Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-10-03
1996-10-29
Lovering, Richard D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546133, C07D45302, A61K 31445
Patent
active
055696627
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel and useful peptidic quinuclidine derivatives of interest to those in the field of medical chemistry and chemotherapy. More particularly, it is concerned with a novel series of peptidic substituted 3-aminoquinuclidine, including their pharmaceutically acceptable salts and pharmaceutical compositions comprising such compounds, which are of special value in view of their ability to antagonize substance P. In this way, these compounds are of use in treating gastrointestinal disorders, central nervous system disorders, inflammatory diseases, asthma and pain or migraine.
BACKGROUND ART
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 either ethylamino, .beta.-phenylethyl amino, .beta.-isopropylamino, or 2-furfurylamino, but in no instance is there any substitution on the phenyl group itself and the 2-benzhydryl moiety is always symmetrically substituted (or unsubstituted).
Furthermore, neither of the aforementioned documents teaches or suggests any of these compounds to be useful as substance P antagonists.
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 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, pp. 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 make 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 previously-discussed prior art agents.
Among documents of interest regarding the present invention, there are WO 90/05729 (corresponding to U.S. Pat. No. 5,162,339), JP (appln.) 325237/91 (corresponding to PCT Patent Publication No. WO 92/20676) and JP (appln.) 065337/92. (All documents cited herein, including the foregoing, are incorporated herein by reference in their entireties for all purposes.)
Particularly, WO 90/05729 discloses a series of cis-3-[(cyclic)methylamino]-2-[(.alpha.-substituted)arylmethyl]quinuclidin es including 2-benzhydryl derivatives, 2-substituted benzhydryl derivatives (wherein the substituents were alkyl, alkoxy, halogen and the like), 2-(bis-(2-thienyl)methyl) derivatives and the like.
JP (appln.) 325237/91 discloses mainly a series of 3-[2-methoxy-5-(substituted)benzylamino]-2-benzhydryl quinuclidines including 4-alkenyl derivatives, 6-ph
REFERENCES:
CA 119: 95339 (JP 91-146826) 910522 (1991).
Nakane Masami
Satake Kunio
Wakabayashi Hiroaki
Butterfield Garth
Ginsburg Paul H.
Kilby Scalzo Catherine
Lovering Richard D.
Pfizer Inc.
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