8,12-DI-ISOPROSTANOIC ACID DERIVATIVES

摘要

1420338 Prostaglandins CARLO ERBA SpA 12 Dec 1972 [17 Dec 1971] 57333/72 Heading C2C The invention comprises prostaglandins of the Formulae I and II wherein R1 is H or C 1-12 alkyl; one of R2 and R3 is H and the other is OH or R2 and R3 together form an oxo group; the symbol = is a single or cis-double bond; R4 is -CH 2 CH 2 -, -OCH 2 -, trans -CH=CH-, or -SCH 2 -; n is 3 or 4; each of R5 and R6 is H or C 1-4 alkyl, one of R' and R8 is H and the other is OH; and double bond a is a trans-double bond, with the proviso that when R4 is trans -CH = CH the symbol = is a cis-double bond, and pharmaceutical acceptable salts thereof when R1 is H and their preparation. The compounds are prepared by reacting lactols of the Formula III wherein one of R7 and R8 is OH or an etherified group and the other is H, and Y is OH or an etherified hydroxy group with Wittig reagents comprising the group CH 2 CH 2 R4COOR1 to give compounds of the Formula IV optionally hydrogenating the 5(6) double bond and if necessary, deetherifying compounds of Formula IV or their hydrogenation products, or (a) oxidizing the 9-hydroxy group of compounds of Formula IV wherein Y is an etherified hydroxy group and one of R7 I and R8 I is an etherified hydroxy group and the other is H or the 5(6) hydrogenation products to give compounds of the Formula V which may either be deetherified, or its 9-oxo group reduced to give the corresponding 9α- and 9#-hydroxy compounds and the mixture, in any order, separated and deetherified; or (b) reacting compounds of Formula IV in which Y is etherified hydroxy and one of R7 I and R8 I is etherified hydroxy and the other is H, or 5(6) hydrogenated products thereof with compounds of the formula R9SO 2 X, wherein R9 is optionally substituted alkyl or aryl and X is halogen to give compounds of the Formula VIII which are then reacted with carboxylic acid salts to yield a mixture of compounds of Formulae IV and V which mixtures are then, in any order, hydrolysed, deetherified and separated. dP-5-Benzyloxy 1-(or -4-methoxybenzyloxy)- methyl-4-hydroxy-2-cyclopentene-1-acetic acid is resolved via its dehydroabietylamine salt. The following intermediates are also prepared: 5α-methoxymethyl (or benzyloxymethyl- or p-methoxybenzyloxymethyl-)-2#,4#-dihydroxy- 3α-iodo-1#-cyclopentane acetic acidγ-lactone and its 4#-acetate, 5α-methoxy methyl-2#,4#- dihydroxy-1#-cyclopentane acetic acidγ-lactone and its 4#-acetate, 4#-p-toluenesulphonate, 4#- methanesulphonate and 4#-benzenesulphonate, 5α-methoxymethyl 2#-hydroxy-3-cyclopentene- 1#-acetic acidγ-lactone, 5α-hydroxymethyl- 2#,4α-dihydroxy-1#-cyclopentane acetic acidγ- lactone 4α-p-phenylbenzoate, 5α-formyl-2#4,α- dihydroxy-1#-cyclopentane acetic acidγ-lactone 4α-p-phenylbenzoate and 4α-acetate, 5α-(3-oxo- 2-R 6 -4-R 5 -oct (or non)-trans-1-enyl)-2#,4α-dihydroxy-1#-cyclopentane acetic acidγlactone 4α-p-phenylbenzoate and 4α-acetate 5α-(3-hydroxy-2-R 6 -4-R 5 -oct (or non)-trans-1-enyl)-2#, 4α-dihydroxy-1#-cyclo pentane acetic acidγ- lactone and its 4α-p-phenylbenzoate and 4α- acetate, compounds of the Formula XXI 5α- p - methoxybenzyloxymethyl - 2#,4# - dihydroxy-1#-cyclopentane acetic acidγ-lactone and its 4#-acetate, 4#-p-toluenesulphonate, 4#- methane-sulphonate and 4#-benzenesulphonate, 5α-benzyloxy (or p-methoxybenzyloxy or methoxy) methyl-2#-4α-dihydroxy-1#-cyclopentaneacetic acidγ-lactone and its 4α-propionate, 4α-formate and its 4α-p-phenylbenzoate. Pharmaceutical compositions, suitable for oral, parenteral or rectal administration, contain the above prostaglandins or salts thereof and pharmaceutical acceptable diluents or carriers. The compounds possess activities similar to those of the naturally occurring prostaglandins.