Patent CA-1325422-C (CA)
Title: Prodrug derivatives of carboxylic acid drugs
Inventor: BUNDGAARD HANS
IPC: A61K31/397
Filed: 1987-08-26
Granted: 1993-12-21
Abstract: ABSTRACT Compounds of the formula I                           wherein R-COO- represents the acyloxy residue of a carboxylic acid drug or medicament, n is an integer from 1 to 3, and R1 and R2 are the same or different and are selected from a group consisting of an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a cycloalkyl group, in which the alkyl, alkenyl, aryl, aralkyl or cycloalkyl group is unsubstituted or substituted with one or more substituents selected from:    - a halogen atom, - a hydroxy group, - a carbonyl group, a straight or branched-chain alkoxy group having the formula R3-O-, wherein R3 represents an alkyl group or an aryl group, which groups may be unsubstituted or substituted with one or more of a halogen atom or a hydroxy group, a carbamoyl group having the formula    , wherein R4 and R5 are the same or different and are hydrogen, an alkyl group or are selected from a group having the formula -CH2NR7R6, wherein R6 and R7 are the same or different and are hydrogen, an alkyl group, or together with the adjacent nitro-gen atom form a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, - an amino group having the formula -NR8Rg, wherein R8 and R9 are the same or different and are hydrogen, an alkyl group or together with the adjacent nitrogen atom form a 4- t 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, - an acyloxy group having the formula -COOR10, wherein R10 is an alkyl, aryl or aralkyl group, - an ocyloxy group having the formula R11COO- wherein R11 is hydrogen, an alkyl group, an aryl group, an aralkyl group, a cycloalkyl group, in which the alkyl, aryl, aralkyl or cyclo-alkyl group is unsubstituted or substituted with one or more of a halogen atom, a hydroxy group, an alkoxy group of the formula R3-O- as defined above, a carbamoyl group of the formula -CONR4R5 as defined above or an amino group having the formula -NR8R9 as defined above; or R1 and R2 are combined so that -NR1R2 forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which heterocyclic ring may be substituted with a hydroxy group, a carbonyl group, an alkyl group or an oxyacyl group having the formula R11COO-, wherein R11 is as defined above, or an acyloxy group of the formula -COOR10, wherein R10 is as defined above; and nontoxic pharmaceutically acceptable acid addition salts thereof with the proviso that if R1 - alkyl then R2 - alkyl, and if R1 -CH2CH2OH then R2 - CH2CH2OH.          Such compounds are highly biolabile prodrug forms of the correspond-ing carboxylic acid drugs and exhibit high susceptibility to undergo enzymatic hydrolysis in vivo while at the same time being highly stable in aqueous solution.