Morphinan compounds
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.
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%.