Treatment of addiction and impulse-control disorders using PDE7 inhibitors

Abstract

To provide a treatment of addictions and primary impulse-control disorders using PDE7 inhibitors.SOLUTION: 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. The present invention provides a method of treating or preventing an addiction by determining that a subject has an addiction or is at risk of developing an addiction and then administering an inhibitor of a phosphodiesterase 7 (PDE7) effective to the subject for the treatment or prevention of the addiction. In one aspect of the invention, the subject is addicted to an addictive agent.SELECTED DRAWING: Figure 15

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of application Ser. No. 61 / 411,431, filed Nov. 8, 2010, application Ser. No. 61 / 411,437, filed Nov. 8, 2010, and U.S. Provisional Patent Application Ser. No. 61 / 482,994, filed May 5, 2011, the disclosures of which are incorporated herein by reference in their entireties.

[0002] I. FIELD OF THE INVENTION The present disclosure relates to the prevention and treatment of substance and behavioral addictions using phosphodiesterase 7 (PDE7) inhibitors, alone or in combination with other therapeutic or addictive agents. [Background technology]

[0003] II. Background of the Invention The World Health Organization (WHO) defines substance addiction as the repeated use of a substance despite the knowledge and occurrence of harmful effects.Substance addiction is a chronic and relapsing disease characterized by the loss of control over excessive drug use, compulsive drug craving and substance craving, continued use despite negative effects, and physical and / or psychological dependence on the substance.Substance addiction typically follows the course of tolerance, withdrawal, compulsive drug-taking behavior, drug-seeking behavior, the performance of addictive behavior, and relapse.Excessive substance use and addiction are public health problems that have a significant social and economic impact on both addiction and society, by contributing significantly to violent crime and the spread of infectious diseases. Addictive substances include alcohol, caffeine, nicotine, cannabis (marijuana) and cannabis derivatives, opium and other morphine-like opioid agonists (such as heroin, phencyclidine and phencyclidine-like compounds), hypnotics-sedatives (such as benzodiazepines and barbiturates), and psychostimulants (such as cocaine, amphetamines and amphetamine-related drugs, e.g., dextroamphetamine and methylamphetamine).

[0004] Alcohol is one of the most commonly consumed substances in excess worldwide. Furthermore, alcoholism can lead to serious liver and cardiovascular disease, and dependence can result in severe mental disorders, social problems, and adverse outcomes, such as family breakdown, tragic accidents, and impaired work performance. According to the WHO, alcohol consumption accounts for 20-30% of esophageal and liver cancers, cirrhosis, homicides, epilepsy, and motor vehicle accidents worldwide. Approximately 1.8 million people die each year from excessive alcohol consumption worldwide. Compulsive behavior toward alcohol consumption is a core symptom of the disorder. In recent years, several approaches have been explored to control not only alcohol consumption but also alcohol craving and relapse in order to help patients with alcoholism (Non-Patent Document 1; Non-Patent Document 2; and Non-Patent Document 3).

[0005] Medications such as naltrexone, acamprosate, ondansetron, disulfiram, gamma-hydroxybutyric acid (GHB), and topiramate have been tested for their potential therapeutic effects on excessive alcohol consumption and belong to several categories (Non-Patent Document 2; Non-Patent Document 3). Some of these medications, such as naltrexone, acamprosate, and disulfiram, have proven useful and are approved for the treatment of alcoholism. Among these medications, naltrexone, a non-selective opioid antagonist, is currently considered the best pharmacological option. However, despite some promising results, the efficacy of all of these medications, including naltrexone, in alcoholism remains insufficient, and the prognosis remains poor.

[0006] Nicotine is also one of the most widely used addictive drugs, and excessive nicotine intake is the most common form of substance abuse. The WHO estimates that there are 1.25 billion smokers worldwide, representing one-third of the world's population over the age of 15. Furthermore, the WHO estimates that five million deaths occur each year directly attributable to smoking, making excessive nicotine intake the single largest preventable cause of death worldwide. In developed countries, nicotine addiction is responsible for 70–90% of lung cancer cases, 56–80% of chronic respiratory disease cases, and 22% of cardiovascular disease cases. In the United States alone, smoking is associated with 430,000 deaths annually, costing the nation an estimated $80 billion in annual health care costs. Smoking contributes to one-third of all cancers (e.g., cancers of the lung, mouth, pharynx, larynx, esophagus, neck, kidney, ureter, and bladder). Overall cancer mortality is twice as high in smokers as in nonsmokers. Smoking also causes lung diseases such as chronic bronchitis and emphysema; worsens asthma symptoms; and increases the risk of heart disease (e.g., stroke, heart attack, vascular disease, and aneurysms). An estimated 20% of deaths from heart disease are attributable to smoking. Pregnant women who smoke are at greater risk than nonsmokers of premature birth, spontaneous abortion, and low birth weight.

[0007] Nicotine use leads to increased levels of the neurotransmitter dopamine, which regulates feelings of pleasure and activates reward pathways that mediate the desire to consume nicotine. Symptoms associated with nicotine withdrawal include craving, irritability, anger, hostility, aggression, fatigue, depression, and cognitive impairment, which lead to a desire for further excessive nicotine intake. Environmental conditioning factors and exposure to psychological stress are additional factors that stimulate nicotine use in smokers. Repeated nicotine use leads to the development of tolerance, requiring higher doses of nicotine to achieve the same initial stimulation.

[0008] Most of the medications developed for nicotine addiction have shown only moderate success in preventing relapse and are associated with high failure rates in attempts to quit. Treatments include the use of nicotine replacement products, antidepressants, anti-hypersensitives, and behavioral therapy.

[0009] The National Institute on Drug Abuse estimates that 72 million Americans, or approximately one-third of the population, have tried marijuana. Acute effects of marijuana use include memory and learning problems, distorted perception, problem-solving difficulties, impaired coordination, and increased heart rate. Long-term, excessive use can cause the same respiratory problems observed in smokers, such as daily coughing, phlegm production, increased risk of lung infections, and increased likelihood of developing head, neck, and lung cancer. Depression, anxiety, and work-related problems are also associated with marijuana use. Long-term marijuana use can lead to addiction, with compulsive use interfering with daily activities. Cravings and withdrawal symptoms, such as irritability, increased aggression, insomnia, and anxiety, make it difficult for addicts to stop using marijuana. No pharmaceutical treatments are available to treat marijuana addiction and relapse.

[0010] According to the WHO, an estimated 13 million people worldwide overdose on opioids, including 9 million heroin addicts. More than 25% of opioid overdosers die within 10 to 20 years of becoming addicted, often through suicide, homicide, or infectious diseases (e.g., HIV and hepatitis). Tolerance and physical dependence can develop within 2 to 3 days. While overdose and addiction to opioid drugs are known phenomena, the problem has worsened in recent years (Non-Patent Documents 4 and 5). A 2003 epidemiological survey of U.S. youth indicated that opioid analgesics were the most commonly overused illicit drug among middle and high school students (12th graders), second only to marijuana (Non-Patent Document 6). Furthermore, the United States has seen a significant increase in opioid medication use over the past few years, further increasing the problems associated with such use. This surge in use and problems is of particular concern because it appears to be escalating down the path to opioid addiction (7).

[0011] Recent epidemiological data indicate that in 2002, 4.7% of U.S. residents aged 12 years or older (i.e., 11 million people) overdosed on opioid medications, and 13.7% of these people (i.e., 1.5 million people) met criteria for DSM-IV opioid use disorder (Non-Patent Document 8; Non-Patent Document 9). As recently reviewed by Compton and Volkow, the annual incidence of opioid analgesic overdose increased from 628,000 new cases in 1990 to 2.4 million in 2001 (Non-Patent Document 10; Non-Patent Document 11). One factor driving the spread of opioid addiction is the increasing use of prescription analgesics as adjuncts. Short-term use of opioid medications is rarely associated with addiction. Conversely, long-term use of these drugs is associated with the development of addiction in up to 18% of patients.

[0012] The goal of treatment for opiate addiction, as with other types of substance addiction, is to discontinue opioid use, minimize painful withdrawal symptoms, and prevent relapse. Current treatment involves replacing the addictive drug with an opioid receptor agonist or mixed agonist / antagonist substitute. An alternative approach consists of using opioid receptor antagonists, which block the effects of the agonist. Antagonists do not relieve pain or other withdrawal symptoms; in fact, they may accelerate withdrawal symptoms, and their therapeutic use has been associated with increased accidental overdose and mortality of opioid agonists. The use of agonists with lower affinity for the receptor rarely results in severe withdrawal symptoms but can lead to dependence on the substitute opiate. Furthermore, most substitution treatments are taken for 3 to 6 months, allowing addicts to discontinue treatment.

[0013] Psychostimulants such as cocaine and amphetamines induce temporary euphoria, increased alertness, and enhanced physical performance in humans. Although these substances initially increase dopamine transmission, prolonged drug use leads to decreased dopamine activity, leading to dysregulation of the brain's reward system and dysphoria. The WHO estimates that 33 million people worldwide consume amphetamines excessively.

[0014] Chronic excessive cocaine use can result in hyperstimulation, tachycardia, hypertension, dilated pupils, muscle spasms, insomnia, extreme nervousness, hallucinations, paranoia, aggression, and depression. Cocaine overdose can result in tremors, convulsions, delirium, and death due to cardiac arrhythmias and cardiovascular failure. Desipramine, amantadine, and bromocriptine have been shown to reduce cocaine withdrawal symptoms.

[0015] Symptoms of amphetamine withdrawal include EEG changes, fatigue, and mental depression. Tolerance develops over time and can be associated with prolonged depression accompanied by tachycardia, auditory and visual hallucinations, delusions, anxiety reactions, paranoid psychosis, exhaustion, confusion, memory loss, and suicidal tendencies. Current treatments for amphetamine addiction include phenothiazines, haloperidol, and chlorpromazine (for hallucinations); however, potential side effects of these drugs include postural hypotension and severe extrapyramidal movement disorders. Subjects addicted to psychostimulants may experience psychological and physiological withdrawal, increasing the likelihood of relapse.

[0016] Although treatment for substance addiction has traditionally focused on behavioral therapy, it is difficult to break dependence on many of these highly addictive substances. Addiction to alcohol, cocaine, and heroin, in particular, is considered a chronic, relapsing disorder. Concurrent excessive use of multiple substances, including nicotine, heroin, cocaine, and alcohol, is also common.

[0017] The long-lasting, chronic nature of many addictions and the high rates of recidivism present significant challenges in the treatment of drug and alcohol addiction, and as such, understanding the neurobiological basis of relapse has emerged as a central issue in addiction research. Among these, emotional and environmental factors (conditioned stimuli) have been identified as major causes of relapse. For example, it has been found that certain stressful conditions (e.g., unemployment and financial difficulties) or cues that predict the presence of alcohol associated with previous use (e.g., a bottle of favorite wine and a bar-like environment) can strongly promote relapse in recovered alcoholics.

[0018] There are two major theoretical hypotheses that explain the persistence of addictive behaviors and relapse-proneness associated with drug and alcohol addiction: the homeostasis hypothesis and the conditioning hypothesis.

[0019] The homeostasis hypothesis links the risk of relapse to neuroadaptive changes and disruptions in neuroendocrine homeostasis, which are believed to be responsible for the anxiety, mood dysregulation, and physical symptoms that accompany acute withdrawal and can persist for a considerable period of time, referred to as the "prolonged withdrawal" phase. This view therefore suggests relief from discomfort and negative affect as a motivational basis for relapse.

[0020] The conditioning hypothesis is based on the observation that relapse is often associated with exposure to drug-associated environmental cues. This view holds that certain environmental cues that have become associated with the rewarding effects of drugs through classical conditioning can induce subjective states that are conducive to resumption of drug use. The homeostatic and conditioning hypotheses are not mutually exclusive. In fact, there appears to be an additive effect of homeostatic and conditioning factors, in that the susceptibility to relapse brought about by homeostatic disruption can be increased by exposure to drug-associated environmental cues.

[0021] Clearly, there is a need in the art for new methods for treating and preventing addiction and relapse use of addictive drugs. The present invention fulfills this need by providing methods and pharmaceutical combinations useful for treating and preventing addiction and recidivism. [Prior art documents] [Non-patent literature]

[0022] [Non-Patent Document 1] Monti et al., J Stud Alcohol 54:235-45 (1993) [Non-patent document 2] Volpicelli et al., Arch Gen Psychiatry 49:876-880 (1992) [Non-patent document 3] O'Brien Science 278:66-70(1997) [Non-patent document 4] Compton and Volkow, Drug Alcohol Depend 83 Suppl 1:S4-7 (2006A) [Non-patent document 5] Compton and Volkow, Drug Alcohol Depend 81(2):103-7 (2006B) [Non-patent document 6] Delva et al., Am J Public Health 95(4):696-702 (2005) [Non-Patent Document 7] Siegal et al., Am Fam Physician 67:942-945 (2003) [Non-patent document 8] American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th edition (1994) [Non-Patent Document 9] Substance Abuse and Mental Health Services Administration, Mortality Data from the Drug Abuse Warning Network, 2002, (2004) [Non-Patent Document 10] Substance Abuse and Mental Health Services Administration,Overview of Findings from the 2002 National Survey on Drug Use and Health,(2003) [Non-Patent Document 11] Substance Abuse and Mental Health Services Administration,Emergency Department Trends From the Drug Abuse Warning Network,Final Estimates 1995-2002,(2003) Summary of the Invention [Means for solving the problem]

[0023] III. Summary of the Invention The present invention provides methods for treating or preventing an addiction by determining that a subject has or is at risk of developing an addiction and then administering to the subject a phosphodiesterase 7 (PDE7) inhibitor effective to treat or prevent the addiction.

[0024] In one aspect of the present invention, the subject is addicted to an addictive drug. Examples of addictive drugs include alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates, and psychostimulants. In one embodiment, the addictive drug is alcohol. In another embodiment, the addictive drug is nicotine. In a further embodiment, the addictive drug is an opioid, such as morphine, methadone, fentanyl, sufentanil, codeine, oxycodeine, and heroin. In a further embodiment, the addictive drug is a psychostimulant, such as cocaine, amphetamine, or an amphetamine derivative. In another embodiment, the addictive drug is cocaine.

[0025] In one aspect of the present invention, the subject is addicted to addictive or compulsive sexual behaviors or suffers from an impulse control disorder.In another aspect of the present invention, the subject is suffering from a primary impulse control disorder, i.e., an impulse control disorder that is a primary disorder that is not iatrogenic (secondary to medical treatment) or secondary to another primary disease or disorder.Addictive or compulsive sexual behaviors that are primary impulse control disorders include the following: overeating, pathological gambling, pathological use of electronic devices, pathological use of video games, pathological use of electronic communication devices, pathological use of mobile phones, pornography addiction, sex addiction, compulsive consumption behavior, anorexia, bulimia, intermittent explosive disorder, kleptomania, pyromania, trichotillomania, compulsive hyperexertion, and compulsive overwork.In another embodiment, the addictive or compulsive sexual behavior is overeating.In another aspect of the present invention, the addictive or compulsive disorder is obsessive-compulsive disorder.

[0026] In one embodiment of the present invention, the PDE7 inhibitor for the treatment of addiction is selected from the following disclosed herein: 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.

[0027] In one embodiment of the invention, the PDE7 inhibitor has an IC of less than about 1 μM with respect to inhibiting PDE7A and / or PDE7B activity. 50 In one embodiment, the PDE7 inhibitor has an IC of less than about 100 nM with respect to inhibiting PDE7A and / or PDE7B activity. 50 In another embodiment, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE1B activity greater than 5 times the smaller of 50 In another embodiment, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE10 activity greater than 5 times the smaller of 50 In a further embodiment, the PDE7 inhibitor has an IC 50 and / or IC for inhibition of PDE7B activity 50 IC for inhibition of PDE3 activity greater than 10 times the smaller of 50 In another embodiment, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE3 and PDE4 activity greater than 10 times the smaller of 50 In a further embodiment, the PDE7 inhibitor has an IC 50and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE4 and PDE8 activity greater than 10 times the smaller of 50 In another embodiment, the PDE7 agent has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE1, PDE2, PDE3, PDE4, PDE8, PDE10, and PDE11 activity greater than 10 times the smaller of 50 In a further embodiment, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 The smaller of these is the IC that the agent has with respect to inhibiting the activity of any other PDE enzyme from the PDE1-6 and PDE8-11 enzyme families. 50 In another embodiment, the PDE7 inhibitor is a selective PDE7 inhibitor having an IC50 or IC60 for inhibiting PDE7A activity that is at least 10-fold lower than that of the PDE7A inhibitor. 50 and IC for inhibition of PDE7B activity 50 The smaller of these is the IC that the agent has with respect to inhibiting the activity of any other PDE enzyme from the PDE1-6 and PDE8-11 enzyme families. 50 In a further embodiment, the PDE7 inhibitor has a molecular weight of less than about 450 g / mol. In another embodiment, the PDE7 inhibitor is capable of crossing the blood-brain barrier.

[0028] The present invention provides a method for treating or preventing addiction by determining that a subject has an addiction or is at risk of developing an addiction, and then administering a chemical compound that inhibits PDE7 activity.The chemical compound has the following characteristics: (i) an IC50 of less than about 1 μM for inhibiting PDE7A and / or PDE7B activity; 50 and (ii) IC for inhibition of PDE7A activity 50 and / or IC for inhibition of PDE7B activity 50 IC for inhibition of PDE3 greater than 10 times the smaller of 50 It has the following characteristics.

[0029] In one embodiment, the chemical compound has an IC of less than about 100 nM with respect to inhibiting PDE7A and / or PDE7B activity. 50 In another embodiment, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE1B activity greater than 5 times the smaller of 50 In another embodiment, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE10 activity greater than 5 times the smaller of 50 In another embodiment, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE4 activity greater than 10 times the smaller of 50 In a further embodiment, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE8 activity greater than 10 times the smaller of 50 In another embodiment, the PDE7 agent has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE1, PDE2, PDE3, PDE4, PDE8, PDE10, and PDE11 activity greater than 10 times the smaller of 50 In a further embodiment, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 The smaller of these is the IC that the agent has with respect to inhibiting the activity of any other PDE enzyme from the PDE1-6 and PDE8-11 enzyme families. 50 In another embodiment, the PDE7 inhibitor is a selective PDE7 inhibitor having an IC50 or IC60 for inhibiting PDE7A activity that is at least 10-fold lower than that of the PDE7A inhibitor. 50and IC for inhibition of PDE7B activity 50 The smaller of these is the IC that the agent has with respect to inhibiting the activity of any other PDE enzyme from the PDE1-6 and PDE8-11 enzyme families. 50 In a further embodiment, the PDE7 inhibitor has a molecular weight of less than about 450 g / mol. In another embodiment, the PDE7 inhibitor is capable of crossing the blood-brain barrier.

[0030] In one aspect of the present invention, the subject is addicted to an addictive drug. Examples of addictive drugs include alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates, and psychostimulants. In one embodiment, the addictive drug is alcohol. In another embodiment, the addictive drug is nicotine. In a further embodiment, the addictive drug is an opioid, such as morphine, methadone, fentanyl, sufentanil, and heroin. In a further embodiment, the addictive drug is a psychostimulant, such as cocaine, amphetamine, or an amphetamine derivative. In another embodiment, the addictive drug is cocaine.

[0031] In one aspect of the present invention, the subject is addicted to addictive or compulsive sexual behaviors or suffers from an impulse control disorder. In another aspect of the present invention, the subject suffers from a primary impulse control disorder, i.e., an impulse control disorder that is a primary disorder that is not iatrogenic (secondary to a medical treatment) or secondary to another primary disease or disorder. Addictive or compulsive sexual behaviors that are primary impulse control disorders include the following: overeating, pathological gambling, pathological use of electronic devices, pathological use of video games, pathological use of electronic communication devices, pathological use of mobile phones, pornography addiction, sex addiction, compulsive consumption behavior, anorexia, bulimia, intermittent explosive disorder, kleptomania, pyromania, trichotillomania, compulsive hyperactivity, and compulsive overwork. In another embodiment, the addictive or compulsive sexual behavior is overeating. In another aspect of the present invention, the subject treated according to the present invention has obsessive-compulsive disorder.

[0032] The present invention also provides a method for treating or preventing addiction in a subject, comprising administering a phosphodiesterase 7 (PDE7) inhibitor and an additional therapeutic agent to the subject, wherein the PDE7 inhibitor and the additional therapeutic agent each contribute to the effective treatment or prevention of addiction. Examples of the additional therapeutic agent include 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.

[0033] Exemplary opioid antagonists include naltrexone and nalmefene. Exemplary antidepressants include fluoxetine, mirtazapine, and bupropion. Exemplary antiepileptic drugs include topiramate, levetiracetam, and gabapentin. Antalarmin is an exemplary CRF-1 receptor antagonist. Ondansetron is an exemplary selective serotonin-3 (5-HT3) antagonist. Exemplary cannabinoid-1 (CB1) receptor antagonists are rimonabant and taranabant. Buprenorphine is an exemplary mixed opioid agonist / antagonist. Exemplary opioid agonists include morphine, methadone, fentanyl, sufentanil, and heroin.

[0034] In one aspect, the subject is addicted to addictive drugs, such as alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates and psychostimulants.In one embodiment, the addictive drug is alcohol, and the additional therapeutic drug is an opioid antagonist (such as naltrexone) or a mixed opioid antagonist / partial agonist (such as buprenorphine).In another embodiment, the subject is addicted to psychostimulants (such as cocaine, amphetamine, amphetamine derivatives or methamphetamine), and the additional therapeutic drug is an antidepressant (such as bupropion).In a further embodiment, the subject is addicted to nicotine, and the additional therapeutic drug is an antidepressant (such as bupropion).

[0035] In another aspect, the subject is addicted to addictive or compulsive behaviors (such as primary impulse control disorders), for example, pathological gambling, overeating, pathological use of electronic devices, pathological use of video games, pathological use of electronic communication devices, pathological use of mobile phones, pornography addiction, sex addiction, compulsive consumption behavior, anorexia, bulimia, intermittent explosive disorder, kleptomania, pyromania, trichotillomania, compulsive hyperexercise and compulsive overwork etc. In one embodiment, the addictive or compulsive behavior is overeating, and the additional therapeutic agent is topiramate.In another aspect of the present invention, the subject treated according to the present invention has obsessive-compulsive disorder.

[0036] The present invention provides a method for preventing the relapse of addictive drug use or the execution of addictive or compulsive sexual behaviors by administering PDE7 inhibitor to the subject who is in a state of abstinence from addictive drugs or addictive or compulsive sexual behaviors or the period of their use being limited or reduced.The present invention also provides a method for preventing the relapse of addictive or compulsive sexual behaviors associated with primary impulse control disorder by administering PDE7 inhibitor to the subject who is in a state of remission from addictive or compulsive sexual behaviors associated with primary impulse control disorder or the execution of these behaviors being limited or reduced.The present invention also provides a method for preventing the relapse of addictive or compulsive sexual behaviors associated with primary impulse control disorder by administering PDE7 inhibitor to the subject who is in a state of remission from addictive or compulsive sexual behaviors associated with obsessive-compulsive disorder or the execution of these behaviors being limited or reduced. Additional therapeutic agents that contribute to the prevention of relapse may be administered in conjunction with PDE7 inhibitors, and may be administered to subjects who have previously been treated with, but are no longer using, a different anti-addiction treatment.

[0037] In one embodiment, the administration of PDE7 inhibitors prevents the relapse of addictive drugs such as alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates and psychostimulants.In a preferred embodiment, the relapse of cocaine, amphetamine or methamphetamine is prevented.

[0038] In another embodiment, the recurrence of addictive or compulsive behaviors, particularly the addictive or compulsive behaviors associated with primary impulse control disorder, is prevented by administering PDE7 inhibitor.In a preferred embodiment, the recurrence of the following behaviors is prevented: overeating, pathological gambling, pathological use of electronic devices, pathological use of video electronic games, pathological use of electronic communication devices, pathological use of mobile phone, pornography addiction, sex addiction, compulsive consumption behavior, anorexia, bulimia, intermittent explosive disorder, kleptomania, pyromania, trichotillomania, compulsive hyperexercise and compulsive fatigue.In one embodiment, addictive or compulsive behavior is stress-induced overeating.In another embodiment, subject is treated to prevent the recurrence of addictive or compulsive behaviors associated with obsessive-compulsive disorder.

[0039] The present invention provides pharmaceutical compositions comprising a PDE7 inhibitor and an additional therapeutic agent, wherein the PDE7 inhibitor and the additional therapeutic agent contribute to the effective treatment or prevention of addiction. Also provided are dosage units of the pharmaceutical compositions.

[0040] In one aspect of the present invention, the subject is addicted to an addictive drug. Examples of addictive drugs include alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates, cocaine, and other psychostimulants. In one embodiment, the addictive drug is alcohol. In another embodiment, the addictive drug is nicotine. In a further embodiment, the addictive drug is an opioid, such as morphine, methadone, fentanyl, sufentanil, and heroin. In a further embodiment, the addictive drug is a psychostimulant, such as cocaine, amphetamine, or an amphetamine derivative. In a preferred embodiment, the addictive drug is cocaine.

[0041] In one aspect of the present invention, the subject is addicted to addictive or compulsive sexual behaviors or suffers from an impulse control disorder. In another aspect of the present invention, the subject suffers from a primary impulse control disorder, i.e., an impulse control disorder that is a primary disorder that is not iatrogenic (secondary to a medical treatment) or secondary to another primary disease or disorder. Addictive or compulsive sexual behaviors that are primary impulse control disorders include the following: overeating, pathological gambling, pathological use of electronic devices, pathological use of video games, pathological use of electronic communication devices, pathological use of mobile phones, pornography addiction, sex addiction, compulsive consumption behavior, anorexia, bulimia, intermittent explosive disorder, kleptomania, pyromania, trichotillomania, compulsive hyperactivity, and compulsive overwork. In a preferred embodiment, the addictive or compulsive sexual behavior is overeating. In another aspect of the present invention, the subject treated according to the present invention has obsessive-compulsive disorder.

[0042] In one embodiment, the additional therapeutic agent of the pharmaceutical composition is an opioid antagonist, a mixed opioid partial agonist / antagonist, an antidepressant, an antiepileptic, an antiemetic, a corticotropin-releasing factor-1 (CRF-1) receptor antagonist, a selective serotonin-3 (5-HT3) antagonist, a 5-HT2A / 2C antagonist, or a cannabinoid-1 (CB1) receptor antagonist.

[0043] Exemplary opioid antagonists include naltrexone or nalmefene. Exemplary antidepressants include fluoxetine, mirtazapine, or bupropion. Exemplary antiepileptic drugs include topiramate, levetiracetam, and gabapentin. Antalarmin is an exemplary CRF-1 receptor antagonist. Ondansetron is an exemplary selective serotonin-3 (5-HT3) antagonist. Exemplary cannabinoid-1 (CB1) receptor antagonists are rimonabant and tanaraban. Buprenorphine is an exemplary mixed opioid agonist / antagonist.

[0044] In one aspect, the subject is addicted to addictive drugs, such as alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates, and psychostimulants. In one embodiment, the addictive drug is alcohol, and the additional therapeutic drug is an opioid antagonist (such as naltrexone) or a mixed opioid antagonist / partial agonist (such as buprenorphine). In another embodiment, the addictive drug is nicotine, and the additional therapeutic drug is varenicline. In another embodiment, the subject is addicted to psychostimulants (such as cocaine, amphetamine, amphetamine derivatives, or methamphetamine), and the additional therapeutic drug is an antidepressant (such as bupropion). In a further embodiment, the subject is addicted to nicotine, and the additional therapeutic drug is an antidepressant (such as bupropion). In another embodiment, the subject is addicted to more than one addictive drug and the additional therapeutic agent is an opioid antagonist (such as naltrexone) or a mixed opioid antagonist / partial agonist (such as buprenorphine).

[0045] The present invention provides a kit for treating or preventing addiction. The kit comprises a first container containing a PDE7 inhibitor and a second container containing an additional therapeutic agent. Both the PDE7 inhibitor and the additional therapeutic agent contribute to the effective treatment or prevention of addiction.

[0046] In one embodiment, the additional therapeutic agent of the pharmaceutical composition is an opioid antagonist, a mixed opioid partial agonist / antagonist, an antidepressant, an antiepileptic, an antiemetic, a corticotropin-releasing factor-1 (CRF-1) receptor antagonist, a selective serotonin-3 (5-HT3) antagonist, a 5-HT2A / 2C antagonist, or a cannabinoid-1 (CB1) receptor antagonist.

[0047] Exemplary opioid antagonists include naltrexone and nalmefene. Exemplary antidepressants include fluoxetine, mirtazapine, and bupropion. Exemplary antiepileptic drugs include topiramate, levetiracetam, and gabapentin. Antalarmin is an exemplary CRF-1 receptor antagonist. Ondansetron is an exemplary selective serotonin-3 (5-HT3) antagonist. Exemplary cannabinoid-1 (CB1) receptor antagonists are rimonabant and taranabant. Buprenorphine is an exemplary mixed opioid agonist / antagonist.

[0048] In one aspect, the subject is addicted to addictive drugs, such as alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates and psychostimulants.In one embodiment, the addictive drug is alcohol, and the additional therapeutic drug is an opioid antagonist (such as naltrexone) or a mixed opioid antagonist / partial agonist (such as buprenorphine).In another embodiment, the subject is addicted to psychostimulants (such as cocaine, amphetamine, amphetamine derivatives or methamphetamine), and the additional therapeutic drug is an antidepressant (such as bupropion).In a further embodiment, the subject is addicted to nicotine, and the additional therapeutic drug is an antidepressant (such as bupropion). In another embodiment, the subject is addicted to more than one addictive drug and the additional therapeutic agent is an opioid antagonist (such as naltrexone) or a mixed opioid antagonist / partial agonist (such as buprenorphine).

