Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-01-24
1998-07-07
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544271, 544311, A61K 3152, C07D47306, C07D23954, C07D23956
Patent
active
057769400
DESCRIPTION:
BRIEF SUMMARY
This application is filed pursuant to 35 U.S.C. .sctn. 371 as a United States National Phase Application of International Application No. PCT/GB95/01808 filed Jul. 31, 1995 which claims priority from GB9415529.8 filed Aug. 1, 1994.
The present invention relates to novel phenyl xanthine derivatives, processes for their preparation, pharmaceutical formulations comprising them, and their use in medicine, particularly in the prophylaxis and treatment of septic shock, allergic, and inflammatory conditions, as well as neurodegeneration.
Septic shock is induced by means of a complex series of events involving many different pathways and mediators of disease response (see for instance, The Lancet, Vol. 338 (1991), p732-739, and annals of internal medicine Vol. 115 (1991), p457-469), including, inter alia, products of arachidonic acid metabolism and platelet aggregation. These mediators are also involved in inflammatory conditions and are now implicated in the neurodegeneration and dementia associated with HIV infection.
The enzymes arachidonate 5-lipoxygenase, arachidonate cyclooxygenase, and lyso-PAF: acetyl -CoA acetyltransferase are all implicated in the mediation of allergic and inflammatory conditions. Inhibitors of each of these enzymes have previously been disclosed, however, there exists a continuing need for further therapies for the treatment of diseases which involve these pathways. Furthermore, some of the compounds of the present invention have been found to inhibit all three of these enzymes and could thus offer the possibility of a synergistic treatment of allergic and inflammatory conditions.
EP-B-0-203-721 describes phenyl xanthine compounds which exhibit activity as adenosine antagonists and are of formula ##STR2## wherein inter alia: X.sub.1 and X.sub.2 are independently selected from hydrogen, C.sub.1-4 alkyl C.sub.2-6 alkenyl and C.sub.7-12 aralkyl; wherein Y is C.sub.2-6 alkenylene and Z is carboxy;
WO 94/03456 discloses further adenosine antagonists of formula ##STR3## wherein inter alia R.sub.1 is hydrogen, C.sub.1-6 alkyl, C.sub.3-6 alkenyl, or C.sub.3-6 alkynyl; alkyl, and C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl;
According to the present invention, there is provided a compound of formula (I): ##STR4## Wherein m and n are independently integers from 0 to 10; X and Y are independently oxygen or sulphur; integer of from 1 to 4; and cycloalkyl or C.sub.3-8 cycloalkenyl; cycloalkyl or C.sub.3-8 cycloalkenyl;
Preferably, X and Y are both oxygen.
Preferably, m and n are independently integers from 0 to 4, more preferably, from 0 to 2.
Preferably Q is --CH.sub.2 CH.sub.2 -- or --CH.dbd.CH--, most preferably --CH.dbd.CH--.
Preferably the invention provides a compound wherein;
Most preferably the invention provides a compound wherein A and B are both C.sub.3-8 cycloalkyl, particularly cyclohexyl.
The compounds of the present invention are capable of existing as geometric and optical isomers. All such isomers, individually and as mixtures, are included within the scope of the present invention. Compounds in the form of the E-geometric isomers are preferred.
Particularly prefered compounds of the invention include 6-dioxo-9H-purin-8-yl)cinnamic acid; and }cinnamic acid;
Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent, ie acidic, compounds. Such salts must clearly have a physiologically acceptable cation. Suitable physiologically acceptable salts of the compounds of the present invention include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth salts such as magnesium and calcium salts and salts formed from organic bases, for example amino salts derived from mono-, di, or tri- (lower alkyl) amines; basic amino acids such as lysine, or (lower alkanol) amines such as triethanolamine and salts with heterocyclic amines such as piperidine, pyridine, piperazine and morpholine. The sodium and ammonium salts are particularly preferred for medical purposes. Salts having a non-
REFERENCES:
patent: 4980379 (1990-12-01), Belardinelli
patent: 5015647 (1991-05-01), Daluge et al.
patent: 5300298 (1994-04-01), La Noue
Daluge Susan Mary
White Helen Lyng
Berch Mark L.
DeWitt LaVonda R.
Glaxo Wellcome Inc.
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