Indole derivatives thromboxane A2 antagonists

Details Indole derivatives thromboxane A2 antagonists Indole derivatives thromboxane A2 antagonists

1996-02-23

1998-04-28

Fan, Jane

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514397, 514415, 5462774, 548503, 548483, 5483121, A61K 3144, C07D40106

Patent

active

057444889

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

This invention relates to certain indole alkanoic 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. In addition, certain of the compounds also selectively inhibit the thromboxane synthetase enzyme. The compounds are thus useful as therapeutic agents and they may be used either alone, or, in the case of compounds which do not inhibit the thromboxane synthetase enzyme, preferably in combination with a thromboxane synthetase inhibitor, for example in the treatment of atherosclerosis and unstable angina and for prevention of reocculsion, both acute and chronic, after percutaneous transluminal coronary and femoral angioplasty. The compounds 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 isohaemic 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.


SUMMARY OF THE INVENTION

The compounds of the invention are of formula (I): ##STR2## and pharmaceutically acceptable salts and biolabile esters thereof, wherein R.sup.1 is H, C.sub.1 -C.sub.4 alkyl, phenyl optionally substituted by up to three substituents independently selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen and CF.sub.3, or is 1-imidazolyl, 3-pyridyl or 4-pyridyl; alkyl, C.sub.1 -C.sub.3 perfluoralkyl(CH.sub.2).sub.p, C.sub.3 -C.sub.6 cycloalkyl(CH.sub.2).sub.p, aryl(CH.sub.2).sub.p or heteroaryl(CH.sub.2).sub.p, p being 0, 1 or 2, or R.sup.4 may be NR.sup.5 R.sup.6 where R.sup.5 is H or C.sub.1 -C.sub.4 alkyl and R.sup.6 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl or aryl, or R.sup.5 and R.sup.6 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic ring which may optionally incorporate a carbon-carbon double bond or a further heteroatom linkage selected from O, S, NH, N(C.sub.1 -C.sub.4 alkyl) and N(C.sub.1 -C.sub.5 alkanoyl); 1-imidazolyl then X is CH.sub.2 ; 5-position when n is 0 or 1, or at the 5- or 4-position when n is 2.
In the above definitions "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. 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, g

REFERENCES:
patent: 4474967 (1984-10-01), Sarges
R. B. Silverman, in "The Synthesis of Radioactive Compounds," The Organic Chemistry of Drug Design and Drug Action, Academic Press, a division of Harcourt Broce & Company, San Diego, California, 1992, pp. 279-284.

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