New bi:cyclooctane carbacyclin analogues - useful as thromboxane-A2 and prostaglandin H2 antagonists

摘要

Bicyclo(3,3,O)octane derivs. of formula (I) and their enantiomers, salts, cyclodextrin clathrates and liposome-encapsulated forms are new; one of the a-b, b-c and b-d bonds is opt. double; R1 = COOR5, CONHR7 or a gp. of formula (II)-(III) etc. R5 = H; 1-10C alkyl opt. substd. by halogen, Ph, 1-4C alkoxy or di(1-4C alkyl)amino; 3-10C cycloalkyl; 7-16C aralkyl; Y-substd. phenacyl or 6-12C aryl; or 5- or 6-membered heterocyclyl contg. at least one N, O or S atom; R7 = H, 1-10C alkanoyl or 1-10C alkylsulphonyl; A = Y-substd. phenylene; R2 = H or 1-10C alkyl; R4 = H, halo or opt. functionally modified OH; Z = a gp. of formula (IV)-(VI); etc. p = 0 or 1; V = O or S; W = Y-substd. 1-10C alkyl, 3-10C cycloalkyl or a gp. of formula (VII)-(IX) etc. r = 0-2; Y and Y1-Y3=H, halo, N3, CN, CF3, OR6, NO2, COOR6, or 1-10C alkyl; R6 = H, 1-10C alkyl, opt. halo-substd. 6-12C aryl or 7-16C aralkyl. USE - (I) are chemically and metabolically stable carbacyclin analogues capable of antagonising the pharmacological effects of thromboxane A2 (TXA2), prostaglandin H2 (PGH2) and their stable analogues (e.g. U46619 and U46609). They may be used to treat disorders associated with PGI2 deficiency and/or excess of TXA2 or PGH2. (I) may be used to treat cardiovascular, gastric, pancreatic, hepatic and renal disorders. (I) have hypotensive and bronchodilatory activity and inhibit platelet aggregation. (I) are potentially useful for treating stroke, heart diseases, arteriosclerosis, ischaemic CNS disorders, migraine, shock, asthma, allergic rhinitis, etc. They may be used to inhibit labour and treat toxicosis in pregnancy. (I) may be used to improve organ function after transplantation, to inhibit rejection, and as additives for haemodialysis and preserved blood prod. (I) have antimetastatic and antiproliferative activity and are potentially useful for treating neoplasms.