Morphinan compounds

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.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from —O—(C 2 -C 4 )alkyl and —(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 ether R 1  or R 2 . 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is —O—(C 2 -C 4 )alkyl substituted with one or more deuterium atoms. 
     
     
         3 . The compound of  claim 1  or  2 , wherein R 2  is CH 3  or CD 3 . 
     
     
         4 . The compound of  claim 1  or  2 , wherein R 1  is —O—CD 2 CD 3 , —O—CD 2 CH 3 , —O—CH 2 CD 3 , —O—CD(CD 3 ) 2 , —O—CH(CD 3 ) 2 , —O—CD(CH 3 ) 2 , —O—CD 2 CH(CH 3 ) 2 , —O—CH 2 CD(CH 3 ) 2 , —O—CH 2 CH(CD 3 ) 2 , —O—CD 2 CD(CH 3 ) 2 , —O—CD 2 CH(CD 3 ) 2 , —O—CH 2 CD(CD 3 ) 2 , or —O—CD 2 CD(CD 3 ) 2 . 
     
     
         5 . The compound of  claim 4 , wherein R 1  is —O—CD 2 CD 3 , —O—CD 2 CH 3 , —O—CH 2 CD 3 , —O—CD(CD 3 ) 2 , —O—CH(CD 3 ) 2 , or —O—CD(CH 3 ) 2 . 
     
     
         6 . The compound of  claim 5 , wherein R 1  is —O—CD 2 CD 3  or —O—CD(CD 3 ) 2 . 
     
     
         7 . The compound of  claim 6 , wherein R 1  is —O—CD(CD 3 ) 2 . 
     
     
         8 . The compound of  claim 3 , wherein the compound is selected from any one of the compounds set forth in the table below: 
       
         
           
                 
                 
                 
               
                     
                 
                   Compound No. 
                   R 1   
                   R 2   
                 
                     
                 
                   100 
                   —O—CD 2 CD 3   
                   CD 3   
                 
                   101 
                   —O—CD 2 CH 3   
                   CD 3   
                 
                   102 
                   —O—CD(CD 3 ) 2   
                   CD 3   
                 
                   103 
                   —O—CD(CH 3 ) 2   
                   CD 3   
                 
                   104 
                   —O—CD 2 CD 3   
                   CH 3   
                 
                   105 
                   —O—CD 2 CH 3   
                   CH 3   
                 
                   106 
                   —O—CD(CD 3 ) 2   
                   CH 3   
                 
                   107 
                   —O—CD(CH 3 ) 2   
                   CH 3   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The compound of  claim 1 , wherein R 1  is —(C 1 -C 4 )alkyl which is optionally substituted with one or more deuterium atoms. 
     
     
         10 . The compound of  claim 9 , wherein R 2  is CH 3  or CD 3 . 
     
     
         11 . The compound of  claim 10 , 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 . 
     
     
         12 . The compound of  claim 11 , 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 . 
     
     
         13 . The compound of  claim 12 , wherein R 1  is —CD 3 , —CD 2 CD 3 , or —CD 2 CD(CD 3 ) 2 . 
     
     
         14 . The compound of  claim 13 , wherein R 1  is —CD 3 . 
     
     
         15 . The compound of  claim 14 , 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 selected from CD 3 . 
     
     
         16 . The compound of  claim 10 , selected from any one of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . The compound of  claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance. 
     
     
         18 . A pyrogen-free pharmaceutical composition comprising the compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         19 . The composition of  claim 18 , further comprising a second therapeutic agent useful in treating a patient suffering from or susceptible to 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. 
     
     
         20 . The composition of  claim 19 , wherein the second therapeutic agent is selected from quinidine, quinidine sulfate, oxycodone, and gabapentin. 
     
     
         21 . A method of treating a subject suffering from or susceptible to 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 the subject in need thereof a therapeutically effective amount of a pharmaceutical composition of  claim 18 . 
     
     
         22 . The method of  claim 21 , wherein the subject is suffering from or susceptible to diabetic neuropathic pain. 
     
     
         23 . The method of  claim 21 , wherein the subject is suffering from or susceptible to epileptic seizures. 
     
     
         24 . A method of treating a subject suffering from or susceptible to conditions related to exposure to chemical agents, comprising the step of administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition of  claim 18 . 
     
     
         25 . A method of treating a subject suffering from or susceptible to pain, comprising the step of administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition of  claim 18 . 
     
     
         26 . The composition of  claim 18 , further comprising a second therapeutic agent useful in treating a patient suffering from or susceptible to pain. 
     
     
         27 . The composition of  claim 18 , further comprising a second therapeutic agent useful in treating a patient suffering from or susceptible to conditions related to exposure to chemical agents.