[0049] In another embodiment of the present invention, the addictive substance is administered to the subject who is at risk of addiction to addictive substance in combination with PDE7 inhibitor.For example, the subject who is administered opioid agonist to relieve acute pain or chronic pain, the opioid agonist is administered to the subject who is administered opioid agonist in combination with PDE7 inhibitor, so as to bring about non-addictive or low-addictive analgesia. Examples of addictive drugs that may be administered in combination with a PDE7 inhibitor, either in a fixed-dose combination or kit, include benzodiazepines, barbiturates, and analgesics, such as alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene. Fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofenitanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, OXYCONTIN®, oxymorphone, papaveretam, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene These include sufentanil, tramadol, tilidine, salts thereof, mixtures of any of the foregoing, and mixed μ-agonist / antagonists.

[0050] In some embodiments, for any of the methods and compositions described herein, the following PDE7 inhibitors are used: 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. For example, the present invention provides the following items: (Item 1) Determining that the subject has an addiction or is at risk of developing an addiction; and administering to said subject a phosphodiesterase 7 (PDE7) inhibitor in an amount effective to treat or prevent said addiction. 10. A method of treating an addiction which is an addiction to an addictive substance or an addiction which is the performance of addictive or compulsive behaviors associated with a primary impulse control disorder or an obsessive-compulsive disorder, comprising: (Item 2) Item 10. The method of item 1, wherein the subject is addicted to an addictive drug. (Item 3) 3. The method of claim 2, wherein the subject is addicted to an addictive drug selected from the group consisting of alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates, and psychostimulants. (Item 4) 4. The method of claim 3, wherein the addictive drug is alcohol. (Item 5) Item 4. The method of item 3, wherein the addictive drug is nicotine. (Item 6) 4. The method of claim 3, wherein the opioid agonist is selected from the group consisting of morphine, methadone, fentanyl, sufentanil, and heroin. (Item 7) 4. The method of claim 3, wherein the psychostimulant is cocaine, amphetamine, or an amphetamine derivative. (Item 8) 8. The method of claim 7, wherein the psychostimulant is cocaine. (Item 9) 2. 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. (Item 10) 10. The method of item 9, wherein the primary impulse control disorder is selected from the group consisting of overeating, pathological gambling, pathological use of electronic devices, pathological use of video and electronic games, pathological use of electronic communication devices, pathological use of mobile phones, pornography addiction, sex addiction, compulsive consumption behavior, anorexia, bulimia, intermittent explosive disorder, kleptomania, pyromania, trichotillomania, compulsive hyperexertion, and compulsive overwork. (Item 11) 11. The method of claim 10, wherein the primary impulse control disorder is overeating. (Item 12) the PDE7 inhibitor has an IC of less than about 1 μM with respect to inhibiting PDE7A and / or PDE7B activity 50 Item 1. The method according to item 1, comprising: (Item 13) the PDE7 inhibitor has an IC of less than about 100 nM with respect to inhibiting PDE7A and / or PDE7B activity 50 Item 1. The method according to item 1, comprising: (Item 14) The PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 The smaller of these is the IC that the agent has with respect to inhibiting the activity of any other PDE enzyme from the PDE1-6 and PDE8-11 enzyme families. 50 2. The method of claim 1, wherein the selective PDE7 inhibitor is at least 10-fold less selective than the selective PDE7 inhibitor. (Item 15) The PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 The smaller of these is the IC that the agent has with respect to inhibiting the activity of any other PDE enzyme from the PDE1-6 and PDE8-11 enzyme families. 502. The method of claim 1, wherein the compound is a highly selective PDE7 inhibitor that is 50-fold less selective than the compound of claim 1. (Item 16) 2. The method of claim 1, wherein the PDE7 inhibitor has a molecular weight of less than about 450 g / mol. (Item 17) 2. The method of claim 1, 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. (Item 18) 2. The method of claim 1, wherein the PDE7 inhibitor is capable of crossing the blood-brain barrier. (Item 19) The method of claim 1, further comprising administering an additional therapeutic agent together with the PDE7 inhibitor, wherein the PDE7 inhibitor and the additional therapeutic agent each contribute to the effective treatment or prevention of addiction. (Item 20) 20. The method of claim 19, 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 corticotropin-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. (Item 21) 21. The method of claim 20, wherein the opioid antagonist is naltrexone or nalmefene. (Item 22) 21. The method of claim 20, wherein the antidepressant is fluoxetine, mirtazapine, or bupropion. (Item 23) 21. The method of claim 20, wherein the antiepileptic drug is selected from the group consisting of topiramate, levetiracetam and gabapentin. (Item 24) Item 25. The method according to Item 20, wherein the CRF-1 receptor antagonist is antalarmin. 21. The method of claim 20, wherein the selective serotonin-3 (5-HT3) antagonist is ondansetron. (Item 26) 21. The method of claim 20, wherein the cannabinoid-1 (CB1) receptor antagonist is rimonabant or taranabant. (Item 27) 21. The method of claim 20, wherein the mixed opioid agonist / antagonist is buprenorphine. (Item 28) 20. The method of claim 19, wherein the additional therapeutic agent is topiramate. (Item 29) A method for treating or preventing recurrent use of an addictive drug or the performance of addictive or compulsive sexual behaviors associated with a primary impulse control disorder or obsessive-compulsive disorder, comprising administering an effective amount of a phosphodiesterase 7 (PDE7) inhibitor to a subject who is in a period of abstinence from, or limited or reduced use of, the addictive drug or the performance of addictive or compulsive sexual behaviors. (Item 30) 30. The method of claim 29, further comprising administering to the subject an additional therapeutic agent, wherein the PDE7 inhibitor and the additional therapeutic agent each contribute to the effective prevention of recurrent use or practice. (Item 31) 30. The method of claim 29, wherein the subject previously reduced or eliminated use of an addictive medication or performance of an addictive or compulsive sexual behavior associated with a primary impulse control disorder or obsessive-compulsive disorder in response to treatment with an effective amount of an anti-addictive treatment, and the subject is no longer exposed to the effective amount of the anti-addictive treatment. (Item 32) 30. The method of item 29, for treating or preventing relapse use of an addictive drug. (Item 33) 30. The method of item 29, for treating or preventing recurrent performance of addictive behaviors or compulsions. (Item 34) A method for preventing a subject from becoming addicted to an addictive therapeutic drug or reducing the likelihood that a subject will become addicted, comprising administering to a subject in need of such prevention or reduction an addictive therapeutic drug and an effective amount of a phosphodiesterase 7 (PDE7) inhibitor, wherein the effective amount of the PDE7 inhibitor is an amount effective to prevent the subject from becoming addicted to the addictive therapeutic drug or to reduce the likelihood that the subject will become addicted to the addictive therapeutic drug. (Item 35) 35. The method of claim 34, further comprising administering to the subject an additional therapeutic agent, wherein the PDE7 inhibitor and the additional therapeutic agent each contribute to preventing the subject from becoming addicted to the addictive therapeutic agent or reducing the likelihood that the subject will become addicted. (Item 36) 35. The method of claim 34, wherein the addiction treatment drug is an opioid agonist. (Item 37) The opioid agonist may be alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, benzylmorphine, β-hydroxy 3-methylfentanyl, bezitramide, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, desomorphine, dextropropoxyphene, dextromoramide, dezocine, diacetylmorphine (heroin), diamorphine, diampromide, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, fentanyl, hydrocodone, hydromo 37. The method of item 36, wherein the medicament is selected from the group consisting of fluoxetine, hydroxypethidine, isomethadone, ketobemidone, LMM, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptizinol, metapon, metazocine, methadone, methadyl acetate, metopon, morphine, mirofine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, noscapine, opium, oxycodone, oxymorphone, papaverine, pentazocine, phenadoxone, phenomorphan, phenoperidine, piminodine, piritramide, propeptadine, promedol, properidine, propoxyphene, remifentanil, sufentanil, thebaine, tilidine, or tramadol, or any combination thereof. (Item 38) 35. The method of item 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. (Item 39) 39. The method of claim 38, wherein the addictive drug is oxycodone or hydrocodone. (Item 40) A pharmaceutical composition comprising a phosphodiesterase 7 (PDE7) inhibitor and an additional therapeutic agent, wherein the PDE7 inhibitor and the additional therapeutic agent each contribute to the effective treatment or prevention of an addiction. (Item 41) 41. The pharmaceutical composition of item 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 corticotropin-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. (Item 42) 42. The pharmaceutical composition of claim 41, wherein the opioid antagonist is naltrexone or nalmefene. (Item 43) 42. The pharmaceutical composition according to item 41, wherein the antidepressant is fluoxetine, mirtazapine or bupropion. (Item 44) 42. The pharmaceutical composition according to item 41, wherein the antiepileptic drug is selected from the group consisting of topiramate, levetiracetam and gabapentin. (Item 45) 42. The pharmaceutical composition of claim 41, wherein the CRF-1 receptor antagonist is antalarmin. (Item 46) 42. The pharmaceutical composition of item 41, wherein the selective serotonin-3 (5-HT3) antagonist is ondansetron. (Item 47) 42. The pharmaceutical composition of item 41, wherein the cannabinoid-1 (CB1) receptor antagonist is rimonabant or taranabant. (Item 48) 42. The pharmaceutical composition of claim 41, wherein the mixed opioid agonist / antagonist is buprenorphine. (Item 49) 41. The pharmaceutical composition of item 40, wherein the additional therapeutic agent is topiramate. (Item 50) 41. The pharmaceutical composition of claim 40, 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. (Item 51) A unit dosage form of a pharmaceutical composition adapted for the treatment of alcohol addiction, said unit dosage form comprising a phosphodiesterase 7 (PDE7) inhibitor and an additional therapeutic agent, said unit dosage form comprising the PDE7 inhibitor and the additional therapeutic agent in combined amounts effective to treat addiction, wherein the PDE7 inhibitor and the additional therapeutic agent each contribute to the effective treatment or prevention of addiction. (Item 52) 52. The unit dosage form of item 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 corticotropin-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. (Item 53) The unit dosage form of item C1, 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. (Item 54) A kit useful for treating or preventing addiction, comprising a first container containing a phosphodiesterase 7 (PDE7) inhibitor; and a second container containing an additional therapeutic agent, wherein the PDE7 inhibitor and the additional therapeutic agent each contribute to the effective treatment or prevention of addiction. (Item 55) 55. The kit of item 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 corticotropin-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. (Item 56) 55. The kit of item 54, 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. [Brief explanation of the drawings]

[0051] IV. Brief Description of the Drawings The invention will now be described in more detail, by way of example, with reference to the accompanying drawings, in which: [Figure 1] FIG. 1 shows the effect of the PDE7 inhibitor OMS182056 on cocaine self-administration by rats. [Figure 2] FIG. 2 shows the effect of the PDE7 inhibitor OMS181869 on cocaine self-administration by rats. [Figure 3] FIG. 3 shows the effect of the dopamine D1 agonist SKF82958 on cocaine self-administration by rats. [Figure 4] FIG. 4 shows the effect of the PDE7 inhibitor OMS182056 on cocaine priming-induced relapse in rats. [Figure 5] FIG. 5 shows the effect of the dopamine D1 agonist SKF82958 on cocaine-priming-induced relapse in rats. [Figure 6] FIG. 6 shows the effect of the PDE7 inhibitor OMS182056 on non-reinforced lever-pressing responses by rats. [Figure 7] FIG. 7 shows the effect of the dopamine D1 agonist SKF82958 on non-reinforced lever-pressing responses by rats. [Figure 8] FIG. 8 shows the effect of the PDE7 inhibitor OMS182056 on lever-pressing responses by rats on the first day of extinction following cocaine addiction. [Figure 9] FIG. 9 shows the effect of the PDE7 inhibitor OMS182056 on yohimbine-induced relapse in rats. [Figure 10] FIG. 10 shows the effect of the PDE7 inhibitor OMS182401 on yohimbine-induced relapse in rats. [Figure 11] FIG. 11 shows the effect of the PDE7 inhibitor OMS182056 on cue-induced relapse in rats. [Figure 12A]Figures 12A-12D show the effects of the PDE7 inhibitor OMS182401 on stress-induced hyperphagia in rats. Figure 12A shows the results for control animals that were not stressed or subjected to a diet. Figure 12B shows the results for experimental animals that were not stressed and subjected to a diet. Figure 12C shows the results for experimental animals that were stressed and not subjected to a diet. Figure 12D shows the results for experimental animals that were stressed and subjected to a diet. [Figure 12B] Figures 12A-12D show the effects of the PDE7 inhibitor OMS182401 on stress-induced hyperphagia in rats. Figure 12A shows the results for control animals that were not stressed or subjected to a diet. Figure 12B shows the results for experimental animals that were not stressed and subjected to a diet. Figure 12C shows the results for experimental animals that were stressed and not subjected to a diet. Figure 12D shows the results for experimental animals that were stressed and subjected to a diet. [Figure 12C] Figures 12A-12D show the effects of the PDE7 inhibitor OMS182401 on stress-induced hyperphagia in rats. Figure 12A shows the results for control animals that were not stressed or subjected to a diet. Figure 12B shows the results for experimental animals that were not stressed and subjected to a diet. Figure 12C shows the results for experimental animals that were stressed and not subjected to a diet. Figure 12D shows the results for experimental animals that were stressed and subjected to a diet. [Figure 12D] Figures 12A-12D show the effects of the PDE7 inhibitor OMS182401 on stress-induced hyperphagia in rats. Figure 12A shows the results for control animals that were not stressed or subjected to a diet. Figure 12B shows the results for experimental animals that were not stressed and subjected to a diet. Figure 12C shows the results for experimental animals that were stressed and not subjected to a diet. Figure 12D shows the results for experimental animals that were stressed and subjected to a diet. [Figure 13] FIG. 13 shows the effect of the PDE7 inhibitor OMS182401 on cue-induced relapse in rats. [Figure 14]FIG. 14 shows the chronic effects of the PDE7 inhibitor OMS182401 on cocaine self-administration in rats. [Figure 15] FIG. 15 shows the effect of the PDE7 inhibitor OMS182401 on nicotine self-administration in rats using the brief access model. [Figure 16] FIG. 16 shows the effect of the PDE7 inhibitor OMS182401 on nicotine self-administration in rats using the long-access model. [Figure 17] FIG. 17 shows the effect of the PDE7 inhibitor OMS182401 on the first day of extinction of nicotine self-administration. [Figure 18] FIG. 18 shows the effect of the PDE7 inhibitor OMS182401 on cue-induced reinstatement of nicotine-seeking behavior. [Figure 19] FIG. 19 shows the effect of the PDE7 inhibitor OMS182401 on yohimbine-induced reinstatement of nicotine-seeking behavior. [Figure 20] FIG. 20 shows the effect of the PDE7 inhibitor OMS182399 on nicotine self-administration in rats using the brief access model. DETAILED DESCRIPTION OF THE INVENTION

[0052] V. Detailed Description of the Preferred Embodiments The present invention is based on the surprising discovery by the inventors that selective inhibitors of cyclic nucleotide phosphodiesterase type 7 (PDE7) significantly reduce relapse to addiction. Using a rat model, this reduction was demonstrated in subjects addicted to addictive drugs and in subjects exhibiting compulsive sexual behavior.

[0053] A. Methods for Treating and Preventing Addiction Using PDE7 Inhibitor(s) Thus, the present invention comprises a method for treating or preventing addiction, comprising administering one or more PDE7 inhibitors to a subject who has addiction or is at risk of developing addiction.In various embodiments, the subject is addicted to addictive drugs or behaviors, for example, but not limited to, any addictive drugs and behaviors described herein.The subject can be physically dependent or physiologically dependent on the substance or behavior; the subject can be psychologically dependent; the subject can be both physically and psychologically dependent.The subject can be addicted to one addictive drug or behavior, or can be addicted to more than one addictive drug or behavior.

[0054] As used herein, unless otherwise clear from the context, "treat" and similar terms (e.g., "treatment," "treating," etc.) are an approach for obtaining beneficial or desired results (e.g., preferably clinical results). Treatment can optionally involve either reducing or ameliorating a disease or condition (e.g., an addiction or relapsing use or behavior) or slowing the progression of a disease or condition (e.g., an addiction or relapsing use or behavior).

[0055] As used herein, unless the context makes clear otherwise, "prevent" and similar terms (e.g., "prevention," "preventing," etc.) refer to an approach to prevent the onset or recurrence of a disease or condition (e.g., an addiction or recurrent use or behavior) or to prevent the occurrence or recurrence of symptoms of the disease or condition, or optionally to delay the onset or recurrence of the disease or condition or to delay the occurrence or recurrence of symptoms of the disease or condition.

[0056] As used herein, the term "PDE7" is used generically to refer to any translation product encoded by the transcript of either or both of these two genes: PDE7A and / or PDE7B.

[0057] As used herein, the term "PDE7 inhibitor" or "PDE7 inhibitor" refers to a drug, such as a chemical compound, peptide, or nucleic acid molecule, that directly or indirectly inhibits or blocks the phosphodiesterase activity of PDE7A, PDE7B, or PDE7A and PDE7B.In ​​some cases, the drug can directly bind to or interact with PDE7 protein.A drug that binds to PDE7 can function to inhibit or block PDE7 activation by any suitable means, for example, by inhibiting the binding of cAMP or substrate ligand to PDE7.In other cases, the PDE7 inhibitor can indirectly inhibit PDE7 activity, for example, by reducing the expression of PDE7 protein.In other cases, the PDE7 inhibitor can inhibit PDE7 activity by changing the cellular distribution of PDE7, for example, by preventing the association between PDE7 and intracellular anchoring proteins.

[0058] As used herein, the term "mammalian subject" includes any mammal, including, but not limited to, humans, non-human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs, and rodents.

[0059] Generally, the subject is given an effective amount of PDE7 inhibitor.As used herein, the "effective amount" or "therapeutically effective amount" of a substance, for example, a PDE7 inhibitor, is an amount that is sufficient to produce desired biological or psychological effects, such as beneficial results (for example, clinical results).For example, in the context of treating addiction using the method of the present invention, the effective amount of a PDE7 inhibitor is an amount that is sufficient to cause the subject to reduce or stop using addictive drugs.In the case of addictive behavior, the effective amount of a PDE7 inhibitor is an amount that is sufficient to cause the subject to reduce or stop addictive behavior.

[0060] In one embodiment, therapeutically effective dose is the amount of PDE7 inhibitor that is sufficient to inhibit PDE7 enzyme activity in neuronal cells.In another embodiment of the method of the present invention, therapeutically effective dose is the amount of PDE7 inhibitor that is sufficient to inhibit PDE7 enzyme activity in striatal neurons or nucleus accumbens.The effective dose of PDE7 inhibitor that is sufficient to cross cell membrane and inhibit PDE7 enzyme activity in cells can be determined by using the cell assay of PDE7 inhibition, such as that described in Smith SJ et al., Molecular Pharmacology 66(6):1679-1689(2004) (incorporated herein by reference).The effective dose of PDE7 inhibitor that is sufficient to inhibit PDE7 enzyme activity in striatum can be determined by using the assay for measuring the effect of PDE inhibitor on cAMP level in striatum, such as that described in Siuciak JA et al., Neuropharmacology 51:386-396(2006) (incorporated herein by reference).

[0061] According to some specific embodiments of the present invention, PDE7 inhibitor is administered alone to subject, while in other embodiments, PDE7 inhibitor is administered in combination with additional therapeutic agent to subject.It should be understood that the effective amount of either or both of PDE7 inhibitor and additional therapeutic agent may be different when administered alone or when administered in combination.For example, when PDE7 inhibitor and additional therapeutic agent act synergistically, the amount of PDE7 inhibitor required to obtain the same therapeutic effect as that obtained by either PDE7 inhibitor or additional therapeutic agent alone may be reduced, or the amount of additional therapeutic agent may be reduced, or the amount of both PDE7 inhibitor and additional therapeutic agent may be reduced.In other embodiments, the same amount of PDE7 inhibitor and additional therapeutic agent is used, and the therapeutic effect obtained is improved compared with that obtained by either PDE7 inhibitor or additional therapeutic agent alone.

[0062] According to certain embodiments of the present invention, a subject is given a PDE7 inhibitor in combination with an addictive therapeutic agent, the dosage of the addictive therapeutic agent being determined to achieve the desired therapeutic effect, and the dosage of the PDE7 inhibitor being determined to eliminate or reduce the likelihood of addiction to the addictive therapeutic agent.

[0063] The subject can be any animal, for example a mammal, particularly a human.

[0064] In one embodiment of the present invention, a subject is first determined or diagnosed as having an addiction or at risk of developing an addiction through diagnostic testing, observation or analysis by a medical provider.An effective amount of a PDE7 inhibitor, or an effective amount of a PDE7 inhibitor and one additional therapeutic agent, is then given to the subject to treat or prevent addiction.In another embodiment of the present invention, a subject is first determined or diagnosed as having an addiction or at risk of developing an addiction through diagnostic testing, observation or analysis by a medical provider, but the subject has not been diagnosed or determined to have diabetes or other insulin disorders.An effective amount of a PDE7 inhibitor, or an effective amount of a PDE7 inhibitor and one additional therapeutic agent, is then given to the subject to treat or prevent addiction.The dosage of a PDE7 inhibitor, or a PDE7 inhibitor and one additional therapeutic agent, can be specifically determined by a medical professional for the treatment or prevention of addiction, not any other disorder or disease.

[0065] In certain embodiments, the subject is a subject suffering from or at risk of addiction to any physically addictive drug or addictive or compulsive behavior, such as any of those described below.In certain embodiments, the subject is addicted to alcohol, cocaine, nicotine, marijuana, opium or other opioid agonists, methamphetamine or other psychostimulants, or phencyclidine and phencyclidine derivatives.In another embodiment, the subject is a subject suffering from primary impulse control disorder.In yet another embodiment, the subject is a subject suffering from obsessive-compulsive disorder.In yet another embodiment, the subject has a history of repeated dieting and is at risk of overeating.

[0066] In certain embodiments, if the subject has previously been addicted to the same or different addictive drug or addictive or compulsive sexual behavior, the subject is considered to be at risk of addiction or relapse to using the addictive drug or performing the addictive behavior.In some specific embodiments, if the subject is psychologically addicted to the addictive drug or addictive or compulsive sexual behavior, the subject is considered to be at risk of addiction or relapse to using the addictive drug or performing the addictive behavior, even if the subject is no longer physically addicted.In one embodiment, the addictive behavior is overeating.The subject at risk of overeating typically has at least one of the following in its history: repeated dietary restriction or yo-yo dieting, eating in response to environmental stress, a preference for highly palatable high-calorie food, eating even when feeling full, and eating until uncomfortable.In another embodiment, the subject is the subject suffering from primary impulse control disorder.

[0067] In some specific embodiments, the subject is addicted to the therapeutic drug (for example, analgesic) that is given to the patient to treat disease or disorder, or is at risk of becoming addicted to the therapeutic drug.In related embodiments, the subject can be the subject at risk of abusing addictive therapeutic drugs such as analgesics.It should be understood that in some specific embodiments, the abuse of addictive therapeutic drugs refers to using the drug for reasons other than or in addition to the prescribed use.In such a situation, the subject can be given both an addictive therapeutic drug and a PDE7 inhibitor, alone or in combination with other therapeutic drugs.For example, the subject who is suffering from pain or at risk of pain can be given an opioid agonist and a PDE7 inhibitor to provide pain relief and prevent or treat addiction to the opioid agonist.

[0068] In various embodiments, the subject is given a PDE7 inhibitor at the same time the subject is using the addictive drug, after the subject has stopped using the addictive drug, or before the subject begins using the addictive drug.

[0069] Addictive drugs The term "addiction" is used to refer to a recurrent compulsion in which an individual engages in some particular activity, despite the harmful consequences to the individual's health, mental state, or social life.The term is often used for drug addiction, but also applies to other problematic compulsions, such as gambling and overeating.The factors that have been suggested to be the causes of addiction include genetic, biological / pharmacological, and social factors.

[0070] The medical community currently makes a careful theoretical distinction between physical or physiological dependence (characterized by withdrawal symptoms) and psychological dependence (sometimes simply referred to as addiction). Addiction is currently narrowly defined as "uncontrollable compulsive use." In the absence of harm that causes suffering or injury to the patient or third parties, this may be considered clinically compulsive, but for some, does not fall under the definition of "addiction." In practice, the two types of addiction (physiological and psychological) are not always easily distinguishable. Addiction often has both physical and psychological components.

[0071] "Physical dependence" (or "drug dependence") refers to the state resulting from habitual use of a drug, the abrupt cessation of which produces negative physical withdrawal symptoms. Examples of addictive drugs to which users can develop physical dependence include nicotine, opioids, barbiturates, benzodiazepines, alcohol, i.e., ethyl alcohol, GHB, and methaqualone.

[0072] Commonly overdosed stimulant drugs, such as cocaine or amphetamines, are not thought to cause significant physical dependence, but their extreme psychological addictive potential can lead users to use physically harmful amounts, although no life-threatening withdrawal effects have been observed.

[0073] As used herein, "addictive drug(s)" encompasses any drug that can cause a subject to become addicted to either physically or psychologically, or both.As mentioned above, addictions include addictions to chemical substances such as drugs (e.g., ethyl alcohol, nicotine, or cocaine), as well as other behaviors, such as binge eating disorder, pathological gambling, pathological use of electronic devices (e.g., BlackBerry®), pathological use of video games, pathological use of electronic communication devices, pathological use of mobile phones, pornography addiction, sex addiction, obsessive-compulsive disorder, compulsive consumption behavior, intermittent explosive disorder, kleptomania, pyromania, trichotillomania, compulsive hyperexercise, and compulsive overwork.

[0074] As used herein, "binge eating disorder" or "binge eating" includes at least one of the following symptoms: eating large amounts of food, eating even when full, eating quickly, feeling unable to control eating, eating large amounts of food even when not hungry, frequent dieting that may not result in weight loss, eating alone, feeling depressed or averse to eating habits, and eating in response to stress. Binge eating disorder is distinct from bulimia and binge eating syndrome.

[0075] Addictive drugs include addictive recreational drugs and addictive medicines.Examples of addictive drugs include but are not limited to alcohol, such as ethyl alcohol, gamma hydroxybutyric acid (GHB), caffeine, nicotine, cannabis (marijuana) and cannabis derivatives, opium and other morphine-like opioid agonists (such as heroin, phencyclidine and phencyclidine-like compounds), hypnotic sedatives (such as benzodiazepines, methaqualone, mecloqualone, etaqualone and barbiturates) and psychostimulants (such as cocaine, amphetamine and amphetamine-related drugs, such as dextroamphetamine and methylamphetamine).Other examples include LSD, psilocybin, ecstasy and other hallucinogens. Examples of addictive drugs include, for example, benzodiazepines, barbiturates, and analgesics, such as alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene. fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofenitanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, OXYCONTIN®, oxymorphone, papaveretam, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propeptadine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, salts thereof, mixtures of any of the foregoing, mixed μ-agonist / antagonists, and the like.

[0076] In certain embodiments, the subject may be addicted to opioid agonists. The terms "opioid agonist," "opioid," and "opiate" are used interchangeably herein to refer to a group of drugs with varying degrees of opiate- or morphine-like properties. Their primary use is pain relief. These drugs work by binding to opioid receptors, which are found primarily in the central nervous system and gastrointestinal tract. Opiates are also addictive drugs. Opiates include alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, benzylmorphine, β-hydroxy-3-methylfentanyl, bezitramide, carfentanil, clonitazene, codeine, desomorphine, dextromoramide, diacetylmorphine (heroin), diampromide, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, ibuprofen, Sometadone, ketobemidone, LMM, levorphanol, levophenacylmorphan, lofentanil, meperidine, metapon, metazocine, methadone, methadyl acetate, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaverine, phenadoxone, phenomorphan, phenoperidine, piminodine, piritramide, propeptadine, promedol, properidine, propoxyphene, remifentanil, sufentanil, thebaine, tilidine, and tramadol.

[0077] Natural opioids include codeine, morphine, noscapine, papaverine, and thebaine.Semisynthetic opioids include diacetylmorphine, hydrocodone, hydromorphone, levorphanol, metapon, nalorphine, naloxone, naltrexone, oxycodone, oxymorphone, and tramadol.Synthetic opioids include ethoheptazine, fentanyl, levorphanol, meperidine, methadone, phenazocine, propoxyphene, and sufentanil.

[0078] Opiates are broadly divided into three classes: phenanthrenes, phenylheptylamines, and phenylpiperidines. Examples of phenanthrenes include codeine, etorpine, hydrocodone, hydromorphone, morphine, oxycodone, and oxymorphone. Examples of phenylheptylamines include dimeheptanol, dimenoxadol, dipipanone, isomethadone, methadone, methadyl acetate, and propoxyphene. Examples of phenylpiperidines include alfentanil, alphaprodine, beta-promedol, carfentanil, fentanyl, lofentanil, meperidine, properidine, and sufentanil.

[0079] Specific psychostimulants include, by way of example only, amphetamine, cocaine, dextroamphetamine, methamphetamine, pemoline, Ritalin, Adderall, and methylenedioxymethamphetamine.

[0080] Although a subject may be addicted to a single addictive drug or behavior, frequently, a subject is addicted to more than one addictive drug or behavior. Addiction to more than one addictive drug or behavior is referred to as polyaddiction.

[0081] B. Methods for treating and preventing addiction using PDE7 inhibitor(s) in combination with other therapeutic agents PDE7 inhibitors can be effectively used in combination with one or more additional therapeutic agents to treat or prevent addiction, for example, addiction to one or more addictive drugs and compulsive or addictive behaviors as described herein.Therefore, the present invention comprises a method for treating or preventing addiction, comprising administering one or more PDE7 inhibitors and one or more additional therapeutic agents to a subject addicted to an addictive drug, wherein each of the PDE7 inhibitor(s) and the additional therapeutic agent(s) contributes to the effective treatment or prevention of addiction.In one embodiment, the subject is given or administered one PDE7 inhibitor and one additional therapeutic agent.In another embodiment, the subject is addicted to two or more addictive drugs.

