Compounds for the treatment of addictive disorders

Abstract

The treatment of addictive disorders, psychoactive substance use disorders, intoxication disorders, inhalation disorders, alcohol addiction, tobacco addiction, and nicotine addiction using a heterocyclic amine, a phenylazacycloalkane, a cabergoline, or an aromatic bicyclic amine active agent, or a pharmaceutically acceptable derivative or salt of any said active agent is described herein.

What is claimed is:  
     
         1 . A method of treating or suppressing the symptoms of at least one disorder selected from addictive disorders, psychoactive substance use disorders, intoxication disorders, inhalation disorders, alcohol addiction, tobacco addiction, and nicotine addiction, said method comprising the step of administering a therapeutically effective, nontoxic amount of an active agent selected from the group consisting of a heterocyclic amine, a phenylazacycloalkane, a cabergoline, an aromatic bicyclic amine, and pharmaceutically acceptable derivatives or salts of any said active agent, to a patient in need of treatment.  
     
     
         2 . The method of  claim 1  wherein the active agent is a heterocyclic amine of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R 1 , R 2 , and R 3  are each independently hydrogen, C 1-6  alkyl, C 3-5  alkenyl, C 3-5  alkynyl, C 3-7  cycloalkyl, C 4-10  cycloalkyl- or phenyl-substituted C 1-6  alkyl, or R 1  and R 2  are joined to form a C 3-7  cyclic amine which can contain additional heteroatoms and/or unsaturation;  
 n is 0 or 1;  
 X is hydrogen, C 1-6  alkyl, halogen, hydroxy, alkoxy, cyano, carboxamide, carboxyl, or carboalkoxyl;  
 A is CH, CH 2 , CH-halogen, CHCH 3 , C═O, C═S, C—SCH 3 , C═NH, C—NH 2 , C—NHCH 3 , C—NHCOOOCH 3 , C—NHCN, SO 2 , or N;  
 B is CH 2 , CH, CH-halogen, C═O, N, NH, N-CH 3 , or O; and  
 D is CH, CH 2 , CH-halogen, C═O, O, N, NH, or N-CH 3 .  
 
     
     
         3 . The method of  claim 2 , wherein: 
 D is N or NH, n is 0, and R 1 , R 2 , R 3 , X, A, and B are as defined in  claim 2;  or    A is CH, CH 2 , CHCH 3 , C═O, C═S, C—SCH 3 , C═NH, C—NH 2 , C—NHCH 3 , C—NHCOOCH 3 , or C—NHCN, and R 1 , R 2 , R 3 , n, X, B, and D are as defined in  claim 2;  or    A is CH or C═O, and R 1 , R 2 , R 3 , n, X, B, and D are as defined in  claim 2 .    
     
     
         4 . The method of  claim 2  wherein the active agent is selected from the group consisting of: 
 (5R)-5-(methylamino)-5,6-dihydro-4H-imidao[4,5,1-ij]quinolin-(2H)-one;  
 (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione;  
 (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione maleate; and  
 (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione 2-butenedioanate.  
 
     
     
