Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-07-01
1999-01-12
Fan, Jane
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514255, 514256, 544365, 544362, 544333, C07D40106, A61K 3150
Patent
active
058590110
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/IB95/00400 filed May 26, 1995.
TECHNICAL FIELD
This invention relates to novel 1,4-dihydropyridine compounds, and more particularly to 1,4-dihydropyridine compounds having a substituted or unsubstituted-piperazinylcarbonylmethyl group attached to the 2-position of the dihydropyridine ring. These compounds are useful as antagonists of bradykinin, and are thus useful in the treatment of inflammation, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma or the like in mammalia, especially humans. The present invention also relates to a pharmaceutical composition useful in the treatment of the above clinical conditions, which comprises the 1,4-dihydropyridine compound of the invention and a pharmaceutically acceptable carrier.
BACKGROUND ART
Bradykinin ("BK") is generated under normal conditions in mammalia by the action of various plasma enzymes such as kallikrein on high molecular weight kininogens. It is widely distributed in mammals, as are its two receptor subtypes, BK.sub.1 and BK.sub.2. The actions of BK at the BK1 receptor include mainly contraction of arterial and venous preparations, although it can cause relaxation of peripheral resistance vessels as well.
Many of the more important functions of BK, as increases in vascular permeability, pain, and vasodilatation, however, are mediated by the BK2 receptor. These effects at the BK.sub.2 receptor are believed to be responsible for BK's role in numerous diseases, such as inflammation, cardiovascular disease, pain, and the common cold. Hence antagonists at the BK.sub.2 receptor should find considerable therapeutic applications. Most of the efforts in this area thus far have been directed at peptidic analogues of the BK structure, some of which have been studied as analgesics and antiinflammatory agents.
It would be desirable if there were provided a non-peptide antagonist of the BK.sub.2 receptor, having a good BK.sub.2 antagonistic activity and a good metabolic stability. A variety of dihydropyridine compounds have been synthesized in the field of antihypertensive agents. However, none of these dihydropyridine compounds have been reported as bradykinin antagonists.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the formula: ##STR2## and its pharmaceutically acceptable salts, wherein A.sup.1 and A.sup.2 are each halo; substituents selected from hydroxy, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, pyridyl, carbamoyl, pyrrolidinocarbonyl, propylaminocarbonyl, piperidinocarbonyl or morpholinocarbonyl; alkyl or C.sub.1-4 alkoxycarbonyl; substituted with one or two substituents selected from oxo, hydroxy, amino, C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino, methoxybenzamido or morpholino; nitrogen atom optionally has a substituent selected from C.sub.1-4 alkyl, benzyl optionally substituted with one or two substituents selected from halo and trihalo C.sub.1-4 alkyl, C.sub.1-4 alkyloxycarbonyl optionally substituted with one or two halogen atoms and C.sub.2-5 acyl; and as herinafter defined; one or two substituents selected from halo, C.sub.1-4 alkyl, trihalo C.sub.1-4 alkyl and C.sub.1-4 alkoxy, or heterocyclic as herinafter defined; and
The dihydropyridine compounds of this invention have excellent bradykinin antagonistic activity and are thus useful for the treatment of inflammation, cardiovascular diseas, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma or the like in mammalia, especially humans.
The present invention also provides a pharmaceutical composition for the treatment of inflammation, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma or the like, which comprises a therapeutically effective amount of the dihydropyridine compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION
REFERENCES:
patent: 5120750 (1992-06-01), Daneshtalab et al.
patent: 5162497 (1992-11-01), Coy et al.
patent: 5610142 (1997-03-01), Mavunkel et al.
Principles pf psychopharmacology Academic Press, Clark et al. p. 166, 1970.
Hageman David L.
Ito Fumitaka
Kondo Hiroshi
Lowe, III John A.
Nakanishi Susumu
Fan Jane
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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