Use of central cannabinoid receptor antagonists for the preparation of drugs

Abstract

The invention relates to the use of a central cannabinoid receptor antagonist, by itself or in association with a compound for regulating metabolic disorders, especially a β 3 -adrenergic receptor agonist, for the preparation of drugs useful in the treatment of appetency disorders.

1 - 18 . (cancelled)  
     
     
         19 . A pharmaceutical composition containing a CB 1  receptor antagonist and a regulator of metabolic functions together with a pharmaceutical excipient.  
     
     
         20 . A pharmaceutical composition according to  claim 19 , wherein said regulator of metabolic functions is a β 3 -agonist.  
     
     
         21 . A pharmaceutical composition according to  claim 20 , wherein the CB 1  receptor antagonist is a compound of the formula  
       
         
           
           
               
               
           
         
         in which:  
         R 1  is hydrogen, a fluorine, a hydroxyl, a (C 1 -C 5 )alkoxy, a (C 1 -C 5 )alkylthio, a hydroxy(C 1 -C 5 ) alkoxy, a group —NR 10 R 11 , a cyano, a (C 1 -C 5 )alkylsulfonyl or a (C 1 -C 5 )alkylsulfinyl;  
         R 2  and R 3  are a (C 1 -C 4 )alkyl or, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated 5- to 10-membered heterocyclic radical which is unsubstituted or monosubstituted or polysubstituted by a (C 1 -C 3 )alkyl or by a (C 1 -C 3 )alkoxy;  
         R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are each independently hydrogen, a halogen or a trifluoromethyl, and if R 1  is a fluorine, R 4 , R 5 , R 6 , R 7 , R 8  and/or R 9  can also be a fluoromethyl, with the proviso that at least one of the substituents R 4  or R 7  is other than hydrogen;  
         R 10  and R 11  are each independently hydrogen or a (C 1 -C 5 )alkyl, or R 10  and R 11 , together with the nitrogen atom to which they are bonded, form a heterocyclic radical selected from pyrrolidin-1-yl, piperidin-1-yl, morpholin4-yl and piperazin-1-yl, which is unsubstituted or substituted by a (C 1 -C 4 )alkyl,  
         one of its salts or one of their solvates.  
       
     
     
         22 . A pharmaceutical composition according to  claim 21 , wherein the CB 1  receptor antagonist is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)4-methylpyrazole-3-carboxamide, one of its pharmaceutically acceptable salts or one of their solvates.  
     
     
         23 . A pharmaceutical composition according to  claim 21  wherein the β 3 -agonist is a compound of the formula  
       
         
           
           
               
               
           
         
         in which:  
         X is hydrogen, a halogen, a trifluoromethyl or a (C 1 -C 4 )alkyl;  
         R is hydrogen or a methyl which is unsubstituted or substituted by a carboxyl or an alkoxycarbonyl in which the alkoxy is (C 1 -C 6 ),  
         or one of its pharmaceutically acceptable salts.  
       
     
     
         24 . A pharmaceutical composition according to any one of  claims 20  to  22 , characterized in that  claim 21  wherein the β 3 -agonist is a compound of the formula  
       
         
           
           
               
               
           
         
         in which:  
         n is 1, 2 or 3;  
         A is a benzofuran-2-yl or a phenyl which is unsubstituted or substituted by one or two halogen atoms or by a (C 1 -C 4 )alkyl or a trifluoromethyl;  
         R′ is: 
 hydrogen;  
 a (C 1 -C 6 )alkyl;  
 a functional group selected from the following groups: hydroxyl; (C 1 -C 6 )alkoxy; (C 2 -C 6 ) alkenyloxy; (C2-C 6 )alkynyloxy; (C 3 -C 8 )cycloalkoxy; (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy; benzyloxy; phenoxy; mercapto; (C 1 -C 6 )alkylthio; (C 2 -C 6 )alkenylthio; (C 2 -C 6 )alkynylthio; (C 3 -C 8 )cycloalkylthio; (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylthio; benzylthio; phenylthio; (C 1 -C 6 ) alkylsulfinyl; (C 2 -C 6 )alkenylsulfinyl; (C 2 -C 6 )alkynylsulfinyl; (C 3 -C 8 )cycloalkylsulfinyl; (C 3 -C 8 )cycloalkyl(Cl-C 6 )alkylsulfinyl; benzylsulfinyl; phenylsulfinyl; (C 1 -C 6 )alkylsulfonyl; (C 2 -C 6 )alkenylsulfonyl; (C 2 -C 6 )alkynylsulfonyl; (C 3 -C 8 )cycloalkylsulfonyl; (C 3 -C 8 )-cycloalkyl(C 1 -C 6 ) alkylsulfonyl; benzylsulfonyl; phenylsulfonyl; cyano; nitro; amino which is unsubstituted or substituted by one or two identical or different radicals selected from (C 1 -C 6 ) alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 ) alkyl, benzyl and phenyl groups; carboxyl; alkoxycarbonyl in which the alkoxy is (C 1 -C 6 ); (C 2 -C 6 )alkenyloxycarbonyl; (C 2 -C 6 )alkynyloxycarbonyl; (C 3 -C 8 )cycloalkoxycarbonyl; (C 3 -C 8 ) cycloalkyl(C 1 -C 6 )alkoxycarbonyl; benzyloxycarbonyl; phenoxycarbonyl; and carbamoyl which is unsubstituted or substituted on the amino group by one or two identical or different radicals selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 ) cycloalkyl(C 1 -C 6 )alkyl, benzyl and phenyl groups;  
 
