Low dose noribogaine for treating nicotine addiction and preventing relapse of nicotine use

Abstract

This invention provides methods and compositions for treating nicotine addiction or treating or preventing nicotine cravings in a subject. The method comprises administering to the patient in need thereof a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt thereof.

1 . A method for treating nicotine addiction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is from about 50 ng to less than 10 μg per kg body weight per day. 
     
     
         2 . The method of  claim 1 , wherein the therapeutically effective amount is from about 50 ng to about 1 μg per kg body weight per day. 
     
     
         3 . The method of  claim 1 , wherein the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered by sublingual, intranasal, or intrapulmonary delivery. 
     
     
         4 . The method of  claim 1 , wherein the therapeutically effective amount is administered once a day. 
     
     
         5 . The method of  claim 1 , wherein the therapeutically effective amount is administered two or more times per day. 
     
     
         6 . A pharmaceutical composition comprising a therapeutically effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is an amount that delivers an aggregate amount of noribogaine of about 50 ng to less than 10 μg per kg body weight per day. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the therapeutically effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is an amount that delivers an aggregate amount of noribogaine of about 50 ng to about 1 μg per kg body weight per day. 
     
     
         8 . The pharmaceutical composition of  claim 6 , wherein the pharmaceutical composition is formulated for sublingual, intranasal, or intrapulmonary delivery. 
     
     
         9 . A method for preventing a nicotine craving in a patient in need thereof, comprising administering to the patient a prophylactically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt thereof, wherein said prophylactically effective amount is from about 50 ng to less than 10 μg per kg body weight per day. 
     
     
         10 . The method of  claim 9 , wherein the patient is no longer physically addicted to nicotine. 
     
     
         11 . The method of  claim 9 , wherein the prophylactically effective amount is from about 50 ng to about 1 μg per kg body weight per day. 
     
     
         12 . The method of  claim 9 , wherein the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered by sublingual, intranasal, or intrapulmonary delivery. 
     
     
         13 . The method of  claim 9 , wherein the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered on an as-needed basis as determined by the subject. 
     
     
         14 . The method of  claim 9 , wherein the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered before the nicotine craving occurs. 
     
     
         15 . The method of  claim 9 , wherein the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered after the nicotine craving occurs. 
     
     
         16 . The method of  claim 1 , wherein the noribogaine derivative is represented by Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R is hydrogen or a hydrolyzable group of the formula: 
       
       
         
           
           
               
               
           
         
         wherein X is an unsubstituted C 1 -C 12  group or a C 1 -C 12  group substituted by lower alkyl or lower alkoxy groups, wherein the noribogaine having the hydrolyzable group hydrolyzes in vivo to form 12-hydroxy ibogamine. 
       
     
     
         17 . The method of  claim 1 , wherein the noribogaine derivative is represented by Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein
    is a single or double bond; 
 R 1  is halo, OR 2 , or C 1 -C 12  alkyl optionally substituted with 1 to 5 R 10 ; 
 R 2  is hydrogen or a hydrolysable group selected from the group consisting of —C(O) R x , —C(O)OR x  and —C(O)N(R y ) 2  where each R x  is selected from the group consisting of C 1 -C 6  alkyl optionally substituted with 1 to 5 R 10 , and each R y  is independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl optionally substituted with 1 to 5 R 10 , C 6 -C 14  aryl optionally substituted with 1 to 5 R 10 , C 3 -C 10  cycloalkyl optionally substituted with 1 to 5 R 10 , C 1 -C 10  heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 , C 1 -C 10  heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 , and where each R y , together with the nitrogen atom bound thereto form a C 1 -C 6  heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10  or a C 1 -C 6  heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 ; 
 R 3  is selected from the group consisting of hydrogen, C 1 -C 12  alkyl optionally substituted with 1 to 5 R 10 , aryl optionally substituted with 1 to 5 R 10 , —C(O)R 6 , —C(O)NR 6 R 6  and —C(O)OR 6 ; 
 R 4  is selected from the group consisting of hydrogen, −(CH 2 ) m OR 8 , —CR 7 (OH)R 8 , —(CH 2 ) m CN, —(CH 2 ) m COR 8 , —(CH 2 ) m CO 2 R 8 , —(CH 2 ) m C(O)NR 7 R 8 , —(CH 2 ) m C(O)NR 7 NR 8 R 8 , —(CH 2 ) m C(O)NR 7 NR 8 C(O)R 9 , and —(CH 2 ) m NR 7 R 8 ; 
 m is 0, 1, or 2; 
 L is a bond or C 1 -C 12  alkylene; 
 R 5  is selected from the group consisting of hydrogen, C 1 -C 12  alkyl substituted with 1 to 5 R 10 , C 1 -C 12  alkeyl substituted with 1 to 5 R 10 , —X 1 R 7 , —(X 1 —Y) n —X 1 —R 7 , —SO 2 NR 7 R 8 , —O—C(O)R 9 , —C(O)OR 8 , —C(O)NR 7 R 8 , —NR 7 R 8 , —NHC(O)R 9 , and —NR 7 C(O)R 9 ; 
 each R 6  is independently selected from the group consisting of hydrogen, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 6 -C 10  aryl, C 1 -C 6  heteroaryl having 1 to 4 heteroatoms, and C 1 -C 6  heterocycle having 1 to 4 heteroatoms, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R 10 ; 
 X 1  is selected from the group consisting of O and S; 
 Y is C 1 -C 4  alkylene or C 6 -C 10  arylene, or a combination thereof; 
 n is 1, 2, or 3; 
 
