Patent GB-1429092-A (GB)
Title: 8-aza-11,12-secoprostaglandins
IPC: C07C49/16
Filed: 1974-04-22
Abstract: 1429092 11,12-Secoprostaglandins MERCK & CO Inc 22 April 1974 [25 April 1973 23 Nov 1973] 17522/74 Heading C2C The invention comprises 11,12-secoprostaglandins of the Formula I: wherein R is COOY, CONR<SP>6</SP>.R<SP>7</SP> or CONHNH 2 , where Y is H, a pharmaceutically acceptable cation, C 1-10  alkyl, 1-(succinimidoethyl), 1- (pivaloyloxy)ethyl, 2-acetamidoethyl or C 4-7 - dialkylaminoalkyl; R<SP>6</SP> and R<SP>7</SP> are H, C 1-4  alkyl or C 4-7  dialkylaminoalkyl; A is ethylene, trimethylene, α- or #-methylethylene, α,α- or #,#- dimethylethylene or oxymethylene; Z is ethylene, cis- or trans-vinylene or ethynylene; R<SP>1</SP> is CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, or (CH 3 ) 2 - CH-; R<SP>2</SP> is H, CH 3 -, CH 3 CH 2 -, or CH 3 CH 2 - CH 2 -; R<SP>3</SP> is H or C 1-5  alkanoyl, each R<SP>4</SP> is, independently of the other, H or CH 3 ; R<SP>5</SP> is W, C 1-5  alkyl vinylene or 2,2,2-trifluoroethyl or R<SP>5</SP> and R<SP>2</SP> are joined together to form, with the intervening carbon atoms, a saturated C 5-9  carbocyclic ring; and y is 1 or 2; and their preparations. The compounds are prepared by reacting compounds of the formula wherein R<SP>8</SP> is C 1-5  alkyl, with strong bases, and then with compounds of the formula wherein X is halogen and R<SP>30</SP> is C 1-5  alkanoyl, recovering the products of the formula and hydrolysing them under mild conditions. Alternatively compounds in which R<SP>5</SP> is H, C 1-4  alkyl or 2,2,2-trifluoroethyl and R<SP>2</SP> is H may be prepared by reacting compounds of the formulµ wherein THP is 2-tetrahydropyranyl, with strong bases and then with compounds of the formula recovering the tetrahydropyranyl ethers of the formula wherein R<SP>9</SP> is H, C 1-4  alkyl or 2,2,2-trifluoroethyl, subjecting the latter to mild acidic hydrolysis and mild basic hydrolysis. The acids obtained in the above processes may be converted to esters, salts, amides and carbazides by standard methods. N - [4 - (2 - Tetrahydropyranyloxy)nonyl]- methanesulphonamide is obtained by reacting methanesulphonyl chloride with 4-(2-tetrahydropyranyloxyl)nonylamine. Ethyl 7 - (methanesulphonamido)heptanoate is prepared by reacting methanesulphonamide with ethyl 7-bromoheptanoate in the presence of sodium hydride. Ethyl 7-(ethanesulphonamido)- heptanoate, ethyl 7 - (propanesulphonamido)- heptanoate, and ethyl [(1 - methylethane)sulphonamido]heptanoate are obtained in a similar manner. 1 - Chloro - 4 - acetoxy - 4 - methylnonane is prepared by acetylating 1-chloro-4-hydroxy-4- methylnonone, obtained by reacting 1-chloro-4- nonanone with methylmagnesium iodide. Ethyl 7-(methanesulphinamido)heptanoate is obtained by reacting methanesulphinamide with ethyl 7-bromoheptanoate in the presence of sodium hydride. 1 - Bromo - 4 - acetoxy - 4 - propyl - 2 - heptyne is prepared by reacting cyanogen bromide with 1 - diethylamino - 4 - acetoxy - 4 - propyl - 2- heptyne, resulting from the reaction between diethylamine, paraformaldehyde and 3-acetoxy-3- propyl-1-hexyne, which is obtained by acetylating 3-propyl-1-hexyn-3-ol. 2 - tent. - Butylamino - 1 - methylvinyl 7 - [N- (4 - hydroxynonyl) methanesulphonamido] heptanoate is prepared by reacting 7-[N-(4-hydroxynonyl) methanesulphonamido] heptanoic acid with N - t - butyl - 5 - methylisoxazolium perchlorate. Pharmaceutical compositions, suitable for oral, parenteral, topical or rectal administration, contain the above 11,12-secoprostaglandins together with pharmaceutically acceptable carriers.