Patent GB-1398838-A (GB)
Title: Prostaglandin analogues and production thereof
IPC: C07C405/00
Filed: 1972-04-27
Abstract: 1398838 Prostaglandins; acylmethane phosphonates ONO PHARMACEUTICAL CO Ltd 27 April 1972 [30 April 1971 10 Dec 1971] 384/75 Divided out of 1398291 Headings C2C and C2P [Also in Division C3] The invention comprises optically active prostaglandins of the Formulµ IX, X, XI, XII XIII and XIV wherein X 1  is 3(S)-hydroxy-2-methyl-trans-1- octenyl, 3 - hydroxy - 5 - methyl - trans - 1- octenyl, 3 - hydroxy - 3,4 - dimethyl - trans - 1- octenyl or 3(S) - hydroxy - 3 - (4 - methylcyclohexyl) - trans - 1 - propenyl, the esters thereof, the cyclodextrin clathrate compounds thereof and of the esters thereof, salts thereof, PG alcohol derivatives thereof and the dihydro- PG 1  compounds thereof and optically active prostaglandins of the Formulµ XV and XVII wherein THP is 2-tetrahydropyranyl and X 2  is 2 - methyl - 3(S) - tetrahydropyran - 21 - yloxytrans - 1 - octenyl, 5 - methyl - 3 - tetrahydropyran - 21 - yloxy - trans - 1 - octenyl, 3,4 - dimethyl - 3 - tetrahydropyran - 2<SP>1</SP> - yloxy - trans- 1 - octenyl or 3 - (4 - methylcyclohexyl) - 3(S)- tetrahydropyran - 2<SP>1</SP> - yloxy - trans - 1 - octenyl and their preparation. The PGA analogues of the Formulµ XIII and XIV are prepared by dehydrating the corresponding PGE analogues of the Formulµ XI and XII, which are made by oxidizing the 9-hydroxy group in compounds of the Formulµ XV and XVII and hydrolysing the resulting products. PGF analogues of the Formulµ IX and X are prepared by hydrolysing the corresponding PGF analogues of the Formulµ XV and XVII. The dihydro-PG 1  analogues are obtained by hydrogenating the corresponding PG 1  analogues. The corresponding ester, alcohols, salts of cyclodextrin clathrates are prepared by standard methods. PGF 1  analogues of the Formula XVII are made by the selective hydrogenation of the corresponding PGF 2  analogues of the Formula XV which are prepared by reacting 4-carboxybutylidenetriphenylphosphorone with cyclopenta[b]furans of the formula obtained by reducing the corresponding lactones, resulting from the etherification of the corresponding 5 - α - hydroxy - 4# - X 1  - 3,3a#,- 4,5,6,6a# - hexahydro - 2H - cyclopenta[b]- furan-2-ones, which are made by hydrolysing the appropriate 5 - α - acetoxy - 4# - X 1  - 3,3a#,4,5- 6,6a# - hexahydro - 2H - cyclopenta[b]furan - 2- ones, obtained by reducing the corresponding 5 - α - acetoxy - 4# - (3 - oxo - octenyl) - 3,3a#,4,- 5,6,6a# - hexahydro - 2H - cyclo - penta[b]furan- 2-ones which are prepared by reacting 5xacetoxy - 4# - formyl - 3,3a#,4,5,6,6a# - hexahydro - 2H - cyclo-penta[b]furan-2-one with the appropriate dimethyl or diethyl 2-oxoheptylphosphonates (see below). Diethyl 2 - oxo - 1 - methylheptylphosphonate, dimethyl 2 - oxo - 3 - methylheptylphosphonate, dimethyl 2 - oxo - 4 - methylheptylphoaphonate and dimethyl - 2 - oxo - 2 - (4 - methylcyclohexyl)- ethylphosphonate are obtained by reacting diethyl ethylphosphonate with ethyl hexanoate and dimethyl methylphosphonate with ethyl 2- methylhexanoate, ethyl 3-methylhexanoate and ethyl 3 - (4 - methylcyclohexyl)propionate respectively in the presence of butyllithium. Pharmaceutical compositions, suitable for oral, parenteral, sublingual, vaginal or rectal administration, contain the above prostaglandins of the Formulµ IX to XIV or derivatives thereof and suitable carriers. The compounds possess pharmacological activities similar to those of naturally occurring prostaglandins. Reference has been directed by the Comptroller to Specification 1,198,071.