Nitric Oxide Releasing Produgs of Therapeutic Agents

摘要

The present invention relates to nitric oxide releasing prodrugs of known drugs or therapeutic agents wherein the drug or therapeutic agents contain at least one carboxylic acid group. The invention also relates to processes for the preparation of these nitric oxide releasing prodrugs, to pharmaceutical compositions containing them and to methods of using these produgs.

主权项

1. The compounds of the invention that are covered within the scope of the formula (I), which are nitric oxide releasing prodrugs of known carboxyl-containing drugs or therapeutic agents useful in the treatment of diseases or disorders that are characteristic of the drugs from which the prodrugs of the present invention are derived, all their geometrical and stereoisomeric forms and also pharmaceutically acceptable salts thereof: Wherein, (X)n-Dx-C(═O)O represents a drug or therapeutic agent containing at least one carboxylic acid group, which is covalently bonded to the specified linker “C(H)(Ry)” via a bio-cleavable ester linkage; where X independently at each occurrence represents OH (i.e., a primary, secondary, tertiary or phenolic hydroxyl group), O-hPG, SH (i.e., a primary, secondary, tertiary or thiophenolic sulfhydryl group), S-sPG, CO2H or C(═O)O-cPG, amino group (i.e., NH2 or NH or N, which correspond to primary or secondary or tertiary amino groups, respectively), HN-aPG, N-aPG, a phosphate group [i.e., P(═O)(OH)2], a protected phosphate group [i.e., P(═O)(O-pPG)2], a carbonyl group (i.e., an aldehyde or keto group in the form of their bio-cleavable derivatives such as an acetal, oxime, hydrazone, semicarbazone and the like) or a mixture of one or more types of these functional groups, where hPG represents a bio-cleavable hydroxyl protecting group such as acetyl group and the like; sPG represents a bio-cleavable sulfhydryl protecting group such as acetyl group, disulfide bond and the like; cPG represents a bio-cleavable carboxyl protecting group such as lower (C1-C6) alkyl esters and the like; aPG represents a bio-cleavable amino protecting group such as acetyl, ethoxycarbonyl, 2-acetylthioethoxycarbonyl or 2-(2-aminoethyl)dithioethoxy-carbonyl group and the like; pPG represents a bio-cleavable phosphate protecting group such as 2-(S-acetylthio)ethyl (SATE), 3-pivaloyloxy-1,3-dihydroxypropyl derivative, dithiodiethanol derivative, 4-acyloxybenzyl phosphate mono or diester derivatives and the like; n represents 0 (zero) or 1-20, preferably 0 (zero) or 1-10, yet preferably 0 (zero) or 1-5, yet most preferably 0 (zero) or 1-2; Ry is an alkyl C1-C6 or cycloalkyl C3-C7; preferably alkyl C1-C4; yet preferably alkyl C1-C2; yet most preferably alkyl C1 (i.e., CH3); ONO2 (a nitrooxy) group is covalently bonded to the other side of the linker;