# US 9,040,552 B2 · Selective opioid compounds

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- Number: US 9,040,552 B2
- Document ID: US9040552B2
- Status: Granted
- Kind: B2
- Application number: 13/693,662
- Filed: 2012-12-04
- Published: 2014-01-02
- Granted: 2015-05-26
- Earliest claimed: 2008-02-14
- Assignees: Alkermes, Inc.
- Applicants: Alkermes, Inc.
- Inventors: Derrick Arnelle; Daniel Deaver; Reginald L. Dean, III; Mark Todtenkopf
- Web page: https://patentgrep.com/patent/US9040552B2

## CPC

- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 31/4748: forming part of bridged ring systems (strychnine A61K31/475; morphinan derivatives A61K31/485)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 1/10: Laxatives
- A61P 1/12: Antidiarrhoeals
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/10: of the bladder
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 19/00: Drugs for skeletal disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 25/32: Alcohol-abuse
- A61P 25/34: Tobacco-abuse
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/08: Bridged systems
- C07D 489/08: Oxygen atom
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to compounds of Formula I or II, or pharmaceutically acceptable salts, esters, or prodrugs thereof: which relates to mophinan compounds useful as μ, δ and/or κ receptor opioid compounds and pharmaceuticals containing same that may be useful for mediating analgesia, combating drug addiction, alcohol addiction, drug overdose, mental illness, bladder dysfunctions, neurogenic bladder, interstitial cystitis, urinary incontinence, premature ejaculation, inflammatory pain, peripherally mediated and neuropathic pain, cough, lung edema, diarrhea, cardiac disorders, cardioprotection, depression, and cognitive, respiratory, diarrhea, irritable bowel syndrome and gastro-intestinal disorders, immunomodulation, and anti-tumor agents.

## Claims

### Claim 1

A method of treating a condition or disease associated with binding opioid receptors in a patient in need thereof, wherein the condition or disease is pain, gastrointestinal dysfunction, or ileus, comprising the step of: administering to said patient a composition comprising an effective amount of a compound of Formula I or II:
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:
R1 is selected from the group consisting of: hydrogen, halogen, ORa, SRa, S(O)Ra, SO2Ra, S(O)NRbRc, SO2NRbRc, NRb-Q-Rc, CN, (C═W)NRbRc, C(O)ORa, CH2ORa, CH2NRbRc, heteroaryl, and substituted heteroaryl;
Ra, Rb, Rc are each independently selected from:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocyclic or substituted heterocyclic; and
(iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
alternatively, Rb and Rc are taken together to form a heterocyclic or substituted heterocyclic;
Q is absent or selected from (C═O), (SO2), (C═NH), (C═S), or (CONRa);
W is O, S, NORa or NRa;
R2 is independently selected from the group consisting of hydrogen, halogen, ORa, SRa, NRbRc;
alternatively, R1 and R2 are taken together to form a heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocylic;
R3 is independently selected from the group consisting of:
(v) hydrogen;
(vi) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(vii) heterocyclic or substituted heterocyclic; and
(viii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
R4 is hydrogen, ORa, or NRb-Q1-Rc, where Q1 is absent or selected from (C═O) or (SO2);
R5 is selected from the group consisting of: hydrogen, halogen, SRa, S(O)Ra, SO2Ra, S(O)NRbRc, SO2NRbRc, NRb-Q-Rc, CN, (C═W)NRbRc, C(O)ORa, CH2ORa, CH2NRbRc, heteroaryl, and substituted heteroaryl;
Y is hydrogen, lower akyl, or lower alkoxy;
V1 is C═O, C1-C6 alkylene or substituted alkylene; V2 is absent, alkylene, substituted alkylene, or C═O; V3 is absent; V4 is absent;
n is 1, 2, 3 or 4; wherein each repeating unit can be the same or different;
Z is hydrogen, (C═W)OH or C(O)NHOH;
alternatively,
can be selected from the group consisting of natural or unnatural amino acids; and
denotes a carbon-carbon single or double bond.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the binding antagonizes the activity of the opioid receptors.

### Claim 3 (depends on 1)

The method of claim 1, wherein the ileus is post-operative ileus.

### Claim 4 (depends on 1)

A method according to claim 1, wherein the condition is pain and the composition further comprises an effective amount of an opioid.

### Claim 5 (depends on 2)

The method according to claim 2, wherein the compound binds to the opioid receptors.

### Claim 6 (depends on 5)

The method according to claim 5, wherein the μ opioid receptors are located in the central nervous system.

### Claim 7 (depends on 5)

The method according to claim 5, wherein the μ opioid receptors are located peripherally to the central nervous system.

### Claim 8 (depends on 2)

The method according to claim 2, wherein the compound does not substantially cross the blood-brain barrier.

### Claim 9

The method of treating a side effect associated with an opioid, wherein the side effect is selected from the group consisting of constipation, opioid-induced bowel dysfunction, nausea, vomiting, and combinations thereof, comprising the step of: administering to a patient in need thereof, a composition comprising an effective amount of a compound of Formula I or II:
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:
R1 is selected from the group consisting of: hydrogen, halogen, ORa, SRa, S(O)Ra, SO2Ra, S(O)NRbRc, SO2NRbRc, NRb-Q-Rc, CN, (C═W)NRbRc, C(O)ORa, CH2ORa, CH2NRbRc, heteroaryl, and substituted heteroaryl;
Ra, Rb, Rc are each independently selected from:
(ix) hydrogen;
(x) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(xi) heterocyclic or substituted heterocyclic; and
(xii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
alternatively, Rb and R, are taken together to form a heterocyclic or substituted heterocyclic;
Q is absent or selected from (C═O), (SO2), (C═NH), (C═S), or (CONRa);
W is O, S, NORa or NRa;
R2 is independently selected from the group consisting of hydrogen, halogen, ORa, SRa, NRbRc;
alternatively, R1 and R2 are taken together to form a heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocylic;
R3 is independently selected from the group consisting of:
(ix) hydrogen;
(x) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(xi) heterocyclic or substituted heterocyclic; and
(xii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
R4 is hydrogen, ORa, or NRb-Q1-Rc, where Q1 is absent or selected from (C═O) or (SO2);
R5 is selected from the group consisting of: hydrogen, halogen, SRa, S(O)Ra, SO2Ra, S(O)NRbRc, SO2NRbRc, NRb-Q-Rc, CN, (C═W)NRbRc, C(O)ORa, CH2ORa, CH2NRbRc, heteroaryl, and substituted heteroaryl;
Y is hydrogen, lower akyl, or lower alkoxy;
V1 is C═O, C1-C6 alkylene or substituted alkylene; V2 is absent, alkylene, substituted alkylene, or C═O; V3 is absent; V4 is absent;
n is 1, 2, 3 or 4; wherein each repeating unit can be the same or different;
Z is hydrogen, (C═W)OH or C(O)NHOH;
alternatively,
can be selected from the group consisting of natural or unnatural amino acids; and
denotes a carbon-carbon single or double bond.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the opioid is endogenous.

### Claim 11 (depends on 9)

The method according to claim 9, wherein the opioid is exogenous.

### Claim 12 (depends on 9)

The method according to claim 9, wherein the composition further comprises an effective amount of at least one opioid.

### Claim 13 (depends on 9)

The method according to claim 9, wherein the administering step occurs before, during or after a step of administering at least one opioid.

### Claim 14 (depends on 12)

The method according to claim 12, wherein the opioid is alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, naloxone, naltrexone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadol, or mixtures thereof.