Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-11-20
1998-04-21
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546133, C07D40302, C07D45302, A61K 31435
Patent
active
057417970
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/JP94/00781, filed May 13, 1994.
TECHNICAL FIELD
This invention relates to novel and useful substituted alkyl benzylaminoquinuclidine compounds of interest to those in the field of medical chemistry and chemotherapy. More particularly, it is concerned with a novel series of heteroatom substituted alkyl benzylaminoquinuclidines, including the pharmaceutically acceptable salts and pharmaceutical composition thereof, 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, migraine or emesis in mammalia. The invention also includes a new method of therapy within its scope.
BACKGROUND ART
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., J. Med. Chem., 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, and in gastrointestinal disorders and diseases of GI tract, such as ulcerative colitis and Crohn's diseases (see D. Regoli in "Trends in Cluster Headache" edited by F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, PP. 85-95).
It is recently reported that substance P antagonists are effective for treatment of emesis (EP 0533280 A). In addition the relationship between substance P and sunburn has been discussed.
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 draw back, being far more stable from a metabolic point of view.
Among the prior art relating to compounds of similar structure and similar pharmacological activity to the object compounds of the present invention, there are WO 90/05729, WO 92/20676 and JP application No. 307179/92. WO 90/05729 discloses a series of quinuclidines including 2-benzhydryl derivatives, 2-substituted benzhydryl derivatives (wherein the substituents are alkyl, alkoxy, halogen and the like), 2-(bis-(2-thienyl)methyl) derivatives and the like. In WO 92/20676 benzylamino!-2-benzhydrylquinuclidine compounds, which include 4-alkenyl derivatives, 6-phenethyl derivatives, 5- and 6-dialkylaminocarbonyl derivatives, 5-dialkylaminoalkyl derivatives, 5- and 6-hydroxyalkyl derivatives, 5-alkylaminocarbonyl derivatives, 5-aminocarbonyl derivatives, 5- and 6-carboxyl derivatives, 5- and 6-alkoxycarbonyl derivatives, 5-(N-alkoxy-N-alkyl)aminocarbonyl derivatives and 5-morpholinocarbonyl derivatives and the like, are disclosed. Additionally, the compounds disclosed in that patent application have various kind of substituents also at 5-position on the benzene ring in benzylamino moiety, i.e. alkoxy such as methoxy, alkyl such as isopropyl, alkylthio such as methylthio, halosubstituted alkoxy such as trifluoromethoxy, halogen, alkylsulfinyl such as methylsulfinyl, dialkylamino such as dimethylamino and the like. JP application No. 307179/92 discl
REFERENCES:
patent: 5294744 (1994-03-01), Godek et al.
Creagan B. Timothy
Ginsburg Paul H.
Grumbling Matthew V.
Pfizer Inc.
Richardson Peter C.
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