Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-10-27
1996-05-14
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546118, A61K 31435, C07D47104
Patent
active
055167837
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/00273 filed Feb. 10, 1993.
This invention relates primarily to novel compounds which are antagonists of platelet activating factor.
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, 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 that 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 5-oxy derivatives of tetrahydrofuran (U.S. Pat. No. 4,888,337) and 2,5-diaryl tetrahydrofurans (EP-A-0144804). Recently a more potent 2,5-diaryl tetrahydrofuran derivative, (trans)-2-(3-methoxy-5-methylsulphonyl-4-propoxyphenyl)-5-(3,4,5-trimethox yphenyl)tetrahydrofuran (L-659,989) has been disclosed (EP-A-0199324). In our International patent application No. WO 91/17157 we disclose a series of .gamma.-butyrolactol derivatives as PAF antagonists. The compounds of WO 91/17157 differ from the 5-oxy derivatives of tetrahydofuran described in U.S. Pat. No. 4,888,337 and from the 2,5-diaryl tetrahydrofurans such as L-659,989, in that they feature an appended heterocycle with an unsubstituted sp.sup.2 nitrogen atom. There are a number of other PAF antagonists, in addition to those of WO 91/17157, for which the presence of a heterocyclic sp.sup.2 nitrogen atom appears to be an important requirement for activity (Whittaker, M., Curr. Opin. Thera. Patents 2(5), 583-623 (1992)).
For the compounds of the present invention the presence of a heterocyclic group possessing an unsubstituted sp.sup.2 nitrogen atom is also a requirement for PAF antagonist activity. However, the compounds of the present invention differ from the other PAF antagonists referred to above in that they are amino acid derivatives.
The present invention provides novel and useful substituted amino acid derivatives and their pharmaceutically acceptable acid addition salts, and pharmaceutical uses thereof as PAF antagonists.
According to a first aspect of the invention there is provided a compound of general formula I; ##STR1## wherein: R.sup.1 represents hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, --COC.sub.1 -C.sub.6 alkyl, --CO.sub.2 C.sub.1 -C.sub.6 alkyl, --(COC.sub.1 -C.sub.6 alkyl)phenyl, --(CO.sub.2 C.sub.1 -C.sub.6 alkyl)phenyl, --(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)CO.sub.2 C.sub.1 -C.sub.6 alkyl, --C.sub.3 -C.sub.8 cycloalkyl, --C.sub.4 -C.sub.8 cycloalkenyl or a group --D wherein D represents a group: ##STR2## wherein n is an integer from 0 to 3, and each of R.sup.3 and R.sup.4 is independently hydrogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.2 -C.sub.6 alkenyl, --C.sub.2 -C.sub.6 alkynyl, halogen, --CN, --CO.sub.2 H, --CO.sub.2 C.sub.1 -C.sub.6 alkyl, --CONH.sub.2, --CONHC.sub.1 -C.sub.6 alkyl, --CONH(C.sub.1 -C.sub.6 alkyl).sub.2, --CHO, --CH.sub.2 OH, --CF.sub.3, --OC.sub.1 -C.sub.6 alkyl, --SC.sub.1 -C.sub.6 alkyl, --SOC.sub.1 -C.sub.6 alkyl, --SO.sub.2 C.sub.1 -C.
Bowles Stephen A.
Miller Andrew
Whittaker Mark
British Biotech Pharmaceuticals Limited
Dentz Bernard
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