[0082] PDE7 inhibitor and additional therapeutic agent can be administered simultaneously (i.e., concurrently), or before each other (i.e., sequentially).Generally, both PDE7 inhibitor and additional therapeutic agent are present in the subject at the same time for a sufficient period and level to provide therapeutic benefit to the subject, i.e., in the treatment or prevention of addiction or the prevention of recurrent use (or relapse) of addictive drugs or compulsive or addictive behaviors.PDE7 inhibitor and additional therapeutic agent can be administered by the same or different administration routes.Typically, PDE7 inhibitor and additional therapeutic agent are each administered to the subject according to the standard route of administration of commercially available or other pharmaceutical compositions.In one embodiment, PDE7 inhibitor and additional therapeutic agent are co-administered using a composition comprising both agents.

[0083] The additional therapeutic agent that is provided in combination with PDE7 inhibitor can be any therapeutic agent that contributes to the effective treatment or prevention of addiction.For example, the additional therapeutic agent can be the drug that is used to treat addiction, or the drug that is used to alleviate the side effects associated with physiological withdrawal of addictive drugs.In addition, the additional therapeutic agent can be any drug that affects the serotonin neurotransmission in the brain, such as selective serotonin reuptake inhibitor (SSRI), and tricyclic and tetracyclic serotonin and norepinephrine reuptake inhibitor (SNRI) (described below), and serotonin agonist (such as sumatriptan, ergonovine, dihydroergotamine and buspirone). In certain embodiments, the additional therapeutic agent is an opioid antagonist, e.g., a mixed opioid partial agonist / antagonist, an antidepressant, an antiepileptic, an antiemetic, a corticotropin-releasing factor-1 (CRF-1) receptor antagonist, a selective serotonin-3 (5-HT3) antagonist, a 5-HT2A / 2C antagonist (such as mianserin, mirtazapine, and ketanserin), or a cannabinoid-1 (CB1) receptor antagonist (such as, but not limited to, a therapeutic agent specifically described herein).

[0084] In one embodiment, the addictive drug is alcohol, and the additional therapeutic agent is an opioid antagonist or a mixed opioid antagonist / partial agonist. In certain embodiments, the opioid antagonist is naltrexone. In another embodiment, the mixed opioid partial agonist / antagonist is buprenorphine.

[0085] In one embodiment, the addictive agent is alcohol and the additional therapeutic agent is topiramate or levetiracetam.

[0086] In one embodiment, the addictive agent is nicotine and the additional therapeutic agent is an antidepressant, hi certain embodiments, the antidepressant is bupropion.

[0087] In one embodiment, the addictive agent is cocaine and the additional therapeutic agent is buprenorphine.

[0088] In one embodiment, the addictive agent is a psychostimulant and the additional therapeutic agent is an antidepressant, hi certain embodiments, the antidepressant is bupropion.

[0089] In one embodiment, the addictive behavior is binge eating and the additional therapeutic agent is an antidepressant or an antiepileptic. In one particular embodiment, the antidepressant is sibutramine. In another particular embodiment, the antidepressant is fluoxetine. In one particular embodiment, the antiepileptic is topiramate.

[0090] In one embodiment, the addictive agent is nicotine and the additional therapeutic agent is an antiepileptic drug. In certain embodiments, the antiepileptic drug is levetiracetam. In another particular embodiment, the antiepileptic drug is naltrexone.

[0091] In one embodiment, the subject is addicted to two or more addictive drugs and the additional therapeutic agent is an opioid antagonist or a mixed opioid partial agonist / antagonist. In certain embodiments, the mixed opioid partial agonist / antagonist is buprenorphine.

[0092] In one embodiment, the subject is addicted to both alcohol and nicotine and the additional therapeutic agent is an antiepileptic drug. In certain embodiments, the antiepileptic drug is naltrexone.

[0093] In the treatment of alcohol addiction, combinations that may be administered in accordance with the present invention include PDE7 inhibitors and opioid agonists or mixed opioid antagonists / partial antagonists, PDE7 inhibitors and antidepressants, PDE7 inhibitors and CB1 receptor antagonists / inverse agonists, PDE7 inhibitors and varenicline, PDE7 inhibitors and acamprosate, and PDE7 inhibitors and disulfiram.

[0094] In the treatment of addiction to psychostimulants, combinations administered in accordance with the present invention include, for example, a PDE7 inhibitor and an antidepressant or a PDE7 inhibitor and a partial opioid agonist / antagonist (eg, buprenorphine).

[0095] In the treatment of nicotine addiction, the combinations that can be administered according to the present invention include, for example, PDE7 inhibitors and antidepressants, PDE7 inhibitors and nicotine (alternatively, orally, transdermally, or in other conventional formulations), PDE7 inhibitors and opioid antagonists, PDE7 inhibitors and CB1 receptor antagonists / inverse agonists, and PDE7 inhibitors and varenicline.In one embodiment, addictive drugs (such as nicotine) and PDE7 inhibitors are administered together using a transdermal patch delivery system.In another aspect of the present invention, a kit is provided that includes a number of transdermal patches containing tapered dosages of nicotine and either constant or tapered dosages of PDE7 inhibitors, so that the nicotine-addicted subject can be continuously used to wean the subject from nicotine addiction.

[0096] In the treatment of multiple substance addictions, combinations administered in accordance with the present invention include, for example, a PDE7 inhibitor and an opioid agonist or mixed opioid antagonist / partial antagonist.

[0097] In the treatment of gambling addiction, combinations that may be administered in accordance with the present invention include, for example, a PDE7 inhibitor and an antidepressant, or a PDE7 inhibitor and an agent that affects dopamine neurotransmission (eg, a direct or indirect dopamine antagonist).

[0098] When PDE7 inhibitor and additional therapeutic agent are administered together, the effective amount of either or both of them can be less than when either is administered alone.For example, when PDE7 inhibitor and additional therapeutic agent act additively or synergistically, the amount of PDE7 inhibitor that is required to obtain the same therapeutic effect that either PDE7 inhibitor or additional therapeutic agent can provide alone can be reduced, or the amount of additional therapeutic agent can be reduced, or the amount of both PDE7 inhibitor and additional therapeutic agent can be reduced.

[0099] 1. Opioid antagonists Opioid antagonists act on one or more types of opioid receptors.At least three types of opioid receptors have been reported: μ, κ, and δ opioid receptors, and opioid antagonists are generally classified according to their effects on opioid receptors.Opioid antagonists can antagonize central receptors, peripheral receptors, or both.Naloxone and naltrexone are commonly used opioid antagonist drugs that bind to opioid receptors with higher affinity than agonists, but do not activate the receptors, making them competitive.This effectively blocks the receptors, preventing the body from responding to opiates and endorphins.

[0100] Many opioid antagonists are not only pure antagonists, but also produce some weak opioid partial agonist effects, which can produce analgesic effects when administered at high doses to opioid-naive individuals. Examples of such compounds include nalorphine and levallorphan. However, the analgesic effects of these drugs tend to be limited and accompanied by dysphoria (likely due to their action at the kappa opioid receptor). These drugs are considered antagonists because they induce opioid withdrawal effects in individuals taking or who have previously used full opioid agonists.

[0101] Naloxone is an example of an opioid antagonist that does not have a partial agonist effect. Rather, it is a weak inverse agonist at the μ-opioid receptor and is used to treat opioid overdose.

[0102] Specific examples of opioid antagonists that can be used in accordance with the present invention include alvimopan, binaltorphimine, buprenorphine, cyclazocine, cyclorphan, cypridime, dinicotinate, β-funaltrexamine, levallorphan, methylnaltrexone, nalbuphine, nalide, nalmefene, nalmexone, nalorphine, nalorphine dinicotinate, naloxone, naloxonazine, naltrindole, naltrexone, naltrindole, oxilorphan, and pentazocine.

[0103] 2. Antidepressants Antidepressants are drugs used to treat depression. Three neurotransmitters thought to be involved in depression are serotonin, dopamine, and norepinephrine. Some types of antidepressants increase the brain levels of one or more of these neurotransmitters by blocking their reuptake.

[0104] Several different classes of antidepressants have been identified, including selective serotonin reuptake inhibitors (SSRIs), tricyclic and tetracyclic serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine reuptake inhibitors (NRIs), norepinephrine and dopamine reuptake inhibitors (NDRIs), azaspirone, monoamine oxidase inhibitors (MAOIs), and atypical antidepressants.

[0105] Examples of SSRIs include cericlamine, citalopram, clomipramine, cyanodothiepin, dapoxetine, duloxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, imipramine, indalpine, indeloxazine, ritoxetine, lofepramine, mianserin, milnacipran, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, sibutramine, tomoxetine, trazodone, venlafaxine, and zimeldine.

[0106] Amitriptyline, amoxapine, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, imipramine, iprindole, lofepramine, maprotiline, melitracen, metapramine, mianserin, mirtazapine, nortriptyline, propizepine, protriptyline, quinupramine, setiptiline, tianeptine, and trimipramine are all tricyclic and tetracyclic antidepressants.

[0107] SNRIs include, for example, amoxapine, atomoxetine, bicifadine, desipramine, desvenlafaxine, duloxetine, maprotiline, milnacipran, nefazodone, reboxetine, sibutramine, and venlafaxine.

[0108] Nisoxetine, nortriptyline, reboxetine, talspram, and tomoxetine are all examples of NRIs.

[0109] NDRIs include, for example, bupropion, hydroxybupropion, and tesofensine.

[0110] Azaspirones include, for example, buspirone, gepirone, ipsapirone, tandospirone, and tiaspirone. Buspirone is an anxiolytic (partial agonist at the 5-HT1 autoreceptor) that may be given in conjunction with an antidepressant such as an SSRI.

[0111] Specific MAOIs include, for example, amiflamine, brofaromine, clorgyline, alpha-ethyltryptamine, iproclozide, iproniazid, isocarboxazid, mebanazine, moclobemide, nialamide, pargyline, phenelzine, pheniprazine, pirlindole, safrazine, selegiline, toloxatone, and tranlcypromine.

[0112] Atypical antidepressants include, for example, amesergide, amineptine, benactyzine, bupropion, clozapine, fezolamine, levoprotiline, lithium, medifoxamine, mianserin, minaprine, olanzapine, oxaflozane, oxitriptan, rolipram, teniloxazine, tofenacin, trazodone, tryptophan, and viloxazine.

[0113] 3. Antiepileptic drugs Anticonvulsants, also known as antiepileptic drugs (AEDs), are a diverse group of drugs used to prevent the occurrence of epileptic seizures and bipolar disorder. AEDs suppress rapid and excessive neuronal firing (which initiates seizures and / or inhibits their spread within the brain) and provide protection against potential excitotoxic effects that may result from brain damage. Many anticonvulsants block sodium channels, calcium channels, AMPA receptors, or NMDA receptors.

[0114] Antiepileptic agents include, but are not limited to, benzodiazepines, barbituates, valproates, GABA agents, iminostilibenes, hydantoins, NMDA antagonists, sodium channel blockers, and succinamides.

[0115] Benzodiazepines include, for example, alprazolam, chlordiazepoxide, clorazepate, clobazam, clonazepam, diazepam, halazapam, lorazepam, oxazepam, and prazepam.

[0116] Barbiturates used as antiepileptics include, for example, amobarbital, mepobarbital, methylphenobarbital, pentobarbital, phenobarbital, and primidone.

[0117] Valproates used as antiepileptic drugs include, for example, sodium valproate, valproic acid, valproate semisodium, and valpromide.

[0118] Antiepileptic GABA agents include, for example, gabapentin, rosigamone, pregabalin, retigabine, rufinamide, and vigabatrin.

[0119] Carbamazepine and oxcarbazepine are examples of iminostilbenes.

[0120] Hydantoins include, for example, fosphenytoin sodium, mephenytoin, and phenytoin sodium.

[0121] NMDA antagonists such as harkoseramide are used as antiepileptic drugs.

[0122] Sodium channel blockers such as lamotrigine are also antiepileptic drugs.

[0123] Succinimides include, for example, ethosuximide, methsuximide, and phensuximide.

[0124] Other antiepileptic medications include acetazolamide, briveracetam, CBD cannabis derivatives, cromthiazole edisilate, divalproex sodium, felbamate, isovaleramide, lacosamide, lamotrigine, levetiracetam, methanesulfonamide, talampanel, tiagabine, topiramate, safinamide, seletracetam, soletolide, stiripentol, sulthiame, vallosemide, and zonisamide.

[0125] 4. Antiemetics Antiemetics are drugs that are effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anesthetics, and chemotherapy.

[0126] Classes of antiemetic drugs include, for example, 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, histamine receptor antagonists, dopamine receptor antagonists, muscarinic receptor antagonists, acetylcholine receptor antagonists, cannabinoid receptor antagonists, limbic system inhibitors, NK-1 receptor antagonists, corticosteroids, tachykinin antagonists, GABA agonists, cannabinoids, benzodiazepines, anticholinergics, and substance P inhibitors.

[0127] 5-HT3 receptor antagonists include, for example, alosetron, azasetron, bemesetron, cilansetron, dolasetron, granisetron, indisetron, itasetron, ondansetron, palonosetron, propisetron, ramosetron, renzapride, tropisetron, and zatosetron.

[0128] Corticosteroid antiemetics include dexamethasone and methylprednisolone.

[0129] Limbic system inhibitors include alprazolam, lorazepam, and midazolam.

[0130] Dopamine receptor antagonists include diphenhydramine, dronabinol, haloperidol, metoclopramide, and prochlorperazine.

[0131] NK-1 receptor antagonists used as antiemetics include aprepitant and morpholine, and an example of a GABA agonist is propofol.

[0132] Thiethylperazine is a type of histamine receptor antagonist.

[0133] Cannabinoid receptor antagonists or agonists used as antiemetics include dronabinol, nabilone, rimonabant, taranabant (tanarabout), and tetrahydrocannabinol.

[0134] Examples of other antiemetics include acetylleucine, monoethanolamine, alizapride, benzquinamide, bietanautine, bromopride, buclizine, chlorpromazine, clebopride, cyclizine, dimenhydrinate, dipheniodol, domperidone, dranisetron, meclizine, methaltal, metopimazine, oxypendyl, pipamazine, piprinehydrinate, scopolamine, thioproperzaine, and trimethobenzamide.

[0135] 5. Cannabinoid receptor antagonists Cannabinoid receptors are a type of G-protein-coupled receptor superfamily. Their ligands are known as cannabinoids. Currently, there are two known subtypes: CB1, which is expressed primarily in the brain but also in the lungs, liver, and kidneys, and CB2, which is expressed primarily in the immune system and hematopoietic cells. Novel cannabinoid receptors, i.e., non-CB1 and non-CB2, are also believed to exist, which are expressed in endothelial cells and the CNS. Cannabinoid receptor antagonists can be selective for either the CB1 receptor or the CB2 receptor. The present invention contemplates the use of either or both CB1 receptor antagonists and CB2 receptor antagonists.

[0136] Addictive drugs (e.g., alcohol, opium, delta(9)-tetrahydrocannabinol (delta(9)-THC) and psychostimulants such as nicotine) induce various chronic, relapsing disorders by interacting with endogenous neural pathways in the brain. In particular, these drugs share the common property of activating the mesolimbic dopamine brain reward system, and virtually all drugs taken in excess increase dopamine levels in the nucleus accumbens. Cannabinoid-1 (CB1) receptors are expressed in this brain reward circuit and modulate the dopamine-releasing effects of delta(9)-THC and nicotine.

[0137] Rimonabant (SR141716) is a CB1 receptor antagonist that blocks both the dopamine-releasing and discriminative rewarding effects of delta(9)-THC in animals. While CB1 receptor blockade is generally ineffective at reducing cocaine self-administration in rodents and primates, it reduces the reinstatement of extinguished cocaine-seeking behavior induced by cocaine-associated conditioned cues and cocaine-priming injections. Similarly, CB1 receptor blockade is effective at reducing nicotine-seeking behavior induced by re-exposure to nicotine-associated cues. In human clinical trials, rimonabant has been shown to block the subjective effects of delta(9)-THC in humans and to inhibit smoking relapse in former smokers.

[0138] Other examples of cannabinoid receptor CB1 antagonists include SR141716A (rimonabant), rosanabant, taranabant and CP-945598.

[0139] C. Methods for Treating and Preventing Recurrence Relapse or relapse refers to the process of returning to the use of alcohol or another addictive drug or to the use of addictive behavior after a period of abstinence, or limited or reduced use of the addictive drug or addictive behavior. In certain circumstances, relapse in the use of an addictive drug refers to a return to the use of an addictive drug in a subject who has previously experienced physical withdrawal from the addictive drug. Typically, the subject will experience physical withdrawal from the addictive drug during a period of non-use or limited or reduced use of the addictive drug. In one embodiment, relapse in use occurs in a subject who has previously undergone a treatment regimen with an effective amount of an anti-addictive drug to reduce or eliminate the use of the addictive drug, but who is no longer using an effective amount of the anti-addictive drug. Anti-addictive drugs include any and all drugs used to treat or prevent addiction or withdrawal symptoms.

[0140] Alcoholism, like many other addictions, is a chronic, relapsing disorder characterized by a high rate of recidivism. Two major factors that induce relapse behavior are stress and environmental conditioning experiences (O'Brien et al. 1997; Monti et al. 1993; Shaham et al. 1995), which likely promote relapse to alcohol seeking through distinct brain mechanisms. For example, activation of the mesolimbic dopamine system through opioid-dependent mechanisms (or through direct alteration of dopamine transmission within the basolateral nucleus of the amygdala) appears to mediate the effects of drug-associated cues (Liu and Wiess 2002; Ciccocioppo et al. 2003). 2001 ), extrahypothalamic CRF within the bed nucleus of the stria terminalis and medial raphe nucleus likely mediates stress-induced reinstatement of drug-seeking behavior ( Erb et al. 1998 ; Shaham et al. 1995 ; Le et al. 2000 ).

[0141] Several lines of evidence suggest that the molecular mechanisms underlying relapse to addiction are common to overdose of various types of drugs. Drug craving and the decreased control over drug-taking behavior that accompanies relapse are directly influenced by stress and environmental conditioning stimuli, two major factors that influence relapse to drug use.

[0142] Chronic excessive drug use leads to neuroadaptive changes not only in systems involved in the acute reinforcing effects of ethanol, but also in other motivational systems, notably stress-regulatory mechanisms in the brain. Stress has an established role in the initiation and maintenance of excessive drug use and is a major determinant of relapse in abstinent individuals (Brown et al., J. Studies Alcohol. 56:538(1995);Marlatt,Relapse prevention:introduction and overview of the model,in Relapse Prevention:Maintenance Strategies in the Treatment of Addictive Behaviors,Guilford,London,(1985);McKay et al.,Drug Alcohol Dep., 38, 35, (1995); and Wallace, J. Substance Abuse Treat, 6:95, (1989). The importance of stress in drug-seeking behavior is also well documented in the animal literature. Physical, social, and emotional stress can facilitate the acquisition or escalation of cocaine, heroin, and ethanol self-administration in rodents and nonhuman primates (Goeders and Guerin, Psychopharmacology, 114, 63, (1994); Haney et al., Brain Res., 698, 46, (1995); Ramsey and Van Ree, Brain Res., 608, 216, (1993); Ahmed and Koob, Psychopharmacology, 132, 289, (1997); Shaham and Stewart, Psychopharmacology 119:334 (1995); Nash and Maickel, Prog Neuropsychopharmacol Biol Psychiatry, 12, 653, (1988); Mollenauer et al., Pharmacol. Biochem. Behav., 46, 35, (1993); Blanchard et al., Pharmacol. Biochem. Behav., 28, 437, (1987) and Higley et al., Proc. Natl. Acad. Sci. USA, 88, 7261, (1991)). Excessive stressful stimuli have also been shown to induce reinstatement of cocaine-, heroin-, and ethanol-seeking behavior in drug-naive animals after extinction, findings that provide experimental support for the role of stress in relapse (Ahmed and Koob (1997); Shaham, Psychopharmacology, 111, 477, (1993); and Shaham and Stewart (1995)).

[0143] Traditionally, stress-related drug-seeking behaviors have been thought to be mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. However, increasing evidence suggests that the non-neuroendocrine corticotropin-releasing factor (CRF) system within the central nucleus of the amygdala (CeA) may play a major independent role in regulating stress-related addictive behaviors. The CeA contains many CRF-immunoreactive cell bodies, terminals, and receptors, and this neuronal CRF system has been implicated in mediating behavioral and emotional responses to excessive stressful stimuli (Dunn and Berridge, Brain Res Brain Res Rev, 15, 71, (1990); and Koob et al., Semin Neurosci 6:221 (1994)). For example, restraint stress increases extracellular CRF levels in the CeA, whereas intra-CeA injection of the CRF receptor antagonist α-helical CRF9-41 reduces the symptoms of anxiety behaviors induced by social and environmental stressors (Merali et al., J. Neurosci., 18, 4758, (1998); Merlo Pich et al., J. Neurosci., 15, 5439, (1995); Heinrichs et al., Brain Res., 581, 190 (1992); Swiergiel et al., Brain Res., 623, 229 (1993)). Anxiety and stress-like symptoms are central to drug and alcohol withdrawal syndromes. Given the evidence for the role of CRF neurons in the CeA in regulating the emotional and anxiogenic effects of stress, it is possible that the anxiogenic and stress-like consequences of withdrawal from excessive drug use may similarly be mediated by the CRF system in the CeA.

[0144] Alterations in the regulation of the activity of the CRF system within the CeA may represent a critical neuroadaptive mechanism contributing to the development of dependence and compulsive drug-seeking behaviors.

[0145] The data discussed above identify neuroadaptive changes in brain circuitry and stress system perturbations as important factors in compulsive drug-seeking behavior and dependence. Another important factor in the potential for excessive drug use and long-lasting addiction is the conditioning of rewarding effects by specific environmental stimuli. Environmental cues that are repeatedly associated with the subjective effects of excessive drug use (e.g., alcohol) can elicit drug craving or automatic behavioral responses that may ultimately lead to relapse (Miller and Gold 1994; Tiffany and Carter 1998) (Childress et al., Conditioned craving and arousal in cocaine addiction: A preliminary report, in NIDA Research Monograph 81, (1988); Ehrman et al., Psychopharmacology, 107, 523, (1992); Monti et al., J Stud Alcohol 54:235-45 (1993); Pomerleau et al., Addict. Behav., 8, 1, (1983); Stormark et al., Addict. Behav., 20, 571, (1995); Miller and Gold Ann. Clin. Psychiatry, 6, 99, (1994); and Tiffany and Carter, J Psychopharmacol. 12, 23, (1998)). Thus, learned responses to drug-associated stimuli may contribute critically to the high rates of relapse associated with cocaine and other drug addictions.

[0146] Data from operant responding-reinstatement models developed to study drug-seeking behavior associated with exposure to drug-associated environmental cues in rats indicate that discriminative cues predicting the availability of cocaine, ethanol, or heroin reliably induce robust reinstatement of extinct drug-seeking behavior, even in the absence of further drug availability (Weiss et al., Proc. Natl. Acad. Sci. USA, 97, 4321, (2000); Katner et al., Neuropsychopharmacology, 20, 471, (1999); Katner and Weiss, Alcohol Clin Exp Res. 23:1751 (1999); and Gracy et al., Pharmacol. Biochem. Behav., 65, 489, (2000)). The reinstating effects of such cues are remarkably resistant to extinction with repeated exposure and, in the case of cocaine, can still be observed after several months of enforced abstinence. Furthermore, in the case of ethanol, drug-seeking behavior elicited by ethanol-predictive discriminative cues was found to be stronger in genetically alcohol-preferring (P) rats compared with non-alcohol-preferring (NP) rats and non-choosing Wistar rats (Weiss and Ciccocioppo, Soc. Neurosci. Abstr., 25, 1081, (1999)). This observation indicates that a genetic predisposition to high ethanol intake is also reflected in greater sensitivity to the motivational effects of ethanol cues (i.e., enhanced drug seeking under conditions in which behavior is not directly reinforced by ethanol itself). Taken together, these findings strongly support the hypothesis that learned responses to drug-associated cues are a significant factor in long-lasting relapse susceptibility.

[0147] In humans, relapse risk likely involves multiple interacting determinants. For example, exposure to drug cues may increase relapse susceptibility in dependent individuals, conferred by prolonged withdrawal symptoms due to neuroadaptive changes. Furthermore, there may be an interactive effect between the motivational effects of stress and drug-associated cues that exacerbates relapse risk. A recent study addressing this issue demonstrated an additive interaction between the response-reinstating effects of ethanol-associated cues and stress, and confirmed that this effect was enhanced in rats with a history of ethanol dependence (Liu and Weiss, Soc. Neurosci. Abstr. 26, 786 (2000)).

[0148] In the laboratory, administration of yohimbine, an alpha-2 adrenergic receptor antagonist that increases brain norepinephrine cell firing and release and acts as a pharmacological stressor, has been shown to reinstate drug seeking. Both footshock stress and yohimbine-induced reinstatement of drug-seeking behavior are valid experimental models for studying stress-induced alcohol relapse (Lee et al., Neuropsychopharmacology 29:686-93 (2004) and Le et al., Psychopharmacology 150:317-24 (2000)).

[0149] As shown in the accompanying examples, PDE7 inhibitors significantly reduce stress-induced relapse use of addictive drugs (Example 1). Thus, this data indicates that PDE7 inhibitors have anti-relapse properties.

[0150] Interestingly, various reports have shown that the nonselective opiate receptor antagonist naltrexone reduces the urge to drink elicited by the presentation of an alcohol cue in human alcoholics (Monti et al. 1993, supra) and reduces the effectiveness of alcohol cues in reinstating extinct responses on a previously drug-paired lever in rats (Katner et al. 1999, supra). However, naltrexone does not reduce stress-induced relapse behavior (Le AD Psychopharmacology 1998).

[0151] In a related embodiment, the present invention comprises a method for treating or preventing relapse of addictive drug use or the performance of addictive or compulsive sexual behavior, comprising administering an effective amount of PDE7 inhibitor to the subject who has previously reduced or eliminated the use of addictive drug or the performance of addictive or compulsive sexual behavior in response to exposure to an effective amount of another anti-addictive treatment, and is no longer exposed to an effective amount of the anti-addictive treatment.Anti-addictive treatment can be anti-addictive drug, or non-pharmacological therapy (such as counseling, psychotherapy or hypnotherapy).Relapse of use can also be caused by stress.

[0152] In certain embodiments, the subject is a subject who has become tolerant to an anti-addictive drug and is no longer exposed to an effective amount of the anti-addictive drug because the plasma concentration of the anti-addictive drug that was previously effective in treating addiction is no longer effective. In other embodiments, the subject is a subject who is currently exposed to a low plasma concentration of the anti-addictive drug and is no longer exposed to an effective amount of the anti-addictive drug because the low plasma concentration is no longer effective.

[0153] In certain embodiments of the methods of the present invention, the subject is in a period of abstinence or limited or reduced use of an addictive drug or performance of an addictive or compulsive sexual behavior. The period of abstinence or limited or reduced use can be, for example, at least 24 hours, at least 48 hours, at least 3 days, at least 5 days, at least 1 week, at least 2 weeks, at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 9 months, at least 1 year, at least 2 years, or at least 5 years.

[0154] In another embodiment, the invention includes a method for treating or preventing relapse use of an addictive drug, comprising providing a PDE7 inhibitor and an opioid antagonist to a subject in physiological withdrawal from the addictive drug.

[0155] In a further embodiment, the invention includes a method for treating or preventing relapse to use of an addictive drug, comprising administering a PDE7 inhibitor and a CB1 antagonist, e.g., disulfiram, topiramate, levetiracetam, an SSRI, or ondansetron, to a subject in physiological withdrawal from the addictive drug.

[0156] In certain embodiments, recurrent use is precipitated by stress, environmental conditioning factors, or both.

[0157] The methods of the present invention can be practiced in subjects addicted to a single addictive drug, but can also be used in subjects addicted to more than one addictive drug. Similarly, the methods can be used to prevent relapse to the addictive drug from which the subject is in withdrawal, but can also be adapted to prevent relapse or initiation of use of an addictive drug other than the one from which the subject is in physiological withdrawal.

[0158] D. Pharmaceutical Compositions, Routes of Administration, Unit Dosage Forms, and Kits The present invention has established the effectiveness of the combination of PDE7 inhibitor and one or more additional therapeutic agents, such as opioid antagonists, antidepressants, antiepileptics, antiemetics and CB1 receptor antagonists.Therefore, the present invention also includes the composition comprising one or more PDE7 inhibitors and one or more additional therapeutic agents, such as opioid antagonists, mixed opioid antagonists / partial agonists, antidepressants, antiepileptics, antiemetics, CRF1 receptor antagonists and CB1 receptor antagonists.

[0159] In certain embodiments, the composition comprises one PDE7 inhibitor and one additional therapeutic agent.In some specific embodiments, the additional therapeutic agent is an opioid antagonist or a mixed opioid antagonist / partial agonist.In one embodiment, the opioid antagonist is naltrexone.In another embodiment, the mixed opioid partial agonist / antagonist is buprenorphine.In some specific embodiments, the additional therapeutic agent is an antidepressant.In certain embodiments, the antidepressant is bupropion.In some specific embodiments, the additional therapeutic agent is an antiepileptic, an antiemetic, or an opioid antagonist or a mixed opioid partial agonist / antagonist.

[0160] The compositions of the present invention can be administered to a subject as pharmaceutical compositions or formulations. In certain embodiments, the pharmaceutical compositions of the present invention can be in any form that allows the composition to be administered to a subject. For example, the composition can be in the form of a solid, liquid, or gas (aerosol). Typical administration routes include, but are not limited to, oral, topical, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, epidural, intrasynovial injection, or infusion techniques.

[0161] The pharmaceutical composition used according to the present invention comprises a PDE7 inhibitor, another therapeutic agent, and a pharmaceutically acceptable diluent, excipient, or carrier. "Pharmaceutically acceptable carriers" for therapeutic use are well known in the pharmaceutical arts and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (Edited by AR Gennaro, 1985). For example, sterile saline and phosphate-buffered saline at physiological pH can be used. Preservatives, stabilizers, dyes, and even flavoring agents can be added to the pharmaceutical composition. For example, sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid can be added as preservatives (ibid., p. 1449). Antioxidants and suspending agents can also be used (ibid.).

