Peripheral Opioid Agonists and Peripheral Opioid Antagonists
The present disclosure provides compositions, and their methods of use, where the compositions comprise a ketone-modified opioid drug, wherein the drug comprises a ketone-modified opioid and a substituent on the opioid that mediates retention of the drug in the peripheral nervous system as opposed to the central nervous system following ingestion by a subject.
1 . A compound of formula (I):
wherein:
X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group or reduced enolic group of the ketone is replaced by a covalent bond to —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ; or wherein the hydrogen atom of an amino group that is generated from reductive amination of the ketone of the ketone-containing opioid is replaced by a covalent bond to —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ;
R 5 is selected from hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or
R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 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 10;
R 3 is selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl;
R 4 is selected from a residue of a D-amino acid; a residue of an N-acyl derivative of a D-amino acid; a residue of a polyethylene glycol derivative of a D-amino acid; a residue of L-proline; a residue of an N-acyl derivative of L-proline; a residue of a polyethylene glycol derivative of L-proline; a residue of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; a residue of an N-acyl derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; and a residue of a polyethylene glycol derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid;
or R 4 is
each R 6 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, R 6 and R 7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
each W is independently —NR 8 —;
each R 8 is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
p is an integer from one to five; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, and polyethylene glycol; and
provided that:
1) when R 3 is hydrogen, then R 4 is selected from a residue of a D-amino acid; a residue of an N-acyl derivative of a D-amino acid; a residue of a polyethylene glycol derivative of a D-amino acid; a residue of L-proline; a residue of an N-acyl derivative of L-proline; a residue of a polyethylene glycol derivative of L-proline; a residue of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; a residue of an N-acyl derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; and a residue of a polyethylene glycol derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid;
2) when R 3 is not hydrogen, then R 4 is selected from a residue of a D-amino acid; a residue of an N-acyl derivative of a D-amino acid; a residue of a polyethylene glycol derivative of a D-amino acid; a residue of L-proline; a residue of an N-acyl derivative of L-proline; a residue of a polyethylene glycol derivative of L-proline; a residue of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; a residue of an N-acyl derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; and a residue of a polyethylene glycol derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; or R 4 is
or a salt, hydrate or solvate thereof.
2 . A compound according to claim 1 , of formula (II):
wherein:
X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group or reduced enolic group of the ketone is replaced by a covalent bond to —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ; or wherein the hydrogen atom of an amino group that is generated from reductive amination of the ketone of the ketone-containing opioid is replaced by a covalent bond to —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ;
R 5 is selected from hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or
R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 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 10;
R 3 is selected from alkyl, substituted alkyl, aryl, and substituted aryl;
R 4 is
each R 6 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, R 6 and R 7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
each W is independently —NR 8 —;
each R 8 is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
p is an integer from one to five; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, and polyethylene glycol;
or a salt, hydrate or solvate thereof.
3 . A compound according to claim 1 , of formula (III):
wherein:
X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group or reduced enolic group of the ketone is replaced by a covalent bond to —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ; or wherein the hydrogen atom of an amino group that is generated from reductive amination of the ketone of the ketone-containing opioid is replaced by a covalent bond to —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ;
R 5 is selected from hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or
R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 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 10;
R 3 is selected from alkyl, substituted alkyl, aryl, and substituted aryl;
R 4 is selected from a residue of a D-amino acid; a residue of an N-acyl derivative of a D-amino acid; a residue of a polyethylene glycol derivative of a D-amino acid; a residue of L-proline; a residue of an N-acyl derivative of L-proline; a residue of a polyethylene glycol derivative of L-proline; a residue of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; a residue of an N-acyl derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; and a residue of a polyethylene glycol derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid;
or a salt, hydrate or solvate thereof.
4 . A compound according to claim 1 , of formula (IV):
wherein:
X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group or reduced enolic group of the ketone is replaced by a covalent bond to —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ; or wherein the hydrogen atom of an amino group that is generated from reductive amination of the ketone of the ketone-containing opioid is replaced by a covalent bond to —C(O)—NR 5 —(C(R 1 )(R 2 )) n —NR 3 R 4 ;
R 5 is selected from hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or
R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 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 10;
R 3 is hydrogen;
R 4 is selected from a residue of a D-amino acid; a residue of an N-acyl derivative of a D-amino acid; a residue of a polyethylene glycol derivative of a D-amino acid; a residue of L-proline; a residue of an N-acyl derivative of L-proline; a residue of a polyethylene glycol derivative of L-proline; a residue of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; a residue of an N-acyl derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; and a residue of a polyethylene glycol derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid;
or a salt, hydrate or solvate thereof.
5 . A compound of formula (V):
wherein:
X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group or reduced enolic group of the ketone is replaced by a covalent bond to —C(O)—N(A ring)-(C(R 1 )(R 2 )) n —NR 3 R 4 ; or wherein the hydrogen atom of an amino group that is generated from reductive amination of the ketone of the ketone-containing opioid is replaced by a covalent bond to —C(O)—N(A ring)-(C(R 1 )(R 2 )) n —NR 3 R 4 ;
the A ring is a heterocyclic 5 to 12-membered ring;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or
R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group;
n is an integer from 1 to 10;
R 3 is selected from hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl;
R 4 is selected from a residue of a D-amino acid; a residue of an N-acyl derivative of a D-amino acid; a residue of a polyethylene glycol derivative of a D-amino acid; a residue of L-proline; a residue of an N-acyl derivative of L-proline; a residue of a polyethylene glycol derivative of L-proline; a residue of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; a residue of an N-acyl derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; and a residue of a polyethylene glycol derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid;
or R 4 is
each R 6 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, R 6 and R 7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
each W is independently —NR 8 —;
each R 8 is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
p is an integer from one to five; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, and polyethylene glycol; and
provided that:
1) when R 3 is hydrogen, then R 4 is selected from a residue of a D-amino acid; a residue of an N-acyl derivative of a D-amino acid; a residue of a polyethylene glycol derivative of a D-amino acid; a residue of L-proline; a residue of an N-acyl derivative of L-proline; a residue of a polyethylene glycol derivative of L-proline; a residue of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; a residue of an N-acyl derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; and a residue of a polyethylene glycol derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid;
2) when R 3 is not hydrogen, then R 4 is selected from a residue of a D-amino acid; a residue of an N-acyl derivative of a D-amino acid; a residue of a polyethylene glycol derivative of a D-amino acid; a residue of L-proline; a residue of an N-acyl derivative of L-proline; a residue of a polyethylene glycol derivative of L-proline; a residue of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; a residue of an N-acyl derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; and a residue of a polyethylene glycol derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; or R 4 is
or a salt, hydrate or solvate thereof.
