Patent GB-1269657-A (GB)
Title: Prostaglandin analogues, their preparation and pharmaceutical compositions containing them
Inventor: NELSON NORMAN ALLAN
IPC: A61K31/22
Filed: 1969-07-29
Abstract: 1,269,657. Prostaglandin derivatives. UPJOHN CO. 16 June, 1970 [29 July, 1969], No. 38073/69. Heading C2C. The invention comprises 3- or 4-oxa-PGE, 3- or 4-oxa PGF, 3- or 4-oxa PGA and 3- or 4-oxa PGB compounds of the formulµ wherein R 1  is H, C 1-8  alkyl, C 3-10  cycloalkyl, C 7-12  aralkyl, phenyl, phenyl substituted with 1 to 3 chlorine atoms or C 1-4  alkyl, or ethyl substituted in the #-position with 3 chlorine, 2 or 3 bromine or 1, 2, 3 iodine atoms; R 2  is H, C 1-10  alkyl substituted with 0 to 3 fluorine atoms, or C 2-10  alkyl substituted with 4 or 5 fluorine atoms on the omega and omega-minus-one carbon atoms; R 3  and R 9  are H or C 1-4  alkyl, A is -CH 2 -CHR 4 - or trans -CH=CR 4 -, and V is -C n H 2n OCR 5 R 6 -, -C m H 2m OCR 5 R 6 -CR 7  R 8 -, cis or trans -CH=CH.C p H 2p OCR 5 R 6 -, cis or trans -CH=CH-C q H 2q -O-CR 5  R 6 -CR 7 R 8 -, -C#C-C p H 2p OCR 5 R 6 - or -C#C-CqH 2q O.CR 5 R 6 -CR 7 R 8 ; with the proviso that V is -C n H 2n -O-CR 5 R 6 - or -C m H 2m -O-CR 5 R 6 -CR 7 R 8 - when A is -CH 2 CHR 4 -; wherein R 4 , R 5 , R 6 , R 7  and R 8  are H or C 1-4  alkyl; wherein C n H 2n  is C 1-10  alkylene, with 1 to 5 carbon atoms, inclusive, between -CHR 9  and -O-; wherein C m H 2m  is C 1-9  alkylene, with 1 to 4 carbon atoms, inclusive, between -CHR 9 - and -O-; wherein C p H 2p  is C 1-8  alkylene, with 1, 2 or 3 carbon atoms between -CHR 9 - and -O-; and wherein C q H 2q  is C 1-7  alkylene with 1 or 2 carbon atoms between -CHR 9  and -O-; and wherein # indicates attachment of the group to the ring in alpha or beta configuration; including C 1-8  alkanoates, and pharmacologically acceptable salts thereof when R 1  is H. Esters of 3- or 4-oxa PGE derivatives of the above formula in which A is trans -CH=CR 4  are prepared by reacting compounds of the Formula LXXXII wherein R 10  is the same as R 1  except that it cannot be H, and R 13  is C 1-5  alkyl, in oxo or endo configuration with respect to the radical attached to the cyclopropane ring with water at temperatures of 0‹ to 60‹ C. The corresponding free acids are obtained by hydrolysing the thus obtained esters, and the corresponding compounds in which A is -CH 2 -CHR 4  by reducing compounds in which A is trans -CH=CR 4 -. 3-Oxa or 4-oxa PGF derivatives are made by the carbonyl reduction of the corresponding 3-oxa or 4-oxa PGE derivatives. 3-Oxa or 4-oxa PGA derivatives are obtained either by reacting the bicyclo-[3,1,0]-hexane derivatives of the above Formula LXXXII with combinations of water, bases characterized by their water solution having pH's of 8 to 12 and sufficient watersoluble organic diluents to form basic substantially homogeneous reaction mixtures at temperatures of 40‹ to 100‹ C., or by reacting the corresponding 3- or 4-oxa PGE or 3- or 4-oxa PGB derivatives with bases whose water solutions have pH's greater than 10. 3-Oxa and 4-oxa PGB derivatives are prepared by the acidic dehydration of the corresponding 3-oxa or 4-oxa PGE derivatives. The following intermediate compounds are also made: endo-6-(1,2-dihydroxyheptyl)-bicyclo [3,1,0] hexan-3-one and its acetonide, ethyl 3 - oxa - 7 - [endo - 6 - (1 - heptenyl) - 3 - oxobicyclo [3,1,0] hex - 2α - yl] heptanoate, ethyl 2,2 - dimethyl - 3 - oxa - 7 - [oxo - 6 - (1 - heptenyl) - 3 - oxobicycio [3,1,0] hex - 2 - yl] heptanoate, ethyl 3 - oxa - 7 - [endo - 6 - (1,2 - dihydroxyheptyl) - 3 - oxobicyclo - [3,1,0] hex-2α- yl] heptanoate acetonide, 3 - oxa - 7 - [endo-6- (1 - heptenyl) - 3 - oxobicyclo [3,1,0] hex - 2α- yl] heptanoic acid, 3 - oxa - 7 - [endo - 6 - (1- heptenyl) - 3 - hydroxybicyclo [3,1,0] hex-2α-yl] heptanoic acid and its ethyl ester, 3-oxa-7- [endo - 6 - (1,2 - dihydroxy - heptyl) 3 - oxabicyclo [3,1,0] hex - 2α - yl] heptanoic acid acetonide, #,#,# - trichloroethyl 3 - oxa - 7- [endo - 6 - (1 - heptenyl) - 3 - oxobicyclo [3,1,0] hex - 2α - yl] heptanoate, #,#,# - trichloroethyl 3 - oxo - 7 - [endo - 6 - (1,2 - dihydroxyheptyl)- 3 - oxobicyclo [3,1,0] hex - 2α - yl] heptanoate acetonide, ethyl 3 - oxa - 7 - [endo - 6 - (1,2- dihydroxyheptyl) - 3 - oxobicyclo [3,1,0] hex-2α- yl] heptanoate, ethyl 3-oxa-7-[endo-6-(1,2- dihydroxyheptyl) - 3 - oxobicyclo [3,1,0] hex- 2α - yl] - trans - 5 - heptenoate acetonide, ethyl 3 - oxa - 7 - [endo - 6 - (1,2 - dimesyloxyheptyl)- 3 - oxobicyclo [3,1,0] hex - 2α - yl] heptanoate, and 3 - oxa - 7 - [endo - 6 - (1 - hydroxy - 2- mesyloxyheptyl) - 3 - oxobicyclo [3,1,0] hex - 2α- yl] heptanoate. Pharmaceutical compositions, suitable for oral or parenteral administration and having prostaglandin-like activity, contain the above novel compounds or pharmaceutically acceptable salts thereof together with pharmaceutically acceptable carriers.