         a group R′″ selected from the following groups: (C 1 -C 6 )alkyl substituted by a functional group; (C 2 -C 6 )alkenyl substituted by a functional group; (C 2 -C 6 )alkynyl substituted by a functional group; phenyl(C 1 -C 6 )alkyl substituted on the phenyl by a (C 1 -C 6 )alkyl or by a functional group; phenyl(C 2 -C 6 )alkenyl substituted on the phenyl by a (C 1 -C 6 )alkyl or by a functional group; phenyl(C 2 -C 6 )alkynyl substituted on the phenyl by a (C 1 -C 6 )alkyl or by a functional group; benzyl substituted on the phenyl by a (C 1 -C 6 )alkyl or by a functional group; and phenyl which is unsubstituted or substituted by a (C 1 -C 6 )alkyl or by a functional group, the functional group being as defined above;  
         a group O—R′″, S—R′″, SO—R′″ or SO 2 —R′″, in which R′″ is as defined above;  
         a group NR′″R°, in which R′″ is as defined above and R° is hydrogen or is as defined above for R′″, or R′″ and R°, together with the nitrogen to which they are bonded, form a group selected from pyrrolidino, piperidino and morpholino groups;  
         a group COOR′″ or a group CO—SR′″, in which R′″ is as defined above;  
         a group CONR′″R°, in which R′″ is as defined above and R° is hydrogen or is as defined above for R′″, or R′″ and R°, together with the nitrogen to which they are bonded, form a group selected from pyrrolidino, piperidino and morpholino groups;  
         a group SO 2 NR′″R°, in which R′″ is as defined above and R° is hydrogen or is as defined above for R′″, or R′″ and R°, together with the nitrogen to which they are bonded, form a group selected from pyrrolidino, piperidino and morpholino groups;  
         R″ is hydrogen; a halogen; a (C 1 -C 6 )alkyl; a functional group as defined above; a group OR′″, R′″ being as defined above; a group COOR′″, R′″ being as defined above; or a group CONR′″R°, in which R′″ is as defmed above and R° is hydrogen or is as defined above for R′″, or R′″ and R°, together with the nitrogen to which they are bonded, form a group selected from pyrrolidino, piperidino and morpholino groups;  
         W is a direct bond or an oxygen atom;  
         X′ is hydrogen, a (C 1 -C 6 )alkyl or a (C 1 -C 6 )alkylcarbonyl;  
         Y is hydrogen or a group A′—CH(OH)—CH 2 —, A′ being identical to A but other than benzofuran-2-yl; or  
         X′ and Y, taken together, form a methylene group optionally substituted by an alkoxycarbonyl in which the alkoxy is (C 1 -C 6 ); an ethylene group optionally substituted by an oxo group; or a 1,3-propylene group;  
         Z is hydrogen or a (C 1 -C 6 )alkyl,  
         or one of its pharmaceutically acceptable salts.  
       
     
     
         25 . A pharmaceutical composition according to wherein the β 3 -agonist is a compound of the formula  
       
         
           
           
               
               
           
         
         in which:  
         E is hydrogen, a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy, a phenyl, a nitro, a halogen atom or a trifluoromethyl;  
         L is hydrogen, a (C 1 -C 4 )alkyl, a (C 1 -C 4 )alkoxy, a phenyl, a nitro or a halogen atom; or E and L together are a group —CH═CH—CH═CH— or —CH 2 —CH 2 —CH 2 —CH 2 —; and  
         G is hydrogen, a chlorine atom, a hydroxyl or a group OG′, in which G′ is a (C 1 -C 4 )alkyl which is unsubstituted or substituted by a hydroxyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl, carboxyl or (C 3 -C 7 )cycloalkyl; a (C 3 -C 7 )cycloalkyl; or a (C 2 -C 4 )alkanoyl, or one of its pharmaceutically acceptable salts.  
       
     
     
         26 . A pharmaceutical composition according to  claim 23 , wherein the β 3  agonist is N-[(2S)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamine or one of its pharmaceutically acceptable salts.  
     
     
         27 . A pharmaceutical composition according to  claim 23  containing from 0.5 to 600 mg of CB 1  receptor antagonist and from 0.5 to 600 mg of β 3 -agonist.  
     
     
         28 . A pharmaceutical composition according to  claim 27  containing from 1 to 400 mg of CB 1  receptor antagonist and from 2 to 400 mg of β 3 -agonist.  
     
     
         29 . A pharmaceutical composition according to  claim 28  containing from 2 to 200 mg of CB 1  receptor antagonist and from 10 to 250 mg of β 3 -agonist.  
     
     
         30 . A kit for the treatment of appetency disorders, which contains: 
 a CB 1  receptor antagonist, and    a regulator of metabolic disorders,    said active principles being in separate compartments and being intended to be administered simultaneously, sequentially or over a period of time.    
     
     
         31 . A kit according to  claim 30  in which said regulator of metabolic disorders is a β 3 -agonist.  
     
     
         32 . A kit according to  claim 31  in which said CB 1  receptor antagonist is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)4-methylpyrazole-3-car-boxanide, one of its pharmaceutically acceptable salts or one of their solvates and said β 3 -agonist is N-[(2S)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamine or one of its pharmaceutically acceptable salts.  
     
     
         33 . A kit according to  claim 30  in which said active principles are in different packagings.  
     
     
         34 - 38 . (cancelled)  
     
     
         39 . A pharmaceutical composition according to  claim 26  wherein the CB 1  antagonist is N-piperidino-5-(4-chlorophenyl)4-methylpyrazole-3-carboxamide or one of its pharmaceutically acceptable solts or one of their solvates.