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 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.   
     
     
         2 . The method of  claim 1 , wherein the subject is addicted to an addictive agent. 
     
     
         3 . The method of  claim 2 , 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. 
     
     
         4 . The method of  claim 3 , wherein the addictive agent is alcohol. 
     
     
         5 . The method of  claim 3 , wherein the addictive agent is nicotine. 
     
     
         6 . The method of  claim 3 , wherein the opioid agonist is selected from the group consisting of: morphine, methadone, fentanyl, sufentanil and heroin. 
     
     
         7 . The method of  claim 3 , 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 addiction is an addictive or compulsive behavior associated with a primary impulse-control disorder or an obsessive-compulsive disorder. 
     
     
         10 . The method of  claim 9 , wherein the primary impulse-control disorder is selected from the group consisting of: binge eating, pathological gambling, pathological use of electronic devices, pathological use of electronic video games, pathological use of electronic communication devices, pathological use of cellular telephones, addiction to pornography, sex addiction, compulsive spending, anorexia, bulimia, intermittent explosive disorder, kleptomania, pyromania, trichotillomania, compulsive over-exercising, and compulsive overworking. 
     
     
         11 . The method of  claim 10 , wherein the primary impulse-control disorder is binge eating. 
     
     
         12 . 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. 
     
     
         13 . 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. 
     
     
         14 . The method of  claim 1 , 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. 
     
     
         15 . The method of  claim 1 , wherein the PDE7 inhibitory agent is a highly 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-fiftieth 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. 
     
     
         16 . The method of  claim 1 , wherein the PDE7 inhibitory agent has a molecular weight of less than about 450 g/mole. 
     
     
         17 . The method of  claim 1 , wherein the PDE7 inhibitory agent is a member selected from the group consisting of formula 1A, formula 1B, formula 29, formula 30, formula 31, formula 32, formula 33, formula 34, formula 35, formula 36, formula 37, formula 38, formula 39, formula 40, formula 41, formula 42, formula 43A, formula 43B, formula 44, formula 45, formula 46, formula 47, formula 48, formula 49, formula 50, formula 51, formula 52, formula 53, formula 54, formula 6A, formula 6B, formula 6C, formula 6D, formula 6E, formula 6F, formula 6G, formula 6H, formula 16A, compound 1, compound 2, compound 3, and compound 4. 
     
     
         18 . The method of  claim 1 , wherein the PDE7 inhibitory agent is able to cross the blood/brain barrier. 
     
     
         19 . The method of  claim 1 , further comprising administering an additional therapeutic agent with the PDE7 inhibitor, wherein each of the PDE7 inhibitor and the additional therapeutic agent contribute to the effective treatment or prevention of the addiction. 
     
     
         20 . The method of  claim 19 , 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. 
     
     
         21 . The method of  claim 20 , wherein the opioid antagonist is naltrexone or nalmefene. 
     
     
         22 . The method of  claim 20 , wherein the antidepressant is fluoxetine, mirtazapine, or bupropion. 
     
     
         23 . The method of  claim 20 , wherein the antiepileptic is selected from the group consisting of: topiramate, levetiracetam, and gabapentin. 
     
     
         24 . The method of  claim 20 , wherein the CRF-1 receptor antagonist is antalarmin. 
     
     
         25 . The method of  claim 20 , wherein the selective serotonin-3 (5-HT3) antagonist is ondansetron. 
     
     
         26 . The method of  claim 20 , wherein the cannabinoid-1 (CB1) receptor antagonist is rimonabant or tanarabant. 
     
     
         27 . The method of  claim 20 , wherein the mixed opioid agonist/antagonist is buprenorphine. 
     
     
         28 . The method of  claim 19 , wherein the additional therapeutic agent is topiramate. 
     
     
         29 . 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. 
     
     
         30 . The method of  claim 29 , 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 prevention of the relapse use or practice. 
     
     
         31 . The method of  claim 29 , wherein the subject previously reduced or eliminated use of the addictive agent or practice of the addictive or compulsive behavior associated with a primary impulse-control disorder or an obsessive-compulsive disorder in response to treatment with an effective amount of an anti-addiction treatment, and wherein the subject is no longer exposed to an effective amount of the anti-addiction treatment. 
     
     
         32 . The method of  claim 29 , wherein the method treats or prevents relapse use of an addictive agent. 
     
     
         33 . The method of  claim 29 , wherein the methods treats or prevents relapse practice of an addictive behavior or compulsion. 
     
     
         34 . A method of preventing a subject from becoming addicted, or reducing the likelihood that a subject will become addicted, to an addictive therapeutic agent, comprising providing to a subject in need thereof an addictive therapeutic agent and an effective amount of an inhibitor of a phosphodiesterase 7 (PDE7), wherein the effective amount of the pde7 inhibitor is an amount effective in preventing the subject from becoming addicted, or reducing the likelihood that the subject will become addicted, to the addictive therapeutic agent. 
     
     
         35 . The method of  claim 34 , further comprising providing to the subject an additional therapeutic agent, wherein each of the PDE7 inhibitor and the additional therapeutic agent contribute to preventing the subject from becoming addicted, or reducing the likelihood that the subject will become addicted, to the addictive therapeutic agent. 
     
     
         36 . The method of  claim 34 , wherein the addictive therapeutic agent is an opioid agonist. 
     