6 . A compound according to claim 5 , of formula (VI):
wherein:
X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group or reduced enolic group of the ketone is replaced by a covalent bond to —C(O)—N(A ring)-(C(R 1 )(R 2 )) n —NR 3 R 4 ; or wherein the hydrogen atom of an amino group that is generated from reductive amination of the ketone of the ketone-containing opioid is replaced by a covalent bond to —C(O)—N(A ring)-(C(R 1 )(R 2 )) n —NR 3 R 4 ;
the A ring is a heterocyclic 5 to 12-membered ring;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or
R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group;
n is an integer from 1 to 10;
R 3 is selected from alkyl, substituted alkyl, aryl, and substituted aryl;
R 4 is
each R 6 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, R 6 and R 7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
each W is independently —NR 8 —;
each R 8 is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
p is an integer from one to five; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, and polyethylene glycol;
or a salt, hydrate or solvate thereof.
7 . A compound according to claim 5 , of formula (VII):
wherein:
X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group or reduced enolic group of the ketone is replaced by a covalent bond to —C(O)—N(A ring)-(C(R 1 )(R 2 )) n —NR 3 R 4 ; or wherein the hydrogen atom of an amino group that is generated from reductive amination of the ketone of the ketone-containing opioid is replaced by a covalent bond to —C(O)—N(A ring)-(C(R 1 )(R 2 )) n —NR 3 R 4 ;
the A ring is a heterocyclic 5 to 12-membered ring;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or
R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group;
n is an integer from 1 to 10;
R 3 is selected from alkyl, substituted alkyl, aryl, and substituted aryl;
R 4 is selected from a residue of a D-amino acid; a residue of an N-acyl derivative of a D-amino acid; a residue of a polyethylene glycol derivative of a D-amino acid; a residue of L-proline; a residue of an N-acyl derivative of L-proline; a residue of a polyethylene glycol derivative of L-proline; a residue of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; a residue of an N-acyl derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; and a residue of a polyethylene glycol derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid;
or a salt, hydrate or solvate thereof.
8 . A compound according to claim 5 , of formula (VIII):
wherein:
X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group or reduced enolic group of the ketone is replaced by a covalent bond to —C(O)—N(A ring)-(C(R 1 )(R 2 )) n —NR 3 R 4 ; or wherein the hydrogen atom of an amino group that is generated from reductive amination of the ketone of the ketone-containing opioid is replaced by a covalent bond to —C(O)—N(A ring)-(C(R 1 )(R 2 )) n —NR 3 R 4 ;
the A ring is a heterocyclic 5 to 12-membered ring;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or
R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group;
n is an integer from 1 to 10;
R 3 is hydrogen;
R 4 is selected from a residue of a D-amino acid; a residue of an N-acyl derivative of a D-amino acid; a residue of a polyethylene glycol derivative of a D-amino acid; a residue of L-proline; a residue of an N-acyl derivative of L-proline; a residue of a polyethylene glycol derivative of L-proline; a residue of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; a residue of an N-acyl derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid; and a residue of a polyethylene glycol derivative of a peptide composed of up to five amino acids wherein the amino acid of the peptide adjacent the nitrogen of —N(R 3 )(R 4 ) is a residue of a D-amino acid;
or a salt, hydrate or solvate thereof.
9 . (canceled)
10 . A method of treating or preventing pain in a patient, which comprises administering an effective amount of a composition comprising the compound of claim 1 .
11 - 13 . (canceled)
14 . A method of treating or preventing an unwanted side effect associated with use of an opioid agonist in a patient, which comprises administering an effective amount of a composition comprising the compound of claim 1 .
15 . (canceled)
16 . A compound selected from the group consisting of the formulae:
or salt or solvate or stereoisomer thereof.
17 - 23 . (canceled)
24 . A compound according to claim 1 , of the formula:
or salt or solvate or stereoisomer thereof.
25 . A composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1 .
26 . A composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 5 .
27 . A method of treating or preventing pain in a patient, which comprises administering an effective amount of a composition comprising the compound of claim 5 .
28 . A method of treating or preventing an unwanted side effect associated with use of an opioid agonist in a patient, which comprises administering an effective amount of a composition comprising the compound of claim 5 .
29 . A method of claim 28 , wherein the unwanted side effect is selected from constipation, cough suppression, dry mouth, heartburn, myocardial depression, nausea, pruritus, urinary retention, vomiting, bloating, dry-mouth or heartburn.
30 . A method of claim 14 , wherein the unwanted side effect is selected from constipation, cough suppression, dry mouth, heartburn, myocardial depression, nausea, pruritus, urinary retention, vomiting, bloating, dry-mouth or heartburn.