Active Agent Prodrugs with Heterocyclic Linkers

摘要

The embodiments provide prodrug compounds of Formulae I-XVII. The present disclosure also provides compositions, and their methods of use, where the compositions comprise a prodrug compound of Formulae I-XVII that provides controlled release of an active agent. Such compositions can optionally provide a trypsin inhibitor that interacts with the enzyme that mediates the controlled release of an active agent from the prodrug so as to attenuate enzymatic cleavage of the prodrug.

主权项

1. A compound of formula I: wherein X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Yc]—(CR1R2)aNH—C(O)—CH(R5)—N(R3)—[C(O)—CH(R6)—N(R3)]b—R7; a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N[(A ring)-Yc]—(CR1R2)aNH—C(O)—CH(R5)—N(R3)—[C(O)—CH(R6)—N(R3)]b—R7; and a residue of an amide-containing active agent, wherein —C(O)—N[(A ring)-Yc]—(CR1R2)a—NH—C(O)—CH(R5)—N(R3)—[C(O)—CH(R6)—N(R3)]b—R7 is connected to the amide-containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer; the A ring is a heterocyclic 5 to 12-membered ring; each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; c is a number from zero to 3; each R1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; each R2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or R1 and R2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R1 or R2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8; provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8; each R3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; R5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; each R6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; b is a number from zero to 100; and R7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;or a salt, hydrate or solvate thereof.