Derivatives of dioxan-2-alkyl carbamates, preparation thereof and application thereof in therapeutics

Abstract

A compound corresponding to general formula (I): in which R 1 represents a phenyl or naphthalenyl group optionally substituted with one or more halogen atoms or hydroxyl, cyano, nitro, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkoxy, trifluoromethyl, trifluoromethoxy, benzyloxy, (C 3 -C 6 )cycloalkyl-O— or (C 3 -C 6 )cycloalkyl(C 1 -C 3 )alkoxy groups; R 2 represents either a group of general formula CHR 3 CONHR 4 in which R 3 represents a hydrogen atom or a methyl group and R 4 represents a hydrogen atom or a (C 1 -C 3 )alkyl, (C 3 -C 5 ) cycloalkyl or (pyridin-4-yl)methyl group; or a 2,2,2-trifluoroethyl group; or an (imidazol-2-yl)methyl group; or a (benzimidazol-2-yl)methyl group; or a phenyl group optionally substituted with one or more halogen atoms or cyano, nitro, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, trifluoromethyl or trifluoromethoxy groups; and n represents a number ranging from 1 to 3; in the form of a base, of an addition salt with an acid, of a hydrate or of a solvate. Also disclosed and claimed are the pharmaceutical compositions derived therefrom and their therapeutic use in treating a wide variety of diseases.

1 . A method for preparing a compound of formula (I):  
       
         
           
           
               
               
           
         
         wherein  
         R 1  represents a phenyl or naphthalenyl group optionally substituted with one or more halogen atoms or hydroxyl, cyano, nitro, (C 1 -C 3 )alkyl, (C 1 -C 3 ) alkoxy, trifluoromethyl, trifluoromethoxy, benzyloxy, (C 3 -C 6 )cycloalkyl-O— or (C 3 -C 6 ) cycloalkyl(C 1 -C 3 ) alkoxy groups;  
         R 2  represents  
         either a group of general formula CHR 3 CONHR 4 ,  
         or a 2,2,2-trifluoroethyl group,  
         or an (imidazol-2-yl)methyl group,  
         or a (benzimidazol-2-yl)methyl group,  
         or a phenyl group optionally substituted with one  
         or more halogen atoms or cyano, nitro, (C 1 -C 3 ) alkyl, (C 1 -C 3 )alkoxy, trifluoromethyl or trifluoromethoxy groups; and  
         wherein 
 R 3  represents a hydrogen atom or a methyl group and  
 R 4  represents a hydrogen atom or a (C 1 -C 3 )alkyl, (C 3 -C 5 )cycloalkyl or (pyridin-4-yl)methyl group;  
 
         n represents a number ranging from 1 to 3;  
         comprising the step of:  
         reacting the amine of formula (II):  
         
           
             
             
                 
                 
             
           
         
         wherein  
         R 1  and n are as defined above for formula (I), with a carbonate of formula (III):  
         
           
             
             
                 
                 
             
           
         
         wherein U represents a hydrogen atom or a nitro group and R 2  is as defined above for formula (I).  
       
     
     
         2 . A compound of formula (III):  
       
         
           
           
               
               
           
         
         wherein  
         R 2  represents a group of general formula CHR 3 CONHR 4  wherein  
         R 3  represents a hydrogen atom or a methyl group and  
         R 4  represents a hydrogen atom or a (C 1 -C 3 )alkyl, (C 3 -C 5 )cycloalkyl or (pyridin-4-yl)methyl group; and  
         U represents a hydrogen atom or a nitro group.  
       
     
     
         3 . A compound, which is chosen from: 
 2-(methylamino)-2-oxoethyl trans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate;    2-amino-2-oxoethyl trans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate;    2-(methylamino)-2-oxoethyl trans-2-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]ethylcarbamate; and    2-(methylamino)-2-oxoethyl trans-3-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate; or 
 a pharmaceutically acceptable salt thereof.  
   
     
     
         4 . A pharmaceutical composition comprising one or more compounds according to  claim 3  or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable excipients.  
     
