Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-09-30
2000-08-22
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514266, 514269, 544238, 544277, 544294, 544296, 544310, C07D40304, C07D40104, C07D41714, A61K 31506, A61K 31513
Patent
active
061072974
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE98/01240 filed Jun. 25, 1998.
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 is 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: D is hydrogen, C.sub.1-6 alkyl or a group of formula (a): ##STR2## where A is a 6-membered heterocyclic ring containing 1 to 3 nitrogen atoms or a fused 5,6-bicyclic ring containing 1 to 4 nitrogen atoms; CO.sub.2 C.sub.1-6 alkyl, phenyl substituted by CH.sub.2 CO.sub.2 H, or CONR.sup.3 R.sup.4 where R.sup.3 and R.sup.4 are independently hydrogen, C.sub.1-6 alkyl optionally substituted by hydroxy and/or optionally interrupted by oxygen, nitrogen or sulfur; SCH.sub.2, CONH, CONHCH.sub.2, CONHCH.sub.2 CONH, NHCH.sub.2 CONH, NHCH(R.sup.3) or --R.sup.5 --CO.sub.2 H where R.sup.5 is a bond, OCH.sub.2, SCH.sub.2, CONHCH.sub.2 or NHCH(R.sup.3) where R.sup.3 is as defined above or R.sup.5 is NR.sup.6 (CH.sub.2).sub.q where R.sup.6 is hydrogen or C.sub.1-6 alkyl and q is 1 or 2, or R.sup.1 is a group of formula (i): ##STR3## where B is a 4-, 5-, or 6-membered saturated ring containing a nitrogen atom optionally substituted by hydroxy and substituted by CO.sub.2 H or CONH-Het where Het is tetrazol-5-yl, or a thiazole or thiadiazole ring substituted by CH.sub.2 CO.sub.2 H, or B is a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur optionally substituted by CF.sub.3, CO.sub.2 H, CH.sub.2 CO.sub.2 H, C(CO.sub.2 H).dbd.N--OMe, tetrazol-5-yl or CH.sub.2 tetrazol-5-yl; and H)--CH.sub.2 --, or a group --CONR.sup.8 (CH.sub.2).sub.p CONR.sup.9 -- or --NR.sup.8 --(CH.sub.2).sub.p- CONR.sup.9 -- where R.sup.8 and R.sup.9 are independently hydrogen or C.sub.1-6 alkyl and p is 1 or 2; ##STR4## where R.sup.10 groups are inde
REFERENCES:
Whitehead et al., Reaction of Pyrimidines with Diarylmethyl Cations, Journal of Organic Chemistry, vol. 39, No. 5, pp. 587-591, Mar. 1974.
Kindon Nicholas
Meghani Premji
Thom Stephen
Astra Pharmaceuticals Limited
Rao Deepak R.
Shah Mukund J.
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