Patent GB-1513913-A (GB)
Title: Prostane derivatives
IPC: C07C405/00
Filed: 1975-06-20
Abstract: 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 R<SP>1</SP> is carboxy, hydroxymethyl, (C 1-4  alkoxy)carbonyl or (C 1-4  alkoxy)methyl; R<SP>2</SP> and R<SP>3</SP> 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 R<SP>4</SP> 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 R<SP>4</SP> is alkyl or optionally substituted phenyl, at least one of R<SP>2</SP> and R<SP>7</SP> is alkyl, and for those compounds in which R<SP>1</SP> 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 R<SP>3</SP> is H; the hydrolysis under acidic conditions of compounds of the Formula II wherein R<SP>5</SP> is carboxy (C 1-4  alkoxy carbonyl) or (C 1-4  alkoxy)methyl; (b) for those compounds in which R<SP>1</SP> is (C 1-4  alkyoxy) carbonyl, the esterification of the corresponding compounds in which R<SP>1</SP> is carboxy; (c) for those compounds in which R<SP>1</SP> is hydroxymethyl, the reaction of compounds of the Formula III wherein R<SP>7</SP> is OH, C 1-4  alkoxy, ureido or thioureido, with nitrites, in acetic acids; (d) for those compounds in which R<SP>3</SP> is C 1-4  alkyl, the hydrolysis of compounds of the Formula IV wherein R<SP>3</SP> is C 1-4  alkyl and R<SP>8</SP>, R<SP>9</SP> and R<SP>10</SP> each are C 1-4  alkyl; or the selective oxidation of compounds of the Formula V wherein R<SP>3</SP> 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 R<SP>2</SP> and R<SP>3</SP> are H, R<SP>1</SP> 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 R<SP>2</SP> and R<SP>3</SP> are both H, Y is trans-vinylene and R<SP>1</SP> 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