     
         5 . A method of treating a disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula (I):  
       
         
           
           
               
               
           
         
         wherein  
         R 1  represents a phenyl or naphthalenyl group optionally substituted with one or more halogen atoms or hydroxyl, cyano, nitro, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, trifluoromethyl, trifluoromethoxy, benzyloxy, (C 3 -C 6 )cycloalkyl-O— or (C 3 -C 6 )cycloalkyl(C 1 -C 3 )alkoxy groups;  
         R 2  represents  
         either a group of general formula CHR 3 CONHR 4 ,  
         or a 2,2,2-trifluoroethyl group,  
         or an (imidazol-2-yl)methyl group,  
         or a (benzimidazol-2-yl)methyl group,  
         or a phenyl group optionally substituted with one or more halogen atoms or cyano, nitro, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, trifluoromethyl or trifluoromethoxy groups; and  
         wherein 
 R 3  represents a hydrogen atom or a methyl group and  
 R 4  represents a hydrogen atom or a (C 1 -C 3 )alkyl, (C 3 -C 5 )cycloalkyl or (pyridin-4-yl)methyl group;  
 
         n represents a number ranging from 1 to 3; or  
         a pharmaceutically acceptable salt thereof, optionally in combination with one more pharmaceutically acceptable excipients, wherein said disease is selected from the group consisting of: acute or chronic pain, dizziness, vomiting, nausea, eating disorder, neurological or psychiatric pathological condition, acute or chronic neurodegenerative disease, epilepsy, sleep disorder, cardiovascular disease, renal ischemia, cancer, disorders of the immune system, allergic disease, parasitic, viral or bacterial infectious disease, inflammatory disease, osteoporosis, ocular condition, pulmonary condition, gastrointestinal disease or urinary incontinence.  
       
     
     
         6 . The method according to  claim 5 , wherein said disease is acute or chronic pain.  
     
     
         7 . The method according to  claim 6 , wherein said pain is of the neurogenic type.  
     
     
         8 . The method according to  claim 7 , wherein said pain is selected from the group consisting of migraine and neuropathic pain including forms associated with the herpes virus and with diabetes.  
     
     
         9 . The method according to  claim 6 , wherein said pain is selected from the group consisting of arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome and acute or chronic peripheral pain.  
     
     
         10 . The method according to  claim 5 , wherein said disease is neurological or psychiatric pathological condition.  
     
     
         11 . The method according to  claim 10 , wherein said neurological or psychiatric pathological condition is selected from the group consisting of shaking, dyskinesia, dystonia, spasticity, obsessive-compulsive behavior, Tourette's syndrome, depression, anxiety, mood disorder and psychoses.  
     
     
         12 . The method according to  claim 10 , wherein said neurological or psychiatric pathological condition is obsessive-compulsive behavior.  
     
     
         13 . The method according to  claim 10 , wherein said neurological or psychiatric pathological condition is Tourette's syndrome.  
     
     
         14 . The method according to  claim 10 , wherein said neurological or psychiatric pathological condition is depression.  
     
     
         15 . The method according to  claim 10 , wherein said neurological and psychiatric pathological conditions is anxiety.  
     
     
         16 . The method according to  claim 10 , wherein said neurological or psychiatric pathological condition is mood disorder.  
     
     
         17 . The method according to  claim 10 , wherein said neurological or psychiatric pathological condition is psychoses.  
     
     
         18 . The method according to  claim 5 , wherein said disease is acute or chronic neurodegenerative disease.  
     
     
         19 . The method according to  claim 18 , wherein said acute or chronic neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, lesions associated with cerebral ischemia and with cranial and medullary trauma.  
     
     
         20 . The method according to  claim 5 , wherein said compound is chosen from: 
 2-(methylamino)-2-oxoethyl trans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate;    2-amino-2-oxoethyl trans-3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate;    2-(methylamino)-2-oxoethyl trans-2-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]ethylcarbamate; and    2-(methylamino)-2-oxoethyl trans-3-[5-(naphthalen-1-yl)-1,3-dioxan-2-yl]propylcarbamate; or 
 a pharmaceutically acceptable salt thereof.