New use of antimineralocorticoid compounds against narcotic withdrawal syndrome

Abstract

A method of treating narcotic withdrawal symptoms in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound having anti-mineralocorticoid activity sufficient to treat narcotic withdrawal sypmtoms.

1 ) Use of compounds having an antimineralocorticoid activity for the preparation of medicaments intended for the prevention or treatment of symptoms linked to drug dependence or to the spontaneous or induced withdrawal syndrome, caused by narcotics and mixtures of narcotics.  
     
     
         2 ) Use according to  claim 1 , characterized in that the narcotic is a morphinomimetic chosen from heroin, morphine and methadone.  
     
     
         3 ) Use according to  claim 1 , characterized in that the narcotic is cocaine.  
     
     
         4 ) Use according to any one of  claims 1  to  3 , characterized in that the compounds having an antimineralocorticoid activity correspond to general formula (I):  
       
         
           
           
               
               
           
         
       
       in which rings A, B and C have one of the following structures:  
       
         
           
           
               
               
           
         
       
       and in which: 
 either X and Y represent the groups:  
                     
 Alk 1  representing an alkyl group containing at most 8 carbon atoms,  
 or X represents a hydroxyl, acetyloxy, propionyloxy, methoxy or ethoxy radical and Y represents a CH 2 CH 2 CO 2 M, CH 2 CH 2 SO 2 M or CH 2 CH 2 CH 2 OH radical, M being a hydrogen atom, an alkali metal atom or an ammonium radical,  
 or X represents a COCH 2 Z radical, in which Z represents a hydrogen atom, a hydroxyl radical or an acyloxy radical containing 1 to 18 carbon atoms, and Y represents a hydrogen atom,  
 or X represents a  
                     
 radical, S being an alkyl radical containing at most 8 carbon atoms, or a hydrogen atom and Y represents a hydrogen atom, A and B are hydrogen atoms or together form a methylenic bridge in position 15α,16α or 15β, 16β, A′ and B′ are hydrogen atoms, alkyl radicals containing 1 to 4 carbon atoms, or form with the carbon which carries them a cyclopropyl radical, R 1  represents a methyl radical or a C C—W group, in which W represents either a hydrogen atom,  
 or an alkyl radical containing at most 8 carbon atoms optionally substituted by a hydroxyl, free, esterified or salified carboxy, amino, tritylamino, chloroacetylamino, trifluoroacetylamino, halogen, monoalkylamino, dialkylamino radical, each alkyl radical containing at most 8 carbon atoms,  
 or an aryl or aralkyl radical containing at most 14 carbon atoms, optionally substituted by a hydroxyl, free esterified or salified carboxy, amino, monoalkylamino, dialkylamino, alkyl, alkoxy or alkylthio radical, each alkyl radical containing at most 8 carbon atoms,  
 or a halogen atom,  
 or a trialkylsilyl radical, each alkyl radical containing at most 8 carbon atoms,  
 R 2  and R 3  are such that  
 either R 2  and R 3  form together a methylenic bridge in position 6α, 7α or 6β, 7β,  
 or R 2  and R 3  are hydrogen atoms,  
 or R 3  is a hydrogen atom and R 2  represents a SCOCH 3 , CO 2 Alk group, Alk being an alkyl radical containing at most 8 carbon atoms, alkyl, alkenyl or alkynyl radicals containing at most 8 carbon atoms and optionally substituted by a hydroxyl, free, esterified or salified carboxy, halogen, amino, monoalkylamino, dialkylamino radical, each alkyl radical containing at most 8 carbon atoms, R 4  represents an alkyl, alkenyl or alkynyl radical containing at most 8 carbon atoms, R 5  represents either an allenyl radical, or a hydroxyl radical, or a hydrogen atom, the dotted lines represent a possible second bond, the wavy lines indicate that the substituents are in position α or β, as well as the salts of the products of formula (I) with pharmaceutically acceptable acids and bases.  
 
     
     
         5 ) Use according to  claim 4 , characterized in that the compounds having an antimineralocorticoid activity correspond to general formula (I a ):  
       
         
           
           
               
               
           
         
       
       in which: 
 either X a  and Y a  represent the groups  
                     
 Alk 1  being as defined in  claim 4 ,  
 or X a  represents a hydroxyl, acetyloxy, propionyloxy, methoxy or ethoxy radical and Y a  represents a CH 2 CH 2 CO 2 M, CH 2 CH 2 SO 2 M or CH 2 CH 2 CH 2 OH radical, M being as defined in  claim 4 ,  
 R 2a , R 3a  and W a  respectively have the same values as R 2 , R 3  and W as defined previously and the dotted or wavy lines have the meaning indicated in  claim 4 .  
 
