Spiro-subsituted glutaramide diuretic agents

Claim 1

A process for preparing a compound having the formula: wherein A completes a 4 or 7 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be fused to a further saturated or unsaturated 5 or 6 membered carbocyclic ring; B is (CH 2 ) m wherein m is an integer of from 1 to 3; each of R and R 4 is independently H, C 1 -C 6 alkyl, benzyl or an alternative biolabile ester-forming group; R 1 is H or C 1 -C 4 alkyl; R 2 and R 3 are ech independently H, OH, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; R 5 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl(C 2 -C 6 alkynyl), C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 1 -C 6 a lkox y, -NR 6 R 7 , -NR 8 COR 9 , -NR 8 SO 2 R 9 or a saturated heterocyclic group; or Ci-C 6 alkyl substituted by one or more substituents chosen from halo, hydroxy, C 1 -C 6 alkoxy, C 2 -C 6 hydroxyalkoxy, C 1 -C 6 alkoxy(C 1 -C 6 alkoxy), C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, aryl, aryloxy, aryloxy(C 1 -C 4 alkoxy), heterocyclyl, heterocyclyloxy, -NR 6 R 7 , -NR 8 COR 9 , -NR 8 S0 2 R 9 , -CONR 6 R 7 , -SH, -S(O) p R 10 , -COR" or -CO 2 R 12 ; wherein R 6 and R 7 are each independently H, C 1 -C 4 alkyl), C 3 -C 7 cycloalkyl (optionally substituted by hydroxy or C 1 -C 4 alkoxy), aryl, aryl(C 1 -C 4 alkyl), C 2 -C 6 alkoxyalkyl, or heterocyclyl; or the two groups R 6 and R 7 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(Ci-C 4 alkyl)-piperazinyl group; R 8 is H or Ci-C 4 alkyl; R 9 is C 1 -C 4 alkyl, CF 3 , aryl, aryl(C 1 -C 4 alkyl), aryl(C 1 -C 4 alkoxy), heterocycyl, C 1 -C 4 alkoxy or NR 6 R 7 wherein R 6 and R 7 are as previously defined; R 10 is C 1 -C 4 alkyl, aryl, heterocyclyl or NR 6 R 7 wherein R 6 and R 7 are as previously defined; R 11 is C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, aryl or heterocyclyl; R 12 is H or C 1 -C 4 alkyl; and p is 0, 1 or 2; or a pharmaceutically acceptable salt thereof or bioprecursor therefor. a) reacting compounds of the formulae:- wherein A, B, R', R 2 and R 3 are as previously defined, R 5 ' is as defined for R 5 with any reactive group therein optionally protected and R 13 and R 14 are as defined for R and R 4 , excluding H, or they are conventional carboxylic acid protecting groups; to produce a compound of the formula:- b) optionally subjecting the product to a conventional chemical transformation reaction; c) in the case where one or both of R 13 and R 14 is independently C 1 -C 6 alkyl or benzyl, removing one or both of said groups; or in the case where one or both of R 13 and R 14 are conventional carboxylic acid protecting groups, removing said carboxylic acid protecting groups; and, in the case where R 5' contains a protecting group, removing said protecting group; to give the compound of formula (I) wherein R and R 4 are both H or wherein one of R and R 4 is H and the other is C 1 -C 6 alkyl, benzyl or an alternative biolabile ester-forming group, and d) optionally esterifying the product wherein one or R 13 and R 14 is C 1 -C 6 alkyl, benzyl or a conventional carboxylic acid protecting group and the other is H, with a biolabile ester-forming group followed by removal of the C 1 -C 6 alkyl, benzyl or carboxylic acid protecting group to yield the compound of formula (I) wherein one of R and R 4 is a biolabile ester-forming group and the other is H; or esterifying the product of formula (I) wherein both the R and R 4 are H with a biolabile ester-forming group to yield the product of formula (I) wherein both R and R 4 are biolabile ester-forming groups, and e) optionally forming a pharmaceutically acceptable salt of the product.