         R 7  and R 8  are each independently selected from the group consisting of hydrogen, C 1 -C 12  alkyl optionally substituted with 1 to 5 R 10 , C 1 -C 6  heterocycle having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 , C 3 -C 10  cycloalkyl optionally substituted with 1 to 5 R 10 , C 6 -C 10  aryl optionally substituted with 1 to 5 R 10  and C 1 -C 6  heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R 10 °;
 R 9  is selected from the group consisting of C 1 -C 12  alkyl optionally substituted with 1 to 5 R 10 , C 1 -C 6  heterocycle having 1 to 4 heteroatoms optionally substituted with 1 to 5 R 10 , C 3 -C 10  cycloalkyl optionally substituted with 1 to 5 R 10 , C 6 -C 10  aryl optionally substituted with 1 to 5 R 10  and C 1 -C 6 heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R 10 ; 
 R 10  is selected from the group consisting of C 1 -C 4  alkyl, phenyl, halo, —OR 11 , —CN, —COR 11 , —CO 2 R 11 , —C(O)NHR 11 , —NR 11 R 11 , —C(O)NR 11 R 11 , —C(O)NHNHR 11 , —C(O)NR 11 NHR 11 , —C(O)NR 11 NR 11 R 11 , —C(O)NHNR 11 C(O)R 11 , —C(O)NHNHC(O)R 11 , —SO 2 NR 11 R 11 , —C(O)NR 11 NR 11 C(O)R 11 , and —C(O)NR 11 NHC(O)R 11 ; and 
 R 11  is independently hydrogen or C 1 -C 12  alkyl; 
 provided that: 
 when L is a bond, then R 5  is not hydrogen; 
 when   is a double bond, R 1  is an ester hydrolyzable group, R 3  and R 4  are both hydrogen, then -L-R 5  is not ethyl; 
 when   is a double bond, R 1  is —OH, halo or C 1 -C 12  alkyl optionally substituted with 1 to 5 R 10 , then R 4  is hydrogen; and 
 when   is a double bond, R 1  is OR 2 , R 4  is hydrogen, -L-R 5  is ethyl, then R 2  is not a hydrolyzable group selected from the group consisting of an ester, amide, carbonate and carbamate. 
 
       
     
