Treatment of Addiction and Impulse-Control Disorders Using PDE7 Inhibitors

Abstract

This disclosure is directed to treatment of addictions and primary impulse-control disorders using phosphodiesterase 7 (PDE7) inhibitors, alone or in combination with other therapeutic agents.

1 . A method of treating or reducing relapse use of an addictive agent in a subject who previously reduced or eliminated use of the addictive agent in response to treatment with an effective amount of an anti-addiction treatment; comprising:
 determining that the subject is no longer exposed to an effective amount of the anti-addiction treatment; and   administering an effective amount of an inhibitor of a phosphodiesterase 7 (PDE7) to the subject who has undergone a period of abstinence from, or limited or reduced use of, the addictive agent, wherein the PDE7 inhibitory agent is a selective PDE7 inhibitor for which the lesser of the IC 50  for inhibiting PDE7A activity and the IC 50  for inhibiting PDE7B activity is less than one-tenth the IC 50  that the agent has for inhibiting the activity of any other PDE enzyme from the PDE1-6 and PDE8-11 enzyme families,   wherein the selective PDE7 inhibitor is a compound of formula 6 or a pharmaceutically acceptable salt or solvate thereof:   
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is substituted or unsubstituted C 3-8  alkyl group, substituted or unsubstituted cycloalkyl group, or substituted or unsubstituted heterocycloalkyl group; 
         R 2  is a hydrogen atom or substituted or unsubstituted C 1-3  alkyl group; 
         R 3  is a hydrogen atom, substituted or unsubstituted C 1-3  alkyl group, or a halogen atom; and 
         R 4  is substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or a group CONR 5 R 6 , or CO 2 R 7 , 
         wherein R 5  and R 6  are same or different and are independently selected from a hydrogen atom; C 1-6  alkyl group optionally substituted by a halogen atom, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted cycloalkyl group, NR 7 COR 8 , COR 8 , NR 9 R 10 ; substituted or unsubstituted cycloalkyl group; substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted aryl group; substituted or unsubstituted heteroaryl group; or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom binding R 5  and R 6 ; 
         wherein R 7  is a hydrogen atom or substituted or unsubstituted C 1-3  alkyl group; 
         wherein R 8  is substituted or unsubstituted heterocycloalkyl group, or a group OH, OR 7 , or NR 9 R 10 ; 
         wherein R 9  and R 10  are, same or different from each other, a hydrogen atom; substituted or unsubstituted C 1-3  alkyl group, substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted acyl; a group SO 2 R 7 , or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom binding R 5  and R 6 . 
       
     
     
         2 . The method of  claim 1 , wherein the subject is addicted to an addictive agent selected from the group consisting of: alcohol, nicotine, marijuana, a marijuana derivative, an opioid agonist, a benzodiazepine, a barbiturate, and a psychostimulant. 
     
     
         3 . The method of  claim 1 , wherein the addictive agent is alcohol. 
     
     
         4 . The method of  claim 1 , wherein the addictive agent is nicotine. 
     
     
         5 . The method of  claim 2 , wherein the opioid agonist is selected from the group consisting of: morphine, methadone, fentanyl, sufentanil, and heroin. 
     
     
         6 . The method of  claim 2 , wherein the opioid agonist is oxycodone or hydrocodone. 
     
     
         7 . The method of  claim 1 , wherein the psychostimulant is cocaine, amphetamine, or an amphetamine derivative. 
     
     
         8 . The method of  claim 7 , wherein the psychostimulant is cocaine. 
     
     
         9 . The method of  claim 1 , wherein the PDE7 inhibitory agent has an IC 50  for inhibiting PDE7A and/or PDE7B activity of less than about 1 μM. 
     
     
         10 . The method of  claim 1 , wherein the PDE7 inhibitory agent has an IC 50  for inhibiting PDE7A and/or PDE7B activity of less than about 100 nM. 
     
     
         11 . The method of  claim 1 , wherein the PDE7 inhibitory agent has a molecular weight of less than about 450 g/mole. 
     
     
         12 . method of  claim 1 , wherein the selective PDE7 inhibitor of formula 6 is a member selected from the group consisting of formula 6A, formula 6B, formula 6C, formula 6D, formula 6E, formula 6F, formula 6G, and formula 6H: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 1 , further comprising administering to the subject an additional therapeutic agent wherein each of the PDE7 inhibitor and the additional therapeutic agent contribute to the effective reduction of the relapse use. 
     
