Morphinan compounds

Patent metadata

Field	Value
Publication number	US-9655895-B2
Application number	US-201615148568-A
Country	US
Kind code	B2
Filing date	May 6, 2016
Priority date	Sep 19, 2008
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

This invention relates to novel morphinan compounds and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a σ 1 receptor agonist that also has NMDA antagonist activity.

First claim

We claim:

1. A method of treating a subject suffering from a disease or condition selected from emotional lability; pseudobulbar affect autism; neurological disorders and neurodegenerative diseases; brain injuries; disturbances of consciousness disorders; cardiovascular diseases; glaucoma; tardive dyskinesia; cancer; rheumatoid arthritis; 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; mouth pain; back pain; central pain syndrome; complex regional pain syndrome; epileptic seizures; epileptic hemiplegia; acquired epileptiform aphasia (Landau-Kleffner syndrome); severe myoclonic epilepsy of infancy (SMEI); early infantile epileptic encephalopathy; post-stroke seizure; febrile seizures; post-traumatic 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 a subject in need thereof a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —(C 1 -C 4 )alkyl, wherein R 1 is optionally substituted with one or more deuterium atoms; and
R 2 is selected from CH 3 , CH 2 D, CHD 2 , and CD 3 ;
provided that at least one deuterium atom is present at either R 1 or R 2 ; wherein any atom not designated as deuterium is present at its natural isotopic abundance.

2. The method of claim 1 , wherein R 2 is CH 3 or CD 3 .

3. The method of claim 2 , wherein R 1 is —CH 3 , —CD 3 , —CH 2 CH 3 , —CD 2 CD 3 , —CD 2 CH 3 , —CH 2 CD 3 , —CH(CH 3 ) 2 , —CD(CD 3 ) 2 , —CH(CD 3 ) 2 , —CD(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CD 2 CH(CH 3 ) 2 , —CH 2 CD(CH 3 ) 2 , —CH 2 CH(CD 3 ) 2 , —CD 2 CD(CH 3 ) 2 , —CD 2 CH(CD 3 ) 2 , —CH 2 CD(CD 3 ) 2 , or —CD 2 CD(CD 3 ) 2 .

4. The method of claim 3 , wherein R 1 is —CD 3 , —CD 2 CD 3 , —CD 2 CH 3 , —CH 2 CD 3 , —CD(CD 3 ) 2 , —CH(CD 3 ) 2 , —CD(CH 3 ) 2 , —CD 2 CH(CH 3 ) 2 , —CH 2 CD(CH 3 ) 2 , —CH 2 CH(CD 3 ) 2 , —CD 2 CD(CH 3 ) 2 , —CD 2 CH(CD 3 ) 2 , —CH 2 CD(CD 3 ) 2 , or —CD 2 CD(CD 3 ) 2 .

5. The method of claim 4 , wherein R 1 is —CD 3 , —CD 2 CD 3 , or —CD 2 CD(CD 3 ) 2 .

6. The method of claim 5 , wherein R 1 is —CD 3 .

7. The method of claim 3 , wherein R 1 is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , or —CH 2 CH(CH 3 ) 2 and R 2 is CD 3 .

8. The method of claim 1 , wherein the compound is selected from any one of:

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , further comprising the step of co-administering to the subject a second therapeutic agent useful in treating a patient suffering from a disease or condition selected from emotional lability; pseudobulbar affect; autism; neurological disorders and neurodegenerative diseases; brain injuries; disturbances of consciousness disorders; cardiovascular diseases; glaucoma; tardive dyskinesia; cancer; rheumatoid arthritis; 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; mouth pain; back pain; central pain syndrome; complex regional pain syndrome; epileptic seizures; epileptic hemiplegia; acquired epileptiform aphasia (Landau-Kleffner syndrome); severe myoclonic epilepsy of infancy (SMEI); early infantile epileptic encephalopathy; post-stroke seizure; febrile seizures; post-traumatic 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.

10. The method of claim 9 , wherein the second therapeutic agent is selected from quinidine, quinidine sulfate, oxycodone, and gabapentin.

11. The method of claim 1 , wherein the subject is suffering from diabetic neuropathic pain.

12. The method of claim 1 , wherein the subject is suffering from epileptic seizures.

13. A method of treating a subject suffering from conditions related to exposure to chemical agents, comprising the step of administering to the subject in need thereof a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —(C 1 -C 4 )alkyl, wherein R 1 is optionally substituted with one or more deuterium atoms; and
R 2 is selected from CH 3 , CH 2 D, CHD 2 , and CD 3 ;
provided that at least one deuterium atom is present at either R 1 or R 2 ; wherein any atom not designated as deuterium is present at its natural isotopic abundance.

14. A method of treating a subject suffering from pain, comprising the step of administering to the subject in need thereof a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —(C 1 -C 4 )alkyl, wherein R 1 is optionally substituted with one or more deuterium atoms; and
R 2 is selected from CH 3 , CH 2 D, CHD 2 , and CD 3 ;
provided that at least one deuterium atom is present at either R 1 or R 2 ; wherein any atom not designated as deuterium is present at its natural isotopic abundance.

15. The method of claim 1 , wherein the neurodegenerative disease is selected from dementia, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and multiple sclerosis.

16. The method of claim 1 , wherein the neurodegenerative disease is dementia or Alzheimer's disease.

17. The method of claim 1 , wherein the neurological disorder is schizophrenia.

18. The method of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 90%.

19. The method of claim 13 , wherein the deuterium incorporation at each designated deuterium atom is at least 90%.

20. The method of claim 14 , wherein the deuterium incorporation at each designated deuterium atom is at least 90%.

Assignees

• Concert Pharmaceuticals Inc

Inventors

• Graham Philip B
• Silverman I Robert

Classifications

• C07D471/08

  Bridged systems · CPC title

• A61K31/485 Primary

  Morphinan derivatives, e.g. morphine, codeine · CPC title

• A61K31/195

  having an amino group · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title