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; 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;; and fatigue caused by cancer; 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 —O—(C 2 -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, and wherein for each site designated as deuterium, deuterium incorporation is at least 90%.
2. The method of claim 1 , wherein the subject is suffering from diabetic neuropathic pain.
3. The method of claim 1 , wherein the subject is suffering from epileptic seizures.
4. The method of claim 1 , wherein the neurological disorder is schizophrenia.
5. 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 —O—(C 2 -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, and wherein for each site designated as deuterium, deuterium incorporation is at least 90%.
6. The method of any one of claim 1 - 4 or 5 wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
7. The method of any one of claim 1 - 4 or 5 wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
8. The method of any one of claim 1 - 4 or 5 wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
9. A method of agonizing sigma-1 receptor activity in a subject 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′ is —O—(C 2 -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, and wherein for each site designated as deuterium, deuterium incorporation is at least 90%.
10. The method of claim 9 , wherein the subject is suffering from a disease or condition selected from emotional lability; pseudobulbar affect; 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.