[0162] The pharmaceutical compositions of the present invention are generally formulated so that the active ingredient contained therein can be bioavailable when administered to a subject. The composition administered to a subject can be in the form of one or more dosage units, where, for example, a tablet, capsule or cachet can be a single dosage unit, and a container containing the pharmaceutical combination of the present invention in aerosol form can contain multiple dosage units.

[0163] In certain embodiments, the composition comprising a PDE7 inhibitor and another therapeutic agent is typically administered in one or more doses in the form of a tablet formulation for oral administration.The tablet formulation can be, for example, an immediate-release formulation, a controlled-release formulation, or a long-term release formulation.In one embodiment, the tablet formulation comprises an effective amount of a composition comprising a PDE7 inhibitor and another therapeutic agent.In certain embodiments, the tablet comprises about 1, 5, 10, 20, 30, 50, 100, 150, 200, 250, or 300 mg of a PDE7 inhibitor and about 1, 5, 10, 20, 30, 50, 100, 150, 200, 250, or 300 mg of another therapeutic agent.

[0164] The present invention further includes unit dosage forms of pharmaceutical compositions comprising a PDE7 inhibitor and another therapeutic agent. Each unit dosage form contains a therapeutically effective amount of the pharmaceutical composition of the present invention, and is used in the recommended amount when used. For example, the unit dosage form may contain a therapeutically effective amount in a single tablet, or the unit dosage form may contain a therapeutically effective amount in two or more tablets, with the prescribed amount constituting a therapeutically effective amount.

[0165] In certain embodiments, the PDE7 inhibitor is provided to the subject in an amount ranging from 0.1 to 1000 mg / day, 1 to 1000 mg / day, 10 to 100 mg / day, or 25 to 50 mg / day. In one embodiment, pioglitazone is provided to the patient at about 30 mg / day.

[0166] The specific combination of PDE7 inhibitor and other therapeutic agent may not be easily compatible with co-formulation.For example, one agent may be more suitable for intravenous administration, while another agent may be more suitable for oral administration.Alternatively, the serum half-life of two agents may be such that one agent must be administered more frequently than the other.Therefore, the present invention contemplates a kit comprising one or more unit dosage forms of PDE7 inhibitor and one or more unit dosage forms of other therapeutic agent, so that the two unit dosage forms can be administered to subjects in a therapeutically effective manner.

[0167] In one embodiment, the present invention comprises a kit comprising a unit dosage form of a PDE7 inhibitor and a unit dosage form of nicotine.In one embodiment, the unit dosage form of nicotine is comprised of a plurality of different unit dosage forms of nicotine, and the different dosage forms of nicotine are in decreasing amounts and can be taken sequentially over time to overcome addiction and achieve withdrawal from nicotine.The unit dosage form of nicotine can be, for example, in the form of a transdermal patch, gum or lozenge.

[0168] E. PDE7 Protein and PDE7 Inhibitors Cyclic nucleotide phosphodiesterase type 7 (PDE7) has been identified as a distinct family based on its primary amino acid sequence and distinct enzymatic activity. The PDE genes identified as PDE7 (PDE7A and PDE7B) encode cAMP-specific PDEs. Biochemical and pharmacological properties of PDE7 reveal that it is a high-affinity cAMP-specific PDE (Km = 0.2 μM) that is unaffected by cGMP or selective inhibitors of other PDEs. PDE7 enzymes selectively degrade cAMP and have been characterized as enzymes that are not inhibited by rolipram, a selective inhibitor of PDE4, a distinct cAMP-specific PDE family. Two subtypes of the PDE7 family have been identified: PDE7A (Michael, T. et al., J. Biol. Chem. 268(17):12925-12932, 1993; Han, P. et al., J. Biol. Chem. 272(26):16152-16157, 1997) and PDE7B (U.S. Patent No. 6,146,876; Gardner, C. et al., Biochem. Biophys. Res. Commun. 272(1):186-192, 2000; and Sasaki, T. et al., Biochem. Biophys. Res. Commun. 271(3):575-583, 2000). The products of the two genes show 70% identity in their C-terminal catalytic domains (Hetman JM et al., PNAS 97(1):472-476 (2000)).

[0169] PDE7A has three splice variants (PDE7A1, PDE7A2, and PDE7A3), which are generated by alternative splicing at both the N- and C-termini (Bloom, TJ, and J.A. Beavo, Proc. Natl. Acad. Sci. USA. 93:14188-14192, 1996). The nucleotide sequence of transcript variant 1, PDE7A, is available in public databases under accession number NM_002603. The human PDE7A1 protein (SEQ ID NO:2, encoded by SEQ ID NO:1) has 456 amino acids and migrates on reducing SDS-PAGE with an apparent molecular weight of 53-55 kDa.

[0170] The nucleotide sequence of transcript variant 2, PDE7A, is available in public databases under accession number NM_002604. The human PDE7A2 protein (SEQ ID NO:4, encoded by SEQ ID NO:3) has 424 amino acids.

[0171] The PDE7A protein has a region of approximately 270 amino acids at its carboxy terminus that shows significant similarity (approximately 23% homology) to homologous regions of other cAMP-hydrolyzing PDEs. This region serves as the catalytic domain. The amino-terminal region of this protein is distinct from that of other PDEs and likely mediates the distinct regulatory properties unique to this enzyme family.

[0172] The protein sequence of human PDE7B is available in the public database under accession number NM_018945 and is shown as SEQ ID NO: 6 (encoded by SEQ ID NO: 5). Three splice variants of PDE7B have been reported: PDE7B1, PDE7B2 and PDE7B3. PDE7B is disclosed in WO01 / 62904 and U.S. Patent No. 6,146,876.

[0173] Both PDE7B2 and PDE7B3 have unique N-terminal sequences. The human PDE7B gene product has an apparent molecular weight of 53-55 kDa on reducing SDS-PAGE (Sasaki, T., Kotera, J., Omori, K., Biochemical J. 361:211-220, 2002). Like PDE7A, PDE7B has a highly conserved region of approximately 270 amino acids at its carboxy terminus, which is shared by all PDEs and serves as the catalytic domain. Like the PDE7A protein, the amino-terminal region of the PDE7B protein is distinct, possibly accounting for the distinct regulatory properties unique to each PDE family. The PDE7B protein shows homology (23%) with other cAMP-dependent PDEs in the catalytic domain. According to WO2004 / 044196, the PDE7B polypeptide is 61% homologous to PDE7A.

[0174] In addition, PDE7A is uniquely localized in mammalian subjects compared with other PDE families.PDE7A expression has been detected in most analyzed tissues, such as brain, heart, kidney, skeletal muscle, spleen and uterus (Bloom et al., PNAS 93:14188, 1996).In the brain, PDE7A is widely distributed in both neuronal and non-neuronal cell populations (Miro et al., Synapse 40:201, 2001).The widespread expression of PDE7A in the brain (for example, basal ganglia and substantia nigra) provides a theoretical basis for the role of PDE7A in brain function.

[0175] In carrying out the method of the present invention, the representative PDE7 inhibitor that inhibits the phosphodiesterase activity of PDE7 includes molecules that bind to PDE7 and inhibit the enzymatic activity of PDE7 (small molecule inhibitors or blocking peptides that bind to PDE7 and reduce its enzymatic activity), and molecules that reduce the expression of PDE7 at the transcriptional level and / or translational level (such as PDE7 antisense nucleic acid molecules, PDE7 specific RNAi molecules and PDE7 ribozymes), thereby preventing PDE7 from cleaving cAMP.PDE7 inhibitors can be used alone as primary therapeutic agents, or in combination with other therapeutic agents (such as dopamine receptor agonists) as adjunctive therapeutic agents to enhance the above-mentioned therapeutic benefits.

[0176] Inhibition of PDE7 is characterized by at least one of the following changes that occur as a result of administration of a PDE7 inhibitor according to the methods of the present invention: inhibition of the formation of 5'-adenosine monophosphate (5'-AMP) by PDE7-dependent enzymatic cleavage of the 3'-phosphodiester bond in cAMP, and a decrease in PDE7 gene or protein expression levels (e.g., as measured by gene expression analysis (e.g., RT-PCR analysis) or protein analysis (e.g., Western blot)).

[0177] In some embodiments, the PDE7 inhibitor is a molecule or composition that inhibits the expression of PDE7A, PDE7B, or both PDE7A and PDE7B, such as an antisense or small inhibitory nucleotide (e.g., siRNA) that specifically hybridizes to intracellular mRNA and / or genomic DNA corresponding to the target PDE7 gene(s) so as to inhibit its transcription and / or translation, or a ribozyme that specifically cleaves the target PDE7 mRNA.

[0178] PDE7 inhibitor efficacy In one embodiment, the PDE7 inhibitors useful in the methods of the present invention are 50 IC of ≦1 μM, preferably about 0.1 μM or less 50and is a compound that is sufficiently potent to inhibit the enzymatic activity of PDE7 (PDE7A, PDE7B, or PDE7A and PDE7B). In one embodiment, the PDE7 inhibitor has an IC of about 0.1 to about 500 nM. 50 In one embodiment, the PDE7 inhibitor has an IC50 of about 1 to about 100 nM. 50 and are effective in inhibiting the enzymatic activity of PDE7 (PDE7A, PDE7B, or PDE7A and PDE7B).

[0179] IC for PDE7 (PDE7A or PDE7B) inhibitors 50 Representative methods for determining β are well known in the art, such as the Scintillation Proximity Assay (SPA) disclosed in Bardelle et al., Anal Biochem 15:275(2):148-55 (1999).

[0180] Selective PDE7A or PDE7B inhibitors In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a PDE7A inhibitor. In one embodiment, the PDE7A inhibitor has an IC of about 0.1 to about 500 nM. 50 In one embodiment, the PDE7A inhibitor has an IC of about 1 to about 100 nM. 50 IC of PDE7A inhibitors 50 A suitable assay for determining PDE7A2 activity uses recombinant human PDE7A2 enzyme expressed in a baculovirus system. This assay is a modification of the SPA assay reported by Bardelle et al. (supra).

[0181] In some embodiments, the PDE7 inhibitor exhibits isozyme-selective activity against PDE7A. A PDE7A-selective inhibitor reduces PDE7A activity by at least 2-fold more than PDE7B activity, more preferably by at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold more. In some embodiments, the PDE7A inhibitor is at least 10-fold (e.g., at least 20-fold, or at least 50-fold, or at least 100-fold) selective for inhibiting PDE7A activity over the enzymatic activity of any other PDE (PDE1-6, 7B, and 8-11).

[0182] In one embodiment, the PDE7B inhibitor has an IC of about 0.1 to about 500 nM. 50 In one embodiment, the PDE7B inhibitor has an IC of about 0.1 to about 500 nM. 50 In one embodiment, the PDE7B inhibitor has an IC of about 1 to about 100 nM. 50 IC of PDE7B inhibitors 50 Methods for measuring are well known in the art, such as the assay disclosed in Bardelle et al. (supra).

[0183] In some embodiments, the PDE7 inhibitor exhibits isozyme-selective activity against PDE7B. A PDE7B-selective inhibitor reduces PDE7B activity by at least 2-fold more than PDE7A activity, more preferably by at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold more. In some embodiments, the PDE7B inhibitor is at least 10-fold (e.g., at least 20-fold, or at least 50-fold, or at least 100-fold) selective for inhibiting PDE7B activity over the enzymatic activity of any other PDE (PDE1-6, 7A, and 8-11).

[0184] PDE7 selectivity over other PDEs In some embodiments, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE1B activity greater than 5-fold (e.g., at least 10-fold, at least 20-fold, or at least 50-fold, or at least 100-fold) the lesser of 50 In other words, the PDE7 inhibitor is more effective (5-fold, 10-fold, 20-fold, 50-fold or 100-fold) in inhibiting the activity of PDE7A or PDE7B (the isozyme of PDE7A or PDE7B on which the PDE7 inhibitor is most effective) than in inhibiting the activity of PDE1B.In the context of this specification, for example, this property can be expressed more simply as the PDE7 inhibitor is more effective (5-fold, 10-fold, 20-fold, 50-fold or 100-fold) in inhibiting the activity of PDE7 than in inhibiting the activity of PDE1B.

[0185] Dual inhibition of both PDE7 and PDE1B may offer additional benefit in the treatment of movement disorders, based on reports that deletion of the PDE1B gene in mice stimulated dopamine metabolism and sensitized the animals to the effects of dopaminergic agonists (Siuciak et al., Neuropharmacology 53(1):113-23 (2007)).

[0186] In some embodiments, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE10 activity greater than 5-fold (e.g., at least 10-fold, or at least 20-fold, or at least 50-fold, or at least 100-fold) the lesser of 50Dual inhibition of PDE7 and PDE10 may provide additional benefits in the treatment of movement disorders. This is based on the report that selective inhibitors of PDE10 cause increased cAMP levels in the striatum (Siuciak JA et al., Neuropharmacology 51(2):386-96 (2006)).

[0187] In some embodiments, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE3 activity greater than 10-fold (e.g., at least 20-fold, at least 50-fold, or at least 100-fold) the lesser of 50 This is because the administration of selective PDE3 inhibitors to patients with heart failure has been shown to increase mortality (Packer M. et al., N Engl J Med. 325(21):1468-75(1991)).

[0188] In some embodiments, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE4 activity greater than 10-fold (e.g., at least 20-fold, at least 50-fold, or at least 100-fold) the lesser of 50 This is because it has been shown that deletion of one of the PDE4 genes in mice leads to cardiomyopathy (Lehnart SE et al., Cell 123(1):25-35 (2005)).

[0189] In some embodiments, PDE7 inhibitors are effective in reducing ED in in vivo assays of PDE4 inhibition (e.g., sedation or inhibition of TNFα levels after endotoxin treatment) and in in vivo assays of PDE7A and PDE7B inhibition (e.g., prevention of relapse to cocaine or other psychostimulant addiction). 50a half-maximal effective dose ("ED") that is greater than 10 times (e.g., at least 20 times, at least 50 times, or at least 100 times) the smaller of 50 According to such embodiments, some compounds having dual PDE4 / PDE7 inhibitory activity are determined to have greater in vivo selectivity for PDE7 than for PDE4, as compared to the PDE4 / PDE7 selectivity of the compounds as determined in in vitro assays.

[0190] In some embodiments, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE3 activity and PDE4 activity greater than 10-fold (e.g., at least 20-fold, at least 50-fold, or at least 100-fold) the smaller of 50 It has.

[0191] In some embodiments, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE8 activity greater than 10-fold (e.g., at least 20-fold, at least 50-fold, or at least 100-fold) the lesser of 50 It has.

[0192] In some embodiments, the PDE7 inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 IC for inhibition of PDE4 activity and PDE8 activity greater than 10-fold (e.g., at least 20-fold, at least 50-fold, or at least 100-fold) the smaller of 50 According to this embodiment, it is found that the PDE family that specifically / preferentially hydrolyzes cAMP includes PDE4, PDE7 and PDE8.

[0193] In some embodiments, the PDE7 inhibitor has an IC 50and IC for inhibition of PDE7B activity 50 IC for inhibition of the activity of PDE1, PDE2, PDE3, PDE4, and PDE8, PDE10, and PDE11 greater than 10 times the smaller of 50 In accordance with this embodiment, it is recognized that the PDE family that specifically / preferentially hydrolyzes cAMP includes PDE4, PDE7, and PDE8, and that the PDE1, PDE2, PDE3, PDE10, and PDE11 families exhibit substantial activity towards both cAMP and cGMP.

[0194] In some embodiments, the PDE inhibitor has an IC 50 and IC for inhibition of PDE7B activity 50 The smaller of these is the IC that the drug has for inhibiting any other PDE enzyme from the PDE1-6 and PDE8-11 enzyme families. 50 The selective PDE7 inhibitor is at least 10-fold less (eg, 20-fold, 50-fold, or 100-fold less) selective than the PDE7 inhibitor.

[0195] Selective PDE7 inhibitors can be identified, for example, by comparing the ability of a drug to inhibit PDE7 (PDE7A, PDE7B, or PDE7A and PDE7B) enzyme activity with the ability of the drug to inhibit PDE enzymes from other PDE families. For example, a drug can be assayed for its ability to inhibit PDE7 activity and its ability to inhibit PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE8, PDE9, PDE10, and PDE11. IC of PDE7 50 IC of each PDE (1–6 and 8–11) isozyme for inhibition (i.e., PDE7A or PDE7B, whichever is more sensitive) 50 The ratio of inhibition can be measured by standard in vitro, in vivo, or ex vivo assays (such as those described herein).

[0196] In some embodiments, PDE7 inhibitor is selective for PDE7 and is substantially inactive against other PDEs (for example, PDE1, PDE2, PDE3, PDE4 and PDE8, PDE10 and PDE11) due to the targeting of PDE7 inhibitor to one or more target tissues (such as brain and / or skeletal muscle).As described herein, PDE7 is uniquely localized in mammalian subjects compared with other PDE families.In the brain, PDE7A is widely distributed in both neuronal and non-neuronal cell populations (for example, basal ganglia and substantia nigra) (Miro et al., Synapse 40:201, 2001).PDE7B is expressed in the striatum in the brain (Reyes-Irisarri et al., Neuroscience 132:1173, 2005).

[0197] Types of PDE7 inhibitors The PDE7 inhibitor can be any type of drug, for example, but not limited to, a chemical compound, a protein or polypeptide, a peptidomimetic, a nucleic acid molecule, or a ribozyme. In some embodiments, the PDE7 inhibitor is a small molecule inhibitor (including natural and synthetic substances) with a low molecular weight (i.e., less than about 450 g / mol), such as a peptide, a peptidomimetic, and a non-peptide inhibitor (such as a chemical compound).

[0198] Chemical compound: The PDE7 inhibitor useful in the method of the present invention includes the drug that can be administered into bloodstream by conventional route (for example, oral, intramuscular, subcutaneous, transdermal, oral, intravenous etc.), and finally be transported through vascular system through blood-brain barrier to brain, thereby inhibiting PDE7.Therefore, for this administration method, the PDE7 inhibitor can pass through blood-brain barrier.The PDE inhibitor described below (for example, has a molecular weight of less than about 450 g / mol and is sufficiently lipophilic) that can pass through blood-brain barrier is useful in the method of the present invention when administered by the route that allows the inhibitor to be transported to brain in bloodstream.

[0199] Below is a description of exemplary PDE7 inhibitors useful in the methods of the present invention. In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in EP1454897, WO2003 / 053975, and US20050148604 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in EP1454897, WO2003 / 053975, and US20050148604 (each of which is expressly incorporated herein by reference in its entirety).

[0200] [ka] It has.

[0201] The substituents for the above compounds are defined as follows:

[0202] A represents N or CR4; B represents a hydrogen atom or a halogen atom. R1 is an optionally substituted C 3~7 represents cycloalkyl or tert-butyl, R2 represents hydrogen, methyl, or ethyl; R3 is hydrogen, nitro, cyano or a halogen atom, NR5R6, C(=X)R7, SO2NR5R6, OR8, NR8CONR5R6, NR8SO2R9, NR8CO2R9, a heteroaryl group, optionally substituted C 1~3 Alkyl, optionally substituted C 1~6 represents alkenyl, or optionally substituted saturated or unsaturated heterocycloalkyl, R4 is hydrogen or C optionally substituted with one or more fluorine atoms. 1~3 represents alkoxy, R5 and R6 are the same or different and are selected from the group consisting of a hydrogen atom, an optionally substituted C 1~6alkyl, optionally substituted heterocycloalkyl, or optionally substituted acyl, or, together with the nitrogen atom to which they are attached, azetidinyl, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino, piperazinyl, or homopiperazinyl, each of which groups represents an optionally substituted C 1~4 Alkyl, OH, C 1~3 optionally substituted with alkoxy, CO2H, NR5R6, oxo group, NR9COR7, or C(=O)R7; R7 is an optionally substituted C 1~6 alkyl, OH, OR8, or NR5R6; R8 is hydrogen, optionally substituted C 1~6 represents an alkyl group, or an optionally substituted heterocycloalkyl; R9 is an optionally substituted C 1~6 represents an alkyl group, X represents O, S or NH.

[0203] With respect to the above compounds, "optionally substituted" includes an optionally substituted straight, branched, or cyclic alkyl group (such as methyl, ethyl, propyl, or cyclohexyl); a hydroxyl group; a cyano group; an alkoxy group (such as methoxy or ethoxy); an optionally substituted amino group (such as amino, methylamino, or dimethylamino); an optionally substituted acyl group (such as acetyl or propionyl); a carboxyl group; an optionally substituted aryl group (such as phenyl or naphthyl); an optionally substituted heteroaryl group (such as phenyl or naphthyl); optionally substituted saturated or unsaturated heterocycloalkyl groups (such as piperazinyl or morpholinyl); optionally substituted carbamoyl groups; optionally substituted amido groups; halogen atoms (such as chlorine, fluorine, or bromine); nitro groups; optionally substituted sulfone groups; optionally substituted sulfonylamido groups; oxo groups; urea groups; and optionally substituted straight-chain, branched, or cyclic alkenyl groups (such as ethenyl, propenyl, or cyclohexenyl).

[0204] R 3 Examples of heteroaryl groups as the heteroaryl group include 5- to 7-membered monocyclic heteroaryl groups having 2 to 8 carbon atoms and 1 to 4 heteroatoms consisting of oxygen, nitrogen, or sulfur atoms, and polycyclic heteroaryl groups containing two or more of the same or different monocyclic compounds fused to each other; examples of such monocyclic and polycyclic heteroaryl groups are pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyridyl, pyrazyl, indolyl, quinolyl, isoquinolyl, and tetrazolyl.

[0205] In one embodiment, the PDE7 inhibitors useful in the present invention have the formula:

[0206] [ka] It has.

[0207] In some other embodiments, the PDE7 inhibitor useful in the methods of the present invention has the formula:

[0208] [ka] It has.

[0209] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention has the formula:

[0210] [ka] It has.

[0211] In other embodiments, the PDE7 inhibitor useful in the methods of the present invention has the formula:

[0212] [ka] It has.

[0213] The preparation of the above compounds is described in EP1454897, WO2003 / 053975, and US20050148604.

[0214] In another embodiment, the PDE7 inhibitor useful in the method of the present invention is selected from the compounds generally or specifically disclosed in US2002 / 0198198, WO2002 / 076953, WO2002 / 074754, WO2006 / 092691, Bioorganic & Medicinal Chemistry Letters 14(2004)4623-4626, and Bioorganic & Medicinal Chemistry Letters 14(2004)4627-4631 (each of which is expressly incorporated herein by reference in its entirety).In one embodiment, the PDE7 inhibitor useful in the method of the present invention is a compound represented by the formula:

[0215] [ka] It has.

[0216] The substituents for the above compounds are defined as follows:

[0217] (a) X1, X2, X3 and X4 are the same or different, N (provided that not more than two of the X1, X2, X3 and X4 groups simultaneously represent nitrogen atoms), or C-R1, wherein R1 is selected from: Q1, or lower alkyl, lower alkenyl, or lower alkynyl (these groups are unsubstituted or substituted with one or several Q2 groups); X5-R5 units wherein X5 is selected from: single bond, lower alkylene, lower alkenylene, or lower alkynylene, optionally interrupted by one or two heteroatoms selected from O, S, S(=O), SO or N, the carbon atoms of which are unsubstituted or substituted by one or several identical or different groups selected from SR, OR, NR, R, =O, =S, or =NR, wherein R and R are the same or different and are selected from hydrogen or lower alkyl; R5 is selected from aryl, heteroaryl, cycloalkyl (optionally interrupted by 1, 2 or 3 heteroatoms selected from C(=O) or O, S, S(=O), SO2 or N), cycloalkenyl (optionally interrupted by 1, 2 or 3 heteroatoms selected from C(=O) or O, S, S(=O), SO2 or N), or a bicyclic group, which are unsubstituted or substituted with one or several groups selected from Q3, heteroaryl, or lower alkyl optionally substituted with Q3; where Q1, Q2 and Q3 are the same or different, selected from hydrogen, halogen, CN, NO2, SO3H, P(=O)(OH)2, OR2, OC(=O)R2, C(=O)OR2, SR2, S(=O)R2, NR3R4, Q-R2, Q-NR3R4, NR2-Q-NR3R4, or NR3-Q-R2, where Q is selected from C(=NR), C(=O), C(=S), or SO2, R is selected from hydrogen or lower alkyl, and R2, R3, and R4 are the same or different; Hydrogen, lower alkyl optionally interrupted by C(=O), (CH2) n -aryl, (CH2) n -heteroaryl, (CH2) n -cycloalkyl (optionally interrupted by C(=O) or by 1 or 2 heteroatoms selected from O, S, S(=O), SO or N, where n is an integer selected from 0, 1, 2, 3 or 4); These groups are unsubstituted or substituted with one or several groups selected from lower alkyl, halogen, CN, CH3, SO3H, SO2CH3, CF3, C(=O)NHSO2CH3, OR6, COOR6, C(=O)R6, NR6R7, C(=O)NR6R7 or SO2NR6R7, where R6 and R7 are the same or different and are selected from hydrogen or lower alkyl, said lower alkyl being optionally substituted with one or two groups selected from OR, COOR or NR8, where R and R8 are hydrogen or lower alkyl, R6 and R7 and / or R3 and R4 together with the nitrogen atom to which they are attached may form a 4-8 membered heterocycle, which may contain one or two heteroatoms selected from O, S, S(=O), SO2 or N, and may be substituted with: a 4-8 membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N and may be substituted with lower alkyl, or lower alkyl, said lower alkyl optionally substituted with OR', NR'R", C(=O)NR'R", or COOR', wherein R' and R" are the same or different and are selected from H, lower alkyl, said lower alkyl optionally substituted with OR or COOR, wherein R is hydrogen or lower alkyl, and R' and R" together with the nitrogen atom to which they are attached may form a 4-8 membered heterocycle, which may contain 1 or 2 heteroatoms selected from O, S, or N; or (b) X is O, S, or NR9, where R9 is selected from hydrogen, CN, OH, NH2, lower alkyl, lower alkenyl, or lower alkynyl, which groups are unsubstituted or cycloalkyl optionally interrupted by one or two heteroatoms selected from O, S, S(=O), SO2, or N, or cycloalkenyl optionally interrupted by one or two heteroatoms selected from O, S, S(=O), SO2, or N, or aryl, heteroaryl, OR 10 , or NR 10 R 11 wherein R 10 and R 11 are the same or different and are selected from hydrogen or lower alkyl; (c) Y is O, S or NR 12 wherein R 12 is selected from hydrogen, CN, OH, NH2, lower alkyl, lower alkenyl, or lower alkynyl, which groups are unsubstituted or cycloalkyl optionally interrupted by one or two heteroatoms selected from O, S, S(=O), SO2, or N, or cycloalkenyl optionally interrupted by one or two heteroatoms selected from O, S, S(=O), SO2, or N, or aryl, heteroaryl, OR 10 , or NR 10 R 11 wherein R 10 and R 11are the same or different and are selected from hydrogen or lower alkyl; (d) Z is CH-NO2, O, S or NR 13 wherein R 13 is hydrogen, CN, OH, NH, aryl, heteroaryl, or cycloalkyl optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO or N, or cycloalkenyl optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO or N, or C(=O)R 14 , C(=O)NR 14 R 15 , OR 14 or lower alkyl, wherein the lower alkyl is unsubstituted or selected from OR 14 Or NR 14 R 15 and substituted with one or several identical or different groups selected from R 14 and R 15 are independently selected from hydrogen or lower alkyl, or R 14 and R 15 may form a 4-8 membered heterocyclic ring together with the nitrogen atom to which they are attached, which heterocyclic ring may contain 1 or 2 heteroatoms selected from O, S or N, and may be substituted with lower alkyl; (e) Z1 is H, CH3, or NR 16 R 17 wherein R 16 and R 17 are the same or different and are hydrogen, CN, aryl, heteroaryl, or cycloalkyl optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO or N, or cycloalkenyl optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO or N, or C(=O)R 14 , C(=O)NR 14 R 15 , OR 14or lower alkyl, wherein the lower alkyl is unsubstituted or selected from OR 14 Or NR 14 R 15 and is substituted with one or more groups selected from R 14 and R 15 is selected from hydrogen or lower alkyl, and R 14 and R 15 and / or R 16 and R 17 may form a 4-8 membered heterocyclic ring together with the nitrogen atom to which they are attached, which heterocyclic ring may contain 1 or 2 heteroatoms selected from O, S or N, and may be substituted with lower alkyl; (f) A is

[0218] [ka] is a ring selected from In the formula, A1, A2, A3, A4, A5 and A6 are the same or different and are O, S, C, C(=O), SO, SO2 or NR 18 wherein R 18 is selected from hydrogen, aryl, heteroaryl, or cycloalkyl optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO2 or N, or cycloalkenyl optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO2 or N, or lower alkyl, wherein the lower alkyl is unsubstituted or selected from aryl, heteroaryl, or cycloalkyl optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO2 or N, or cycloalkenyl optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO2 or N, or CN, NR 19 R 20 , C(=O)NR 19 R 20 , OR 19 , C(=O)R19 or C(=O)OR 19 wherein R 19 and R 20 are the same or different and are selected from hydrogen or lower alkyl; * represents a carbon atom shared by ring A and the main skeletal ring containing X and / or Y; Each carbon atom of ring A is unsubstituted or is a lower alkyl (OR 21 , N.R. 21 R 22 , COOR 21 , or CONR 21 R 22 optionally substituted with), lower haloalkyl, CN, F, =O, SO2NR 19 R 20 , OR 19 , S.R. 19 , C(=O)OR 19 , C(=O)NR 19 R 20 , or NR 19 R 20 wherein R 19 and R 20 are the same or different and are selected from hydrogen or lower alkyl, and the lower alkyl is OR 21 , N.R. 21 R 22 , COOR 21 or CONR 21 R 22 wherein R 21 and R 22 are the same or different and are selected from hydrogen or lower alkyl; R 19 and R 20 and / or R 21 and R 22 may form a 4- to 8-membered heterocycle together with the nitrogen atom to which they are attached; Two atoms of ring A that are not adjacent may be connected by a chain of 2, 3 or 4 carbon atoms, which chain may be interrupted by one heteroatom selected from O, S or N; provided that no more than two of the A1, A2, A3, A4, A5 and A6 groups simultaneously represent a heteroatom; and its tautomeric forms, its racemic forms, its isomers, and its pharmaceutically acceptable derivatives.

