Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-07-20
1992-11-10
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514816, 546133, 546134, 546135, 546136, 424 11, C07D45302, C07D23902, A61K 31445, A61K 31505
Patent
active
051623390
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to new and useful quinuclidine derivatives of interest to those in the field of medicinal chemistry and chemotherapy. More particularly, it is concerned with a novel series of cis-3-[(cyclic)methylamino]-2-[(.alpha.-substituted)arylmethyl]quinuclidin es, 3-[(cyclic)methylimino]-2-[.alpha.-substituted)arylmethyl]quinuclidines and cis-3-[(cyclic)methyleneamino]-2](.alpha.-substituted)arylmethyl]quinuclid ines, including their pharmaceutically acceptable salts, which are of especial 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 and pain or migraine. The invention also includes a new method of therapy within its scope.
BACKGROUND ART
E. J. Warawa in U.S. Pat. No. 3,560,510 discloses certain 3-amino-2-benzhydrylquinuclidines 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.-phenylethylamino, .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 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, 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 disease, 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 posses this drawback, being far more stable from a metabolic point of view than the previously-discussed prior art agents.
DISCLOSURE OF THE INVENTION
In accordance with the present invention, it has now been surprisingly found that various novel cis-3-[cyclic]methylamino-2-[(.alpha.-substituted)arylmethyl]quinuclidine compounds, as well as the corresponding cis-3-[(cyclic)methylamino]-2-[(.alpha.-substituted)arylmethyl]quinuclidin es and cis-3-[(cyclic)methyleneamino]-2-[(.alpha.-substituted)arylmethyl]quinucli dines, are useful when employed in therapy as substance P antagonists for treating gastrointestinal disorders, central nervous system disorders, inflammatory diseases and pain or migraine in a mammalian subject so afflicted. More specifically, the
REFERENCES:
patent: 3560510 (1971-02-01), Warawa
patent: 3917612 (1975-11-01), Grethe et al.
patent: 4657911 (1987-04-01), Imbert et al.
Snider ". . . Antagonist of Substance P", Science, vol. 251, pp. 435-437, Jan. 25, 1991.
Cintins Marianne M.
DeBenedictis Karen
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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