     
     
         6 ) Use according to claims  4  or  5 , characterized in that the compounds corresponding to general formulae (I) and (I a ) are chosen from the following list: 
 γ-lactone of 10β-ethynyl 17β-hydroxy 3-oxo-19-nor-17α-pregna-4,9(11)-diene-21-carboxylic acid,  
 γ-lactone of 17β-hydroxy 3-oxo-10β-(1-propynyl)-19-nor-17α-pregna-4,9(11)-diene-21-carboxylic acid,  
 γ-lactone of 17β-hydroxy 3-oxo-10β-(1-propynyl)-19-nor-17α-pregn-4-ene-21-carboxylic acid,  
 γ-lactone of 10β-ethynyl 17β-hydroxy 3-oxo-19-nor-17α-pregn-4-ene-21-carboxylic acid.  
 
     
     
         7 ) Use according to  claim 4 , characterized in that the compounds having an antimineralocorticoid activity correspond to general formula (I b ):  
       
         
           
           
               
               
           
         
       
       in which: 
 either X b  and Y b  represent the groups  
                     
 or X b  represents a hydroxyl radical and Y b  represents a CH 2 CH 2 CO 2 M radical, M being as defined in  claim 4 ,  
 R 2b  and R 3b  are such that  
 either R 2b  represents an alkyl, alkenyl or alkynyl radical optionally substituted as defined previously and R 3b  is a hydrogen atom,  
 or R 2b  and R 3b  together form a methylenic bridge in position 6α,7α or in position 6β,7β.  
 
     
     
         8 ) Use according to one of claims  4  or  7 , characterized in that the compounds corresponding to general formulae (I) or (I b ) are chosen from the following list: 
 (17R)-6β,7β-methylene-2′-oxydospiro-(androst-4-ene-17,5′-(1′,2′)-oxathiolane)-3-one  
 (17R)-6α,7α-methylene-2′-oxydospiro-(androst-4-ene-17,5′-(1′,2′)-oxathiolane)-3-one  
 (17R)-7α-methyl-2′-oxydospiro-(androst-4-ene-17,5′-(1′,2′)-oxathiolane)-3-one  
 (17R)-7α-n-propyl-2′-oxydospiro-(androst-4-ene-17,5′-(1′,2′)-oxathiolane)-3-one  
 γ-lactone of 17β-hydroxy-3-oxo-7α-propyl-17α-pregna-1,4-diene-21-carboxylic acid,  
 potassium 17β-hydroxy-3-oxo-7α-propyl-17α-pregna-1,4-diene-21-carboxylate,  
 γ-lactone of 17β-hydroxy-3-oxo-7α-propyl-(17α)-pregn-4-ene-21-carboxylic acid,  
 potassium 17β-hydroxy-3-oxo-7α-propyl-(17α)-pregn-4-ene-21-carboxylate.  
 
     
     
         9 ) Use according to  claim 4 , characterized in that the compounds having an antimineralocorticoid activity, corresponding to general formula (I c ):  
       
         
           
           
               
               
           
         
       
       in which 
 either X c  and Y c  represent a group  
                     
 or X c  represents a hydroxyl radical and Y c  represents a CH 2 CH 2 CO 2 M or CH 2 CH 2 SO 2 M group, M being as defined in  claim 4 ,  
 or X c  represents a COCH 2 Z radical in which Z is as defined in  claim 4  and Y c  is a hydrogen atom,  
 A′ c  and B′ c  respectively have the same values as A′ and B′ as defined in  claim 4 ,  
 R 4c  is a methyl or ethyl radical, R 5c  is either a hydrogen atom, or an allenyl radical, it being understood that when R 5c  is an allenyl radical, A′ c  and B′ c  are hydrogen atoms, R 4c  is a methyl radical, X c  and Y c  together form a  
                     
 group, the dotted lines in position 9-10 form a second bond, and those in position 11-12 do not form a second bond.  
 
