| 主权项 |
1. A prodrug or its pharmaceutically acceptable salt thereof, comprising a nitrogen-containing or hydroxyl-containing drug or a pharmaceutically active agent conjugated to a promoiety via a covalent bond hydrolytically labile at physiological conditions (e.g. pH between 7.0 and 7.6, 37° C.), wherein the promoiety is of the following formula: wherein X is selected from OH, SH, NH2, and HN—R0; Y is selected from NH, N—RO, CH2, C—RpRq, O (provided that X is not OH or SH), S (provided that X is not OH or SH), C—RpRq when X is HN—R0, wherein R0 and Rp together with the atoms to which they are attached can form a 4, 5, or 6 membered heterocyclic ring, and C(O); Y1 is selected from C(R3R4), C(O) (provided that Y is not C(O)), O (provided that Y is not OH or SH), S and SO2 (provided that Y is not OH or SH), N—Rn, and a covalent bond between Y and A; J1 is C(R10R11) or a covalent bond between B and C(O)-drug/pharmaceutically active agent; A, B, a, b, R0, RO, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, Rm, Rn, Rp, Rq, R′, R′1, R′2, R″, R′″ are independently selected from straight or branched chain alkyl having from 1 to 20 carbon atoms; aryl having from 6 to 15 carbon atoms; cycloalkyl having a 3, 4, 5, 6, 7, 8, 9, or 10 membered ring; alkenyl having from 2 to 20 carbon atoms; cycloalkenyl having a 3, 4, 5, 6, 7, 8, 9, or 10 membered ring; alkynyl having from 2 to 20 carbon atoms; cycloalkynyl having a 3, 4, 5, 6, 7, 8, 9, or 10 membered ring; monocyclic or polycyclic; acyl group, aryl carbonyl, alkyl carbonyl; aryl amide, alkyl amide; aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, alkynylaryl, loweracyloxyalkyl, and carboxyalkyl, wherein alkyl, aryl, alkenyl and alkynyl are defined as above; mono- or poly-substituted derivatives of the above; saturated or unsaturated monoheterocyclic or polyheterocyclic, or fused heterocyclic, containing from 1 to 3 of any one or more of the heteroatoms N, S or O in each heterocyclic ring thereof and each such ring being from 3- to 8-membered; and mono- or poly-substituted derivatives of the above, each of said substituents being selected from loweralkyl, loweralkoxy, loweracyl, lower acyloxy, phenyl, benzyl, halo, haloformyl, haloloweralkyl, trifluoromethyl cyanate, cyanide, isocyanide, isocyanate, isothiocyanate, carbethoxy, loweralkylthio, hydroxyl, amine, ammonio, imine, imide, aminoloweralkyl, hydroxyloweralkyl, carboxamide, nitro, nitrate, nitrite, nitroso, nitrosooxy, pyridyl, azide, azo, loweralkylamino, diloweralkylamino, aldehyde, carbonyl, carboxyl, ether, ester, carbonate ester, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl, sulfonic acid, sulfonamide, loweralkylsulfonate, loweralkylsulfonyl, loweralkylsulfite, loweralkylsulfoxide, sulfide, disulfide, sulfinyl, mercapto (or sulfhydryl)thiocyanate, loweralkylcarbonate, phosphino, phosphodiester, phosphono, phosphate; or a, b, R0, RO, R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, Rm, Rn, Rp, and Rq are selected from hydrogen (H), loweralkyl, loweralkoxy, loweracyl, lower acyloxy, phenyl, benzyl, halo, haloformyl, haloloweralkyl, trifluoromethyl, cyanate, cyanide, isocyanide, isocyanate, isothiocyanate, carbethoxy, loweralkylthio, hydroxyl, amine, ammonio, imine, imide, aminoloweralkyl, hydroxyloweralkyl, carboxamide, nitro, nitrate, nitrite, nitroso, nitrosooxy, pyridyl, azide, azo, loweralkylamino, diloweralkylamino, aldehyde, carbonyl, carboxyl, ether, ester, carbonate ester, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl, sulfonic acid, sulfonamide, loweralkylsulfonate, loweralkylsulfonyl, loweralkylsulfite, loweralkylsulfoxide, sulfide, disulfide, sulfinyl, mercapto (or sulfhydryl)thiocyanate, loweralkylcarbonate, phosphino, phosphodiester, phosphono, phosphate; or A and B, or a and b, together with the atoms to which they are attached form a C3-C10 cycloalkyl ring (e.g. cycloalkane, cycloalkene, and cycloalkyne) optionally substituted by at least one group; or saturated or unsaturated monocyclic or polycyclic, or fused cyclic ring optionally substituted by at least one group; or saturated or unsaturated monoheterocyclic or polyheterocyclic, or fused heterocyclic ring optionally substituted by at least one group; or A and B together with the atoms to which they are attached form an aromatic ring optionally substituted by at least one group selected from the above; or A and B together with the atoms to which they are attached form a polyaromatic ring; or A and/or B can be —NR′, —SR″, or —OR″, where R′ R″ and R′″ have the same definition as R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13; or two R groups (selected from R0, RO, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, Rm, Rn, Rp, Rq, R′, R′1, R′2, R″, and R′″) attached to the same atom or separated by one bond form a C3-C8 cycloalkyl, cycloalkenyl, or cycloalkynyl ring, or saturated or unsaturated heterocyclic ring optionally substituted by at least one group selected from the above; or two R groups together with the atoms to which they are attached form an aromatic ring optionally substituted by at least one group selected from the above; or a promoiety conjugated to a modifying moiety of the following formula:
-L-M wherein; L is an optional linker moiety selected from, but not limited to, —(CH2)n—, —(CH2O)n—, —O—, —S—, —C(O)—, —NH—, —NHC(O)—, —C(O)NH—, —SO2NH—, —HNSO2—, —C(O)O—, —OC(O)—; M is a modifying moiety, which includes any hydrophilic moieties, lipophilic moieties, amphiphilic moieties, salt forming moieties, carrier proteins (e.g. serum albumin, immunoglobulin) and combinations of two or more of the above thereof. |