     
         18 . The method of  claim 1 , wherein the noribogaine derivative is represented by Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein
    is a single or double bond; 
 R 12  is halo, —OH, —SH, —NH 2 , —S(O) 2 N(R 17 ) 2 , —R z -L 1 -R 18 , —R z -L 1 -R 19 , —R z -L 1 -R 20  or —R z -L 1 - CHR 18 R 19 , where R z  is O, S or NR 17 ; 
 L 1  is alkylene, arylene, —C(O)-alkylene, —C(O)-arylene, —C(O)O-arylene, —C(O)O-alkylene, —C(O)NR 20 -alkylene, —C(O)NR 20 -arylene, —C(NR 20 )NR 20 -alkylene or —C(NR 20 )NR 20 -arylene, wherein L 1  is configured such that —O-L 1 -R 18  is —OC(O)-alkylene-R 18 , —OC(O)O-arylene-R 18 , —OC(O)O-alkylene-R 18 , —OC(O)-arylene-R 18 , —OC(O)NR 20 -alkylene-R 18 , —OC(O)NR 20 -arylene-R 18 , —OC(NR 20 )NR 20 -alkylene-R 18  or —OC(NR 20 )NR 20 -arylene-R 18 , and wherein the alkylene and arylene are optionally substituted with 1 to 2 R 16 ; 
 R 13  is hydrogen, —S(O) 2 OR 20 , —S(O) 2 R 20 , —C(O)R 15 , —C(O)NR 15 R 15 , —C(O)OR 15 , C 1 -C 12  alkyl optionally substituted with 1 to 5 R 16 , C 1 -C 12  alkenyl optionally substituted with 1 to 5 R 16 , or aryl optionally substituted with 1 to 5 R 16 ; 
 R 14  is hydrogen, halo, —OR 17 , —CN, C 1 -C 12  alkyl, C 1 -C 12  alkoxy, aryl or aryloxy, where the alkyl, alkoxy, aryl, and aryloxy are optionally substituted with 1 to 5 R 16 ; 
 each R 15  is independently selected from the group consisting of hydrogen, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, aryl, heteroaryl, and heterocycle, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R 16 ; 
 R 16  is selected from the group consisting of phenyl, halo, —OR 17 , —CN, —COR 17 , —CO 2 R 17 , —NR 17 R 17 , —NR 17 C(O)R 17 , —NR 17 SO 2 R 17 , —C(O)NR 17 R 17 , —C(O)NR 17 NR 17 R 17 , —SO 2 NR 17 R 17  and —C(O)NR 17 NR 17 C(O)R 17 ; 
 each R 17  is independently hydrogen or C 1 -C 12  alkyl optionally substituted with from 1 to 3 halo; 
 R 18  is hydrogen, —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2  or —N(R 20 )C(O)R 20 ; 
 R 19  is hydrogen, —N(R 20 ) 2 , —C(O)N(R 20 ) 2 , —C(NR 20 )N(R 20 ) 2 , —C(NSO 2 R 20 )N(R 20 ) 2 , —NR 20 C(O)N(R 20 ) 2 , —NR 20 C(S)N(R 20 ) 2 , —NR 20 C(NR 20 )N(R 20 ) 2 , —NR 20 C(NSO 2 R 20 )N(R 20 ) 2  or tetrazole; and 
 each R 20  is independently selected from the group consisting of hydrogen, C 1 -C 12  alkyl and aryl; 
 provided that: 
 when   is a double bond and R — and R 14  are hydrogen, then R 12  is not hydroxy; 
 when   is a double bond, R 14  is hydrogen, R 12  is —O-L 1 -R 18 , —O-L 1 -R 19 , —O-L 1 -R 20 , and L 1  is alkylene, then —O-L 1 -R 18 , —O-L 1 -R 19 , —O-L 1 -R 20  are not methoxy; 
 when   is a double bond, R 14  is hydrogen, R z  is O, L 1  is —C(O)-alkylene, —C(O)-arylene, —C(O)O-arylene, —C(O)O-alkylene, —C(O)NR 20 -alkylene, or —C(O)NR 20 -arylene, then none of R 18 , R 19  or R 20  are hydrogen. 
 
       
     
     
         19 . The method of  claim 1 , wherein the noribogaine derivative is represented by Formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein 
         R 21  is selected from the group consisting of hydrogen, a hydrolysable group selected from the group consisting of —C(O)R 23 , —C(O)NR 24 R 25  and —C(O)OR 26 , where R 23  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, R 24  and R 25  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, R 26  is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that R 21  is not a saccharide or an oligosaccharide; 
         L 2  is selected from the group consisting of a covalent bond and a cleavable linker group; 
         R 22  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, provided that R is not a saccharide or an oligosaccharide; 
         provided that when L 2  is a covalent bond and R 22  is hydrogen, then R 21  is selected from the group consisting of —C(O)NR 24 R 25  and —C(O)OR 26 ; and 
         further provided that when R 21  is hydrogen or —C(O)R 23  and L 2  is a covalent bond, then R 22  is not hydrogen. 
       
     
     
         20 - 21 . (canceled) 
     
     
         22 . The method of  claim 1 , wherein noribogaine or a pharmaceutically acceptable salt thereof is administered. 
     
     
         23 . (canceled)