Methadone Active Agents and Methods of Use Thereof

A compound of formula ME-(II):

• wherein:
• R5 is selected from hydrogen, 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 R2 or R3 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 1 to 4;
• 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;
• R3 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• W is independently a bond, —CH2—, —NR8—, —O— or —S—;
• 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;
• or a salt, hydrate or solvate thereof.

A compound of formula ME-(III):

• wherein:
• R5 is selected from hydrogen, 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 R2 or R3 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 1 to 4;
• 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;
• R3 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• W is independently a bond, —CH2—, —NR8—, —O— or —S—;
• 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;
• or a salt, hydrate or solvate thereof.

A compound of formula ME-(IV):

• wherein:
• 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 R2 or R3 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 1 to 4;
• 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;
• R3 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• W is independently a bond, —CH2—, —NR8—, —O— or —S—;
• 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;
• or a salt, hydrate or solvate thereof.

A compound of formula ME-(IV):

• wherein:
• R5 is selected from hydrogen, 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 R2 or R3 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 0 to 4;
• m is an integer from 0 to 4;
• 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;
• R3 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• W is independently a bond, —CH2—, —NR8—, —O— or —S—;
• 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;
• or a salt, hydrate or solvate thereof.

A compound selected from:

• a) (R, E)-6-(dimethylamino)-4,4-diphenylhept-2-en-3-yl (1-aminopropan-2-yl)(methyl)carbamate:
• or a salt, hydrate or solvate thereof;
• b) (R, E)-6-(dimethylamino)-4,4-diphenylhept-2-en-3-yl ((R)-2-aminopropyl)(methyl)carbamate:
• or a salt, hydrate or solvate thereof;
• c) (R, E)-6-(dimethylamino)-4,4-diphenylhept-2-en-3-yl ((S)-2-aminopropyl)(methyl)carbamate:
• or a salt, hydrate or solvate thereof.
• d) (R, E)-6-(dimethylamino)-4,4-diphenylhept-2-en-3-yl (4-aminobutyl)(methyl)carbamate:
• or a salt, hydrate or solvate thereof;
• or
• e) (R,E)-6-(dimethylamino)-4,4-diphenylhept-2-en-3-yl(2-aminobutyl)(methyl)carbamate:
• or a salt, hydrate or solvate thereof.