     
         37 . The method of  claim 36 , wherein the opioid agonist is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, benzylmorphine, beta-hydroxy 3-methylfentanyl, bezitramide, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, desomorphine, destropropoxyphene, dextromoramide, dezocine, diacetylmorphine (heroin), diamorphine, diampromide, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, LMM, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptizinol, metapon, metazocine, methadone, methadyl acetate, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, noscapine, opium, oxycodone, oxymorphone, papaverine, pentazocine, phenadoxone, phenomorphan, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, remifentanil, sufentanil, thebaine, tildine, or tramadol, or any combination thereof. 
     
     
         38 . The method of  claim 34 , wherein the PDE7 inhibitor is a member selected from the group consisting of formula 1A, formula 1B, formula 29, formula 30, formula 31, formula 32, formula 33, formula 34, formula 35, formula 36, formula 37, formula 38, formula 39, formula 40, formula 41, formula 42, formula 43A, formula 43B, formula 44, formula 45, formula 46, formula 47, formula 48, formula 49, formula 50, formula 51, formula 52, formula 53, formula 54, formula 6A, formula 6B, formula 6C, formula 6D, formula 6E, formula 6F, formula 6G, formula 6H, formula 16A, compound 1, compound 2, compound 3, and compound 4. 
     
     
         39 . The method of  claim 38 , wherein the addictive therapeutic agent is oxycodone or hydrocodone. 
     
     
         40 . A pharmaceutical composition, comprising an inhibitor of a phosphodiesterase 7 (PDE7) and an additional therapeutic agent, wherein each of the PDE7 inhibitor and the additional therapeutic agent contribute to the effective treatment or prevention of an addiction. 
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein the 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. 
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein the opioid antagonist is naltrexone or nalmefene. 
     
     
         43 . The pharmaceutical composition of  claim 41 , wherein the antidepressant is fluoxetine, mirtazapine, or bupropion. 
     
     
         44 . The pharmaceutical composition of  claim 41 , wherein the antiepileptic is selected from the group consisting of: topiramate, levetiracetam, and gabapentin. 
     
     
         45 . The pharmaceutical composition of  claim 41 , wherein the CRF-1 receptor antagonist is antalarmin. 
     
     
         46 . The pharmaceutical composition of  claim 41 , wherein the selective serotonin-3 (5-HT3) antagonist is ondansetron. 
     
     
         47 . The pharmaceutical composition of  claim 41 , wherein the cannabinoid-1 (CB1) receptor antagonist is rimonabant or tanarabant. 
     
     
         48 . The pharmaceutical composition of  claim 41 , wherein the mixed opioid agonist/antagonist is buprenorphine. 
     
     
         49 . The pharmaceutical composition of  claim 40 , wherein the additional therapeutic agent is topiramate. 
     
     
         50 . The pharmaceutical composition of  claim 40 , wherein the PDE7 inhibitory agent is a member selected from the group consisting of formula 1A, formula 1B, formula 29, formula 30, formula 31, formula 32, formula 33, formula 34, formula 35, formula 36, formula 37, formula 38, formula 39, formula 40, formula 41, formula 42, formula 43A, formula 43B, formula 44, formula 45, formula 46, formula 47, formula 48, formula 49, formula 50, formula 51, formula 52, formula 53, formula 54, formula 6A, formula 6B, formula 6C, formula 6D, formula 6E, formula 6F, formula 6G, formula 6H, formula 16A, compound 1, compound 2, compound 3, and compound 4. 
     
     
         51 . A unit dosage form of a pharmaceutical composition adapted for the treatment of alcohol addiction, wherein said unit dosage form comprises an inhibitor of a phosphodiesterase 7 (PDE7) and an additional therapeutic agent, wherein said unit dosage form comprises the PDE7 inhibitor and the additional therapeutic agent in a combined amount effective in the treatment of an addiction, and wherein each of the PDE7 inhibitor and the additional therapeutic agent contribute to the effective treatment or prevention of the addiction. 
     
     
         52 . The unit dosage form of  claim 51 , wherein the 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. 
     
     
         53 . The unit dosage form of claim C 1 , wherein the PDE7 inhibitory agent is a member selected from the group consisting of formula 1A, formula 1B, formula 29, formula 30, formula 31, formula 32, formula 33, formula 34, formula 35, formula 36, formula 37, formula 38, formula 39, formula 40, formula 41, formula 42, formula 43A, formula 43B, formula 44, formula 45, formula 46, formula 47, formula 48, formula 49, formula 50, formula 51, formula 52, formula 53, formula 54, formula 6A, formula 6B, formula 6C, formula 6D, formula 6E, formula 6F, formula 6G, formula 6H, formula 16A, compound 1, compound 2, compound 3, and compound 4. 
     
     
         54 . A kit useful for the treatment or prevention of an addiction, comprising: a first container comprising an inhibitor of a phosphodiesterase 7 (PDE7); and a second container comprising an additional therapeutic agent, wherein each of the PDE7 inhibitor and the additional therapeutic agent contribute to the effective treatment or prevention of an addiction. 
     
     
         55 . The kit of  claim 54 , wherein the 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. 
     
     
         56 . The kit of  claim 54 , wherein the PDE7 inhibitory agent is a member selected from the group consisting of formula 1A, formula 1B, formula 29, formula 30, formula 31, formula 32, formula 33, formula 34, formula 35, formula 36, formula 37, formula 38, formula 39, formula 40, formula 41, formula 42, formula 43A, formula 43B, formula 44, formula 45, formula 46, formula 47, formula 48, formula 49, formula 50, formula 51, formula 52, formula 53, formula 54, formula 6A, formula 6B, formula 6C, formula 6D, formula 6E, formula 6F, formula 6G, formula 6H, formula 16A, compound 1, compound 2, compound 3, and compound 4.