Compositions comprising enzyme-cleavable ketone-modified opioid prodrugs and optional inhibitors thereof

摘要

A method of providing a patient with controlled release of ketone-containing opioid using a prodrug capable, upon enzymatic activation and intramolecular cyclization, of releasing the ketone-containing opioid is disclosed. The disclosure also provides such prodrug compounds and pharmaceutical compositions comprising such compounds. Such pharmaceutical compositions can optionally include an enzyme inhibitor that interacts with the enzyme(s) to mediate the enzymatically-controlled release of the ketone-containing opioid from the prodrug so as to modify enzymatic cleavage of the prodrug. Also included are methods to use such compounds and pharmaceutical compositions.

主权项

1. A compound of formula KC-(IIIa): wherein: X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to —C(O)—NR5—(C(R1)(R2))n—NR3R4; R5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; each R1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; each R2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or R1 and R2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R1 and R2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; n is an integer from 2 to 4; R3 is hydrogen; R4 is 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, or optionally, R6 and R7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W is independently —NR8—, —O— or —S—; each R8 is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R6 and R8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; p is an integer from one 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; or, a compound of formula KC-(IIIb): wherein: X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to —C(O)—NR5—(C(R1)(R2))n—NR3R4; R5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; each R1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; each R2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or R1 and R2 together with the carbon to which they are attached 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, form a cycloalkyl or substituted cycloalkyl group; n is an integer from 2 to 4; R3 is hydrogen; R4 is 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, or optionally, R6 and R7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W is independently —NR8—, —O— or —S—; each R8 is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R6 and R8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; p is an integer from one 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.