         5 . The method of  claim 1  wherein the active agent is a phenylazacycloalkane compound of the formula:,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 n2 is 0-3;  
 R 1  and R 5  are independently hydrogen, —OH, CN, CH 2 CN, 2-CF 3 , 4-CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH═CF 2 , (CH 2 ) 2 CF 3 , ethenyl, 2-propenyl, OSO 2 CH 3 , OSO 2 CF 3 , SSO 2 CF 3 , COR 7 , COOR 7 , CON(R 7 ) 2 , SO x1 CH 3 , wherein x1 is 0-2, SO x1 CF 3 , O(CH 2 ) x1 CF 3 , SO 2 N(R 7 ) 2 , CH═NOR 7 , COCOOR 7 , COCOON(R 7 ) 21  C 1-8  alkyl, C 3-8  cycloalkyl, CH 2 OR 7 , CH 2  (R 7 ) 21  NR 7 SO 2 CF 3 , NO 2 , halogen, a phenyl at positions 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine; provided that at least one of R 4  and R 5  is a substituent other than hydrogen and provided that when R 4  or R 5  is —OH R 7  is other than hydrogen;  
 R 6  is hydrogen, CF 3 , CH 2 CF 3 , C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, —(CH 2 ) m —R 8 , wherein m is 1-8, CH 2 SCH 3  or a C 4 -C 8  alkyl bonded to said nitrogen and one of its adjacent carbon atoms inclusive to form a heterocyclic structure;  
 R 7  is independently hydrogen, CF 3 , CH 2 CF 3 , C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, —(CH 2 ) m —R 8 , wherein m is 1-8;  
 R 8  is phenyl optionally substituted with a CN, CF 3 , CH 2 CF 3 , C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 2-thiophenyl, 3-thiophenyl, —NR 9 CONR 9 R 10 , or —CONR 9 R 10 ; and  
 R 9  and R 10  are each independently hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkylmethyl, C 2 -C 8  alkenyl or C 2 -C 8  alkynyl.  
 
     
     
         6 . The method of  claim 5  wherein: 
 R 4  is CN, and n2, R 5 , R 5 , and R 7  are as defined in  claim 5;  or  
 R 5  is H, R 6  is n-propyl, and n2, R 4 , and R 7  are as defined in  claim 5;  or  
 R 4  is —OSO 2 CF 3 , and n2 and R 5 -R 7  are as defined in  claim 5;  or  
 R 5  is H, R 6  is C 1-8  alkyl, and n2, R 4 , and R 7  are as defined in  claim 5;  or  
 R 4  is 3-OH, R 5  is H, R 6  is n-propyl, R 7  is a C 1-8  alkyl, and n is as defined in  claim 5;  or  
 n2 is 2, and R 4 -R 7  are as defined in  claim 5;  or  
 n2 is 0, and R 4 -R 7  are as defined in  claim 5 .  
 
     
     
         7 . The method of  claim 5  wherein the phenylazacycloalkane compound is selected from the group consisting of: 
 (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride;  
 (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide; and  
 (3S)-3-[3-methylsulfonyl)phenyl]-1-propylpiperidine (2E)-2-butenedioate.  
 
     
     
         8 . The method of  claim 1  wherein the active agent is a cabergoline of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R 11  is hydrogen or methyl;  
 R 12  is independently hydrogen, halogen, methyl, formyl, S—R 17 , or SO—R 17 , wherein R 17  is C 1 -C 4  alkyl or phenyl;  
 R 13  is hydrogen or methoxy;  
 R 14  is independently C 1 -C 4  alkyl, C 1 -C 4  alkenyl, C 1 -C 4  alkynyl, benzyl, or phenyl; and  
 R 15  and R 16  are each independently C 1 -C 4  alkyl, cyclohexyl, benzyl, phenyl optionally substituted with halogen or methoxy, or (CH 2 ) n3 N(CH 3 ) 21  wherein n3 is an integer.  
 
     
     
         9 . The method of  claim 8  wherein the active agent is 1-((6-allylergolin-8β-yl)carbonyl)-1-(3-(dimethylamino)propyl)-3-ethylurea.  
     
     
         10 . The method of  claim 1  wherein the active agent is an aromatic bicyclic amine compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 n3 is 0 or 1;  
 n4 is 0 or 1, provided that R 20  is not present when n4 is 0;  
 R 18  is α-R 18−1 :β-R 18−2  where one of R 18−1  or R 18−2  is selected from the group consisting of H or C 1 -C 6  alkyl, and the other of R 18−1  or R 18−2  is a group of the formula:  
                     
 wherein R 26  and R 27  are independently selected from H or C 1 -C 6 -alkyl; R 28  is oxygen (O) or R 28  is α-R 28−1 :β-R 28−2 , wherein R 28−1  and R 28−2  are independently selected from H or C 1 -C 6 alkyl; R 29  is selected from the group consisting of:  
                     
