Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-03-15
1997-04-08
Nazario-Gonzalez, Porfirio
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549 6, 549504, 549491, 549497, 560147, 560157, C07C31119, C07C23351, A61K 3119
Patent
active
056189419
DESCRIPTION:
BRIEF SUMMARY
This application is filed under 35 U.S.C. .sctn.371 based on PCT/EP93/02488, which was filed on Sep. 14, 1993 which claims priority from Great Britain application 9220137.5 which was filed on Sep. 23, 1992.
This invention relates to certain di-substituted benzenealkanoic acids. Such compounds are able to selectively antagonise the effect of thromboxane A.sub.2 (TXA.sub.2), and its precursor prostaglandin H.sub.2 (PGH.sub.2) at the thromboxane receptor. The compounds are thus useful as therapeutic agents and they may be used either alone, or preferably in combination with a thromboxane synthetase inhibitor, for example in the treatment of atherosclerosis and unstable angina and for prevention of reocclusion, both acute and chronic, after percutaneous transluminal coronary and femoral angioplasty. The combination may also find clinical utility in a further variety of disease conditions in which thromboxane A.sub.2 has been implicated such as in the treatment of myocardial infarction, stroke, cardiac arrhythmias, transient ischaemic attack, tumour metastasis, peripheral vascular disease, bronchial asthma, renal disease, cyclosporin-induced neprotoxicity, renal allograft rejection, vascular complications of diabetes and endotoxin shock, trauma, pre-eclampsia and in coronary artery bypass surgery and haemodialysis.
The compounds of the invention are of formula: ##STR1## and pharmaceutically acceptable salts and biolabile esters thereof, wherein -C.sub.4 alkyl; NHCOR.sup.6 ; substituted by aryl, aryl or heteroaryl; selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, OCF.sub.3, CN, CONH.sub.2 and S(O).sub.n (C.sub.1 -C.sub.4 alkyl);
In the above definition aryl means phenyl or naphthyl, and heteroaryl means furyl, thienyl or pyridyl, any of which ring systems may optionally be substituted with one to three substituents each independently chosen from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo, CF.sub.3, OCF.sub.3 and CN. Unless otherwise indicated, alkyl and alkoxy groups having three or more carbon atoms may be straight-chain or branched-chain. Halo means fluoro, chloro, bromo or iodo.
Compounds containing asymmetric centres can exist as enantiomers and diastereisomers, and the invention includes the separated individual isomers as well as mixtures of isomers.
Also included in the invention are radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
The term biolabile ester in the above definition means a pharmaceutically acceptable, biologically degradable ester derivative of a compound of formula (I), that is a prodrug which, upon administration to an animal or human being, is converted in the body to a compound of formula (I). In the case of the compounds of formula (I), such biolabile ester prodrugs are particularly advantageous in providing compounds of formula (I) suitable for oral administration. The suitability of any particular ester-forming group can be assessed by conventional in vivo animal or in vitro enzyme hydrolysis studies. Thus desirably, for optimum effect, the ester should only be hydrolysed after absorption is complete. Accordingly, the ester should be resistant to premature hydrolysis by digestive enzymes before absorption, but should be productively hydrolysed by, for example, gut-wall, plasma or liver enzymes. In this way, the active acid is released into the bloodstream following oral absorption of the prodrug.
Suitable biolabile esters may include alkyl, alkanoyloxyalkyl, cycloalkanoyloxyalkyl, aroyloxyalkyl and alkoxycarbonyloxyalkyl esters, including cycloalkyl and aryl substituted derivatives thereof, aryl esters and cycloalkyl esters, wherein said alkyl, alkanoyl or alkoxy groups may contain from 1 to 8 carbon atoms and be branched-chain or straight-chain, said cycloalkyl groups may contain from 3-7 carbon atoms and said cycloalkanoyl groups from 4-8 carbon atoms wherein both are optionally benzo-fused, and said aryl and aroyl groups include substituted phenyl, naphthyl or indanyl ring systems. Preferab
REFERENCES:
patent: 4258058 (1981-03-01), Witte et al.
patent: 4443477 (1984-04-01), Witte et al.
Dack Kevin N.
Dickinson Roger P.
Steele John
Benson Gregg C.
Jones Dwayne C.
Nazario-Gonzalez Porfirio
Olson A. Dean
Pfizer Inc.
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