[0219] In the above compounds, halogens include fluoro, chloro, bromo, and iodo. Preferred halogens are F and Cl. Lower alkyls include straight-chain and branched-chain carbon chains having 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, isopropyl, and tert-butyl. Lower alkenyls include straight-chain and branched-chain hydrocarbon groups having 2 to 6 carbon atoms and at least one double bond. Examples of such alkenyl groups are ethynyl, 3-butyn-1-yl, 2-ethenylbutyl, and 3-hexen-1-yl. Lower alkynyls include straight-chain and branched-chain hydrocarbon groups having 2 to 6 carbon atoms and at least one triple bond. Examples of such alkynyl groups are ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl. Lower haloalkyls include the above-defined lower alkyls substituted with one or more halogens. An example of a haloalkyl is trifluoromethyl. Aryl is understood to refer to an aromatic carbocyclic ring containing 6 to 10 carbon atoms. An example of an aryl group is phenyl. Heteroaryl includes aromatic rings having 5 to 10 ring atoms, of which 1 to 4 are independently selected from the group consisting of O, S, and N. Representative heteroaryl groups are those having 1, 2, 3, or 4 heteroatoms in a 5- or 6-membered aromatic ring. Examples of such groups are tetrazole, pyridyl, and thienyl. Representative cycloalkyl groups are those containing 3 to 8 carbon atoms. Examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "interrupted" means that a carbon atom in the main chain is replaced with a heteroatom or a group as defined herein. For example, in "cycloalkyl or cycloalkenyl optionally interrupted by C(=O) or one heteroatom selected from O, S, S(=O), SO or N", the term "interrupted" means that the C(=O) or heteroatom can be in place of a carbon atom in the ring. Examples of such groups are morpholine or piperazine.Cycloalkenyl includes 3- to 10-membered cycloalkyl containing at least one double bond. Heterocycle includes heteroaryl as defined above, and cycloalkyl or cycloalkenyl as defined above interrupted by 1, 2, or 3 heteroatoms selected from O, S, S(=O), SO2, or N. Bicyclic substituent refers to two rings, the same or different, selected from aryl, heterocycle, cycloalkyl, or cycloalkenyl, fused together to form the bicyclic substituent. An example of a bicyclic substituent is indolyl.

[0220] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has the formula:

[0221] [ka] It has.

[0222] In other embodiments, the PDE7 inhibitor useful in the methods of the present invention has the formula:

[0223] [ka] It has.

[0224] The preparation of the above compounds is described in US2002 / 0198198, WO2002 / 076953, WO2002 / 074754, WO2006 / 092691, Bioorganic & Medicinal Chemistry Letters 14(2004)4623-4626, and Bioorganic & Medicinal Chemistry Letters 14(2004)4627-4631.

[0225] In another embodiment, the PDE7 inhibitor useful in the method of the present invention is selected from the compounds generally or specifically disclosed in EP1193261, WO2002 / 28847, US20030045557, U.S. Patent No. 7,122,565, Bioorganic & Medicinal Chemistry Letters 14(2004)4607-4613, and Bioorganic & Medicinal Chemistry Letters 14(2004)4615-4621 (each of which is expressly incorporated herein by reference in its entirety).In one embodiment, the PDE7 inhibitor useful in the method of the present invention is a compound of the formula:

[0226] [ka] It has.

[0227] The substituents for the above compounds are defined as follows:

[0228] Y is S or O; R1 is C1~C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, or polycyclic group; each optionally substituted with one or several identical or different X1-R4 groups, where X1 is a single bond, lower alkylene, C2-C6 alkenylene, cycloalkylene, arylene, or a divalent heterocyclic ring, and R4 is (1) to (3) below: (1) H, =O, NO2, CN, halogen, lower haloalkyl, lower alkyl, carboxylic acid bioisostere; (2)COOR5, C(=O)R5, C(=S)R5, SO2R5, SOR5, SO3R5, SR5, OR5; (3) C(=O)NR7R8, C(=S)NR7R8, C(=CH-NO2)NR7R8, C(=N-CN)NR7R8, C(=N-SO2NH2)NR7R8, C(=NR7)NHR8, C(=NR7)R8, C(=NR9)NHR8, C(=NR9)R8, SO2NR7R8, or NR7R8, where R7 and R8 are the same or different, and are selected from the group consisting of OH, R5, R6, C(=O)NR5R6, C(=O)R5, SO2R5, C(=NR9)NHR 10 , C(=NR9)R 10 , C(=CH-NO2)NR9R 10 , C(=N-SO2NH2)NR9R 10 , C(=N-CN)NR9R 10 , or C(=S)NR9R 10 Selected from; R2 is lower alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl; each of which is optionally substituted with one or several identical or different groups selected from the following (1) to (3): (1) H, carboxylic acid bioisostere, lower haloalkyl, halogen, (2) COOR5, OR5, SO2R5, (3) SO2NR 11 R 12 , C(=O)NR 11 R 12 , N.R. 11 R 12 , where R 11 and R 12 are the same or different and are OH, R5, R6, C(=O)NR5R6, C(=O)R5, SO2R5, C(=S)NR9R 10 , C(=CH-NO2)NR9R 10 , C(=N-CN)NR9R 10 , C(=N-SO2NH2)NR9R 10 , C(=NR9)NHR 10 , or C(=NR9)R 10 Selected from; R3 is X2-R'3, where X2 is a single bond or a group selected from C1-C4 alkylene, C2-C6 alkenylene, and C2-C6 alkynylene, each of which is optionally substituted with one or several identical or different groups selected from the following (1) to (3): (1) H, C1-C3 alkyl, C3-C4 cycloalkyl, aryl, heterocycle, ═O, CN, (2) OR5, =NR5; or (3)NR 13 R 14 , where R 13 and R 14 are the same or different and are R5, R6, C(=O)NR5R6, C(=O)R5, SO2R5, C(=S)NR9R 10 , C(=CH-NO2)NR9R 10 , C(=NR9)NHR 10 , or C(=NR9)R 10 Selected from; R'3 is a cycloalkyl, cycloalkenyl, aryl, heterocyclic, or polycyclic group; each is selected from one or several X3-R 17 group, wherein X3 is a single bond, lower alkylene, C2-C6 alkenylene, C2-C6 alkynylene, cycloalkylene, arylene, a divalent heterocycle, or a divalent polycyclic group; R 17 are (1) to (4) below: (1) H, ═O, NO2, CN, lower haloalkyl, halogen, carboxylic acid bioisostere, cycloalkyl, (2)COOR5, C(=O)R5, C(=S)R5, SO2R5, SOR5, SO3R5, SR5, OR5; (3)C(=O)NR 15 R 16 , C(=S)NR 15 R 16 , C(=N-CN)NR 15 R 16 , C(=N-SO2NH2)NR 15 R 16 , C(=CH-NO2)NR 15 R 16, SO2NR 15 R 16 , C(=NR 15 )NHR 16 , C(=NR 15 )R 16 , C(=NR9)NHR 16 , C(=NR9)R 16 , or NR 15 R 16 , where R 15 and R 16 are the same or different and are OH, R5, R6, C(=O)NR5R6, C(=O)R5, SO2R5, C(=S)NR9R 10 , C(=CH-NO2)NR9R 10 , C(=N-CN)NR9R 10 , C(=N-SO2NH2)NR9R 10 , C(=NR9)NHR 10 or C(=NR9)R 10 Selected from: (4) a heterocycle optionally substituted with one or several R5 groups; wherein R5 and R6 are the same or different and are selected from H, lower alkyl, C2-C6 alkenyl, C2-C6 alkynyl, X4-cycloalkyl, X4-cycloalkenyl, X4-aryl, X4-heterocycle, or X4-polycyclic group, wherein X4 is a single bond, lower alkylene, or C2-C6 alkenylene; each is selected from halogen, ═O, COOR 20 , CN, OR 20 , OR 20 O-lower alkyl optionally substituted with C(=O)-lower alkyl, lower haloalkyl,

[0229] [ka] (Wherein, X5 is a single bond or lower alkylene, R 18 , R 19 and R 20 are the same or different and are selected from H or lower alkyl; X6 is optionally substituted with one or several identical or different groups selected from X6-heterocycle, X6-aryl, X6-cycloalkyl, X6-cycloalkenyl, or X6-polycyclic groups, wherein X6 is a single bond or lower alkylene, and these groups are not limited to halogen, COOR 21 , OR 21 , or (CH2) n NR 21 R 22 wherein n is 0, 1, or 2; and R 21 and R 22 are the same or different and are selected from H or lower alkyl; R9 is H, CN, OH, lower alkyl, O-lower alkyl, aryl, heterocycle, SO2NH2, or

[0230] [ka] (Wherein, X5 is a single bond or lower alkylene, R 18 and R 19 are the same or different and are selected from H or lower alkyl. Selected from; R 10 is selected from hydrogen, lower alkyl, cyclopropyl, or heterocycle; or a pharmaceutically acceptable derivative thereof.

[0231] In the above compounds, aryl refers to an unsaturated carbocyclic ring containing only carbon atoms within the ring structure, with the number of carbon atoms being 5 to 10, such as phenyl, naphthyl, or tetrahydronaphthyl. Heterocycle refers to an unsaturated or saturated monocyclic ring containing 1 to 7 carbon atoms within the ring structure and at least one heteroatom, such as nitrogen, oxygen, or sulfur, within the ring structure, preferably 1 to 4 heteroatoms, the same or different, selected from nitrogen, sulfur, and oxygen atoms. Suitable heterocycles include morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, pyrimidinyl, 2- and 3-furanyl, 2- and 3-thienyl, 2-pyridyl, 2- and 3-pyranyl, hydroxypyridyl, pyrazolyl, isoxazolyl, tetrazole, imidazole, triazole, and the like. A polycyclic group includes at least two rings, the same or different, selected from aryl, heterocyclic, cycloalkyl, and cycloalkenyl groups, fused together to form the polycyclic group (e.g., 2- and 3-benzothienyl, 2- and 3-benzofuranyl, 2-indolyl, 2- and 3-quinolinyl, acridinyl, quinazolinyl, indolylbenzo[1,3]dioxolyl, and 9-thioxanthanyl). A bicyclic group includes two rings, the same or different, selected from aryl, heterocyclic, cycloalkyl, and cycloalkenyl, fused together to form the bicyclic group. Halogen refers to fluorine, chlorine, bromine, or iodine. Lower alkyl refers to straight- or branched-chain alkyl containing 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, isobutyl, n-butyl, pentyl, hexyl, and the like. Alkenyl refers to a straight or branched unsaturated carbon atom chain containing one or several double bonds, preferably one or two double bonds. Alkynyl refers to a straight or branched unsaturated carbon atom chain containing one or several triple bonds, preferably one or two triple bonds. Lower haloalkyl refers to a lower alkyl substituted with one or several halogens. Preferred lower alkynylhaloalkyl groups include perhaloalkyl groups (e.g., CF).Cycloalkyl refers to a saturated monocyclic carbocyclic ring containing 3 to 10 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkenyl refers to an unsaturated monocyclic carbocyclic ring containing 3 to 10 carbon atoms. Examples of suitable cycloalkenyls are 3-cyclohexene and 3-cycloheptene. Carboxylic acid bioisosteres have their classical meanings. Common carboxylic acid bioisosteres are tetrazol-5-yl, C(=O)N(H)OH, isoxazol-3-yl, hydroxythiadiazolyl, sulfonamide, sulfonylcarboxamide, phosphonic acid, phosphonamide, phosphinic acid, sulfonic acid, acylsulfonamide, mercaptoazole, and acylcyanamide.

[0232] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has the formula:

[0233] [ka] It has.

[0234] In other embodiments, the PDE7 inhibitor useful in the methods of the present invention has the formula:

[0235] [ka] It has.

[0236] The preparation of the above compounds is described in EP1193261, WO02 / 28847, US20030045557, U.S. Pat. No. 7,122,565, Bioorganic & Medicinal Chemistry Letters 14(2004)4607-4613, and Bioorganic & Medicinal Chemistry Letters 14(2004)4615-4621.

[0237] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds disclosed generally or specifically in WO2004 / 111054, US20060128728, and US20070270419 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds disclosed generally or specifically in WO2004 / 111054, US20060128728, and US20070270419 (each of which is expressly incorporated herein by reference in its entirety).

[0238] [ka] It has.

[0239] The substituents for the above compounds are defined as follows:

[0240] R1 is a substituted or unsubstituted C 3~8 a cycloalkyl group or a tert-butyl group; R2 is a hydrogen atom or C 1~3 is an alkyl group; R3 is NR5R6, C(=O)R7, or S(O) 0~2 is an R8 group; R4 is a hydrogen atom or a C 1~3 is an alkoxyl group; R5 and R6 are the same or different from each other and are each a hydrogen atom, a substituted or unsubstituted C 1~6 alkyl groups, substituted or unsubstituted acyl groups, substituted or unsubstituted heterocycloalkyl groups, and substituted or unsubstituted heterocycloalkyl rings (formed together with the nitrogen atom bound to R5 and R6); R7 is an OR9 or NR5R6 group; R8 is a hydrogen atom, a halogen atom, an NR5R6 group, a substituted or unsubstituted C 1~6 is an alkyl group, or a substituted or unsubstituted aryl group; R9 is a hydrogen atom or a substituted or unsubstituted C 1~6 is an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.

[0241] With respect to the above compounds, the term "C1-C3 alkyl group" includes straight-chain or branched-chain alkyl groups having 1 to 3 carbon atoms. The term "C3-C8 cycloalkyl group" includes cycloalkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. The term "heterocycloalkyl group" refers to a 3- to 7-membered heterocyclic group containing 1 to 4 identical or different heteroatoms (oxygen, nitrogen, or sulfur atoms), examples of which may include pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, and azetidinyl. The term "C1-C3 alkoxy group" refers to an alkoxy group having 1 to 3 carbon atoms. The term "acyl group" refers to an acyl group having 1 to 8 carbon atoms. The term "aryl group" refers to a phenyl, naphthyl, or biphenyl group having 6 to 12 carbon atoms. The term "heteroaryl group" refers to a 5- to 7-membered monocyclic or polycyclic group containing 2 to 8 carbon atoms and 1 to 4 heteroatoms (oxygen, nitrogen, or sulfur atoms), which may be the same or different. Examples include pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridinyl, pyrazolylpyridazinyl, and pyrimidinyl. Suitable examples of substituents for the "substituted or unsubstituted C1-C6 alkyl group" include a hydroxyl group and a halogen atom, and suitable examples of substituents for the "substituted or unsubstituted acyl group" include a halogen atom and a nitro group. Furthermore, suitable examples of substituents for the "substituted or unsubstituted aryl group" include a C1-C3 alkyl group, a halogen atom, an amino group, an acyl group, an amido group, a hydroxyl group, an acylamino group, a carboxyl group, and a sulfonyl group.Examples of suitable substituents for the "substituted or unsubstituted C3 to C8 cycloalkyl group" include C1 to C3 alkyl, a hydroxyl group, and an oxo group, and examples of suitable substituents for the "substituted or unsubstituted heterocycloalkyl group" include a carboxy group, an acyl group, an alkoxy group, an amino group, an alkylamino group, an acylamino group, a hydroxyl group, an oxo group, an ethylenedioxy group, a methyl group, an ethyl group, and a hydroxyethyl group.

[0242] In other embodiments, the PDE7 inhibitor useful in the methods of the present invention has the formula:

[0243] [ka] It has.

[0244] The preparation of the above compounds is described in WO2004 / 111054, US20060128728, and US20070270419.

[0245] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 6,903,109, U.S. Patent No. 20040082578, WO2003 / 088963, and U.S. Patent No. 20060154949 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound represented by the formula:

[0246] [ka] It has.

[0247] The substituents for the above compounds are defined as follows:

[0248] (a) R1 is selected from the group consisting of (i) to (vi) below: (i) COR5, where R5 is H, optionally substituted C 1~8selected from straight or branched chain alkyl, optionally substituted aryl, and optionally substituted arylalkyl; the substituents on the alkyl, aryl, and arylalkyl groups are selected from C 1~8 Alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21 wherein R 20 and R 21 are independently hydrogen, C 1~8 Straight or branched chain alkyl, C 3~7 selected from the group consisting of cycloalkyl, benzyl, or aryl; (ii) COOR6, where R6 is H, optionally substituted C 1~8 selected from straight or branched chain alkyl, optionally substituted aryl, and optionally substituted arylalkyl; the substituents on the alkyl, aryl, and arylalkyl groups are selected from C 1~8 Alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21 wherein R 20 and R 21 are independently hydrogen, C 1~8 Straight or branched chain alkyl, C 3~7 selected from the group consisting of cycloalkyl, benzyl, or aryl; (iii) cyano; (iv) lactone or lactam formed with R4; (v) CONR7R8, wherein R7 and R8 are independently H, C 1~8 Straight or branched chain alkyl, C 3~7selected from cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl, and heterocyclyl; said alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl, and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy, or arylalkyl; Alternatively, R7 and R8 together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group; (vi) carboxylic acid esters or carboxylic acid bioisosteres containing optionally substituted heteroaryl groups; (b) R2 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3~7 cycloalkyl, optionally substituted heterocyclyl, wherein the heterocyclyl is 1,3-dioxolane or furan, or R2 is

[0249] [ka] is; (c) R3 is independently 1 to 4 groups selected from the group consisting of the following (i) to (iii): (i) Hydrogen, Halo, C 1~8 Straight or branched chain alkyl, aryl alkyl, C 3~7 Cycloalkyl, C 1~8 Alkoxy, Cyano, C 1~4 Carboalkoxy, trifluoromethyl, C 1~8 Alkyl sulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1~8 carboxylates, aryl, heteroaryl, and heterocyclyl; (ii)NR 10 R 11 , where R 10 and R 11 are independently H, C 1~8 Straight or branched chain alkyl, aryl alkyl, C 3~7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, or heterocyclyl, or R 10 and R 11 together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group; (iii)NR 12 COR 13 , where R 12 is selected from hydrogen or alkyl, and R 13 is hydrogen, alkyl, substituted alkyl, C 1~3 Alkoxyl, carboxyalkyl, R 30 R 31 N(CH2) p , R 30 R 31 NCO(CH2) p , aryl, arylalkyl, heteroaryl, or heterocyclyl, or R 12 and R 13 together with the carbonyl group form a carbonyl-containing heterocyclyl group, where R 30 and R 31 is independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1 to 6, wherein the alkyl group is optionally substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy, or arylalkyl; (d) R4 is (i) hydrogen, (ii) C 1~3 (iii) straight or branched chain alkyl, and (iv) NR 13 R 14 (In the formula, R 13 and R 14 are independently hydrogen and C 1~6alkyl); 1~3 Alkyl and benzyl groups are C 3~7 Cycloalkyl, C 1~8 Alkoxy, Cyano, C 1~4 Carboalkoxy, trifluoromethyl, C 1~8 Alkyl sulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1~8 Carboxylate, Amino, NR 13 R 14 , aryl, and heteroaryl; and (e) X is selected from S and O; and pharmaceutically acceptable salts, esters and prodrug forms thereof.

[0250] In an alternative embodiment, R1, R3 and R4 are as described above and R2 is NR 15 R 16 where R 15 and R 16 are independently hydrogen, C 1~8 Straight or branched chain alkyl, aryl alkyl, C 3~7 cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R 15 and R 16 together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group.

[0251] In reference to the above compounds, "alkyl" refers to straight-chain, cyclic, and branched-chain alkyl. The alkyl group may be optionally substituted with one or more groups, such as halogen, OH, CN, mercapto, nitro, amino, C1-C8 alkyl, C1-C8 alkoxyl, C1-C8 alkylthio, C1-C8 alkyl-amino, di(C1-C8 alkyl)amino, (mono-, di-, tri-, and per-)haloalkyl, formyl, carboxy, alkoxycarbonyl, C1-C8 alkyl-CO—O—, C1-C8 alkyl-CO—NH—, carboxamido, hydroxamic acid, sulfonamido, sulfonyl, thiol, aryl, aryl(C1-C8)alkyl, heterocyclyl, and heteroaryl. The term "bioisostere" is defined as "a group or molecule having chemical and physical properties that result in broadly similar biological properties" (Burger's Medicinal Chemistry and Drug Discovery, M.E. Wolff, ed., 5th ed., Vol. 1, 1995, p. 785). The term "acyl," as used herein, whether alone or as part of a substituent group, refers to an organic group (branched or straight-chain) having 2 to 6 carbon atoms derived by removal of a hydroxyl group from an organic acid. "Aryl" or "Ar," whether alone or as part of a substituent group, refers to a carbocyclic aromatic group, including, but not limited to, phenyl, 1- or 2-naphthyl, and the like. The carbocyclic aromatic group may be substituted by one to five independent substitutions of hydrogen atoms on the group with halogen, OH, CN, mercapto, nitro, amino, C1-C8 alkyl, C1-C8 alkoxyl, C1-C8 alkylthio, C1-C8 alkyl-amino, di(C1-C8 alkyl)amino, (mono-, di-, tri-, and per-)haloalkyl, formyl, carboxy, alkoxycarbonyl, C1-C8 alkyl-CO—O—, C1-C8 alkyl-CO—NH—, or carboxamido.Illustrative examples of aryl groups include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carbethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl, and the like. The term "heteroaryl" refers to a cyclic, fully unsaturated group having 5 to 10 ring atoms, of which one ring atom is selected from S, O, and N; 0 to 2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The group may be attached to the rest of the molecule through any ring atom. The terms "heterocycle," "heterocyclic," and "heterocyclic ring" refer to an optionally substituted fully or partially saturated cyclic group, such as a 4- to 7-membered monocyclic, a 7- to 11-membered bicyclic, or a 10- to 15-membered tricyclic ring system, containing at least one heteroatom within a ring containing at least one carbon atom. Each ring of a heteroatom-containing heterocyclic group can have one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur atoms, and the nitrogen and sulfur heteroatoms can be optionally oxidized. The nitrogen atom can be optionally quaternized. The heterocyclic group can be bonded at any heteroatom or carbon atom.

[0252] In other embodiments, the PDE7 inhibitor useful in the methods of the present invention has the formula:

[0253] [ka] It has.

[0254] The preparation of the above compounds is described in US Pat. No. 6,903,109, US20040082578, WO2003 / 088963, and US20060154949.

[0255] In another embodiment, the PDE7 inhibitor useful in the method of the present invention is selected from the compounds generally or specifically disclosed in US Patent No. 6,958,328, WO2002 / 085894 and US20030212089 (each of which is expressly incorporated herein by reference in its entirety).These PDE7 inhibitors have the same formula as those described above (for example, US Patent No. 6,903,109), except that R1 is not carboxylic acid ester or carboxylic acid bioisostere.The preparation of such compounds is described in US Patent No. 6,958,328, US20030212089 and WO2002 / 085894.

[0256] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds disclosed generally or specifically in WO2006 / 004040 and EP1775298 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0257] [ka] It has.

[0258] The substituents for the above compounds are defined as follows:

[0259] R1 is a substituted or unsubstituted C 3~8 an alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group (e.g., cyclohexyl, cycloheptyl, or tetrahydropyranyl); R2 is a hydrogen atom or a substituted or unsubstituted C 1~3 is an alkyl group (e.g., methyl); R3 is a hydrogen atom, a substituted or unsubstituted C 1~3 is an alkyl group, or a halogen atom; and R4 is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a CONR5R6 or CO2R7 group; In the formula, R5 and R6 are the same or different from each other and represent a hydrogen atom; 1~6 Alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted heterocycloalkyl groups, substituted or unsubstituted cycloalkyl groups, NR7COR8, COR8, NR9R 10 a substituted or unsubstituted cycloalkyl group; a substituted or unsubstituted heterocycloalkyl group; a substituted or unsubstituted aryl group; a substituted or unsubstituted heteroaryl group; or a substituted or unsubstituted heterocycloalkyl group in which a ring is formed together with the nitrogen atom connecting R5 and R6; In the formula, R7 is a hydrogen atom or a substituted or unsubstituted C 1~3 is an alkyl group; wherein R8 is a substituted or unsubstituted heterocycloalkyl group, or an OH group, OR7, or NR9R 10 is; In the formula, R9 and R 10 are the same or different from each other, and are hydrogen atoms; substituted or unsubstituted C 1~3 an alkyl group, a substituted or unsubstituted heterocycloalkyl group; a substituted or unsubstituted acyl; a SO2R7 group, or a substituted or unsubstituted heterocycloalkyl group in which a ring is formed together with the nitrogen atom connecting R5 and R6; or a pharmaceutically acceptable salt or solvate thereof.

[0260] In the above compounds, the term "cycloalkyl group" refers to a cycloalkyl group having 3 to 8 carbon atoms. The term "heterocycloalkyl group" can be a 3- to 7-membered monocyclic or polycyclic heterocyclic group containing 1 to 4 identical or different heteroatoms (oxygen, nitrogen, or sulfur atoms). Examples include piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, azetidinyl, imidazolidinyl, oxazolidinyl, hexahydropyrrolidinyl, octahydroindolizinyl, octahydroquinolidinyl, octahydroindolyl, and their oxo derivatives. The term "aryl group" refers to aromatic hydrocarbon groups consisting of a benzene ring or linked or fused benzene rings (e.g., phenyl, naphthyl, biphenyl, etc.); and bicyclic or tricyclic groups consisting of a benzene ring fused to a cycloalkyl or heterocycle (e.g., 1,2,3,4-tetrahydronaphthalene, 2,3-dihydroindene, indoline, coumarone, etc.). The term "heteroaryl group" refers to 5- to 7-membered monocyclic or polycyclic heteroaryl groups having 2-8 carbon atoms and 1-4 heteroatoms (oxygen, nitrogen, sulfur atoms), the polycyclic heteroaryl groups having fused ring systems with the same or different monocyclic heteroaryl or benzene rings, or the polycyclic groups consisting of a heteroaryl group fused to a cycloalkyl or heterocycloalkyl ring.Examples of suitable substituents of the present invention include linear, branched, or cyclic C1-C8 alkyl groups (which may be substituted with one or more methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, cyclohexyl, cycloheptyl, methoxymethyl, hydroxymethyl, trifluoromethyl, C1-C3 alkoxy groups, halogen atoms, and hydroxyl groups); hydroxyl groups; cyano groups; substituted or unsubstituted alkoxy groups (such as methoxy and ethoxy groups); amino groups (which may be substituted with C1-C6 alkyl groups or acyl groups (such as amino, methylamino, ethylamino, dimethylamino, and acylamino)); may include); carboxylic acid groups; substituted or unsubstituted ester groups; phosphoric acid groups; sulfonic acid groups; substituted or unsubstituted aryl groups; substituted or unsubstituted heteroaryl groups; saturated or unsaturated heterocycloalkyl groups (which may be substituted); substituted or unsubstituted carbamoyl groups; substituted or unsubstituted amido groups; substituted or unsubstituted thioamide groups; halogen atoms; nitro groups; substituted or unsubstituted sulfone groups; substituted or unsubstituted sulfonylamido groups; oxo groups; substituted or unsubstituted urea groups; linear, branched, or cyclic alkenyl groups (such as ethenyl, propenyl, cyclohexenyl, etc.), and the like.

[0261] In other embodiments, the PDE7 inhibitor useful in the methods of the present invention has the formula:

[0262] [ka]

[0263] [ka] It has.

[0264] The preparation of the above compounds is described in EP1775298 and WO2006 / 004040.

[0265] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in WO2004 / 111053 and US20060128707 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in WO2004 / 111053 and US20060128707 (each of which is expressly incorporated herein by reference in its entirety).

[0266] [ka] It has.

[0267] The substituents for the above compounds are defined as follows:

[0268] A is N or CR4; B is N or CH; R1 is a substituted or unsubstituted C 3~8 a cycloalkyl group or a tert-butyl group; R2 is a hydrogen atom or C 1~6 is an alkyl group; R3 is a hydrogen atom; a nitro group; a cyano group; a halogen atom; a heteroaryl group; a substituted or unsubstituted C 1~6 Alkyl group; substituted or unsubstituted C 2~6 alkenyl groups; substituted or unsubstituted saturated or unsaturated heterocycloalkyl groups; NR5R6, C(O)R7, SO2R7, OR8, NR8COR7, NR8SO2R7 groups; R4 is a hydrogen atom or a C 1~3 is an alkoxy group; R5 and R6 are the same or different from each other and are each a hydrogen atom; a substituted or unsubstituted C 1~6 an alkyl group; a substituted or unsubstituted acyl group; or a substituted or unsubstituted heterocycloalkyl group; R7 is a hydrogen atom; a substituted or unsubstituted C 1~6 an alkyl group; a substituted or unsubstituted heterocycloalkyl group; OH; OR or NR; R8 is a hydrogen atom, a substituted or unsubstituted C 1~6 an alkyl group; or a substituted or unsubstituted heterocycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof.

