Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-12-30
1997-06-10
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142342, 5142355, 5142368, 514300, 514336, 514337, 514374, 544124, 544127, 544133, 546118, 546121, 5462801, 5462817, 5462821, 5462834, 548203, C07D47104, C07D40512, A61K 3144, A61K 31425
Patent
active
056375956
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB92/01189 filed July 1, 1992. 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, glomerulonephfitis, 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 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 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).
The compounds of the present invention differ from those such as L-659,989, in that they are substituted lactol ether derivatives rather than 2,5-diaryl tetrahydrofurans. The compounds of the present invention also differ from the 5-oxy derivatives of tetrahydofuran described in U.S. Pat. No. 4,888,337 in that they do not contain a quaternised nitrogen heterocycle and from the derivatives described in U.S. Pat. No. 4,888,337 in that they do not contain a quaternary ammonium group. The present invention provides novel and useful substituted lactol ether 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; ##STR2## wherein:
W represents a 5- or 6-membered aromatic heterocyclic ring containing one or more non-quatemised sp2 nitrogen atoms in its ting, which heterocyclic ring may be optionally fused to a benzene ring or to a further 5- or 6-membered aromatic heterocyclic ting containing one or more nitrogen atoms, wherein at least one of the said heterocyclic rings may also contain an oxygen or sulphur atom, and wherein any of the rings may be optionally substituted with one or more substituents selected from --C.sub.1 -C.sub.6 alkyl, --OC.sub.1 -C.sub.6 alkyl, halo, --CF.sub.3 and --CN;
Z represents a) a divalent alkanediyl group from 1 to 8 carbon atoms which may be a straight or branched-chain, wherein the said group is either unsubstituted or substituted by one or more substituents selected from hydroxy, --OC.sub.1 -C.sub.6 alkyl, --SC.sub.1 -C.sub.6 alkyI and halo; or
b) a divalent alkenediyl or alkynediyl group from 2 to 8 carbon atoms which may be a straight or branched-chain, wherein the said group is either unsubstituted or substituted by one or more substituents selected from hydroxy, --OC.sub.1 -C.sub.6 alkyl, --SC.sub.1 -C.sub.6 aIkyl and halo;
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 each represents a hydrogen atom, a --C.sub.1 -C.sub.18 alkyl or a --C.sub.2 -C.sub.18 alkenyl group;
or R.sup.3 and R.sup.5 together with the carbon atoms to which they are attached can form a five to ten membered monocycloalkyl or bicycloalkyl ring which may be optionally substituted wi
REFERENCES:
patent: 4888337 (1989-12-01), Godfroid et al.
Whittaker et al. (1992), Curr. Opin. Thera. Patents, vol. 2, pp. 583-623.
Kishimoto CA 108: 221494 (EP 249170) Dec. 16, 1987.
Bowles Stephen A.
Miller Andrew
Whittaker Mark
British Bio-technology Limited
Raymond Richard L.
LandOfFree
Cyclic ether acetal PAF antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cyclic ether acetal PAF antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyclic ether acetal PAF antagonists will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-764837