Patent GB-1386146-A (GB)
Title: Cyclopentane derivatives
IPC: C07D307/935
Filed: 1972-05-03
Abstract: 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 R<SP>1</SP> is CH 2 OH, COOH or C 2-11  alkoxycarbonyl; A is -CH 2 -CH 2 - or trans- CH=CH-; R<SP>4</SP> 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; R<SP>2</SP> is OH or C 1-4  alkanoyloxy and R<SP>3</SP> is H, or R<SP>2</SP> and R<SP>3</SP> 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 R<SP>1</SP> is COOH, pharmaceutically and veterinarily acceptable salts thereof, and their preparation. Compounds of the above formula in which R<SP>1</SP> is CH 2 OH are prepared by reducing the corresponding compounds in which R<SP>1</SP> is alkoxycarbonyl, which are made by esterifying the corresponding compounds in which R<SP>1</SP> is COOH. Those compounds of the above formula in which R<SP>1</SP> is COOH, R<SP>2</SP> is OH and R<SP>3</SP> 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 - R<SP>4</SP>- 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 - R<SP>4</SP> - 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<SP>(-)</SP>COR<SP>4</SP> or phosphoranes of the formula Ph 3 P : CHCOR<SP>4</SP>. Compounds of Formula I above in which R<SP>2</SP> is OH and R<SP>3</SP> is H may be prepared by reducing compounds of the Formula IV: wherein R<SP>6</SP> and R<SP>7</SP> are OH or protected OH, and, if necessary, removing the protecting groups, the compounds of Formula IV (R<SP>1</SP> is COOCH 3 ) being obtained by reacting phosphonates of the formula (CH 3 O) 2 POCH 2 COR<SP>4</SP> 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 R<SP>1</SP> is COOH may be prepared by hydrolysing compounds of the Formula V wherein A is trans-CH = CH- and R<SP>8</SP> 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 R<SP>1</SP> is COOH may be obtained by hydrolysing compounds of Formula V above in which A is -CH 2 CH 2 - and R<SP>8</SP> 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 R<SP>4</SP>COOEt 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.