Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-10-23
1995-06-27
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
544335, 546280, 5482678, 548151, C07D47104, C07D40512, C07D40312
Patent
active
054281687
DESCRIPTION:
BRIEF SUMMARY
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 conditions including asthma, endotoxin shock, glomerulonephritis, immune regulation, transplant rejection, gastric ulceration, psoriasis, embryo implantation and cerebral, myocardial and renal ischemia.
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 butyrolactol ether derivatives rather than 2,5-diaryl tetrahydrofurans. The compounds of the present invention also differ from the 5-oxy derivatives of tetrahydrofuran described in U.S. Pat. No. 4,888,337 in that they do not contain a quaternised nitrogen heterocycle. The present invention provides novel and useful substituted butyrolactol 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-quaternised sp2 hybridized nitrogen atoms in its ring, which heterocyclic ring may be optionally fused to a benzene ring or to a further 5- or 6-membered aromatic heterocyclic ring 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, C.sub.1 -C.sub.6 alkoxy, halo, CF.sub.3 and CN; atoms which may be a straight or branched-chain having at least 3 carbon atoms in the chain linking W to the oxygen atom, wherein the said group is either unsubstituted or substituted by one or more substituents selected from hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio and halo; or ##STR3## group wherein n is an integer from 0-3, X is O, S or CH.sub.2 and each of R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1 -C.sub.6 alkyl; or from 0-2, r is an integer from 1-3 and U is a phenylene, furandiyl, tetrahydrofurandiyl, thiophenediyl, tetrahydrothiophenediyl, thiazolediyl or tetrahydrothiazolediyl group; ##STR4## group wherein t is an integer from 0-3 and each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, halo, CN, NO.sub.2, SOC.sub.1 -C.sub.6 alkyl, SO.sub.2 C.sub.1 -C.sub.6 alkyl, SO.sub.2 (CH.sub.2).sub.1-4 CH.sub.2 OH, SO.sub.2 NH.sub.2, CO.sub.2 H, CO.sub.2 C.sub.1 -C.sub.6 alkyl, CHO, COC.sub.1 -C.sub.6 alkyl, CH.sub.2 OH, OH, benzyl, benzoyl, CF.sub.3, CONH.sub.2, NHCOC.sub.1 -C.sub.6 alkyl, or an NR.sup.15 R.sup.16 group wherein each of R.sup.15 and R.sup.16 is independently hydrogen or C.sub.1 -C.sub.6 alkyl; and independently hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, halo, C.sub.1 -C.su
REFERENCES:
patent: 4888337 (1989-12-01), Godfroid et al.
Chemical Abstracts, vol. 117, No. 3, Abst. No. 26321Q, Jul. 20, 1992.
Bowles Stephen A.
Davidson Alan H.
Spavold Zoe M.
Whittaker Mark
British Biotech Pharmaceuticals Limited
Rotman Alan L.
LandOfFree
Lactol 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 Lactol PAF antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Lactol PAF antagonists will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-288707