Heterocyclic sulfonamide derivatives as antagonists of PAF and a

Details Heterocyclic sulfonamide derivatives as antagonists of PAF and a Heterocyclic sulfonamide derivatives as antagonists of PAF and a

1994-09-01

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...

514262, 514303, 514398, 514399, 514602, 544264, 544265, 546118, 546 14, 5483391, 5483395, 5483421, 5483425, 5483431, 564 85, 564 88, 564 92, 564 93, A61K 31435, A61K 31505, C07D47104, C07D40302

Patent

active

057417946

DESCRIPTION:

BRIEF SUMMARY
This invention relates primarily to novel substituted amino acid derivatives that possess pharmaceutical activity as antagonists of PAF and/or as antagonists of angiotensin II.
Platelet activating factor (PAF) is a bioactive phospholipid which has been identified as 1-O-hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphoryl choline. PAF is released directly from cell membranes and mediates a range of potent and specific effects on target cells resulting in a variety of physiological responses which include hypotension, thrombocytopenia, bronchoconstriction, circulatory shock, and increased vascular permeability (oedema/erythema). It is known that these physiological effects occur in many inflammatory and allergic diseases and PAF has been found to be involved in a number of such disorders including asthma, endotoxin shock, adult respiratory distress syndrome, glomerulonephritis, immune regulation, transplant rejection, gastric ulceration, psoriasis, and cerebral, myocardial and renal ischemia. Thus the compounds of the invention, by virtue of their ability to antagonise the actions of PAF, should be of value in the treatment of any of the above conditions and any other conditions in which PAF is implicated (e.g. embryo implantation).
Compounds which have been disclosed as possessing activity as PAF antagonists include compounds which are structurally related to the PAF molecule such as glycerol derivatives (EP-A-0238202), and heterocyclic compounds such as 2,5-diaryl tetrahydrofurans (EP-A-0144804) and imidazopyridine derivatives (EP-A-0260613 and WO-A-8908653).
Angiotensin II is a bioactive octapeptide which is formed from angiotensin I by the action of angiotensin converting-enzyme. Angiotensin H is a powerful vasopressor agent which has been implicated as a causative agent of high blood pressure in various mammalian species, such as the rat, dog and man. Angiotensin II elevates blood pressure via binding to specific angiotensin II receptors on cell membranes. Thus the compounds of the invention, by virtue of their ability to antagonise the actions of angiotensin H, should be of value in the treatment of elevated blood pressure and congestive heart failure, glaucoma and intraocular hypertension, cognitive dysfunction, psoriasis and any other conditions in which angiotensin II is implicated.
Compounds which have been disclosed as possessing activity as angiotensin II antagonists include compounds which are structurally related to the angiotensin II peptide, but the experimental and clinical applications of these compounds have been limited by partial agonist activity (M. A. Ondetti and D. W. Cushman, Annual Reports in Medicinal Chemistry, 1978, 13, 82-91). Recently, several non-peptide compounds have been described as angiotensin II antagonists. Illustrative of such compounds are heterocyclic substituted biphenyl derivatives (D. J. Carini et al., J. Med. Chem., 1991, 34, 2525-2547; P. R. Bovy et al., Med. Chem. Res., 1991, 1, 86-94) and heterocyclic substituted benzofurans (EP-A-434,249).
The present invention provides novel and useful substituted sulphonyl amino acid derivatives and their pharmaceutically acceptable acid addition salts, and pharmaceutical uses thereof as PAF antagonists and angiotensin II antagonists.
According to a first aspect of the invention there is provided a compound of general formula I; ##STR1## wherein: A represents: --CH.sub.2 O--, --CH.sub.2 OC(.dbd.O)--, --C(.dbd.S)--, --CH.sub.2 OC(.dbd.O)NH--, --C(.dbd.S)O--, --CH.sub.2 S--, --C(.dbd.O)NHSO.sub.2 --, --SO.sub.2 NHC(.dbd.O)-- or --CH.sub.2 OSiPh.sub.2 --; and --C.sub.2 -C.sub.18 alkynyl, --(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)SC.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.6 alkyl)O(C.sub.1 -C.sub.6 alkyl)OC.sub.1 -C.sub.6 alkyl, --C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkenyl or pyridyl, (any of which may optionally be substituted with one or more substituents selected from halogen, hydroxyl, nitro, nitrile or carboxyl), C.sub.1 -C.sub.4 perfluoroalkyl, a group --D or a --(C.s

REFERENCES:
patent: 5180723 (1993-01-01), Whittaker et al.
John V. Duncia, et al., Three Synthetic Routes to a Sterically Hindered Tetrazole. A New One-Step Mild Conversion of an Amide into a Tetrazole., J. Org. Chem., 56, pp. 2395-2400 (1991).

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