[0269] With respect to the above compounds, the term "C 1~ "C6 alkyl group" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, 2~ The term "C6 alkenyl group" refers to a straight-chain or branched-chain alkenyl group having 2 to 6 carbon atoms. The term "cycloalkyl group" refers to a cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "heterocycloalkyl group" refers to a 3 to 7-membered heterocyclic group containing 1 to 4 identical or different heteroatoms (oxygen, nitrogen, or sulfur atoms), examples of which may include piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, azetidinyl, and homopiperazinyl. The term "heteroaryl group" refers to a 5 to 7-membered monocyclic or polycyclic group containing 2 to 8 carbon atoms and 1 to 4 identical or different heteroatoms (oxygen, nitrogen, or sulfur atoms). Examples include pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl, pyridazinyl, and pyrimidinyl. "Halogen atoms" include fluorine, chlorine, bromine, and iodine. "Substituted or unsubstituted C 1~Examples of suitable substituents for the "C6 alkyl group," "substituted or unsubstituted C3-C8 cycloalkyl group," "substituted or unsubstituted alkenyl group," "substituted or unsubstituted heterocycloalkyl group," and "substituted or unsubstituted acyl group" include straight-chain or branched, or substituted or unsubstituted alkyl groups (methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, etc.), substituted or unsubstituted cycloalkyl groups (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); hydroxyl groups; cyano groups; alkoxy groups (methoxy, ethoxy, etc.). substituted or unsubstituted amino groups (such as amino, methylamino, ethylamino, and dimethylamino); substituted or unsubstituted acyl groups (such as acetyl and propionyl); substituted or unsubstituted aryl groups; substituted or unsubstituted heteroaryl groups; substituted or unsubstituted saturated or unsaturated heterocycloalkyl groups; substituted or unsubstituted carbamoyl groups; substituted or unsubstituted amido groups; halogen atoms; nitro groups; substituted or unsubstituted sulfone groups; oxo groups; urea groups; and substituted or unsubstituted straight-chain, branched-chain, or cyclic alkenyl groups (such as ethenyl, propenyl, and cyclohexenyl).

[0270] In other embodiments, the PDE7 inhibitor useful in the methods of the present invention has the formula:

[0271] [ka] It has.

[0272] The preparation of the above compounds is described in US20060128707 and WO2004 / 111053.

[0273] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 6,617,357, US20020156064, and Molecular Pharmacology, 66:1679-1689, 2004 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 6,617,357, US20020156064, and Molecular Pharmacology, 66:1679-1689, 2004 (each of which is expressly incorporated herein by reference in its entirety).

[0274] [ka] It has.

[0275] The substituents for the above compounds are defined as follows:

[0276] R1 is NR a R b where R a and R b are independently H or C 1~6 is alkyl or represents a 5- to 7-membered ring composed of carbon or carbon and one or more additional heteroatoms selected from O, N or S; R2 is H, C 1~8 Alkyl, C 1~3 Alkyl-Ar, C 1~3 Alkyl-C 3~6 Cycloalkyl, C 2~8 Alkenyl, C 2~4 Alkenyl-Ar, or C 2~4 Alkenyl-C 3~6 cycloalkyl, wherein Ar is substituted or unsubstituted phenyl; R3 is NO2, halo, CN, C(O)OR7, COR1, or NR a R b where R a and R b are independently H or C 1~6 is alkyl; R4 is H, OC 1~6 Alkyl, halo, C(O)NR a R b, C(O)OR7, C 1~8 Alkyl, OCHF2, CH2OR8, OC 1~3 alkyl-Ar, or CH2NHC(O)CH3; R5 is H, halo, or alkyl; R6 is C 1~8 Alkyl, OC 1~4 alkyl, or halo; R7 is hydrogen or an ester- or amide-forming group; R8 is hydrogen or C 1~6 is alkyl; or a pharmaceutically acceptable salt or solvate thereof.

[0277] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has the formula:

[0278] [ka] It has.

[0279] The preparation of the above compounds is described in US Pat. No. 6,617,357, US20020156064, and Molecular Pharmacology, 66:1679-1689, 2004.

[0280] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 6,852,720, EP 1348433, and WO 2003 / 082277 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound represented by the formula:

[0281] [ka] It has.

[0282] The substituents for the above compounds are defined as follows:

[0283] R1 is a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, which groups are, independently of one another, halogen, trifluoromethyl, nitro, cyano, oxo, NR4R5, CO2R4, CONR4R5, OR4, S(O) n R4, S(O) n optionally substituted with one or more groups, which may be the same or different, selected from NR4R5, tetrazolyl and (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted with 1 to 3 groups, which may be the same or different, selected from OR4, NR4R5 and CO2R4, independently of one another; wherein n is an integer from 0 to 2 (inclusive), R4 and R5 are the same or different and are each independently a hydrogen atom or a group of the formula X1-R a wherein X1 is a single bond or a (C1-C6) alkylene group, and R a is a group selected from (C1-C6) alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R2 is a group selected from (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, aryl, and cycloalkyl; R3 is a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, which groups are, independently of one another, halogen, nitro, cyano, trifluoromethyl, oxo, (C1-C6) alkyl, OR6, NR6R7, COR6, CO2R6, CONHOH, CONR6R7, S(O) m R6, S(O) m and one or more identical or different groups optionally substituted selected from NR6R7, NR6COR7, NR6SO2R7, N(SO2R7)2, NR6CONR7R8, C(=NCN)NR6R7, NR8C(=NCN)NR6R7, and tetrazolyl (optionally substituted with (C1-C4)alkyl), wherein m is an integer from 0 to 2 inclusive, and R6 and R7 are the same or different and independently represent a hydrogen atom or a group of formula X2R bwherein X2 is a single bond or a (C1-C6) alkylene group, and R b is a group selected from (C1-C6) alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl (these groups are optionally substituted with 1 to 3 identical or different groups selected from hydroxy, (C1-C6) alkoxy, (C1-C6) alkyl, amino, mono(C1-C6) alkylamino, di(C1-C6) alkylamino (each alkylamino is the same or independently different from each other), carboxy, (C1-C6) alkoxycarbonyl and benzyl), and R8 represents a hydrogen atom or a (C1-C6) alkyl group; its racemic form, its isomers, its N-oxide, or its pharmaceutically acceptable acid or base salt.

[0284] The preparation of the above compounds is described in US Pat. No. 6,852,720, EP 1348433, and WO 2003 / 082277.

[0285] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 6,753,340, U.S. Patent No. 20030191167, EP1348701, and WO2003 / 082839 (each of which is expressly incorporated herein by reference in its entirety).In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound represented by the formula:

[0286] [ka] It has.

[0287] The substituents for the above compounds are defined as follows:

[0288] R 1a is a group selected from hydrogen, (C1-C6) alkyl and aryl(C1-C6) alkyl, R 1bis a cycloalkyl, heterocycloalkyl, aryl and heteroaryl These groups are, independently of one another, halogen, trifluoromethyl, nitro, cyano, oxo, NR4R5, CO2R4, CONR4R5, OR4, S(O) n R4, S(O) n optionally substituted with one or more groups, which may be the same or different, selected from NR4R5, tetrazolyl, and (C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted with 1 to 3 groups, which may be the same or different, selected from OR4, NR4R5, and CO2R4, independently of one another, wherein n is an integer from 0 to 2 (inclusive), and R4 and R5 are the same or different and are each independently a hydrogen atom or a group of the formula X1-R a wherein X1 is a single bond or a (C1-C6) alkylene group, and R a is a group selected from (C1-C6) alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R2 is a group selected from (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, aryl and cycloalkyl; R3 is cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. These groups are, independently of one another, halogen, nitro, cyano, trifluoromethyl, oxo, (C1-C6) alkyl, OR6, NR6R7, COR6, CO2R6, CONHOH, CONR6R7, S(O) m R6, S(O) m optionally substituted with one or more identical or different groups selected from NR6R7, NR6COR7, NR6SO2R7, N(SO2R7)2, NR6CONR7R8, C(=N-CN)NR6R7, NR8C(=N-CN)NR6R7, and tetrazolyl (optionally substituted with (C1-C4)alkyl), wherein m is an integer from 0 to 2 inclusive, and R6 and R7 are the same or different and independently represent a hydrogen atom or a group of formula X2-Rb wherein X2 is a single bond or a (C1-C6) alkylene group, and R b is a group selected from (C1-C6) alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl (which groups are optionally substituted independently with 1 to 3 identical or different groups selected from hydroxy, (C1-C6) alkoxy, (C1-C6) alkyl, amino, mono(C1-C6) alkylamino, di(C1-C6) alkylamino (each alkylamino is the same or independently different from each other), carboxy, (C1-C6) alkoxycarbonyl and benzyl), and R8 is a hydrogen atom or a (C1-C6) alkyl group; or its racemic form, its isomers, its N-oxides or its pharmaceutically acceptable acid or base salts.

[0289] The preparation of such compounds is described in US Pat. No. 6,753,340, US20030191167, EP1348701, and WO2003 / 082839.

[0290] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 6,849,638, US20030119829, and WO2002 / 088138 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound represented by the formula:

[0291] [ka] It has.

[0292] The substituents for the above compounds are defined as follows:

[0293] R1 and R2 are independently selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, fully saturated heterocycle of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S and O, aryl of 6 to 12 carbon atoms, which may be substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and the number of halogen atoms up to the perhalo level, haloalkoxy of 1 to 6 carbon atoms and the number of halogen atoms up to the perhalo level, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 or 2 heteroatoms selected from N, S and O, heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S and O, and the substituents may be substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and the number of halogen atoms up to the perhalo level, haloalkoxy of 1 to 6 carbon atoms and the number of halogen atoms up to the perhalo level, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 or 2 heteroatoms selected from N, S and O, and heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S and O, and the substituents may be substituted with and R4-R5 or R1 and R2 are bonded together with the nitrogen atom to form a 5-7 membered saturated ring, which may contain 1-2 additional heteroatoms selected from the group consisting of NH, NR8, S, and O; or R4-R5 or R1 and R2 are bonded together with the nitrogen atom to form a 5-7 membered unsaturated ring, which may contain 1-2 additional heteroatoms selected from the group consisting of N, S, and O; or R4-R5 or R1 and R2 are bonded together with the nitrogen atom to form a 5-7 membered unsaturated ring, which may contain 1-2 additional heteroatoms selected from the group consisting of N, S, and O; The saturated or unsaturated ring may be selected from the group consisting of OH, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, fully saturated heterocycle of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S and O, halogen, haloalkyl of 1 to 2 carbon atoms and up to a perhalo level of halogen atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, and R-R 10 or may be substituted with 1 to 2 substituents selected from the group consisting of R1 and R2 are joined together with the nitrogen atom to which they are attached to form an 8- to 10-membered bicyclic saturated ring; R3 is selected from the group consisting of NH, S, S(=O)2 and O; R4 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, C(=C), S(=O)2, and C(=O)O; R5 is selected from hydrogen, OH, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, aryl of 6 to 12 carbon atoms, which are selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level, haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level, aryl of 6 to 12 carbon atoms, and heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, and heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O. It may be substituted with a heteroaryl having 1 to 2 selected heteroatoms, and the substituents may be alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms and heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S and O, cycloalkyl of 3 to 7 carbon atoms, fully saturated heterocyclic ring of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S and O, and NR6R7. R6 and R7 are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and alkynyl of 2 to 8 carbon atoms, or R6 and R7 are joined together with the nitrogen atom to which they are attached to form a 5-7 membered unsaturated ring, which may contain 1-2 additional heteroatoms selected from N, S, and O, or R6 and R7 are joined to form a 5-7 membered saturated ring, which may contain 1-2 additional heteroatoms selected from NH, S, and O; R8 is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, R 11 -R12 , cycloalkyl of 3 to 7 carbon atoms, fully saturated heterocycle of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S and O, aryl of 6 to 12 carbon atoms, which are selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level, haloalkoxy of 1 to 6 carbon atoms and up to a perhalogen level, aryl of 6 to 12 carbon atoms or 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S and O heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, which may be substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O; R9 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and alkynyl of 2 to 8 carbon atoms; R 10is selected from OH, aryl of 6 to 12 carbon atoms, which are alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S and O, and heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S and O. and O, which may be substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O; R 11 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and alkynyl of 2 to 8 carbon atoms; and R 12is selected from cycloalkyl of 3 to 7 carbon atoms, fully saturated heterocycle of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S and O, aryl of 6 to 12 carbon atoms, which are selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalogen level of halogen atoms, aryl of 6 to 12 carbon atoms or aryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S and O and heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, which may be substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalogen level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O; and pharmaceutically acceptable salts thereof.

[0294] The preparation of such compounds is described in US Pat. No. 6,849,638, US20030119829, and WO2002 / 088138.

[0295] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in US2005222138 and WO2003 / 064389 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound represented by the formula:

[0296] [ka] It has.

[0297] The substituents for the above compounds are defined as follows:

[0298] R1 and R2 are each independently (1) a hydrogen atom or (2) C 1~8 is alkyl, or R1 and R2 together with the carbon atoms to which they are attached may form Cyc1; In the formula, R1 and R2 cannot simultaneously be hydrogen atoms; Z is (1) CR3R4, (2) O, (3) S, or (4) a bond; R3 and R4 each independently represent (1) a hydrogen atom, (2) C 1~8 Alkyl, (3)C 1~8 alkoxy, or (4) hydroxy; R3 and R4 together with the carbon atom to which they are attached may form Cyc1 or C(O); R5 and R6 each independently represent (1) a hydrogen atom or (2) C 1~8 alkyl, or R5 and R6 together with the carbon atom to which they are attached may form Cyc1; Cyc1 is represented by R1 and R2, R3 and R4, and R5 and R6, each of which independently represents (1) C 3~10 cycloalkyl, or (2) a 3- to 10-membered monocyclic heterocycle containing 1 to 2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cyc1 is R 10 may be substituted with; R 10 (1)C 1~8 Alkyl, (2) C 1~8 Alkoxy, (3) Hydroxy, (4) COOR 11 , (5) Oxo, (6) SO2R 12 , or (7) COR 13 is; R 11 is a hydrogen atom or C 1~8 is alkyl; R12 and R 13 (1)C 1~8 alkyl, or (2) C 1~8 phenyl optionally substituted with alkyl; R7 and R8 each independently represent (1) a hydrogen atom, (2) C 1~8 Alkyl, (3)C 1~8 Alkoxy, (4) hydroxy, (5) cyano, (6) halogen atom, (7) COOR 14 , (8)CONR 15 R 16 , (9)Cyc2, (10)C 2~8 Alkenyl, (11)C 2~8 Alkynyl, (12)NR 51 R 52 , (13) nitro, (14) formyl, (15) C 2~8 Acyl, (16) Hydroxy, C 1~8 Alkoxy, Cyc2, NR 51 R 52 , or NR 53 -C substituted with Cyc2 1~8 Alkyl, (17)NR 54 COR 55 , (18)NR 56 SO2R 57 , (19)SO2NR 58 R 59 , (20)COOR 14 C replaced with 2~8 Alkenyl, (21) CH═N—OH, (22) C 1~8 Alkylene-NR 60 -(C 1~8 alkylene)-R 61 , (23)C 1~8 Alkylthio, (24) C substituted with 1 to 3 halogen atoms 1~8 Alkyl, (25) C substituted with 1 to 3 halogen atoms 1~8 Alkoxy, (26)Cyc2-substituted C 1~8 Alkoxy, (27)O-Cyc2, (28)OSO2R 65 , or (29) CH=N-OR 137 is; R 14 is a hydrogen atom or C 1~8is alkyl; R 15 and R 16 are each independently a hydrogen atom or C 1~8 is alkyl; R 51 and R 52 , R 58 and R 59 are each independently a hydrogen atom or C 1~8 is alkyl; R 53 , R 54 , R 56 and R 60 are each independently a hydrogen atom or C 1~8 is alkyl; R 55 is a hydrogen atom, C 1~8 Alkyl or C 1~8 is alkoxy; R 57 is C 1~8 is alkyl; R 61 is NR 62 R 63 or hydroxy; R 62 and R 63 are each independently a hydrogen atom or C 1~8 is alkyl; R 65 is C 1~8 is alkyl; R 137 is C 1~8 is alkyl;

[0299] [ka] (hereinafter abbreviated as "ring") is Cyc2 in which the group bonded to the carbonyl is carbon; R7, R8 and Cyc2 represented by the ring each independently represent (1) C 3~15 (2) a monocyclic, bicyclic, or tricyclic (fused or spiro) carbocycle, or (3) a 3- to 15-membered monocyclic, bicyclic, or tricyclic (fused or spiro) heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur; Cyc2 has 1 to 5 R 17 or R 17’ may be substituted with; R 17 (1) C1-8 alkyl, (2) C 2~8 Alkenyl, (3)C 2~8 Alkynyl, (4)C 1~8 Alkoxy, (5)C 1~8 Alkylthio, (6) hydroxy, (7) halogen atom, (8) nitro, (9) oxo, (10) carboxy, (11) formyl, (12) cyano, (13) NR 18 R 19 (14) phenyl, phenoxy, or phenylthio, which are each a group having 1 to 5 R 20 (15)C 1~8 Alkyl, C 2~8 Alkenyl, C 1~8 Alkoxy or C 1~8 Alkylthio, these are 1 to 5 R 21 (16) OCOR 22 , (17)CONR 23 R 24 , (18)SO2NR 25 R 26 (19) COOR 27 , (20) COCOOR 28 , (21)COR 29 , (22) COCOR 30 , (23)NR 31 COR 32 , (24)SO2R 33 , (25)NR 34 SO2R 35 , or (26)SOR 64 is; R 18 and R 19 , R 31 and R 34 are each independently a hydrogen atom or C 1~8 is alkyl; R 20 and R 21 is C 1~8 Alkyl, C 1~8 Alkoxy, hydroxy, halogen atom, nitro, or COOR36 is; R 22 and R 64 are each independently C 1~8 is alkyl; R 23 , R 24 , R 25 and R 26 are each independently a hydrogen atom, C 1~8 alkyl, or phenyl; R 27 , R 28 , R 29 , R 30 , R 32 , R 33 and R 35 (1)C 1~8 Alkyl, (2) C 2~8 alkenyl, (3) 1 to 5 R 37 C replaced with 1~8 C substituted with alkyl, (4) diphenylmethyl, (5) triphenylmethyl, (6) Cyc3, (7) Cyc3 1~8 Alkyl or C 2~8 Alkenyl, (8) C substituted with O-Cyc3, S-Cyc3 or SO2-Cyc3 1~8 is alkyl; R 36 is a hydrogen atom or C 1~8 is alkyl; R 37 is C 1~8 Alkoxy, C 1~8 Alkylthio, benzyloxy, halogen atom, nitro or COOR 38 is; R 38 is a hydrogen atom, C 1~8 Alkyl or C 2~8 is alkenyl; Cyc3 is (1)C 3~15 (2) a monocyclic, bicyclic, or tricyclic (fused or spiro) carbocycle, or (3) a 3- to 15-membered monocyclic, bicyclic, or tricyclic (fused or spiro) heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur; Cyc3 has 1 to 5 R 39 may be substituted with; R 39 (1)C 1~8 Alkyl, (2) C 2~8 Alkenyl, (3)C 2~8 Alkynyl, (4)C 1~8 Alkoxy, (5)C 1~8 alkylthio, (6) hydroxy, (7) halogen atom, (8) nitro, (9) oxo, (10) cyano, (11) benzyl, (12) benzyloxy, (13) 1 to 5 R 40 C replaced with 1~8 Alkyl, C 1~8 Alkoxy or C 1~8 alkylthio, (14) phenyl, phenoxy, phenylthio, phenylsulfonyl or benzoyl, which are each a group having 1 to 5 R 41 (15) OCOR 42 , (16)SO2R 43 , (17)NR 44 COR 45 , (18)SO2NR 46 R 47 , (19) COOR 48 , or (20)NR 49 R 50 is; R 40 is a halogen atom; R 41 is C 1~8 Alkyl, C 1~8 is alkoxy, a halogen atom, or nitro; R 42 , R 43 and R 45 is C 1~8 is alkyl; R 44 and R 48 is a hydrogen atom or C 1~8 is alkyl; R 46 and R 47 , R 49 and R 50 are each independently a hydrogen atom or C 1~8 is alkyl; R 17’ are (1) SH, (2) NR 66CHO, (3) Cyc5, (4) C substituted with Cyc5 1~8 Alkyl, C 2~8 Alkenyl or C 2~8 Alkynyl, (5) CO—(NH-amino acid residue-CO)n-OH, (6) NR 67 CONR 68 R 69 , (7)CONR 70 NR 71 R 72 , (8)CONR 73 OR 74 , (9)CONR 75 COR 76 , (10)C(S)NR 77 R 78 , (11)CONR 79 C(S)COOR 80 , (12)NR 81 COCOOR 82 , (13)NR 83 COOR 84 , (14)CONR 85 C(S)R 86 , (15)OCOR 87 , (16)SOR 88 , (17)CONR 89 R 90 , (18)SO2NR 91 R 92 , (19) COOR 93 , (20) COCOOR 94 , (21)COR 95 , (22) COCOR 96 , (23)NR 97 COR 98 , (24)SO2R 99 , (25)NR 100 SO2R 101 , or (26)NR 102 R 103 is; n is an integer of 1 or 2; R 66 , R 73 , R 75 , R 77 , R 79 , R 81 , R 83 , R 85 , R 97 , R100 and R 102 is a hydrogen atom or C 1~8 is alkyl; R 67 and R 68 , R 70 and R 71 are each independently a hydrogen atom or C 1~8 is alkyl; R 89 and R 91 are (1) hydrogen atoms, (2) C 1~8 C substituted with alkyl, (3) phenyl, or (4) cyano 1~8 Alkyl or C 1~8 is alkoxy; R 103 is Cyc6; R 69 , R 72 , R 74 , R 76 , R 78 , R 80 , R 82 , R 84 , R 86 , R 87 , R 88 , R 90 and R 92 are (1) hydrogen atoms, (2) C 1~8 Alkyl, (3)C 2~8 Alkenyl, (4)C 2~8 alkynyl, (5) 1 to 5 R 104 C replaced with 1~8 C substituted with alkyl, (6) diphenylmethyl, (7) triphenylmethyl, (8) Cyc6, (9) Cyc6 1~8 Alkyl or C 2~8 C substituted with alkenyl, or (10) O-Cyc6, S-Cyc6, or SO2-Cyc6 1~8 is alkyl; R 104 (1)C 1~8 Alkoxy, (2)C 1~8 Alkylthio, (3) benzyloxy, (4) halogen atom, (5) nitro, (6) COOR 105 , (7) Cyano, (8) NR 106 R 107 , (9)N108 COR 109 , (10) Hydroxy, (H) SH, (12) SO3H, (13) S(O)OH, (14) OSO3H, (15) C 2~8 Alkenyloxy, (16)C 2~8 Alkynyloxy, (17)COR 110 , (18)SO2R 111 , or (19) hydroxy-substituted C 1~8 Alkoxy or C 1~8 It is alkylthio; R 105 is a hydrogen atom, C 1~8 Alkyl, or C 2~8 is alkenyl; R 106 and R 107 are each independently a hydrogen atom or C 1~8 is alkyl; R 108 is a hydrogen atom or C 1~8 is alkyl; R 109 and R 111 is C 1~8 is alkyl; R 110 is C 1~8 alkyl, or halogen atoms; R 93 , R 94 , R 95 , R 96 , R 98 , R 99 and R 101 (1)C 2~8 alkynyl, (2) 1 to 4 R 29 R may be substituted with 128 C replaced with 1~8 Alkyl, (3) Cyc8, (4) Cyc8-substituted C 1~8 Alkyl or C 2~8 alkenyl, or (5) C substituted with O-Cyc8, S-Cyc8, or SO2-Cyc8 1~8 Alkyl; R 128 are (1) cyano, (2) NR 106 R 107 , (3)NR 108 COR109 , (4) Hydroxy, (5) SH, (6) SO3H, (7) S(O)OH, (8) OSO3H, (9) C 2~8 Alkenyloxy, (10)C 2~8 Alkynyloxy, (11)COR 110 , (12)SO2R 111 or (13) hydroxy-substituted C 1~8 Alkoxy or C 1~8 It is alkylthio; R 129 is R 104 has the same meaning as; Cyc5 and Cyc6 contain 1 to 5 R 112 may be substituted with; R 112 (1)C 1~8 Alkyl, (2) C 2~8 Alkenyl, (3)C 2~8 Alkynyl, (4)C 1~8 Alkoxy, (5)C 1~8 alkylthio, (6) hydroxy, (7) halogen atom, (8) nitro, (9) oxo, (10) cyano, (11) benzyl, (12) benzyloxy, (13) 1 to 5 R 113 C replaced with 1~8 Alkyl, C 1~8 Alkoxy or C 1~8 alkylthio, (14) phenyl, phenoxy, phenylthio or benzoyl, which are 1 to 5 R 114 (15) COR 115 , (16)SO2R 116 , (17)NR 117 COR 118 , (18)SO2NR 119 R 120 , (19) COOR 121 , (20)NR 122 R 123 , (21)COR 124 , (22)CONR 125 R 126 , (23) SH, (24) hydroxy or NR 127 -benzoyl-substituted C 1~8 alkyl, or (25)Cyc7; R 113 is a halogen atom; R 114 is C 1~8 Alkyl, C 1~8 is alkoxy, a halogen atom, or nitro; R 115 , R 116 and R 118 is C 1~8 is alkyl; R 117 , R 121 , R 124 and R 127 is a hydrogen atom or C 1~8 is alkyl; R 119 and R 120 , R 122 and R 123 , R 125 and R 126 are each independently a hydrogen atom or C 1~8 is alkyl; Cyc7 is (1)C 1~8 Alkyl, (2) C 1~8 (3) optionally substituted with 1 to 5 groups selected from alkoxy, (4) halogen atoms, or (5) nitro; Cyc8 is R 130 and may be substituted with 1 to 4 R 131 may be substituted with; R 130 (1) COR 124 ,(2)CONR 125 R 126 , (3) SH, (4) hydroxy or NR 127 -benzoyl-substituted C 1~8 alkyl, or (5) Cyc7; R 131 is R 112 has the same meaning as; Cyc5, Cyc6, Cyc7, and Cyc8 are (1)C 3~15(2) a monocyclic, bicyclic, or tricyclic (fused or spiro) carbocycle, or (3) a 3-15 membered monocyclic, bicyclic, or tricyclic (fused or spiro) heterocycle containing 1-4 heteroatoms selected from 1-4 oxygen, nitrogen, or sulfur; where R 17’ When Cyc5 is Cyc5, C 1~8 Alkyl, C 1~8 Alkoxy, hydroxy, halogen atom, nitro, COOH or COO(C 1~8 alkyl); where Cyc7 is not phenyl; Cyc4 is (1)C 5~7 (2) a monocyclic carbocycle, or (3) a 5- to 7-membered monocyclic heterocycle containing 1 to 2 heteroatoms selected from oxygen, nitrogen, and sulfur; (hereinafter abbreviated as dotted line a) and (hereinafter abbreviated as dotted line b) are (1) a bond, or (2) a double bond; R9 is (1) absent or (2) a hydrogen atom; where: (1) When the dotted line a is a bond, the dotted line b is a double bond and R9 is absent. (2) When the dotted line a is a double bond, the dotted line b is a bond, R9 is a hydrogen atom, and R6 is absent; and (3) 2-(3,3-dimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-phenylethan-1-one is excluded, or a pharmacologically acceptable salt thereof.

[0300] The preparation of such compounds is described in US2005222138 and WO2003 / 064389.

[0301] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds disclosed generally or specifically in WO2003 / 057149 (expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0302] [ka] It has.

[0303] The substituents for the above compounds are defined as follows:

[0304] (1) X is selected from halogen and NR1R2; (2) Y is selected from NR3, S, and O, provided that when X is Cl, Y is not S; (3) R1 and R2 are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, polycycloalkyl of 5 to 9 carbon atoms, heterocycloalkyl of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S, and O, and aryl of 6 to 12 carbon atoms, which are selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo and optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level, haloalkoxy of 1 to 6 carbon atoms and up to a perhalogen level, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, wherein the substituents are alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, and optionally substituted with alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, wherein R4R5 or R1 and R2 are bonded together with the nitrogen atom to which they are attached to form a 5-7 membered monocyclic saturated ring, which saturated ring is optionally substituted with NH, NR6 , S and O, or R4R5 or R1 and R2 are combined together with the nitrogen atom to which they are attached to form a fused 6-10 membered polycyclic saturated ring, which optionally contains 1-2 additional heteroatoms selected from the group consisting of NH, NR6, S and O, or R4R5 or R1 and R2 are combined together with the nitrogen atom to which they are attached to form a 5-7 membered unsaturated ring, which optionally contains N,and containing 1 to 2 additional heteroatoms selected from the group consisting of S and O, wherein the monocyclic saturated ring, polycyclic saturated ring, or unsaturated ring may be substituted with 1 to 2 substituents selected from the group consisting of OH, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, heterocycloalkyl of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S, and O, halogen, haloalkyl of 1 to 2 carbon atoms and up to a perhalo level of halogen atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, and R7R8. (4) R3 is selected from hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, and heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, which may be substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalogen level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O; (5) R4 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, C(=O), S(=O)2, and C(=O)O; (6) R5 is selected from hydrogen, OH, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, thioxy of 1 to 8 carbon atoms, aryl of 6 to 12 carbon atoms, which are alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level, haloalkoxy of 1 to 6 carbon atoms and up to a perhalogen level, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, 4 to 11 and optionally substituted with a heteroaryl of carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, the substituents being alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, cycloalkyl of 3 to 7 carbon atoms, heterocycloalkyl of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S, and O, and NR 10 may be substituted with, (7) R6 and R7 are independently selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and alkynyl of 2 to 8 carbon atoms; (8) R8 is selected from OH, aryl of 6 to 12 carbon atoms, which is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalogen level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O. and heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, which may be substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to the perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O; (9) R9 and R 10 are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and alkynyl of 2 to 8 carbon atoms, or R and R 10 are bonded together with the nitrogen atom to which they are bonded to form a 5- to 7-membered unsaturated ring, which may contain 1 to 2 additional heteroatoms selected from N, S, and O; or R and R 10 are bonded to each other, and together with the nitrogen atom to which they are bonded, form a 5- to 7-membered saturated ring, and the saturated ring is 11 , and may contain 1 to 2 additional heteroatoms selected from S and O; (10) R1 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and alkynyl of 2 to 8 carbon atoms, and pharmaceutically acceptable salts thereof.

[0305] The preparation of such compounds is described in WO2003 / 057149.

[0306] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in US20030092721, U.S. Patent No. 7,022,849, WO2002 / 102315, and US2006116516 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound represented by the formula:

[0307] [ka] It has.