 wherein R 31  and R 33  are independently selected from H or C 1 -C 6 alkyl; R 32  is nitrogen (N—) or methine (HC—); and s is 1 or 2;  
                     
 wherein R 34  is selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, -C 1 -C 3  alkyl-(C 3 -C 7  cycloalkyl); and S2 is 0, 1, or 2;  
                     
 wherein R 34  and s2 are as defined above;  
 R 19  is oxygen (0) or sulfur (S);  
 R 20  is α-R 20−1 :β-R 20−1 , wherein one of R 20−1  and R 20−2  is H, C 1 -C 6  alkyl, and the other of R 20−1  or R 20−2  is H, C 1 -C 6  alkyl, phenyl, hydroxy, and —O—(C 1 -C 3  alkyl);  
 R 21  is α-R 21−1:β-R 21−1 , wherein one of R 21−1  and R 21−2  is H, C 1 -C 6  alkyl, and the other of R 21−1  or R 21−2  is H, C 1 -C 6  alkyl, phenyl, hydroxy, and —O—(C 1 -C 3  alkyl);  
 and when n4 is 1, one of R 20−1  or R 20−2  and one of R 21−1  or R 21−2  can be taken together with the carbon atoms to which they are attached to form a carbon ring of 5-, 6-, or 7-members;  
 R 22  is H, F, Cl, Br, I, —CONR 35 R 36 , —SONR 35 R 36 , CF 3 , NR 35 R 36 , NO 2 , CN, —NR 35 —CO—R 36 , —SO 2 CF 3 , C 1 -C 4  alkyl, Si(CH 3 ) 3 , and phenyl optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, I, and —CO—NR 35 R 36 , wherein R 35  and R 36  are independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, and -C 1 -C 3  alkyl-(C 3 -C 7  cycloalkyl);  
 and where R 22  and one of R 21−1  or R 21−2 are taken together with the carbon atoms to which they are attached to form a carbon ring of 5-, 6-, or 7-members;  
 R is H, F, Cl, Br, I, —CONR 37 R 38 , —SONR 37 R 38 , CF 3 , NR 37 R 38 , NO 2 , CN, —NR 37 —CO—R 38 , —SO 2 CF 3 , C 1 -C 4  alkyl Si (CH 3 ) 3 , and phenyl optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, I, and —CO—NR 3 R 38 , wherein R 37  and R 38  are independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, and -C 1 -C 3  alkyl-(C 3 -C 7  cycloalkyl);  
 R 24  is H, F, Cl, Br, I, —CONR 39 R 40 , —SONR 39 R 40 , CF 3 , NR 39 R 40 , NO 2 , CN, —NR 39 —CO—R 40 , —SO 2 CF 3 , C 1 -C 4  alkyl, Si(CH 3 ) 3 , and phenyl optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, I, and —CO—NR 39 R 40 , wherein R 39  and R 40  are independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, and -C 1 -C 3  alkyl-(C 3 -C 7  cycloalkyl);  
 R is H, F, Cl, Br, I, —CONR 41 R 42 , —SONR 41 R 42  CF 3 , NR 41 R 42 , NO 2 , CN, —NR 41 —CO—R 42 , —SO 2 CF 3 , C 1 -C 4  alkyl, Si(CH 3 ) 3 , and phenyl optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, I, and —CO—NR 41 R 42 , wherein R 41  and R 42  are independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, and -C 1 -C 3  alkyl-(C 3 -C 7  cycloalkyl);  
 with the proviso that not more than two of R 22 , R 23 , R 24 , and R 25  are other than H; and  
 R 30  is selected from the group consisting of: 
 phenyl optionally substituted with one or two substituents selected from the group consisting of CF 3 , COR 43 , COOR 43 , CN, NO 2 , NR 44 —CO—R 45 , —S—(C 1 -C 6  alkyl), NR 44 R 45 , or a group represented by R 46 ;  
 2-, 3-, and 4-pyridinyl optionally substituted with one or two substituents represented by R 46 ; and  
 2-, 4-, and 5-pyrimidinyl optionally substituted with one or two substituents represented by R 46 ;  
 
