Azetidine derivatives, their preparation and their application in therapy

Abstract

The invention relates to azetidine derivatives having the formula (I): Wherein R′, R1, R2, R3, R6, R7, R, Y, A and B are as defined herein. The invention also relates to a method for preparing the same and therapeutic use thereof.

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         9 . A method of treatment or prevention of psychiatric disorders, substance dependence and withdrawal, tobacco withdrawal, cognitive and attention disorders, and acute and chronic neurodegenerative diseases, metabolic disorders, appetence disorders, appetite disorders, obesity, diabetes, metabolic syndrome, dyslipidemia and sleep apnoea, pain, neuropathic pain and neuropathic pain induced by anticancer drugs, gastrointestinal disorders, vomiting, ulcers, diarrhoea disorders, bladder and urinary disorders, disorders of endocrine origin, cardiovascular disorders, hypotension, haemorrhagic shock, septic shock, liver diseases, chronic liver cirrhosis, fibrosis, non-alcoholic steatohepatitis (NASH), steatohepatitis and hepatic steatosis, irrespective of the etiology of these conditions (alcohol, medicament, chemical product, autoimmune disease, obesity, diabetes, congenital metabolic disease), immune system diseases, rheumatoid arthritis, demyelination, multiple sclerosis and inflammatory diseases Alzheimer's disease, Parkinson's disease, schizophrenia and cognitive disorders associated with schizophrenia, with diabetes, with obesity or with metabolic syndrome, asthma, chronic obstructive pulmonary diseases, Raynaud's syndrome, glaucoma and fertility disorders, infectious and viral diseases such as encephalitis, cerebral strokes, Guillain-Barré syndrome, osteoporosis and sleep apnoea, and for anticancer chemotherapy in a patient comprising administering to said patient a therapeutically acceptable amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R represents a (C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl group; 
         R′ represents an NR4R5 or OR8 group; 
         A and B, which can be present or not, which if they are present, are, independently of one another, one or two carbon atoms, these carbon atoms being substituted with one or more hydrogens or (C 1 -C 6 )alkyl group; the (C 1 -C 6 )alkyl group(s) being optionally substituted with one or more hydroxyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylS(O) p , NR4R5 or CONR4R5 groups; 
         A+B represents at most two carbons; 
         R1 represents a hydrogen atom or a (C 1 -C 6 )alkyl group; 
         R2 and R3 are, independently of one another, a hydrogen atom or a (C 1 -C 6 )alkyl group; the (C 1 -C 6 )alkyl group being optionally substituted with one or more hydroxyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylS(O) p , NR4R5 or CONR4R5 groups; 
         R4 and R5 are, independently of one another, a hydrogen atom or a (C 1 -C 6 )alkyl group, or R4 and R5, together with the nitrogen atom which carries them, form an azetidine, pyrrolidine, piperidine, azepane, piperazine, homopiperazine, morpholine, thiomorpholine, thiomorpholine S-oxide or thiomorpholine S-dioxide group, the NR4R5 group being optionally substituted by a (C 1 -C 6 )alkyl group; 
         R6 and R7 each represent a phenyl group, the phenyl group being optionally substituted with one or more substituents selected from a hydrogen atom, a halogen, a (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy or cyano group; 
         Y represents a hydrogen atom, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylS(O) p  or cyano group; 
         R8 represents a hydrogen atom, a (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl group, allyl or a phenyl(C 1 -C 6 )alkyl group, the phenyl group being optionally substituted with 1 or 2 O-methyl groups; and 
         p is 0, 1 or 2 
       
       , or a pharmaceutically acceptable salt thereof. 
     
     
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         22 . A compound selected from the group consisting of:
 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid methyl ester;   3-({1-[bis(4-fluorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid methyl ester;   3-({1-[bis(4-fluorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid   3-({1-[bis(4-bromophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid ethyl ester;   3-({1-[bis(4-bromophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid;   3-({1-[bis(4-trifluoromethylphenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid ethyl ester;   3-({1-[bis(4-trifluoromethylphenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid;   3-({1-[bis(4-methoxyphenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid ethyl ester;   3-({1-[bis(4-methoxyphenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid;   3-({1-[bis(4-methylphenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid methyl ester;   3-({1-[bis(4-methylphenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid;   3-({1-[bis(4-cyanophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid ethyl ester;   3-({1-[bis(4-cyanophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid;   3-({1-[bis(4-trifluoromethoxyphenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid methyl ester;   3-({1-[bis(4-trifluoromethoxyphenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-2-fluorobenzoic acid methyl ester;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-2-fluorobenzoic acid;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-4-fluorobenzoic acid ethyl ester;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-4-fluorobenzoic acid;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-6-fluorobenzoic acid methyl ester;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-6-fluorobenzoic acid;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-methoxybenzoic acid methyl ester;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-methoxybenzoic acid;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-methylbenzoic allyl ester;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-methylbenzoic acid;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-chlorobenzoic acid methyl ester;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-chlorobenzoic acid;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-bromobenzoic acid methyl ester;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-bromobenzoic acid;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-trifluoromethylbenzoic acid methyl ester;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-trifluoromethylbenzoic acid;   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-cyanobenzoic acid methyl ester and   3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-cyanobenzoic acid.