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 . Use of a CB 1  receptor antagonist for the preparation of drugs useful in the treatment of appetency disorders.  
     
     
         2 . Use according to  claim 1  for the preparation of drugs intended for regulating consumption desires.  
     
     
         3 . Use according to  claim 1  for the preparation of drugs useful in the treatment of disorders associated with a substance.  
     
     
         4 . Use according to  claim 1  for the preparation of drugs useful in the treatment of disorders of food behaviors.  
     
     
         5 . Use according to  claim 1  for the preparation of drugs useful in the treatment of obesity.  
     
     
         6 . Use according to  claim 5  for the preparation of drugs useful in the treatment of obesity associated with non-insulin-dependent diabetes.  
     
     
         7 . Use according to  claim 1  for the preparation of drugs useful in the treatment of any disease resulting in the patient becoming overweight.  
     
     
         8 . Use according to  claim 1  for the preparation of drugs useful in the treatment of bulimia.  
     
     
         9 . Use according to  claim 1  for the preparation of drugs useful in the treatment of drug abuse or drug dependency.  
     
     
         10 . Use according to any one of  claims 1  to  9 , characterized in that 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, morpholin-4-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.  
 
     
     
         11 . Use according to  claim 10 , characterized in that 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.  
     
     
         12 . Use according to any one of  claims 1  to  8 ,  10  or  11 , characterized in that the CB 1  receptor antagonist is associated with a regulator of metabolic disorders.  
     
     
         13 . Use according to  claim 12 , characterized in that said regulator of metabolic disorders is a β 3 -agonist.  
     
     
         14 . Use according to  claim 13 , characterized in that said 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; and  
 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.  
 
     
     
         15 . Use according to  claim 14 , characterized in that 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.  
     
     
         16 . Use according to  claim 13 , characterized in that said 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; (C 2 -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 -C6)alkylsulfinyl; (C 2 -C 6 )alkenylsulfinyl; (C 2 -C 6 )alkynylsulfinyl; (C 3 -C 8 )cycloalkylsulfinyl; (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylsulfinyl; benzylsulfinyl; phenylsulfinyl; (C 1 -C 6 )alkylsulfonyl; (C 2 -C 6 )alkenylsulfonyl; (C 2 -C6)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 -C8)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 )alkynyloxycarbonyl; (C 2 -C 6 )alkenyloxycarbonyl; (C 3 -C 8 )cycloalkoxycarbonyl; (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxycarbonyl; benzyloxycarbonyl; phenoxycarbonyl; or 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 0 , in which R′″ is as defined above and R 0  is hydrogen or is as defined above for R′″, or R′″ and R 0 , 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 0 , in which R′″ is as defined above and R 0  is hydrogen or is as defined above for R′″, or R′″ and R 0 , 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 0 , in which R′″ is as defined above and R 0  is hydrogen or is as defined above for R′″, or R′″ and R 0 , 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 0 , in which R′″ is as defined above and R 0  is hydrogen or is as defined above for R′″, or R′″ and R 0 , 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.  
 
     
     
         17 . Use according to  claim 13 , characterized in that said 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.  
 
     
     
         18 . Use according to  claim 13 , characterized in that 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 and 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.  
     
     
         19 . A pharmaceutical composition containing a CB 1  receptor antagonist and a regulator of metabolic functions with a pharmaceutical excipient.  
     
     
         20 . A pharmaceutical composition according to  claim 19 , characterized in that said regulator of metabolic functions is a β 3 -agonist.  
     
     
         21 . A pharmaceutical composition according to  claim 19  or  20 , characterized in that 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, morpholin-4-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 , characterized in that 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 any one of  claims 20  to  22 , characterized in that 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 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; (C 2 -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(C 1 -C6)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(C1-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 )alkennyl 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 0 , in which R′″ is as defined above and R 0  is hydrogen or is as defined above for R′″, or R′″ and R 0 , 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 0 , in which R′″ is as defined above and R 0  is hydrogen or is as defined above for R′″, or R′″ and R 0 , 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 0 , in which R′″ is as defined above and R 0  is hydrogen or is as defined above for R′″, or R′″ and R 0 , 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 0 , in which R′″ is as defined above and R 0  is hydrogen or is as defined above for R′″, or R′″ and R 0 , 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 any one of  claims 20  to  22  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 , characterized in that 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 any one of  claims 20  to  26  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 30  or  31  in which said 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 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 any one of  claims 30  to  32  in which said active principles are in different packagings.  
     
     
         34 . Use according to  claim 1  for the preparation of a drug useful for regulating the desire to consume non-essential food items.  
     
     
         35 . Use according to  claim 34  in which the non-essential food items are excess sugars, excess carbohydrates, alcohol and drugs.  
     
     
         36 . Use of a CB 1  receptor antagonist for the preparation of a drug useful to suppress spontaneous appetency for a food item which usually brings pleasure.  
     
     
         37 . Use according to  claim 36  in which the food item found pleasurable is alcohol or sugar.  
     
     
         38 . Use according to any one of  claims 34  to  37  in which 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.