Compounds

Details Compounds Compounds

1998-06-10

2000-12-19

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514274, 544298, 544301, A61K 31505, C07D23902, C07D40300

Patent

active

061628085

DESCRIPTION:

BRIEF SUMMARY
The invention provides new pharmaceutically active compounds, compositions containing them and processes for their preparation. The compounds are useful in therapy because they are P2-purinoceptor 7-transmembrane (TM) G-protein coupled receptor antagonists.
ATP receptors have been shown to be present on a wide number of different cell types (Dubyak et al Am J Physiol (1993) 265, C577-C606). Neutrophils, monocytes and macrophages have been isolated from several species including humans and ATP and/or UTP have been shown to increase intracellular calcium levels. Activation of these receptors on leukocytes can either directly stimulate certain types of inflammatory response or can prime the effector cells to other inflammatory mediators in vivo. ATP can upregulate the expression of adhesion molecules (Freyer et al J Immun. (1988) 141, 580-586) which causes enhanced adhesion of circulating leukocytes to endothelial cells and their enhanced migration into the tissue space. ATP has also been shown to promote chemotaxis of both neutrophils and eosinophils (Verghese et al J. B. C. (1996) 271, 15597-15601 and Burders et al Blood (1993) 81, 49-55) which may promote an inflammatory response. ATP priming of neutrophils can also potentiate superoxide production (Seifert et al Eur J Biochem (1989) 181, 277-285). ATP receptors are also present on a number of other cell types such as chondrocytes, keratinocytes, microglia and goblet cells (Leong et al BBA (1994) 1201, 298-304; Pillai et al J Clin Invest (1992) 90, 42-51; Walz et al J Neuroscience (1993) 13, 4403-4411 and Abdullah et al Biochem J (1996) 316, 943-951). Stimulation of the receptors on these cells can stimulate or enhance inflammatory responses and antagonist of the receptor may therefore be of use in a number of inflammatory diseases such as asthma, inflammatory bowel disease, ARDS, psoriasis, rheumatoid arthritis, myocardial ischaemia, COPD, cystic fibrosis, arthereosclerosis, restenosis, peridontal disease, septic shock, osteoarthritis and stroke. ATP receptors have also been reported on tumour cells (Dubyak et al J. Biol. Chem., (1985) 260, 10653-10661 and Wagner et al Gastroenterolgy, (1997), 112(4) suppl. page A1198) and may be involved in the development of cancer. Antagonists may therefore be useful in treatment of cancer.
According to the invention there is provided a compound of formula (I) or salts thereof: ##STR1## in which: A is a 5-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur; tetrazol-5-yl where q is 0, 1 or 2 or R.sup.1 is COR.sup.3 where R.sup.3 is amino, alkylamino, dialkyl amino, NHOalkyl, NHSO.sub.2 alkyl, OH, N(CH.sub.2 CO.sub.2 H).sub.2 or a group of formula (i): ##STR2## in which p is 1 or 2, or R.sup.3 is a group of formula (ii): ##STR3## where B is a 5-membered heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur and R.sup.8 is hydrogen or a group CH.sub.2 CO.sub.2 H, CH.sub.2 CON(CH.sub.2 CO.sub.2 H).sub.2 or CH.sub.2 COR.sup.9 where R.sup.9 is a group of formula (i) as defined above or a group of formula (iii): ##STR4## R.sup.2 is a group of formula (iv) or (v): ##STR5## where R.sup.4 groups are independently hydrogen, halogen, methoxy, methylthio or C.sub.1-2 alkyl (optionally substituted by one or more fluorine atoms); alkylthio, C.sub.1-4 alkyl (optionally substituted by one or more fluorine atoms), C.sub.3-4 cycloalkyl, MeOCH.sub.2, MeSCH.sub.2 or C.sub.1-2 alkoxy; substituted by one or more fluorine atoms); CH.dbd.CHCH.sub.2 or a C.sub.1-4 alkylene group optionally interrupted by an oxygen or sulphur atom; group; when Q.sup.1 is oxygen, R.sup.2 is a group of formula (iv).
Alkyl groups, whether alone or as part of another group, can be straight chain or branched.
Unless stated otherwise the term alkyl means C.sub.1-6 alkyl such as methyl, ethyl, propyl, butyl etc.
Suitably A is a 5-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur. Preferred rings A include thiazole, oxazole, furan and thiophen

REFERENCES:
J.Org.Chem.35/5,587-591(1974);C.W.Whitehead et al. Reacn.of Pyrimidines with Diaryl Cats, Mar. 1974.
J. Org. Chem.35/5,591-595(1974),C.W. Whitehead et al. 37 Reacn. of Diaryl Cats. W/Amino-pyrimids. Mar. 1974.

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