PROSTANE DERIVATIVES

摘要

1513913 15 - Cycloalkylprostaglandins IMPERIAL CHEMICAL INDUSTRIES Ltd 27 May 1976 26352/75 Heading C2C [Also in Division C3] The invention comprises 15-cycloalkylprostaglandins of the formula wherein R1 is carboxy, hydroxymethyl, (C 1-4 alkoxy)carbonyl or (C 1-4 alkoxy)methyl; R2 and R3 each are H or C 1-4 alkyl; X is ethylene or vinylene; Y is ethylene or trans-vinylene; n is 1, 2 or 3; and R4 is C 1-4 alkyl or a phenyl, phenoxy, phenylthio or phenyl-(C 1-4 alkyl) radical in which the benzene ring is optionally substituted by one or more halogen atoms or nitro, phenyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or di(C 1-4 alkyl)amino radicals, provided that when n is 1 and R4 is alkyl or optionally substituted phenyl, at least one of R2 and R7 is alkyl, and for those compounds in which R1 is carboxy, the pharmaceutically or veterinarily acceptable salts thereof; and their preparation. The compounds are obtained by one of the following methods: (a) for those compounds wherein R 1 is carboxy, (C 1-4 alkoxy) carbonyl or (C 1-4 alkoxy) methyl and R3 is H; the hydrolysis under acidic conditions of compounds of the Formula II wherein R5 is carboxy (C 1-4 alkoxy carbonyl) or (C 1-4 alkoxy)methyl; (b) for those compounds in which R1 is (C 1-4 alkyoxy) carbonyl, the esterification of the corresponding compounds in which R1 is carboxy; (c) for those compounds in which R1 is hydroxymethyl, the reaction of compounds of the Formula III wherein R7 is OH, C 1-4 alkoxy, ureido or thioureido, with nitrites, in acetic acids; (d) for those compounds in which R3 is C 1-4 alkyl, the hydrolysis of compounds of the Formula IV wherein R3 is C 1-4 alkyl and R8, R9 and R10 each are C 1-4 alkyl; or the selective oxidation of compounds of the Formula V wherein R3 is C 1-4 alkyl. The following intermediates are also prepared: 1 - butylcyclopentanecarboxylic acid and the methyl ester thereof; 1-butylcyclohexanecarboxylic acid and the methyl ester thereof; methyl 1 - (3 - chlorobenzyl) - cyclobutanecarboxylate; methyl 1-phenethylcyclobutanecarboxylate, methyl 1 - benzylcyclobutanecarboxylate; 1 - bromocyclobutanecarboxylic acid and its methyl ester; methyl 1 - (3 - chlorophenoxy)cyclobutanecarboxylate; methyl (2- chlorophenoxy)cyclobutanecarboxylate, methyl 1 - (3 - trifluoromethylphenoxy)cyclobutanecarboxylate; compounds of the Formula II above in which R2 and R3 are H, R1 is carboxyl and Y is trans-vinylene; 4#À{3-[1-butylcyclopentyl (or cyclohexyl)] - 3 - oxo - 1 - transpropenyl} - 5α - (4 - phenylbenzoyloxy) - 3,3a#,- 4,5,6,6a# - hexahydro - 2H - cyclo - penta[b]- furan - 2 - one; 4# - {3 - [1 - butylcyclopentyl (or cyclohexyl)] - 3 - hydroxy - 1 - trans - propenyl} - 5α - (4 - phenylbenzoyloxy) - 3,3a#,- 4,5,6,6α# - hexahydro - 2H - cyclopenta[b]furon- 2 - one; 4# - {3 - [1 - butylcyclopentyl (or cyclohexyl)] - 3 - hydroxy - 1 - trans - propenyll - 5α- hydroxy - 3,3a#,4,5,6,6a# - hexahydro - 2H- cyclopenta[b]furan - 2 - one and the bis(2- tetrahydropyronyl)ether thereof; 4# - 3 - {[1- butylcyclopentyl (or cyclohexyl) - 3 - (tetrahydropyran - 2 - yloxy] - 1 - trans -propenyl}- 3,3a#,4,5,6,6a# - hexahydro - 2H - cyclopenta- [b]furan - 2 - ol; and the 11,15 - bis(2 - tetrahydropyranyl) ethers of compounds of the Formula V in which R2 and R3 are both H, Y is trans-vinylene and R1 is earboxy; Dimethyl 2 - (1 - butylcyclopentyl) - 2 - oxoethylphosphonate and diisopropyl 2 - ( 1- butylcyclohexyl) - 2 - oxoethylphosphonate are prepared by reacting the appropriate dialkyl methylphosphonate with methyl 1-butylcyclopentane carboxylate and methyl 1-butylcyolohexanecarboxylate respectively in the presence of butyllithium. Pharmaceutical compositions, suitable for oral administration contain the above prostaglandins or salts thereof together with pharmaceutically or veterinarily acceptable diluents or carriers. The compounds inhibit gastric acid production in mammals