     
     
         10 ) Use according to any one of claims  4  or  9 , characterized in that the compounds corresponding to general formulae (I) or (I c ) chosen from the following list: 
 2,2-dimethyl 19-nor pregn-4-ene-3,20-dione,  
 21-acetoxy 2,2-dimethyl 19-nor-pregn-4-ene 3,20-dione,  
 2,2-dimethyl 21-hydroxy 19-nor-pregn-4-ene 3,20-dione,  
 2,2-dimethyl 19-nor-pregna-4,9-diene 3,20-dione,  
 21-acetoxy 2,2-dimethyl 19-nor-pregna-4,9-diene 3,20-dione,  
 2,2-dimethyl 21-hydroxy 19-nor-pregna-4,9-diene 3,20-dione,  
 2,2-dimethyl 19-nor-pregna-4,9,11-triene 3,20-dione,  
 21-acetoxy 2,2-dimethyl 19-nor-pregna-4,9,11-triene 3,20-dione,  
 2,2-dimethyl 21-hydroxy 19-nor-pregna-4,9,11-triene 3,20-dione,  
 (17R) 2′-oxydospiro-(estra-4,9-diene-17,5′-(1′,2′)-oxathiolane) 3-one,  
 (17R) 2′-oxydospiro-(estra-4,9,11-triene-17,5′-(1′,2′)-oxathiolane) 3-one,  
 (17R) 11β-hydroxy 2′-oxydospiro-(estra-4,9-diene-17,5′-(1′,2′)-oxathiolane) 3-one,  
 2,2-dimethyl-13-ethyl-21-hydroxy-18,19-dinor-pregn-4-ene 3,20-dione,  
 γ-lactone of 11β-allenyl-17β-hydroxy-3-oxo-19-nor-17α-pregna-4,9-diene-21-carboxylic acid.  
 
     
     
         11 ) Use according to  claim 4 , characterized in that the compounds having an antimineralocorticoid activity correspond to general formula (I d ):  
       
         
           
           
               
               
           
         
       
       in which: 
 either X d  and Y d  represent the group  
                     
 or X d  represents a hydroxyl radical and Y d  represents a CH 2 CH 2 CO 2 M radical, M being as defined in  claim 4 ,  
 A d  and B d  respectively have the same values as A and B as defined in  claim 4 ,  
 R 2d  represents either a thioacetyl radical, or a CO 2 Alk radical, Alk being an alkyl radical containing at most 8 carbon atoms and the dotted line in position 1-2 represents an optional double bond.  
 
     
     
         12 ) Use according to one of claims  4  or  11 , characterized in that the compounds corresponding to general formula (I) or (I d ) are chosen from the following list: 
 γ-lactone of 7α-acetylthio-17β-hydroxy-15β,16β-methylene-3-oxo-17α-pregna-1,4-diene-21-carboxylic acid,  
 γ-lactone of 17β-hydroxy-7α-methoxycarbonyl-15β,16β-methylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid,  
 γ-lactone of 7α-acetylthio-17β-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acid,  
 γ-lactone of 17β-hydroxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21-carboxylic acid,  
 the potassium salt of 17β-hydroxy-7α-methoxycarbonyl-3-oxo-pregn-4-ene-21-carboxylic acid.  
 
     
     
         13 ) Use according to  claim 4 , characterized in that the compounds having an antimineralocorticoid activity correspond to general formula (I e ):  
       
         
           
           
               
               
           
         
       
       in which: 
 either X e  and Y e  represent the group  
                     
 or X e  represents a hydroxyl radical and Y e  represents a CH 2 CH 2 CO 2 M radical, M being as defined previously,  
 R 2e  or R 3e  are such that:  
 either R 2e  and R 3e  together form a methylenic bridge in position 6α,7α or 6β,7β,  
 or R 2e  and R 3e  are hydrogen atoms,  
 A e  and B e  respectively have the same values as A and B as defined in  claim 4 , the dotted or wavy lines keeping the same meaning as in  claim 4 .  
 
     
     
         14 ) Use according to one of claims  4  or  11 , characterized in that the compounds corresponding to general formula (I) or (I e ), are chosen from the following list: 
 γ-lactone of 17β-hydroxy-6β,7β,15β,16β-dimethylene-3-oxo-17α-pregna-1,4-diene-21-carboxylic acid,  
 γ-lactone of 17β-hydroxy-6β,7β,15β,16β-dimethylene-3-oxo-17α-pregna-4-ene-21-carboxylic acid,  
 γ-lactone of 17β-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid,  
 the potassium salt of 17β-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid  
 γ-lactone of 17β-hydroxy-3-oxo-17α-pregna-4,6,11-triene-21-carboxylic acid,  
 γ-lactone of 17β-hydroxy-6β,7β-methylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid,  
 potassium salt of 17β-hydroxy-6β,7β-methylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid.  
 