[0308] The substituents for the above compounds are defined as follows:

[0309] R1 is H or alkyl; R2 is (a) heteroaryl or heterocyclo, either of which may be optionally substituted with 1-3 T1, T2, T3 groups; or (b) aryl fused to a heteroaryl or heterocyclo ring, where the linked ring system may be optionally substituted with 1-3 T1, T2, T3 groups; L is (a) OR4, C(O)R4, C(O)OR4, SR4, NR3R4, C(O)NR3R4, NR3SO2R 4b , halogen, nitro, or haloalkyl; or (b) alkyl, aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which may be optionally substituted with 1-3 T1a, T2a, and / or T3a groups; Y l , Y2 and Y3 are independently (a) hydrogen, halo, or -OR 4a or (b) alkyl, alkenyl, or alkynyl, any of which may be optionally substituted with 1 to 3 T1b, T2b, and / or T3b groups; R3 and R4 are independently H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which may be optionally substituted with 1-3 T1a, T2a, and / or T3a groups; or R3 and R4, together with the nitrogen atom to which they are attached, may be joined to form a 4-8 membered heterocyclic ring optionally substituted with 1-3 T1a, T2a and / or T3a groups; R 4a is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, cycloalkyl, or (cycloalkyl)alkyl, each of which is selected from 1 to 3 groups may be optionally substituted with T1b, T2b and / or T3b; R 4b is alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which may be optionally substituted with 1 to 3 T1a, T2a, and / or T3a groups; Z is N or CH; T1 to 1b, T2 to 2b, and T3 to 3b each independently represent: (1) hydrogen or T6, where T6 is (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (ii) a group (i) that is itself substituted with one or more of the same or different groups (i); or (iii) a group (i) or (ii) that is independently substituted with one or more groups (2) to (13) in the definitions of T1-1b, T2-2b, and T3-3b below; (2) -OH or -OT6; (3)-SH or -ST6; (4)-C(O) t H, -C(O) t T6, or -OC(O)T6, where t is 1 or 2; (5) -SO3H, -S(O) t T6, or S(O) t N(T9)T6; (6) Halo; (7) Cyano; (8) Nitro; (9)-T4-NT7T8; (10)-T4-N(T9)-T5-NT7T8; (11)-T4-N(T10)-T5-T6; (12)-T4-N(T10)-T5-H; and (13) Oxo is; T4 and T5 each independently represent a single bond, T11S(O) t T12-, T11C(O)T12-, T11C(S)T12, T11OT12, T11ST12, T11OC(O)T12, T11C(O)OT12, TllC(=NT9a)T12, or T11C(O)C(O)T12; T7, T8, T9, T9a and T10 (1) each independently represents hydrogen or a group as defined in the definition of T6; (2) T7 and T8 together may be alkylene or alkenylene and, together with the atoms to which they are attached, complete a 3-8 membered saturated or unsaturated ring, which is unsubstituted or substituted with one or more groups listed in the descriptions of T1-1b, T2-2b, and T3-3b, or (3) T7 or T8 together with T9 may be alkylene or alkenylene, and together with the nitrogen atom to which they are attached, complete a 3-8 membered saturated or unsaturated ring, which is unsubstituted or substituted with one or more groups listed in the descriptions of T1-1b, T2-2b, and T3-3b, or (4) T7 and T8 or T9 and T10 may be bonded together with the nitrogen atom to which they are attached to form a group N=CT13T14, where T13 and T14 are each independently H or a group as defined in the definition of T6; and T11 and T12 are each independently a single bond, alkylene, alkenylene, or alkynylene. is.

[0310] The preparation of such compounds is described in US20030092721, US Pat. No. 7,022,849, WO2002 / 102315, and US2006116516.

[0311] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 6,838,559, US20030100571, and WO2002 / 102314 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound represented by the formula:

[0312] [ka] It has.

[0313] The substituents for the above compounds are defined as follows:

[0314] R1 is H or alkyl; R2 is (a) heteroaryl, or heterocyclo, either of which may be optionally substituted with 1-3 T1, T2, T3 groups; (b) aryl substituted with 1-3 T1, T2, T3 groups, provided that at least one of T1, T2, T3 is other than H; or (c) aryl fused to a heteroaryl or heterocyclo ring, wherein the attached ring system may be optionally substituted with 1-3 T1, T2, T3 groups; Y is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl, or (heteroaryl)alkyl, any of which may be optionally substituted with 1 to 3 T1a, T2a, T3a groups; J is (a) hydrogen, halo, or OR4, or (b) alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which may be optionally substituted with 1-3 T1b, T2b, T3b groups; Z is (a) OR4, SR4, NR3R4, NR3SO2R 4a halogen, nitro, haloalkyl; or (b) alkyl, aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which may be optionally substituted with 1 to 3 T1c, T2c, T3c groups; R3 is H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which may be optionally substituted, where valences allow, with 1 to 3 T1c, T2c, T3c groups independently; R4 is alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which may be optionally substituted, where valences allow, with 1 to 3 T1d, T2d, or T3d groups independently; or R3 and R4, together with the nitrogen atom to which they are attached, may be joined to form a 4-8 membered heterocyclic ring optionally substituted with 1-3 T1c, T2c, or T3c groups; R 4ais hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, cycloalkyl, or (cycloalkyl)alkyl, any of which may be optionally substituted with 1 to 3 T1d, T2d, or T3d groups; T1, T1a, T1b, T1c, T1d, T2, T2a, T2b, T2c, T2d, T3, T3a, T3b, T3c, and T3d (hereinafter abbreviated as T1 to T1d, T2 to T2d, and T3 to T3d in this specification) are independently (1) to (13) below: (1) Hydrogen or T6, wherein T6 is one of the following (a) to (c): (a) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (b) a group (a) that is itself substituted with one or more of the same or different groups (a); or (c) a group (a) or (b) independently substituted with one or more (preferably 1 to 3) of the following groups (2) to (13) in the definitions of T1 to 1d, T2 to 2d, and T3 to 3d, (2) OH or OT6, (3) SH or ST6, (4) C(O) t H, C(O) t T6, or OC(O)T6, where t is 1 or 2; (5) SO3H, S(O) t T6, or S(O) t N(T9)T6, (6) Halo, (7) Cyano, (8) nitro, (9)T4NT7T8, (10)T4N(T9)-T5NT7T8, (11)T4N(T10)-T5-T6, (12)T4N(T10)-T5H, (13) oxo, T4 and T5 each independently represent a single bond, T11-S(O) t -T12, T11-C(O)-T12, T11-C(S)-T12, T11-O-T12, -T11S-T12, -T11OC(O)-T12, -T11-C(O)O-T12, -T11C(=NT9a)-T12, or T11-C(O)-C(O)-T12; T7, T8, T9, T9a and T10 are (1) to (4) below: (1) each independently represents hydrogen or a group as defined in the definition of T6; (2) T7 and T8 together may be alkylene or alkenylene, and together with the atoms to which they are attached complete a 3-8 membered saturated or unsaturated ring, which is unsubstituted or substituted with one or more groups listed in the descriptions of T1-1d, T2-2d, and T3-3d, or (3) T7 or T8 together with T9 may be alkylene or alkenylene, and together with the nitrogen atom to which they are attached, complete a 3-8 membered saturated or unsaturated ring, which is unsubstituted or substituted with one or more groups listed in the descriptions of T1-1d, T2-2d, and T3-3d, or (4) T7 and T8 or T9 and T10 may be joined together with the nitrogen atom to which they are attached to form a group N=CT13T14, wherein: T13 and T14 are each independently H or a group as defined in the definition of T6; and T11 and T12 are each independently a single bond, alkylene, alkenylene, or alkynylene.

[0315] The preparation of such compounds is described in US Pat. No. 6,838,559, US20030100571, and WO2002 / 102314.

[0316] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 7,087,614, U.S. Patent No. 20030162802, and WO2002 / 102313 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound represented by the formula:

[0317] [ka] It has.

[0318] The substituents for the above compounds are described below.

[0319] In a related embodiment, the PDE7 inhibitor useful in the methods of the invention has the formula:

[0320] [ka] It has.

[0321] The substituents for the above compounds are defined as follows:

[0322] R 1a is hydrogen or alkyl; R 2a teeth,

[0323] [ka] wherein W is S; X1 is alkoxy; and X2 is alkyl; Z * is halogen, haloalkyl, oxazolyl, NR 3a R 4a , C(O)—N(H)-alkylene-COOH, or phenyl, wherein the phenyl is unsubstituted or heteroaryl, CO t H or CO t those substituted with T6; R 3ais hydrogen or alkyl; R 4a is alkyl, alkoxy, unsubstituted or substituted (heteroaryl)alkyl, unsubstituted or substituted heterocyclo, unsubstituted or substituted (heterocyclo)alkyl, or (aryl)alkyl, where the aryl group is substituted with one or two T1 and / or T2 groups and / or further substituted with a T3 group; or R 3a and R 4a are joined together with the nitrogen atom to which they are attached to form an unsubstituted or substituted heterocyclic ring; R 5a is an unsubstituted or substituted (heteroaryl)alkyl or (aryl)alkyl, wherein the aryl group is substituted with one or two T1 and / or T2 groups and / or further substituted with a T3 group; or R5 a and R 6a are joined together with the nitrogen atom to which they are attached to form an unsubstituted or substituted heterocyclic ring; R 6a is hydrogen or alkyl; J * is hydrogen or alkyl; T1 and T2 are independently alkoxy, alkoxycarbonyl, heteroaryl, SO3H, or SO2R 8a where R 8a is alkyl, amino, alkylamino, or dialkylamino; or T1 and T2, together with the aryl ring to which they are attached, are joined to form a bicyclic ring; T3 is H, alkyl, halo, haloalkyl, or cyano; t is 1 or 2; and T6 is alkyl, haloalkyl, cycloalkyl, alkoxy, or heteroaryl.

[0324] The preparation of such compounds is described in US Pat. No. 7,087,614, US20030162802, and WO2002 / 102313.

[0325] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds disclosed generally or specifically in US20030104974, WO2002 / 088080, and WO2002 / 088079 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound represented by the formula:

[0326] [ka] It has.

[0327] The substituents for the above compounds are defined as follows:

[0328] R1 is H or alkyl; R2 is optionally substituted heteroaryl or 4-substituted aryl; R3 is hydrogen or alkyl; R4 is alkyl, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted heterocyclo, or optionally substituted (heterocyclo)alkyl; or R3 and R4 may be joined together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclo ring; R5 is alkyl, optionally substituted (aryl)alkyl, or optionally substituted (heteroaryl)alkyl; and R6 is hydrogen or alkyl.

[0329] In a related embodiment, the PDE7 inhibitor useful in the methods of the invention has the formula:

[0330] [ka] It has.

[0331] In the formula, R 1a is H or alkyl; R 2ais an optionally substituted heteroaryl; Z is halogen, alkyl, substituted alkyl, haloalkyl, or NR 3a R 4a R 3a is hydrogen or alkyl; R 4a is alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted heterocyclo, optionally substituted (heterocyclo)alkyl, or (aryl)alkyl, where the aryl group is substituted with one or two T1 and T2 groups and optionally further substituted with a T3 group; or R 3a and R 4a may be joined together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring; R 5a is (aryl)alkyl, wherein the aryl group is substituted with one or two T1 and T2 groups and optionally with a T3 group; R 6a is hydrogen or alkyl; R 7a is hydrogen or alkyl; T1 and T2 are independently alkoxy, alkoxycarbonyl, heteroaryl, or SO2R 8a where R 8a is alkyl, amino, alkylamino, or dialkylamino; or T1 and T2, together with the atoms to which they are attached, may be joined to form a ring (e.g., benzodioxole); T3 is H, alkyl, halo, haloalkyl, or cyano.

[0332] In another related embodiment, the PDE7 inhibitor useful in the methods of the invention has the formula:

[0333] [ka] It has.

[0334] In the formula, R 1b is H or alkyl; R 2bis optionally substituted heteroaryl; R 3b is H or alkyl; R 4b is an optionally substituted (aryl)alkyl; R 5b is H, alkyl, or C(O)(CH2) v OYR 6b where Y is a bond or C(O), and R 6b is hydrogen or alkyl, and v is an integer from 0 to 2; J1 and J2 are independently optionally substituted C 1~13alkylene, provided that J and J are not both greater than C alkylene; X and X are optional substituents attached to any available carbon atom of one or both of J and J and are independently selected from hydrogen, OR, NR, R, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl; R is hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(O)alkyl, C(O)substituted alkyl, C(O)cycloalkyl, C(O)substituted cycloalkyl, C(O)aryl, C(O)substituted aryl, C(O)O-alkyl, C(O)O-substituted alkyl, C(O)heterocycloalkyl, C(O)heteroaryl, aryl, substituted aryl, heterocycloalkyl, and hetero and R and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(O)alkyl, C(O)substituted alkyl, C(O)cycloalkyl, C(O)substituted cycloalkyl, C(O)aryl, C(O)substituted aryl, C(O)Oalkyl, C(O)Osubstituted alkyl, C(O)heterocycloalkyl, C(O)heteroaryl, S(O)alkyl, S(O)substituted alkyl, S(O)cycloalkyl, S(O)substituted cycloalkyl, S(O)aryl, S(O)substituted aryl, S(O)heterocycloalkyl, S(O)heteroaryl, aryl, substituted aryl, heterocycloalkyl, and heteroaryl, or R and R together with the nitrogen atom to which they are attached complete an optionally substituted heterocycloalkyl or heteroaryl ring.

[0335] In further related embodiments, the PDE7 inhibitor useful in the methods of the invention has the formula:

[0336] [ka] It has.

[0337] In the formula, R 1c is H or alkyl; R 2C is optionally substituted heteroaryl; R 3c is H or alkyl; R 4c is an optionally substituted (aryl)alkyl; and X and X are optional substituents bonded to any available carbon atom of one or both of J and J and are independently selected from hydrogen, OR, NR, R, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl.

[0338] The preparation of such compounds is described in US20030104974, WO2002 / 088080, and WO2002 / 088079.

[0339] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in US20030092908 and WO2002 / 087513 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in US20030092908 and WO2002 / 087513 (each of which is expressly incorporated herein by reference in its entirety).

[0340] [ka] It has.

[0341] The substituents for the above compounds are defined as follows:

[0342] R1 is hydrogen or alkyl; R2 is (a) heteroaryl, or heterocyclo, either of which may be optionally substituted with 1-3 T1, T2, T3 groups; (b) aryl substituted with 1-3 T1, T2, T3 groups, provided that at least one of T1, T2, T3 is other than H; or (c) aryl fused to a heteroaryl or heterocyclo ring, wherein the attached ring system may be optionally substituted with 1-3 T1, T2, T3 groups; Z is NR3R4, NR3SO2R 4a , OR4, SR4, haloalkyl, or halogen; R3 and R4 are independently H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which may be optionally substituted, where valences allow, with 1 to 3 T1a, T2a, or T3a groups; or R3 and R4, together with the nitrogen atom to which they are attached, may, where valences allow, form a heterocyclo or heteroaryl ring optionally substituted with 1 to 3 T1a, T2a, or T3a groups; R 4a is alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which may be optionally substituted, where valences allow, independently with 1 to 3 T1a, T2a, or T3a groups; R 3b and R 4b is independently H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl; R5 is the following (1) to (3): (1) Hydrogen, or cyano; (2) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, any of which may be optionally substituted, where valences allow, independently with 1 to 3 T1b, T2b, or T3b groups; or (3) C(O)R6, C(O)OR6, C(O)-C(O)OR, or SO2R 6a ; R6 is H, alkyl, alkenyl, NR 3b R 4b , heterocyclo, (heterocyclo)alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (NR 3b R 4b ) alkyl, heteroaryl, aryl, or (aryl)alkyl, any of which may be optionally substituted, where valences allow, independently with 1 to 3 T1b, T2b, or T3b groups; R 6a is alkyl, alkenyl, NR 3b R 4b , heterocyclo, (heterocyclo)alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (NR 3b R 4b ) alkyl, heteroaryl, aryl, or (aryl)alkyl, any of which may be optionally substituted, where valences allow, independently with 1 to 3 T1b, T2b, or T3b groups; J1 and J2 are independently optionally substituted C 1~3 alkylene, provided that J1 and J2 are not both greater than C2 alkylene; and T1 to 1b, T2 to 2b, and T3 to 3b are each independently the following (1) to (13): (1) hydrogen or T6, where T6 is (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (ii) a group (i) that is itself substituted with one or more of the same or different groups (i); or (iii) a group (i) or (ii) that is independently substituted with one or more (preferably 1 to 3) of the following groups (2) to (13) in the definitions of T1-1b, T2-2b, and T3-3b, (2) OH or OT6, (3) SH or ST6, (4) C(O) t H, C(O) t T6, or OC(O)T6, where t is 1 or 2; (5) SO3H, S(O) t T6, or S(O) t N(T9)T6, (6) Halo, (7) Cyano, (8) nitro, (9)T4-NT7T8, (10)T4-N(T9)-T5-NT7T8, (11)T4-N(T10)-T5-T6, (12)T4-N(T10)-T5H, (13) oxo, T4 and T5 each independently represent (1) a single bond, (2) T11-S(O) t -T12, (3) T11-C(O)-T12, (4) T11-C(S)-T12, (5) -T11-O-T12, (6) T11-S-T12, (7) T11-OC(O)-T12, (8) T11-C(O)-O-T12, (9) T11-C(=NT9a)-T12, or (10) T11-C(O)-C(O)-T12. T7, T8, T9, T9a and T10 are (1) to (4) below: (1) each independently represents hydrogen or a group as defined in the definition of T6; or (2) T7 and T8 together may be alkylene or alkenylene, and together with the atoms to which they are attached complete a 3-8 membered saturated or unsaturated ring, which is unsubstituted or substituted with one or more groups listed in the descriptions of T1-1b, T2-2b, and T3-3b, or (3) T7 or T8 together with T9 may be alkylene or alkenylene, and together with the nitrogen atom to which they are attached, complete a 3-8 membered saturated or unsaturated ring, which is unsubstituted or substituted with one or more groups listed in the descriptions of T1-1b, T2-2b, and T3-3b, or (4) T7 and T8 or T9 and T10 may be bonded together with the nitrogen atom to which they are attached to form a group N=CT13T14, where T13 and T14 are each independently H or a group defined in the definition of T6; and T11 and T12 are each independently a single bond, alkylene, alkenylene, or alkynylene.

[0343] The preparation of such compounds is described in US20030092908 and WO2002 / 087513.

[0344] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in US20040127707 and WO2002 / 085906 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in US20040127707 and WO2002 / 085906 (each of which is expressly incorporated herein by reference in its entirety).

[0345] [ka] It has.

[0346] The substituents for the above compounds are defined as follows:

[0347] R1 is 1-2C alkoxy or 1-2C alkoxy, fully or predominantly substituted with fluorine; R2 is fluorine, bromine, or chlorine; R3 and R4 are both hydrogen or together form an additional bond; R5, R6, C m H 2m -R7, C n H 2n -C(O)R8, CH(R9)2, C p H 2p -Y-aryl 1, R 12 or R 26 and During the ceremony, R6 is 1-8C alkyl, 3-10C cycloalkyl, 3-7C cycloalkylmethyl, 3-7C alkenyl, 3-7C alkynyl, phenyl-3-4C-alkenyl, 7-10C polycycloalkyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, quinazolinyl, quinoxalinyl, cinnolinyl, isoquinolinyl, quinolinyl, indanyl, indazolyl, benzoxazolyl, benzothiazolyl, oxazolyl, thiazolyl, N- Methylpiperidyl, tetrahydropyranyl, 6-methyl-3-trifluoromethyl-pyridin-2-yl, 1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl, 3-thiophen-2-yl[1,2,4]thiadiazol-5-yl, 1,1-dioxide-tetrahydrothiophen-3-yl, 1-oxo-1,3-dihydro-isobenzofuran-5-yl, 4-(4-yl-but-1-oxy)benzoic acid, or unsubstituted or R 61 and / or R 62 a phenyl group substituted with R 61is hydroxyl, 1-4C alkyl, 1-4C alkoxy, nitro, cyano, halogen, carboxyl, hydroxycarbonyl-1-4C-alkyl, 1-4C alkoxycarbonyl, hydroxy-1-4C-alkyl, amino, mono- or di-1-4C-alkylamino, 1-4C alkylcarbonylamino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, aminosulfonyl, mono- or di-1-4C-alkylaminosulfonyl, 4-methylphenylsulfonamido, imidazolyl; tetrazol-5-yl, 2-(1-4C-alkyl)tetrazol-5-yl or 2-benzyltetrazol-5-yl, and R 62 is 1-4C alkyl, 1-4C alkoxy, nitro, or halogen; R7 is hydroxyl, halogen, cyano, nitro, nitroxy (O-NO2), carboxyl, carboxyphenyloxy, phenoxy, 1-4C alkoxy, 3-7C cycloalkoxy, 3-7C cycloalkylmethoxy, 1-4C alkylcarbonyl, 1-4C alkylcarbonyloxy, 1-4C alkylcarbonylamino, 1-4C alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, amino, mono- or di-1-4C-alkylamino, or unsubstituted or R 71 and / or R 72 a piperidyl, piperazinyl, pyrrolidinyl or morpholinyl group substituted with R 71 is hydroxyl, 1-4C alkyl, hydroxy-1-4C-alkyl or 1-4C alkoxycarbonyl, and R 72 is 1-4C alkyl, carboxyl, aminocarbonyl or 1-4C alkoxycarbonyl, R8 is unsubstituted or R 81 and / or R 82 a phenyl, naphthyl, phenanthrenyl or anthracenyl group substituted with R 81is hydroxyl, halogen, cyano, 1-4C alkyl, 1-4C alkoxy, carboxyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C alkylcarbonyloxy, 1-4C alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino, 1-4C alkylcarbonylamino, or 1-4C alkoxy, which is completely or predominantly substituted by fluorine, and R 82 is hydroxyl, halogen, 1-4C alkyl, 1-4C alkoxy or 1-4C alkoxy, which is completely or predominantly substituted with fluorine, R9 is C q H 2q -phenyl, Y is a bond or O (oxygen); Aryl 1 is an unsubstituted phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl, isoquinolyl, quinolyl, coumarinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, furyl, thienyl, pyrrolyl, 2-(1-4C-alkyl)-thiazol-4-yl group, or R 10 and / or R 11 is a phenyl group substituted with R 10 is hydroxyl, halogen, nitro, cyano, 1-4C alkyl, trifluoromethyl, 1-4C alkoxy, carboxyl, hydroxycarbonyl-1-4C-alkyl, 1-4C alkylcarbonyloxy, 1-4C alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino, 1-4C alkylcarbonylamino, aminocarbonyl, mono- or di-1-4C-alkylamino-carbonyl, imidazolyl or tetrazolyl, and R 11 is hydroxyl, halogen, nitro, 1-4C alkyl or 1-4C alkoxy, m is an integer of 1 to 8, n is an integer of 1 to 4, p is an integer of 1 to 6, and q is an integer of 0 to 2. R 12 is expressed as equation (a)

[0348] [ka] is the basis of In the formula, R 13 is S(O)2-R 14 , S(O)2-(CH2) r -R15, (CH2) S -S(O)2R16, C(O)R 17 , C(O)-(CH2) r -R 18 , (CH2) s -C(O)-R 19 , hetaryl1, aryl2 or aryl3 is 1-4C-alkyl, and R 14 is 1-4C alkyl, 5-dimethylaminonaphthalen-1-yl, N(R 20 )R 21 , phenyl or R 22 and / or R 23 is phenyl substituted with R 15 is N(R 20 )R 21 and R 16 is N(R 20 )R 21 That is, R 17 is 1-4C alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl, 4-ethyl-piperazine-2,3-dione-1-yl, 2-oxo-imidazolidin-1-yl or N(R 20 )R 21 and R 18 is N(R 20 )R 21 and R 19 is N(R 20 )R 21 , phenyl, R 22 and / or R 23 and / or R 24 is phenyl substituted with R20 and R 21 are, independently of each other, hydrogen, 1-7C alkyl, 3-7C cycloalkyl, 3-7C cycloalkylmethyl or phenyl, or R 20 and R 21 are, together with the nitrogen atom to which they are attached, a 4-morpholinyl ring, a 1-pyrrolidinyl ring, a 1-piperidinyl ring, a 1-hexahydroazepino ring or a ring represented by formula (b)

[0349] [ka] It forms a 1-piperazinyl ring of In the formula, R 25 is pyrid-4-yl, pyrid-4-ylmethyl, 1-4C alkyl-dimethylamino, dimethylaminocarbonylmethyl, N-methyl-piperidin-4-yl, 4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl-, and R 22 is halogen, nitro, cyano, carboxyl, 1-4C alkyl, trifluoromethyl, 1-4C alkoxy, 1-4C alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino, aminocarbonyl 1-4C alkylcarbonylamino or mono- or di-1-4C-alkylaminocarbonyl, and R 23 is halogen, amino, nitro, 1-4C alkyl or 1-4C alkoxy, and R 24 is a halogen, Hetaryl 1 is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl, 1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl, thiazolyl, imidazolyl or furanyl, and aryl 2 is pyridyl, phenyl or R 22 and / or R 23 aryl 3 is pyridyl, phenyl, R 22 and / or R 23 phenyl substituted with 2-oxo-2H-chromen-7-yl or 4-(1,2,3-thiadiazol-4-yl)phenyl, r is an integer from 1 to 4, and s is an integer from 1 to 4. R 26 is expressed as equation (c)

[0350] [ka] is the basis of In the formula, R 27 is C(O)R 28 , (CH2) t -C(O)R 29 , (CH2) u R 30 , aryl4, hetaryl2, phenylprop-1-en-3-yl or 1-methylpiperidin-4-yl, and R 28 is hydrogen, 1-4C alkyl, OR 31 , furanyl, indolyl, phenyl, pyridyl, R 34 and / or R 35 Phenyl substituted with or R 36 and / or R 37 pyridyl substituted with R 29 is N(R 32 )R 33 and R 30 is N(R 32 )R 33 , tetrahydrofuranyl, or pyridinyl, and R 31 is 1-4C alkyl, and R 32 is hydrogen, 1-4C alkyl, 3-7C cycloalkyl or 3-7C-cycloalkylmethyl, and R 33 is hydrogen, 1-4C alkyl, 3-7C cycloalkyl or 3-7C-cycloalkylmethyl, or R 32 and R 33 are taken together with the nitrogen atom to which they are attached to form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl ring, Aryl 4 is phenyl, pyridyl, pyrimidinyl, R 34 and / or R 35 phenyl substituted with R 36 and / or R37 pyridyl substituted with R 34 is halogen, nitro, 1-4C alkyl, trifluoromethyl or 1-4C alkoxy, and R 35 is halogen or 1-4C alkyl, and R 36 is halogen, nitro, 1-4C alkyl, trifluoromethyl or 1-4C alkoxy, and R 37 is halogen or 1-4C alkyl; hetaryl 2 is indol-4-yl, 2-methyl-quinolin-4-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl, 3-phenyl-1,2,4-thiadiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl, t is an integer of 1 to 4, u is an integer of 1 to 4, v is an integer of 1 to 2, and X is -C(O)- or -S(O)2-, as well as salts of such compounds.

[0351] The preparation of such compounds is described in US20040127707 and WO2002 / 085906.

[0352] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 6,818,651, US20040044212, and WO2002 / 040450 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0353] [ka] It has.

[0354] The substituents for the above compounds are defined as follows:

[0355] R1 represents hydrogen and R2 represents fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or R1 represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and R2 represents hydrogen, R' and R" together represent hydrogen or together represent a bond, and Ar is a group of formula IIa, IIb, or IIc

[0356] [ka] represents a phenyl group of the formula wherein R3 is hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C alkoxy, trifluoromethoxy, 1-4C alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl. R4 represents 1-4C alkyl, naphthalenyl, 5-dimethylaminonaphthalen-1-yl, phenylethen-2-yl, 3,5-dimethylisoxazol-4-yl, 5-chloro-3-methylbenzo[b]thiophen-2-yl, 6-chloro-imidazo[2,1b]-thiazol-5-yl, or a phenyl or thiophene group that is unsubstituted or substituted by one or more identical or different groups, the substituents being selected from the group halogen, cyano, 1-4C alkyl, trifluoromethyl, 1-4C alkoxy that is fully or mainly substituted by fluorine, 1-4C alkoxy, 1-4C alkylcarbonylamino, 1-4C alkoxycarbonyl, phenylsulfonyl or isoxazolyl, or its hydrates, solvates, salts, hydrates of salts, or solvates of salts;

[0357] The preparation of such compounds is described in US Pat. No. 6,818,651, US20040044212, and WO2002 / 040450.

[0358] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds disclosed generally or specifically in WO2002 / 040449 (expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0359] [ka] It has.

