.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula ##STR2## wherein X.sup.1 is hydrogen, (C.sub.1 -C.sub.10) alkoxy optionally substituted with from one to three flourine atoms or (C.sub.1 -C.sub.10) alkyl optionally substituted with from one to three fluorine atoms; (C.sub.1 -C.sub.10) alkyl optionally substituted with from one to three fluorine atoms, (C.sub.1 -C.sub.10) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C.sub.1 -C.sub.6)-alkylamino, di-(C.sub.1 -C.sub.6)alkylamino, ##STR3## hydroxy(C.sub.1 -C.sub.4) alkyl, (C.sub.1 -C.sub.4)alkoxy(C.sub.1 -C.sub.4) alkyl, ##STR4## and Q is a group of
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CA 115:232089 (EP 436334 Jul. 10, 1991).
Lowe, III John Adams
Rosen Terry Jay
DeBenedictis Karen
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Wu Shean C.
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