Bridges – Draw – Locking devices
Patent
1999-02-01
2000-10-17
Rotman, Alan L.
Bridges
Draw
Locking devices
51425301, 51425303, 51425304, 544333, 544362, 544365, A61K 31495, A61K 314436, A61K 31439, C07D40106, C07D40306
Patent
active
061312266
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel 1,4-dihydropyridine compounds, and more particularly to 1,4-dihydropyridine compounds having a substituted or unsubstituted-carbamoylmethyl 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, B.sub.1 and B.sub.2. The actions of BK at the B. 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, such as increases in vascular permeability, pain, and vasodilatation, however, are mediated by the B.sub.2 receptor. These effects at the B.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 B.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 B.sub.2 receptor, having a good B.sub.2 antagonistic activity and a good metabolic stability.
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; X is CO, S(O).sub.2 or S(O)--(CH.sub.2)n wherein S atom is directly attached to the phenyl and n is 0, 1 or 2 (preferably n is 0); and R.sup.1 is 8-azabicyclo[3.2.1]octyl, quinuclidinyl, bicyclo[3.3.0]octyl, C.sub.3-10 cycloalkyl, 2,3,5,6-tetrahydro-4H-thiopyranyl or C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl, optionally substituted with C.sub.1-4 alkyl, hydroxy, dioxolanespiro or oxo.
The dihydropyridine compounds of this invention have excellent bradykinin antagonistic activity and are thus useful for the treatment of medical conditions caused by bradykinin such as 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 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 (1) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
The present also provides a method for the treatment of disease conditions caused by bradykinin, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (1).
DETAILED DESCRIPTION OF THE INVENTION
Preferably, A.sup.1 and A.sup.2 are chloro.
Preferably, R.sup.1 is 8-methyl-8-azabicyclo[3.2.1]oct-3-yl, quinuclidin-3-yl, 3-hydroxy-bicyclo[3.3.0]oct-7-yl, [1-(hydroxy) cyclopentyl]ethyl or 3-oxo-bicyclo[3,3,0]oct-7-yl.
Among the dihydropyridine compounds of this invention, preferred individual compounds are: 4-(2,6-dichlorophenyl)-2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piper azinyl]carbonylmethyl-6-phenylsulfinylmethy
REFERENCES:
patent: 5859011 (1999-01-01), Ito et al.
patent: 5861402 (1999-01-01), Ikeda
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Rotman Alan L.
Waldron Roy F.
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