Compositions Comprising Enzyme-Cleavable Ketone-Modified Opioid Prodrugs and Optional Inhibitors Thereof

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)—NRS—(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.