 wherein R 43 , R 44  and R 4 s are independently selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl,  
 -C 1 -C 3  alkyl-(C 3 -C 7  cycloalkyl); and R 46  is selected from the group consisting of F, Cl, Br, I, —CO—NR 44 R 45 , —SO 2 NR 44 R 45 , OH, SH, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, —OR 47 , —CH 2 —(C 3 -C 6  cycloalkyl), —CH 2 -phenyl, C 3 -C 6  cycloalkyl, —SO 2 CF 3 , and  
 —CH 2 CF 3 , wherein R 44  and R 45  are as previously defined and R 47  is C 1 -C 6  alkyl; and  
 enantiomers and diasteromers thereof, where such exist, and pharmaceutically acceptable salts thereof.  
 
     
     
         11 . The method of  claim 10  wherein: one of the substituents represented by R 18−1  or R 18−2  is H, and the other substituent represented by R 18−1  or R 18−2  is a group of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 26 , R 27 , R 28 , R 29  and R 30  are as defined in  claim 10 .  
     
     
         12 . The method of  claim 10  wherein the active agent is selected from the group consisting of: 
 1-(4-fluorophenyl)-4-[2-(isochroman-1-yl)ethyl]piperazine;  
 1-[2-(isochroman-1-yl)ethyl]-4-phenylpiperazine;  
 1-[2-(isochroman-1-yl)ethyl]-4-(4-methoxyphenyl)piperazine;  
 (−)-4-[4-[2-(isochroman-1-yl)ethyl]piperazin-1-yl]benzamide; and  
 (−)-4-[4-[2-(isochroman-1-yl)ethyl]piperazin-1-yl]benzenesulfonamide.  
 
     
     
         13 . The method of  claim 1  wherein the active agent is used to treat or enhance the treatment of tobacco and/or nicotine addiction.  
     
     
         14 . The method of  claim 1  wherein the active agent is used to reduce the craving for tobacco and/or nicotine containing products.  
     
     
         15 . The method of  claim 1  wherein the active agent is used to reduce the smoking and/or chewing of tobacco- or nicotine-containing products.  
     
     
         16 . The method of  claim 1  wherein the active agent is administered to the patient three times a day.  
     
     
         17 . The method of  claim 1  wherein the active agent is selected from the group consisting of a heterocyclic amine, a phenylazacycloalkane, and a cabergoline administered in a dose of about 0.01 mg/day to about 10.0 mg/day.  
     
     
         18 . The method of  claim 17  wherein the active agent is selected from the group consisting of a heterocyclic amine, a phenylazacycloalkane, a cabergoline, and a cabergoline-type derivative administered in a dose of about 0.125 mg/day to about 6 mg/day.  
     
     
         19 . The method of  claim 18  wherein the active agent is administered in an amount from about 0.375 mg/day to about 5 mg/day.  
     
     
         20 . The method of  claim 19  wherein the active agent is administered in an amount from about 0.75 mg/day to about 4.5 mg/day.  
     
     
         21 . The method of  claim 17  wherein an initial dose of active agent of about 0.125 mg/day administered to the patient three times a day is titrated to higher levels every five to seven days until therapeutic effect is achieved.  
     
     
         22 . The method of  claim 1  wherein the active agent is an aromatic bicyclic amine administered in an amount of from about 5 mg/day to about 120 mg/day.  
     
     
         23 . The method of  claim 22  wherein the aromatic bicyclic amine is administered in an amount of from about 20 mg/day to about 100 mg/day.  
     
     
         24 . The method of  claim 23  wherein the aromatic bicyclic amine is administered in an amount of from about 40 mg/day to about 80 mg/day.  
     
     
         25 . The method of  claim 22  wherein an initial dose of active agent of about 5 mg/day is administered to the patient three times a day and is titrated to higher levels every five to seven days until therapeutic effect is achieved.