Phosphate compounds and their use as medicaments

Details Phosphate compounds and their use as medicaments Phosphate compounds and their use as medicaments

1998-05-04

1999-11-16

Wilson, James O.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

514 49, 514 50, 514885, 536 2626, 536 263, 536 268, 536 2853, 536 2854, 536 2855, A01N 4304

Patent

active

059858494

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.


BACKGROUND OF THE INVENTION

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.


DESCRIPTION OF THE INVENTION

According to the invention there is provided a compound of formula (I) or salts thereof: ##STR2## wherein X represents H or a group of formula (i), (ii) or (iii): ##STR3## R.sup.1 represents a C.sub.1-6 -alkyl, C(R.sup.4).sub.2 R.sup.5, CHR.sup.6 R.sup.5, Si(R.sup.4).sub.3, C(O)R.sup.6, or SR.sup.6 group or ##STR4## R.sup.2 represents a hydrogen atom or methyl; R.sup.3 represents a hydrogen atom or a C.sub.1-6 -alkyl group which is optionally substituted by one or more C.sub.1-6 -alkoxy, C.sub.1-6 -alkylthio, C.sub.3-8 -cycloalkyl, and/or phenyl groups (wherein the one or more phenyl groups are optionally substituted by one or more halogen atoms and/or hydroxy, C.sub.1-4 -alkyl and/or C.sub.1-4 -alkoxy groups); atoms and/or one or more C.sub.1-4 -alkoxy, C.sub.1-4 -alkylthio and/or C.sub.1-4 -alkyl groups (wherein the one or more alkyl groups are optionally substituted by one or more F atoms); -alkylthio, C.sub.1-6 -alkyl or a phenyl group; by one or more halogen atoms and/or one or more C.sub.6-10 -aryl, C.sub.6-10 -aryloxy, C.sub.6-10 -arylthio, C.sub.3-8 -cycloalkyl, C.sub.1-6 -alkylthio, C.sub.1-6 -alkyl and/or C.sub.1-6 -alkoxy groups, each of which substituents are optionally substituted by one or more halogen atoms and/or one or more C.sub.1-6 -alkyl, phenyl and/or C.sub.1-6 -alkoxy groups; C.sub.1-4 -alkoxy, C.sub.1-4 -alkylthio or C.sub.1-4 -alkyl group (wherein the one or more alkyl groups are optionally substituted by one or more F atoms); C.sub.1-4 -alkoxy, C.sub.1-4 -alkylthio, C.sub.1-4 -alkyl (optionally substituted by a phenyl group) or a C.sub.3-8 -cycloalkyl group; phenyl; greater than 1, one of the CH.sub.2 moieties is optionally replaced by an O or S

REFERENCES:
patent: 5627165 (1997-05-01), Glazier
patent: 5639867 (1997-06-01), Brill

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