     
     
         15 ) Use according to  claim 4 , characterized in that the compounds having an antimineralocorticoid activity correspond to general formula (I f ):  
       
         
           
           
               
               
           
         
       
       in which S represents an alkyl radical containing 1 to 8 carbon atoms, or a hydrogen atom.  
     
     
         16 ) Use according to  claim 4 , characterized in that the compounds having an antimineralocorticoid activity correspond to general formula (I g ):  
       
         
           
           
               
               
           
         
       
       in which A g  and B g  respectively have the same values as A and B as defined in  claim 4 .  
     
     
         17 ) Use according to  claim 4 , characterized in that the compounds having an antimineralocorticoid activity correspond to general formula (I h ):  
       
         
           
           
               
               
           
         
       
       in which A h , B h  and R 2h  respectively have the same values as A, B and R 2  as defined in  claim 4 .  
     
     
         18 ) Use according to  claim 4 , characterized in that the compounds having an antimineralocorticoid activity correspond to general formula (I i ):  
       
         
           
           
               
               
           
         
       
       in which A i , B i , R 2i  and R 3i  respectively have the same values A, B, R 2  and R 3  as defined in  claim 4 .  
     
     
         19 ) Use according to  claim 4 , characterized in that the compounds having an antimineralocorticoid activity correspond to general formula (I j ):  
       
         
           
           
               
               
           
         
       
       in which R 4j  is an alkenyl or alkynyl group containing 1 to 8 carbon atoms and R 5j  is a hydroxyl radical or a hydrogen atom.  
     
     
         20 ) The pharmaceutical compositions, containing as active ingredient at least one medicament as defined in  claim 1 , intended for the prevention or treatment of symptoms linked to drug dependence or to the spontaneous or induced withdrawal syndrome, caused by narcotics or mixtures of narcotics.  
     
     
         21 ) The pharmaceutical compositions according to  claim 20 , containing as active ingredient at least one medicament as defined in any one of claims  2  or  3 , intended for the prevention or treatment of symptoms linked to drug dependence or to the spontaneous or induced withdrawal syndrome, caused by narcotics or mixtures of narcotics.  
     
     
         22 ) The pharmaceutical compositions according to  claim 20 , containing as active ingredient at least one medicament as defined in  claim 4 , intended for the prevention or treatment of symptoms linked to drug dependence or to the spontaneous or induced withdrawal syndrome, caused by narcotics or mixtures of narcotics.  
     
     
         23 ) The pharmaceutical compositions according to  claim 20 , containing as active ingredient at least one medicament as defined in any one of claims  5 ,  7 ,  9 ,  11 ,  13 ,  15 ,  16 ,  17 ,  18  or  19 , intended for the prevention or treatment of symptoms linked to drug dependence or to the spontaneous or induced withdrawal syndrome, caused by narcotics or mixtures of narcotics.  
     
     
         24 ) The pharmaceutical compositions according to  claim 20 , containing as active ingredient at least one medicament as defined in  claim 4 , intended for the prevention or treatment of symptoms linked to drug dependence or to the spontaneous or induced withdrawal syndrome, caused by narcotics or mixtures of narcotics, chosen form the following list: 
 γ-lactone of 10β-ethynyl, 17β-hydroxy 3-oxo-19-nor-17α-pregna-4,9(11)-diene-21-carboxylic acid,    potassium 17β-hydroxy-3-oxo-7α-propyl-17α-pregn-4-ene-21-carboxylate,    γ-lactone of 11β-allenyl-17β-hydroxy-3-oxo-19-nor-17α-pregna-4,9(11)-diene-21-carboxylic acid,    γ-lactone of 17β-hydroxy-7α-methoxycarbonyl-15β,16β-methylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid,    γ-lactone of 7α-acetylthio-17β-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acid,    γ-lactone of 17β-hydroxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21-carboxylic acid,    γ-lactone of 17β-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid    13β-(propen-2-yl)-18-nor-pregn-4-ene-3,20-dione.