Morphinan Compounds

• US 20080280936A1
• Filed: 04/30/2008
• Published: 11/13/2008
• Est. Priority Date: 05/01/2007
• Status: Active Grant

• Current Assignee: Concert Pharmaceuticals Inc.
• Original Assignee: Concert Pharmaceuticals Inc.
• Inventors: Tung, Roger
• Granted Patent: US 7,973,049 B2
• Time in Patent Office: Days
• US Class Current: 514/282
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/49 Cinchonan derivatives, e.g. quinine
• CPC Class Codes: A61P 11/04 for throat disorders
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: 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
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07B 59/002 : Heterocyclic compounds
• CPC Class Codes: C07D 221/28 : Morphinans
• CPC Class Codes: C07D 471/08 : Bridged systems

Abstract

This disclosure relates to novel morphinan compounds and their derivatives, pharmaceutically acceptable salts, solvates, and hydrates thereof. This disclosure also provides compositions comprising a compound of this disclosure and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σ₁ receptor agonist that also has NMDA antagonist activity.

Claims

1. A compound of Formula I:

2. The compound of claim 1 wherein R¹ is selected from CH₂D, CHD₂, CD₃, CHF₂, and CF₃.

3. The compound of claim 2 wherein R¹ is selected from CH₂D, CHD₂, and CD₃.

4. The compound of claim 3 wherein R¹ is CD₃.

5. The compound of any one of claims 1 to 4, where R² is CH₃, CHD₂ or CD₃.

6. The compound of claim 5 wherein R² is CH₃.

7. The compound of claim 5 wherein R² is CD₃.

8. The compound of claim 2 wherein R¹ is CF₃.

9. The compound of claim 2 wherein R¹ is CHF₂.

10. The compound of claim 8 wherein R² is selected from CH₃, CHD₂, and CD₃.

12. The compound of any one of claims 1 to 4, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

13. A pyrogen-free composition comprising the compound of claim 1 and an acceptable carrier.

14. The composition of claim 13 formulated for pharmaceutical administration and wherein the carrier is a pharmaceutically acceptable carrier.

15. The composition of claim 13 or 14, further comprising a second therapeutic agent useful in the treatment or prevention of a disease or condition selected from emotional lability;

pseudobulbar affect;

autism;

neurological disorders;

neurodegenerative diseases;

brain injury;

disturbances of consciousness disorders;

cardiovascular diseases;

glaucoma;

tardive dyskinesia;

diabetic neuropathy;

retinopathic diseases;

diseases or disorders caused by homocysteine-induced apoptosis;

diseases or disorders caused by elevated levels of homocysteine;

chronic pain;

intractable pain;

neuropathic pain;

sympathetically mediated pain;

pain associated with gastrointestinal dysfunction;

epileptic seizures;

tinnitus;

sexual dysfunction;

intractable coughing;

dermatitis;

addiction disorders;

Rett syndrome (RTT);

voice disorders due to uncontrolled laryngeal muscle spasms;

methotrexate neurotoxicity; and

fatigue caused by cancer.

16. The composition of claim 15, wherein the second therapeutic agent is selected from quinidine, quinidine sulfate, oxycodone, and gabapentin.

21. The composition of claim 14, wherein said composition is used for the treatment of neuropathic pain.

11. A compound of Formula I selected from the following:

17. A method of treating a subject suffering from or susceptible to a disease or condition selected from emotional lability;

pseudobulbar affect;

autism;

neurological disorders;

neurodegenerative diseases;

brain injury;

disturbances of consciousness disorders;

cardiovascular diseases;

glaucoma;

tardive dyskinesia;

diabetic neuropathy;

retinopathic diseases;

diseases or disorders caused by homocysteine-induced apoptosis;

diseases or disorders caused by elevated levels of homocysteine;

chronic pain;

intractable pain;

neuropathic pain;

sympathetically mediated pain;

pain associated with gastrointestinal dysfunction;

epileptic seizures;

tinnitus;

sexual dysfunction;

intractable coughing;

dermatitis;

addiction disorders;

Rett syndrome (RTT);

voice disorders due to uncontrolled laryngeal muscle spasms;

methotrexate neurotoxicity; and

fatigue caused by cancer, comprising the step of administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising;

a. compound of Formula I;

18. The method of claim 17, wherein the subject is suffering from or susceptible to diabetic neuropathic pain.

19. The method of claim 17 or 18 comprising the additional step of administering to the subject in need thereof a second therapeutic agent selected from quinidine, quinidine sulfate, oxycodone, and gabapentin.

20. The method of claim 19, wherein the subject is suffering from or susceptible to diabetic neuropathy and the second therapeutic agent is quinidine sulfate.