Patent GB-1356581-A (GB)
Title: Cyclopentane derivatives
IPC: C07C405/00
Filed: 1970-10-09
Abstract: 1356581 Prostaglandins; acylmethanephosphonic acid esters IMPERIAL CHEMICAL INDUSTRIES Ltd 14 Sept 1971 [9 Oct 1970 14 Jan 1971 26 Feb 1971] 48131/70 1814/71 and 5543/71 Headings C2C and C2P Novel prostaglandins of the Formula I wherein R<SP>1</SP> is OH, NH 2 , C 1-6  alkylamino, C 1-6  alkoxy, or C 2-3  alkoxy which bears as substituent a #- or γ-di-(C 1-4  alkyl)amino or a #- or γ- (1-pyrrolidinyl), piperidino or morpholino radical ; either 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 the oxo radical; R<SP>4</SP> is n-hexyl bearing a C 1-4  alkyl substituent on any one of carbon atoms 1 to 5 of the hexyl radical, or a methyl, ethyl methylene, ethylidene or vinyl substituent, or a methyl and a methylene substituent, or two methyl substituents on carbon atom 6 of the n-hexyl radical, and A is -CH 2 CH 2 - or trans-vinylene; and for those compounds wherein R<SP>1</SP> is OH, the pharmaceutically acceptable base addition salts thereof are prepared by hydrolysing cyclopentane derivatives of Formula II or mixed anhydrides thereof wherein R<SP>2</SP> is OH C 1-4  alkanoyloxy or tetrahydropyran-2-yloxy and R<SP>3</SP> is H, or R<SP>2</SP> and R<SP>3</SP> together form the oxo radical, and R<SP>5</SP> and R<SP>6</SP> are each tetrahydropyran-2-yloxy or C 1-6  acyloxy, or for those compounds which R<SP>1</SP> is C 1-6  alkoxy by reacting the appropriate acids with the corresponding diazoalkanes, or reacting lactols of the Formula IV with (4 - carboxybutyl)triphenylphosphonium salts. The mixed anhydride of acetic acid and 9α-acetoxy - 20 - ethyl - 11α,15 - bis - (tetrahydropyran-2- yloxy)-5-cis-13-trans-prostadienoic acid is obtained by reacting the puitadienoic acid with acetic acid and pyridine.  2 - Dimethylaminoethyl 20 - ethyl - 9α,11α,15- tris - (tetrahydropyran - 2 - yloxy) - 5 - cis - 13- trans-prostadienoate is obtained by reacting 2- dimethylaminoethanol and sodium hydride with the corresponding methyl ester, obtained adding a solution of diazomethane in ether to the corresponding acid, which is made by hydrolysing tetrahydropyran - 2 - yl 20 - ethyl- 9α,11α - 15 - tris - (tetrahydropyran - 2 - yloxy)- 5-cis-13-trans-prostadienoate resulting from the treatment of 20-ethyl-9α-hydroxy-11α,15-bis (tetrahydropyran - 2 - yloxy) - 5 - cis - 13- trans-prostadienoic acid with 2,3-dihydropyran. 20 - Ethyl - 9α,11α,15 - tris - (tetrahydropyran- 2 - yloxy) - 5 - cis - 13 - trans - protadienamide is obtained by reacting the corresponding acid with N-methylmorpholine, isobutyl chloroformate, and ammonia. 20 - Ethyl - 9α - hydroxy - 11α,15 S - bis - (tetrahydropyran - 2 - yloxy) - 5 - cis - prostenoic acid is obtained by reacting (4-carboxybutyl)triphenylphosphonium bromide with 2-hydroxy-4-(3- tetrahydropyran - 2<SP>1</SP> - yloxy)decyl - 5 - (tetrahydropyra - 2 - yloxy) 3,3a,4,5,6,6a - hexahydro- 2H-cyclopenta[b]furan resulting from the hydrogenation of 2-hydroxy-4-(3-tetrahydropyran-2<SP>1</SP>- yloxy - 1 - decenyl) - 5 - (tetrahydropyran - 2- yloxy) - 3,3a,4,5,6,6a - hexahydro - 2H - cyclopenta[b]furan. 20 - Ethyl - 9 - oxo - 11α,15 - bis - (tetrahydropyran - 2 - yloxy) - 5 - cis - 13 - trans - prostadienoic acid, 9 - oxo - 11α,15 - bis - (tetrahydropyran - 2 - yloxy) - 20 - vinyl - 5 - cis - 13 - transprostadienoic acid and 16,20 - dimethyl - 9 - oxo- 11α,15 - bis - (tetrahydropyran - 2 - yloxy) - 5- cis-13-trans-prostadienoic acid are prepared by oxidizing the corresponding 9-hydroxy compounds. Cyclopentane derivatives of Formula II above in which R<SP>1</SP> is OH, A is trans-CH=CH-, R<SP>2</SP> is OH, R<SP>3</SP> is H and R<SP>5</SP> and R<SP>6</SP> are each tetrahydropyran-2-yloxy are obtained by reacting the phosphonium ylide anion obtained from (4- carboxybutyl)triphenylphosphonium bromide and a strong base with lactols of the formula resulting from the reduction of the corresponding lactones, which are prepared by reacting dihydropyran with the appropriate 5α-hydroxy- 4# - (3 - hydroxy - trans - 1 - alkenyl) - 3,3a,4,5, 6,6a - hexahydro - 2H - cyclopenta[b]furan - 2- ones, obtained by hydrolysing the corresponding 5α - acetoxy - 2H - cyclopenta[b]furan - 2 - ones, resulting from the reduction of the appropriate 5α - acetoxy - 4# - (3 - oxo - trans - 1 - alkenyl) - 3, 3a,4,5,6,6a - hexahydro - 2H - cyclopenta[b]furan- 2-ones, the latter being prepared by reacting phosphonates of the formula with 5α - acetoxy - 4# - formyl - 3,3a,4,5,6,6ahexahydrocyclopenta[b]furan-2-one. N - butyl - 20 - ethyl - 9α,11α,15S - tris - (tetrahydropyran - 2 - yloxy - 5 - cis, 13 - trans - prostadienamide is obtained by reacting the corresponding acid with butylamine in the presence of N-methylmorpholine and isobutyl chloroformate. Phosphonates of the formula are prepared by reacting dimethyl methylphosphonate with esters of the formula R<SP>4</SP>.COO-alkyl in the presence of butyl-lithium. Pharmaceutical compositions, suitable for oral, parenteral or rectal administration, or in form suitable for inhalation, contain the above prostaglandins or salts thereof and pharmaceutically acceptable carriers or diluents. The compounds are used for the induction of labour in childbirth, the termination of pregnancy, control of the oestrus cycle, or relief of bronchospasm, and as hypotensive or contraceptives. Reference has been directed by the Comptroller to Specification 1,282,661.