Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-12-20
1998-02-10
Wu, Shean C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546133, 546134, 546135, 546136, 546137, A61K 31445, C07D45302
Patent
active
057169659
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 PCT/US 92/04002 filed May 19, 1992.
BACKGROUND OF THE INVENTION
This invention relates to novel and useful quinuclidine derivatives of interest to those in the field of medical chemistry. More particularly, it is concerned with a novel series of substituted 3-aminoquinuclidines, including their pharmaceutically acceptable salts, which are of special value in view of their ability to antagonize substance P. These compounds are useful in treating gastrointestinal disorders, central nervous system disorders, inflammatory diseases, asthma, pain and migraine. The invention also includes a new method of therapy within its scope.
E. J. Warawa, in U.S. Pat. No. 3,560,510, discloses certain 3-amino-2-benzhydryl-quinuclidines as being useful as diuretic agents, with the corresponding unsubstituted 3-benzylamino compounds acting as intermediates for same. Additionally, E. J. Warawa et al. in the Journal of Medicinal Chemistry, Vol.18, p.587 (1975) extends this work to other members of the series wherein the 3-amino moiety is ethylamino, .beta.-phenylethylamino, .beta.-isopropylamino, or 2-furfurylamino.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt stimulatory action on smooth muscle tissue. More specially, substance P is a pharmaceutically 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, Vol. 25, p.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, and in gastrointestinal disorders and diseases of the GI tract, like ulcerative colitis and Crohn's diseases, etc. (see D. Regoli in "Trends in Cluster Headache" edited by F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, pages 85-95).
In the recent past, some attempts have been made to provide peptide-like substances that are antagonists for substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases listed above. The peptide-like nature of such substances renders them 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 peptic-like prior art agents.
Other non-peptide substance P receptor antagonists are referred to in pending patent applications assigned in common with the present application. 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 published as WO 90/05729 on May 31, 1990, and U.S. patent application Ser. No. 557,442, filed Jul. 23, 1990. Other quinuclidine derivatives and related compounds that exhibit activity as substance P receptor antagonists are referred to in the PCT patent applications entitled "3-Amino-2-Aryl Quinuclidines" and "Quinuclidine Derivatives" and filed, respectively, on Apr. 25, 1991 and May 15, 1991. 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. Azanorbornane derivatives that exhibit activity as substance P receptor antagonists are referred to in U.S. patent app
REFERENCES:
patent: 5569662 (1996-10-01), Satake et al.
patent: 5604241 (1997-02-01), Ito et al.
CA114:81592, Lowe, "Preparation of 3-amino-2 benzyl quinuclidines as substance P antagonists", PCT WO 9005525 May 31, 1990.
Ito Fumitaka
Kokura Toshihide
Nakane Masami
Satake Kunio
Wakabayashi Hiroaki
DeBenedicts Karen
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Wu Shean C.
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