     
         14 . The method of  claim 13 , wherein said additional therapeutic agent is selected from the group consisting of: an opioid antagonist, a mixed opioid partial agonist/antagonist, an antidepressant, an antiepileptic, an antiemetic, a corticotrophin-releasing factor-1 (CRF-1) receptor antagonist, a selective serotonin-3 (5-HT3) antagonist, a 5-HT2A/2C antagonist, and a cannabinoid-1 (CB1) receptor antagonist. 
     
     
         15 . A method of treating or preventing relapse use of an addictive agent or practice of an addictive or compulsive behavior associated with a primary impulse-control disorder or an obsessive-compulsive disorder, comprising administering an effective amount of an inhibitor of a phosphodiesterase 7 (PDE7) to a subject who has undergone a period of abstinence from, or limited or reduced use of, the addictive agent or practice of the addictive or compulsive behavior, wherein the inhibitor of a phosphodiesterase 7 is a compound of formula 6: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is substituted or unsubstituted C 3-8  alkyl group, substituted or unsubstituted cycloalkyl group, or substituted or unsubstituted heterocycloalkyl group; 
         R 2  is a hydrogen atom or substituted or unsubstituted C 1-3  alkyl group; 
         R 3  is a hydrogen atom, substituted or unsubstituted C 1-3  alkyl group, or a halogen atom; and 
         R 4  is substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or a group CONR 5 R 6 , or CO 2 R 7 , 
         wherein R 5  and R 6  are same or different and are independently selected from a hydrogen atom; C 1-6  alkyl group optionally substituted by a halogen atom, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted cycloalkyl group, a group NR 7 COR 8 , COR 8 , NR 9 R 10 ; substituted or unsubstituted cycloalkyl group; substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted aryl group; substituted or unsubstituted heteroaryl group; or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom binding R 5  and R 6 ; 
         wherein R 7  is a hydrogen atom or substituted or unsubstituted C 1-3  alkyl group; 
         wherein R 8  is substituted or unsubstituted heterocycloalkyl group, or a group OH, OR 7 , or NR 9 R 10 ; 
         wherein R 9  and R 10  are, same or different from each other, a hydrogen atom; substituted or unsubstituted C 1-3  alkyl group, substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted acyl; a group SO 2 R 7 , or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom binding R 5  and R 6 . 
       
     
     
         16 . A method of treating an addiction that is an addiction to an addictive substance or that is the practice of an addictive or compulsive behavior associated with a primary impulse-control disorder or an obsessive-compulsive disorder, comprising:
 determining that a subject has or is at risk of developing an addiction; and   administering to the subject an amount of an inhibitor of a phosphodiesterase 7 (PDE7) effective for the treatment or prevention of the addiction,   wherein the inhibitor of a phosphodiesterase 7 is a compound of formula 6:   
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is substituted or unsubstituted C 3-8  alkyl group, substituted or unsubstituted cycloalkyl group, or substituted or unsubstituted heterocycloalkyl group; 
         R 2  is a hydrogen atom or substituted or unsubstituted C 1-3  alkyl group; 
         R 3  is a hydrogen atom, substituted or unsubstituted C 1-3  alkyl group, or a halogen atom; and 
         R 4  is substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or a group CONR 5 R 6 , or CO 2 R 7 , 
         wherein R 5  and R 6  are same or different and are independently selected from a hydrogen atom; C 1-6  alkyl group optionally substituted by a halogen atom, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted cycloalkyl group, a group NR 7 COR 8 , COR 8 , NR 9 R 10 ; substituted or unsubstituted cycloalkyl group; substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted aryl group; substituted or unsubstituted heteroaryl group; or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom binding R 5  and R 6 ; 
         wherein R 7  is a hydrogen atom or substituted or unsubstituted C 1-3  alkyl group; 
         wherein R 8  is substituted or unsubstituted heterocycloalkyl group, or a group OH, OR 7 , or NR 9 R 10 ; 
         wherein R 9  and R 10  are, same or different from each other, a hydrogen atom; substituted or unsubstituted C 1-3  alkyl group, substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted acyl; a group SO 2 R 7 , or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom binding R 5  and R 6 . 
       
     
     
         17 . The method of  claim 15 , wherein the PDE7 inhibitory agent of formula 6 is a member selected from the group consisting of formula 6A, formula 6B, formula 6C, formula 6D, formula 6E, formula 6F, formula 6G, and formula 6H: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 16 , wherein the PDE7 inhibitory agent of formula 6 is a member selected from the group consisting of formula 6A, formula 6B, formula 6C, formula 6D, formula 6E, formula 6F, formula 6G, and formula 6H: