CYCLOPENTANE DERIVATIVES

摘要

1386146 Prostoglandins IMPERIAL CHEMICAL INDUSTRIES Ltd 5 April 1973 [3 May 1972] 20566/72 Headings C2C and C2P [Also in Division C3] The invention comprises prostaglandins of the Formula I: wherein R1 is CH 2 OH, COOH or C 2-11 alkoxycarbonyl; A is -CH 2 -CH 2 - or trans- CH=CH-; R4 is an aryl, furyl or thienyl radical which is unsubstituted or which is substituted by halogen atoms, nitro, phenyl, halophenyl, C 1-4 alkyl, C 2-4 alkoxyalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 acylamino or di- (C 1-4 alkyl)amino; R2 is OH or C 1-4 alkanoyloxy and R3 is H, or R2 and R3 together form an oxo radical, which compounds contain 0, 1 or 2 C 1-4 alkyl radicals as substituents on carbon atoms 2, 3, or 4, and for those compounds wherein R1 is COOH, pharmaceutically and veterinarily acceptable salts thereof, and their preparation. Compounds of the above formula in which R1 is CH 2 OH are prepared by reducing the corresponding compounds in which R1 is alkoxycarbonyl, which are made by esterifying the corresponding compounds in which R1 is COOH. Those compounds of the above formula in which R1 is COOH, R2 is OH and R3 is H are obtained by reacting (4-carboxybutyl)triphenylphosphonium salts, optionally bearing 0, 1 or 2 alkyl radicals on carbon atoms 2, 3 or 4 with lactols of the Formula II: obtained by reducing the corresponding lactones resulting from the hydrolysis of the appropriate 4α - (4 - phenylbenzoyloxy) - 4# - (3 - hydroxy- 3 - R4- trans - 1 - propenyl) - 3,3aα,4,5,6,6aα- hexahydro - 2H - cyclopenta[b]furan - 2 - ones, obtained by reducing the corresponding 4α-(4- phenylbenzoyloxy) - 4# - (3 - oxo - 3 - R4 - trans- 1 - propenyl) - 3,3aα,4,5,6,6aα - hexahydro - 2H- cyclopenta[b]furan-2-ones, which is prepared by reacting 4α - (4 - phenylbenzoyloxy) - 3,3aα,4,- 5,6,6aα - hexahydro - 2 - oxo - 2H - cyclopenta- [b]furan-4-carbonaldehyde with phosphonates of the formula (CH 3 O) 2 P(+)OCH(-)COR4 or phosphoranes of the formula Ph 3 P : CHCOR4. Compounds of Formula I above in which R2 is OH and R3 is H may be prepared by reducing compounds of the Formula IV: wherein R6 and R7 are OH or protected OH, and, if necessary, removing the protecting groups, the compounds of Formula IV (R1 is COOCH 3 ) being obtained by reacting phosphonates of the formula (CH 3 O) 2 POCH 2 COR4 with methyl [2# - formyl - 3α,5α - di - (hydroxy or protected hydroxy) cyclopent - 1α - yl] hept - 5- cis-enoates. Compounds of the Formula I above in which A is trans-CH=CH- and R1 is COOH may be prepared by hydrolysing compounds of the Formula V wherein A is trans-CH = CH- and R8 is an alkoxy-dialkylmethyl radical of 4 to 8 carbon atoms. Compounds of Formula I above in which A is -CH 2 CH 2 - and R1 is COOH may be obtained by hydrolysing compounds of Formula V above in which A is -CH 2 CH 2 - and R8 is 2-tetrahydropyranyl. The following intermediates and starting materials are also prepared:-4#-dimethoxymethyl - 3,3aα,4,5,6,6aα - hexahydro - 5α - hydroxy - 2H - cyclopenta[b]furan - 2 - one and its tetrahydropyranyl ether, 4#-dimethoxymethyl - 3,3aα,4,5,6,6aα - hexahydro - 2 - hydroxy - 5α - (tetrahydropyran - 2 - yloxy) - 2H- cyclopenta[b]furan, [2# - dimethoxymethyl- 5α - hydroxy - 3α - (tetrahydropyran - 2 - yloxy)- cyclopent - 1α - yl]hept - cis - 5 - enoic acid, methyl (2# - dimethoxymethyl - 3α,5α - dihydroxycyclopent - 1α - yl)hept - cis - 5 - enoate, methyl [2# - dimethoxymethyl - 3α,5α - di - (4- phenylbenzoyloxylcyclopent - 1α - yl]hept - cis- 5 - enoate, methyl [2# - formyl - 3α,5α - di - (4- phenylbenzoyloxy)cyclopent - 1α - yl) hept - cis- 5 - enoate, 15 - (4 - chlorophenyl) - 9α - hydroxy- 11α,15 - bis(tetrahydropyran - 2 - yloxy)- 16,17,18,19,20 - pentanor - 5 - cis - prostenoic acid, 4# - [3 - (4 - chlorophenyl) - 3 - oxopropyl]- 3,3aα,4,5,6,6aα - hexahydro - 5α - (4 - phenylbenzoyloxy) - 2H - cyclopenta[b]furan - 2 - one, 4# - [3 - (4 - chlorophenyl) - 3 - hydroxypropyl]- 3,3aα,4,5,6,6aα - hexahydro - 5α - (4 - phenylbenzoyloxy) - 2H - cyclopenta[b]furan - 2 - one, 4# - [3 - (4 - chlorophenyl) - 3 - hydroxypropyl]- 3,3aα,4,5,6,6aα - hexahydro - 5α - hydroxy- 2H-cyclopenta[b]furan-2-one, and the bis-(tetrahydropyran - 2 - yl) ethers thereof, 4# - [3 - (4- chlorophenyl - 3 - (tetrahydropyran - 2 - yloxy)- propyl] - 3,3aα,4,5,6,6aα - hexahydro - 2- hydroxy - 5α - (tetrahydropyran - 2 - yloxy)- 2H - cyclopenta[b]furan, 15 - (4 - chlorophenyl)- 9 - oxo - 11α,15 - bis - (tetrahydropyran - 2- yloxy) - 16,17,18,19,20 - pentanor - 5 - cisprostenoic acid, 15-(4-chlorophenyl-11α,15-bis- (1-methoxy - 1 - methylethoxy) - 9 - oxo 16,17,18,19,20 - pentanor - 5 - cis,13 - transprostadienoic acid, 4#-[3-(4-chlorophenyl-3-(1- methoxy - 1 - methylethoxy) - trans - 1 - propenyl] - 3,3aα,4,5,6,6aα - hexahydro - 5α- (1- methoxy - 1 - methylethoxy) - 2H - cyclopenta- [b]furan - 2 - one, and the corresponding lactol, and 15(4-chlorophenyl)-9a-hydroxy-11α, 15 - bis - (1 - methoxy - 1 - methylethoxy)- 16,17,18,19,20 - pentanor - 5 - cis,13 - transprostadienoic acid. Phosphonates of the formula are prepared by reacting dimethyl methylphosphonate with esters of the formula R4COOEt in the presence of butyl lithium. Pharmaceutical compositions, in forms suitable for oral, rectal or parenteral administration or inhalation spraying or intra-uterine infusion, contain the above novel prostaglandins or salts thereof together with pharmaceutically- or veterinarily-acceptable diluents or carriers. The compounds possess similar activities to the natural prostaglandins. Reference has been directed by the Comptroller to Specification 1,324,737.