[0360] The substituents for the above compounds are defined as follows:

[0361] either R1 represents hydrogen and R2 represents fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or R1 represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and R2 represents hydrogen; R' and R" together represent hydrogen or together represent a bond; R3 represents hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C alkoxy, trifluoromethoxy, 1-4C alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl, and R4 represents C(O)—X—R5, N(H)—C(O)—R6 or N(H)—C(O)—N(H)—R2, in which X represents O or N(H); R5 is hydrogen, 1-4C alkyl, 3-7C cycloalkylmethyl, 6,6-dimethylbicyclo[3,3,I]hept-2-yl, 3-7C alkynyl, 1-4C alkylcarbonyl-1-4C-alkyl, aminocarbonyl-1-4C-alkyl, furan-2-ylmethyl, 2-pyridin-2-yleth-1-yl, 2-pyridin-3-ylmethyl, N-methylpiperidin-3-yl, 1-benzylpiperidin-4-yl, morpholin-4-yl-eth-2-yl, morpholin-4-yl-eth-1-yl, 2-benzo[1,3]dioxol-4-yl-eth-1-yl, chroman-4-yl , 1-methoxycarbonyl-2-indol-3-yl-eth-1-yl, 1,3-bis-methoxycarbonylprop-1-yl, 1-methoxycarbonyl-3-methylsulfanyl-eth-1-yl, 1-methoxycarbonyl-2-thiazol-2-yl-eth-1-yl or 4-methylthiazol-5-yl-eth-2-yl, or a benzyl-, phenyl-eth-1-yl or 1-methoxycarbonyl-2-phenyl-eth-2-yl group which is unsubstituted or substituted by one or more groups, the substituents being selected from the group consisting of halogen, trifluoromethyl and phenyl, R6 represents 2,4-dichlorophenoxymethyl, 2-tert-butoxycarbonylamino-eth-1-yl, 1-acetylpiperidin-4-yl, Ar1 or Ar2-CH=CH-; In the formula, Ar1 represents 3-chlorophenyl, 4-trifluoromethoxyphenyl, 3-phenoxyphenyl, indol-5-yl, 2-methylpyridin-5-yl, quinolin-6-yl, or 2-benzothiazol-6-yl; Ar2 represents furan-2-yl, furan-3-yl, thiophen-2-yl, indol-3-yl, 3-trifluoromethylphenyl, 3-methoxyphenyl, or pyridin-3-yl; R7 represents 1-4C alkyl, 3-7C alkenyl, 3-7C cycloalkyl, 1-ethoxycarbonyl-2-phenyl-eth-1-yl, thiophen-2-yleth-1-yl or a phenyl group that is unsubstituted or substituted by one or more groups, the substituents being selected from the group consisting of halogen, cyano, 1-4C alkyl, trifluoromethyl, 1-4C alkylthio, 1-4C alkoxy, 1-4C alkoxy that is fully or mainly substituted by fluorine, 1-4C alkylcarbonyl and phenoxy, or a salt thereof.

[0362] The preparation of such compounds is described in WO2002 / 040449.

[0363] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds disclosed generally or specifically in WO2001 / 098274 (expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0364] [ka] It has.

[0365] The substituents for the above compounds are defined as follows:

[0366] W, X, Y and Z may be the same or different and each represents a nitrogen atom or a C(R 5 ) group, wherein R5 is a hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, -NO2 or -CN group, provided that two or more of W, X, Y and Z are C(R5) groups; R1, R2 and R3 may be the same or different and each represents an atom or -L1(Alk1) r -L2(R6) sgroup, wherein L and L may be the same or different and each is a covalent bond or a linker atom or group; r is zero or the integer 1; Alk is an aliphatic or heteroaliphatic chain; s is an integer of 1, 2, or 3; R is a hydrogen or halogen atom, or an alkyl, —OR, where R is a hydrogen atom or an optionally substituted alkyl group, —SR, NR, R, where R is as defined for R and may be the same or different, —NO, CN, CO, R, SO, H, S(O)R, SO, R, OCO, R 7, CONR7R8, OCONR7R8, CSNR7R8, OCR7, OCOR7, N(R7)COR8, N(R7)CSR8, S(O)NR7R8, SO2NR7R8, N(R7)S02R8, N(R7)CON(R8)(R9) [wherein R9 is a hydrogen atom or an optionally substituted alkyl group], N(R7)CSN(R8)(R9), N(R7)SON(R8)(R9), C(R7)=NO(R8), a cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl group; provided that one or more of R1, R2, or R3 is a substituent other than a hydrogen atom; R4 represents an optionally substituted phenyl, 1- or 2-naphthyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group; and its salts, solvates, hydrates and N-oxides.

[0367] The preparation of such compounds is described in WO2001 / 098274.

[0368] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds disclosed generally or specifically in WO2001 / 074786 (expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0369] [ka] It has.

[0370] The substituents for the above compounds are defined as follows:

[0371] R1 represents an aryl or heteroaryl group; A, B, P and E, which may be the same or different, each represent a nitrogen atom or a C(R) group, where R is a hydrogen or halogen atom or an alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, -NO or -CN group, provided that two or more of A, B, D and E are C(R); X represents an oxygen or sulfur atom or an N(R) group, where R is a hydrogen atom or an alkyl group; Q, R, S and T may be the same or different and each represent a nitrogen atom or a C(R4) group, where R4 is an atom or a -L1(Alk1)rL2(R5) group, where L1 and L2 may be the same or different and each represent a covalent bond or a linker atom or group; r is zero or the integer 1; Alky1 is an aliphatic or heteroaliphatic chain; s is an integer of 1, 2 or 3; R5 is a hydrogen or halogen atom, or an alkyl, OR6, where R6 is a hydrogen atom or an optionally substituted alkyl group, SR6, NR6R7, where R7 is as defined for R6 and may be the same or different. ], NO2, CN, CO2R6, SO3H, S(O)R6, SO2R6, OCO2R6, CONR6R7, OCONR6R7, CSNR7R7, OCR6, OCOR6, N(R6)COR7, N(R6)CSR7, S(O)NR6R7, SO2NR6R7, N(R6)S02R7; N(R6)CON(R7)(R8) [wherein R8 is a hydrogen atom or an optionally substituted alkyl group], N(R6)CSN(R7)(R8), N(R6)SON(R7)(R8), C(R6)=NO(R7) is a cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl group, with the proviso that two or more of Q, R, S, and T are C(R4) groups. and salts, solvates, hydrates and N-oxides thereof.

[0372] The preparation of such compounds is described in WO2001 / 074786.

[0373] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds disclosed generally or specifically in WO2000 / 068230 (expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0374] [ka] It has.

[0375] The substituents for the above compounds are defined as follows:

[0376] XYZ represents NR4-C=N or N=C-NR4; R1 represents H, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl; R2 is OR8, NR8R9, SR 13 , alkyl or CF3; R3 represents halogen, alkyl, CF3 or OR8; R4 may be attached to either X or Z;

[0377] [ka] is a residue selected from During the ceremony, The bond is at any position on the saturated ring, provided that the bond is not adjacent to V, and the saturated ring may be substituted at any position with one or more R6; A, B, D and E are the same or different, and each nR5, representing N or NO; V is O, S, NR7 or C(L 1 m R 14 )(L 2 n R 14 ) represents; Q and W may be the same or different, and each n Represents R5 or N; T represents O, S or NR7; L 1 and L 2 are the same or different, and each C(R 15 )2 represents; m and n are the same or different and each represent 0, 1, 2, 3, 4, or 5; R5 may be the same or different and each may be H, halogen, alkyl, cycloalkyl, OR8, NR8R9, CO2R 10 ,CONR 11 R 12 , CONHOH, SO2NR 11 R 12 ,SON 11 R 12 , C.O.R. 13 , SO2R 13 , SOR 13 , S.R. 13 , representing CF3, NO2 or CN; R6 is H, alkyl, cycloalkyl, OR8, NR8R9, CO2R 10 ,CONR 11 R 12 , SO2NR 11 R 12 ,SON 11 R 12 , C.O.R. 13 , SO2R 13 , SOR 13 , S.R. 13 , CF3, CN or =O; R7 represents H or alkyl; R8 represents H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl; R9 represents R8 or alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, cycloalkylsulfonyl, cycloalkylalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkylsulfonyl, arylcarbonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclocarbonyl, heterocyclosulfonyl, arylalkylcarbonyl, arylalkoxycarbonyl, arylalkylsulfonyl, heteroarylalkylcarbonyl, heteroarylalkoxycarbonyl, heteroarylsulfonyl, heterocycloalkylcarbonyl, heterocycloalkoxycarbonyl, or heterocycloalkylsulfonyl; or NR8R9 represents a heterocycle such as morpholine; R 10 represents H, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl; R 11 and R 12 are the same or different and are each R8 or NR 11 R 12 represents a heterocycle such as morpholine; R 13 represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl; R 14 are the same or different and are each H, alkyl, cycloalkyl, OR, NR, R, CO, R 10 ,CONR 11 R 12 , CONHOH, SO2NR 11 R 12 ,SON 11 R 12 , C.O.R. 13 , SO2R 13 , SOR 13 , S.R. 13, CF3, NO2 and CN, provided that when both m and n are 0, one of R 14 OR8, NR8R9 or SR 13 If the other is OR8, NR8R9 or SR 13 shall not be; and R 15 represents H, alkyl or F; or and pharmaceutically acceptable salts thereof.

[0378] The preparation of such compounds is described in WO2000 / 068230, which is incorporated herein by reference in its entirety.

[0379] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in US20040106631, EP1400244, and WO2004 / 026818 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound represented by the formula:

[0380] [ka] It has.

[0381] The substituents for the above compounds are defined as follows:

[0382] m is 1, 2 or 3; R1 is methyl, chloro, bromo or fluoro; R2 is -Q 1 -Q 2 -Q 3 -Q 4 or (C1-C6) alkyl, wherein the (C1-C6) alkyl is substituted with 1 to 3 OR4, COOR4, NR4R5, NRC(=O)R4, C(=O)NR4R5 or SO2NR4R5; R4 is (C1-C6)alkyl substituted with 1-3 of F, CN, S(=O)R6, SO3H, SO2R6, SR7, C(=O)-NH-SO2-CH3, C(=O)R7, NR'C(=O)R7, NR'S02R6, C(=O)NR7R8, OC(=O)NR7R8 or SO2NR7R8; R5 is H or (C1-C6) alkyl optionally substituted with 1 to 3 of F, CN, S(=O)R6, SO3H, SO2R6, SR7, C(=O)-NH-SO2-CH3, C(=O)R7, NR'C(=O)R7, NR'S02R6, C(=O)NR7R8, OC(=O)NR7R8 or SO2NR7R8; or the (C1-C6) alkyl is (1) and (2) below: (1) 1 to 3 OC(=O)R 4a , S.R. 4a , S(=O)R3, C(=NR9)R 4a , C(=NR9)-NR 4a R 5a , NR-C(=NR9)-NR 4a R 5a , NRCOOR 4a , NR-C(=O)NR 4a R 5a , NR-SO2-NR 4a R 5a , NR-C(=NR9)-R 4a or substituted with NR-SO2-R3; and (2) 1 or 2 OR 4a , COOR 4a , C(=O)-R 4a , N.R. 4a R 5a , NRC(=O)R 4a , C(=O)NR4R 5a or SO2NR 4a R 5a optionally replaced by; R9 is H, CN, OH, OCH3, SO2CH3, SO2NH2 or (C1-C6)alkyl; and R3 is (C1-C6)alkyl optionally substituted with 1-3 of F, CN, S(=O)R6, SO3H, SO2R6, C(=O)-NH-SO2-CH3, OR7, SR7, COOR7, C(=O)R7, OC(=O)NR7R8, NR7R8, NR'C(=O)R7, NR'S02R6, C(=O)NR7R8 or SO2NR7R8; R 4a and R 5a are the same or different and are H or (C1-C6)alkyl optionally substituted with 1-3 of F, CN, S(=O)R6, SO3H, SO2R6, C(=O)-NH-SO2-CH3, OR7, SR7, COOR7, C(=O)R7, OC(=O)NR7R8, NR7R8, NR'C(=O)R7, NR'S02R6, C(=O)NR7R8 or SO2NR7R8; Q 1 is a single bond or (C1-C6) alkylene; Q 2 is a 4-6 membered saturated heterocyclyl containing one or two O or N; Q 3 is (C1-C6) alkylene; Q 4 is a 4-8 membered aromatic or non-aromatic heterocyclyl containing 1-4 of O, S, S(=O), SO or N, said heterocyclyl optionally substituted with 1-3 of OR, NRR', -CN or ((C1-C6)alkyl; R is H or (C1-C6) alkyl; R6 is (C1-C6) alkyl optionally substituted with 1 or 2 OR'; R7 and R8 are the same or different and are H or (C1-C6) alkyl optionally substituted with 1 or 2 OR'; R9 is H, CN, OH, OCH3, SO2CH3, SO2NH2 or (C1-C6) alkyl; R' is H or (C1-C6) alkyl; and R" is H or (C1-C6) alkyl; However, (1)Q 1 Q bonded to 2 are carbon atoms; and (2) Q 3 Q bonded to 4 shall be carbon atoms; or a racemic form, isomer, or pharmaceutically acceptable derivative thereof.

[0383] The preparation of such compounds is described in US20040106631, EP1400244, and WO2004 / 026818.

[0384] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 6,936,609 and U.S. Patent No. 20040249148 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0385] [ka] It has.

[0386] The substituents for the above compounds are defined as follows:

[0387] R1 is (C6~C 10)-aryl, which is optionally substituted by groups, which may be identical or different, selected from the group consisting of halogen, formyl, carbamoyl, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, nitro, (C1-C6)-alkyl or (C1-C6)-alkoxy, and which is optionally substituted by a group of the formula SO2NR5R6, in which R5 and R6, independently of one another, are hydrogen or (C1-C6)-alkyl, or NR5R6 is a 4- to 8-membered heterocyclyl bonded via a nitrogen atom and which is optionally substituted by groups, which may be identical or different, selected from the group consisting of oxo, halogen, (C1-C6)-alkyl and (C1-C6)-acyl, R2 represents a saturated or partially unsaturated hydrocarbon group having 1 to 10 carbon atoms; R3 represents methyl or ethyl; A represents O, S or NR7, where R7 represents hydrogen or (C1-C6)-alkyl optionally substituted with (C1-C3)-alkoxy, E represents a bond or a (C1-C3)-alkanediyl; R4 is (C6~C 10 )-aryl or 5-10 membered heteroaryl, the aryl and heteroaryl being identical or different and optionally substituted by groups selected from the group consisting of halogen, formyl, carboxyl, carbamoyl, -SO3H, aminosulfonyl, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, nitro, (C1-C6)-alkyl, (C1-C6)-alkoxy, 1,3-dioxa-propane-1,3-diyl, (C1-C6)-alkylthio, (C1-C6)-alkylsulfinyl and (C1-C6)-alkyl-sulfonyl, -NR8R9 and 5-6 membered heteroaryl or phenyl, optionally substituted by methyl, wherein R8 and R9 independently represent hydrogen, (C1-C6)-alkyl or (C1-C6)-acyl, or a salt thereof.

[0388] The preparation of such compounds is described in US Pat. No. 6,936,609 and US20040249148.

[0389] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds disclosed generally or specifically in WO2006 / 092692 (expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0390] [ka] It has.

[0391] wherein n is an integer from 1 to 4, and if stereocenters are present, each center may independently be R or S.

[0392] The preparation of such compounds is described in WO2006 / 092692.

[0393] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in US2006229306 and WO2004 / 065391 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in US2006229306 and WO2004 / 065391 (each of which is expressly incorporated herein by reference in its entirety).

[0394] [ka] It has.

[0395] The substituents for the above compounds are defined as follows:

[0396] R1 and R2 are either (1) or (2) below: (1) Independently represent the following (a) to (c): (a) Hydrogen atom; (b) a group selected from alkyl, alkenyl, and alkynyl groups, each of which is independently optionally substituted with one or more substituents selected from halogen atoms, hydroxy, alkoxy, aryloxy, alkylthio, hydroxycarbonyl, alkoxycarbonyl, mono- and di-alkylaminoacyl, oxo, amino, and mono- and di-alkylamino groups; or (c) Formula (CH2) n -R6 group, where n is an integer from 0 to 4 and R6 represents a cycloalkyl or cycloalkenyl group; (2) R1 and R2, together with the nitrogen atom to which they are attached, form a 3-8 membered ring containing 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur, which ring is saturated or unsaturated and optionally substituted with one or more substituents selected from halogen atoms, alkyl, hydroxy, alkoxy, acyl, hydroxycarbonyl, alkoxycarbonyl, alkylenedioxy, amino, mono- and di-alkylamino, mono- and di-alkylaminoacyl, nitro, cyano, and trifluoromethyl groups; R3 is a group of the formula (CH2) n-G wherein n is an integer of 0 to 4, and G represents a monocyclic or bicyclic aryl or heteroaryl group containing 0 to 4 heteroatoms, which is optionally substituted with one or more substituents selected from the following (1) to (3): (1) halogen atoms; (2) alkyl and alkylene groups, each of which is optionally substituted with one or more substituents independently selected from halogen atoms; and (3) phenyl, hydroxy, hydroxyalkyl, alkoxy, alkylenedioxy, aryloxy, alkylthio, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, cyano, difluoromethoxy, and trifluoromethoxy groups; R4 represents a hydrogen atom, an alkyl group, or an aryl group.

[0397] The preparation of such compounds is described in US2006229306 and WO2004 / 065391.

[0398] Other compounds useful in the methods of the present invention include imidazopyridine derivatives (WO2001 / 34601), dihydropurine derivatives (WO2000 / 68203), pyrrole derivatives (WO2001 / 32618), benzothiopyranoimidazolone derivatives (DE 19950647), heterocyclic compounds (WO2002 / 87519), guanine derivatives (Bioorg.Med.Chem.Lett.11:1081-1083, 2001), and benzothienothiadiazine derivatives (Eur.J.Med.Chem.36:333, 2001). The disclosures of each of the above-mentioned published patent applications and journal articles are expressly incorporated herein by reference in their entirety.

[0399] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds disclosed generally or specifically in WO2008 / 130619 (expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0400] [ka] It has.

[0401] The substituents for the above compounds are defined as follows:

[0402] X is SO or SO; R1 is H or alkyl; R2 is alkyl or halogen.

[0403] In a specific embodiment, R1 is Me. In another specific embodiment, R1 is F. In some embodiments, R2 is t-Bu. In a specific embodiment, R1 is methyl. In a more specific embodiment, the compound is

[0404] [ka] It is selected from:

[0405] In a related embodiment, the PDE7 inhibitor useful in the methods of the invention has the formula:

[0406] [ka] (In the formula, R1 is alkyl, R2 is aryl or heteroaryl; R3 is alkyl, aryl, cycloakyl, or alkylaryl. It has.

[0407] In a specific embodiment, R1 is methyl. In some embodiments, R2 is furanyl or thiophenyl. In other specific embodiments, R2 is substituted phenyl or benzyl. In a preferred embodiment, R3 is isobutyl. In a more specific embodiment, the compound is

[0408] [ka] It is selected from:

[0409] In another related embodiment, the PDE7 inhibitor useful in the methods of the invention has the formula:

[0410] [ka] (In the formula, R1 is a nitrile or an alkyl carboxylate; R2 is alkyl, aryl, or heteroaryl. It has.

[0411] In specific embodiments, R1 is nitrile or methyl carboxylate. In some embodiments, R2 is a 5-membered heteroaryl. In more specific embodiments, R2 is furanyl or thienyl. In other embodiments, R2 is a 6-membered aryl. In more specific embodiments, R2 is substituted phenyl.

[0412] [ka] In another related embodiment, the PDE7 inhibitor useful in the methods of the invention has the formula:

[0413] [ka] (In the formula, R1 is an alkyl, alkenyl or alkylcarboxylic acid; R2 is a halogen It has.

[0414] In some embodiments, R1 is butyl. In other embodiments, R1 is terminal alkenyl. In more specific embodiments, R1 is allyl or vinyl. In other embodiments, R1 is C 1-4 In a specific embodiment, R1 is methylcarboxylic acid. In an embodiment, R2 is Cl or Br. In a more specific embodiment, the compound is

[0415] [ka] It is selected from:

[0416] In other related embodiments, the PDE7 inhibitor useful in the methods of the invention has the formula:

[0417] [ka] (In the formula, R1 is CO or alkyl alcohol, R2 is alkyl, R3 is alkoxy, and the C4 and C9 stereocenters are independently (R) or (S). It has.

[0418] In certain embodiments, R1 is carbonyl or 2-methylpropan-1-ol. In specific embodiments, R2 is methyl. In certain embodiments, R3 is methoxy. In more specific embodiments, the compound is

[0419] [ka] It is selected from:

[0420] In another related embodiment, the PDE7 inhibitor useful in the methods of the invention has the formula:

[0421] [ka] (In the formula, R1 is hydrogen, hydroxyl, carbonyl or alkyl alcohol; R2 and R3 are independently selected from hydrogen, alkyl, alkyl carboxylate, or carboxylic acid; R4 is hydrogen or alkyl; R5 is hydrogen, alkyl, hydroxyl or acetate; R6 is hydrogen or alkoxy, and the C4 and C9 stereocenters are independently (R) or (S). It has.

[0422] In certain embodiments, R1 is 2-methylpropan-1-ol. In specific embodiments, R2 is methyl. In certain embodiments, R2 is methyl carboxylate. In specific embodiments, R2 and R3 are both methyl. In other embodiments, R2 is methyl and R3 is methyl carboxylate. In specific embodiments, R4 is isopropyl. In specific embodiments, R5 is methyl. In certain embodiments, R6 is methoxy. In more specific embodiments, the compound is

[0423] [ka] It is selected from:

[0424] With respect to the compounds described above, the terms "alkyl," "alkenyl," and the prefix "alk-" include both straight-chain and branched-chain groups and cyclic groups (i.e., cycloalkyl and cycloalkenyl). Unless otherwise specified, these groups contain 1 to 20 carbon atoms, and alkenyl groups contain 2 to 20 carbon atoms. Preferred groups have a total of up to 10 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have 3 to 10 ring carbon atoms. Typical cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, adamantyl, norbornane, and norbornene. This also applies to groups containing the prefix "alkyl-" (e.g., alkylcarboxylic acid, alkyl alcohol, alkylcarboxylate, alkylaryl, etc.). Examples of suitable alkylcarboxylic acid groups include methylcarboxylic acid, ethylcarboxylic acid, etc. Examples of suitable alkyl alcohols include methyl alcohol, ethyl alcohol, isopropyl alcohol, 2-methylpropan-1-ol, etc. Examples of suitable alkyl carboxylates are methyl carboxylate, ethyl carboxylate, etc. Examples of suitable alkylaryl groups are benzyl, phenylpropyl, etc.

[0425] The term "aryl," as used herein, includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl, and indenyl. The term "heteroaryl" includes aromatic rings or ring systems containing at least one ring heteroatom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, thiazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and the like.

[0426] Aryl and heteroaryl groups can be unsubstituted or independently selected from alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, arylcarbonyloxy, arylcarbonylthio, alkylaminosulfonyl, alkylsulfonyl, aryl ... and, in the case of heterocyclyl, may be substituted with one or more substituents selected from the group consisting of aryl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, arylcarbonylaminoalkyl, heteroarylcarbonylatnino, heteroarylalkylcarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonylamino, heteroarylaminocarbonylamino, heteroarylalkylaminocarbonylamino, and, in the case of heterocyclyl, oxo.Where other groups are described as "substituted" or "optionally substituted," those groups may also be substituted with one or more of the above-listed substituents.

[0427] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds disclosed generally or specifically in WO2008 / 142550 (expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0428] [ka] It has.

[0429] The substituents for the above compounds are defined as follows:

[0430] m is 0, 1 or 2, and n is 0, 1, 2 or 3; X is O, S or N-CN; R 1 is a halogen or CN, A is a single bond, CH, O or S; B is a single bond, CH2 or OCH2, and R 2 are each independently selected from halogen, (optionally substituted with 1 to 3 fluorine atoms) (C 1-6 ) alkyl, OH, (C 1-6 ) alkylthio or CN; R 3 is selected from the following groups (i) to (x):

[0431] [ka] R is H or (optionally substituted with 1 to 3 fluorine atoms) (C 1-6 ) alkyl, and R' is (optionally substituted with 1 to 3 fluorine atoms) (C 1-6) alkyl or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.

[0432] In the above compounds, the term "alkyl" refers to a monovalent, straight or branched, saturated hydrocarbon chain containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylbutyl, and 2,2-dimethylbutyl. Preferred alkyl groups are especially methyl and ethyl, especially methyl.

[0433] Here, the alkyl group may be substituted with 1 to 3 fluorine atoms. The substitution may be at any position on the alkyl chain. Preferably, the fluorinated alkyl group has 1 to 4 carbon atoms, more preferably 1 or 2 carbon atoms. Monofluoromethyl, difluoromethyl, and trifluoromethyl groups (especially trifluoromethyl), as well as monofluoroethyl, difluoroethyl, and trifluoroethyl groups (especially 2,2,2-trifluoroethyl) are particularly preferred.

[0434] The term "alkoxy" means "alkyl-O-", where "alkyl" is defined as above, i.e., in its broadest or preferred embodiment. Preferred alkoxy groups are the groups, particularly methoxy and ethoxy. The term "alkylthio" means "alkyl-S-", where "alkyl" is defined as above, i.e., in its broadest or preferred embodiment. Preferred alkylthio groups are (C 1-4 ) alkylthio groups, especially methylthio and ethylthio. The term "halogen" means fluoro, chloro, bromo or iodo. Preferred halogen groups are fluoro and chloro.

[0435] Preferably, m is 0 or 1, more preferably 1.

[0436] Preferably, n is 0 or 1, more preferably 0.

[0437] Preferably, X is O or N-CN, more preferably O.

[0438] Preferably, R 1 is F or Cl, more preferably Cl.

[0439] Preferably, A is a single bond or O, more preferably O.

[0440] When B is OCH2, the oxygen atom is attached to the benzene ring and the methylene group is 3 Attaches to the group.

[0441] Preferably, B is a single bond.

[0442] Preferably, R 2 is F or Cl, more preferably F.

[0443] Preferably, R 3 is group (i), (ii), (iii), (iv), (v) or (vi), more preferably group (i) or (ii), especially group (ii).

[0444] In one embodiment, -BR 3 The group is located at the 2-position of the phenyl ring (the A group is located at the 1-position). 3 In a further embodiment, the -BR group is at position 3. 3 The group is in the 4-position.

[0445] PDE7 inhibitors useful in the methods of the invention include those in which each variable in the formula above is selected from the preferred and / or preferred groups for each variable. Even more preferred PDE7 inhibitors useful in the methods of the invention include those in which each variable in the formula above is selected from the more preferred or most preferred groups for each variable.

[0446] In related embodiments, the following PDE7 inhibitors are useful in the methods of the invention: 5-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazolin]-5'-yl)]-2-fluorobenzoic acid, 3-(8'-chloro-2-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazolin]-5'-ylbenzoic acid, 5-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-4'-yl)]-2-fluorobenzoic acid, 8-chloro-5'-[4-fluoro-3-(2H-tetrazol-5-yl)phenyl]-1'H-spiro[cyclohexane-1,4'-quinazoline]-2'(3'H)-one, [3-(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)phenoxy]acetic acid, 2-{(8'-chloro-2'-oxo-2,3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)oxy}-3-fluorobenzoic acid, 2-{(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclopentane-1,4'-quinazoline]-5'-oxy}-3-fluorobenzoic acid, 3-chloro-2-{(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)oxy}benzoic acid, 3-chloro-2-{(8'-fluoro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)oxy}benzoic acid, 8'-chloro-5'-[2-fluoro-6-(2H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[4-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[6-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[4-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[6-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[6-chloro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[2-fluoro-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[2-fluoro-6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 2-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)oxy]-3-fluoro-N-(methylsulfonyl)benzamide, N-{2-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)oxy]-3-fluorophenyl}-1,1,1-trifluoromethanesulfonamide, {2-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)oxy]-3-fluorophenyl}acetic acid, {2-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)oxy]phenoxy}acetic acid, {4-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazolin-5'-yl)oxy]phenoxy}acetic acid, methyl 2-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)oxy]-3-fluorobenzoate, and pharmaceutically acceptable salts, solvates and prodrugs thereof.

[0447] In another related embodiment, the following PDE7 inhibitors are useful in the methods of the invention: 8'-chloro-5'-[2-fluoro-6-(2H-tetrazol-5-yl)phenoxy]-1'H-spirocyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[4-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[6-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[4-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[6-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[6-chloro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, and pharmaceutically acceptable salts, solvates and prodrugs thereof.

[0448] The following compounds are most preferred: 8'-chloro-5'-[2-fluoro-6-(2H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[4-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[6-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, and pharmaceutically acceptable salts, solvates and prodrugs thereof.

[0449] The preparation of such compounds is described in WO2008 / 142550.

[0450] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 7,498,334, US 2005 / 0059686, and WO 2003 / 055882 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0451] [ka] It has.

[0452] The substituents for the above compounds are defined as follows:

[0453] X is phenyl or Het, each of which is unsubstituted or mono- or polysubstituted by R1 and / or R2, R1 and R2 are each independently A, OH, OA, SA, SOA, SO2A, SO2NH2, SO2NHA, SO2AA', CN, NO2, NH2, NHA, NAA', NHCOA, NHCOOA, COOH, COOA, CONH2, CONHA, CONAA' or Hal, R' and R2 are both alternatively -OCHO- or -OCH2CH2O-, and R3 is , A, OH, OA, SA, SOA, SO2A, SO2NH2, SO2NHA, SO2AA', CN, NO2, NH2, NHA, NHB, NAA', NHCOA, NHCOOA, NHCOB, NHCOOB, COOH, COOA, COOB, CONH2, CONHA, CONHB, CONAA' or Hal, and R4 is a branched or unbranched alkyl or alkenyl having up to 10 carbon atoms, said alkyl or alkenyl optionally substituted with 1 to 5 F and / or Cl atoms, and / or said alkyl or in the alkenyl, one or more CH groups may be replaced by O, S, SO, SO, NH, NA, NHCO, NACO, NHCOO or NACOO, or a cycloalkyl or cycloalkenyl having 3 to 7 carbon atoms, in which one or two CH groups may be replaced by O, S, SO, SO, SONH, SONA, NH, NHA, NHCONH, NACONH, NACONA, NHCO, NACO, NHCOO or NACOO; and R is O R6 is H, OH, OA, SA, SOA, SO2A, SO2NH2, SO2NHA, SO2AA', CN, NO2, NH2, NHA, NAA', NHCOA, NHCOOA, COOH, COOA, CONH2, CONHA, CONAA' or Hal; R6 is H, OH, OA, SA, SOA, SO2A, SO2NH2, SO2NHA, SO2AA', CN, NO2, NH2, NHA, NAA', NHCOA, NHCOOA, COOH, COOA, CONH2, CONHA, CONAA' or Hal; A and A' are each independentlyA is a branched or unbranched alkyl or alkenyl having up to 10 carbon atoms, wherein the alkyl or alkenyl is optionally substituted with 1 to 5 F and / or Cl atoms, and / or wherein one or more CH groups are optionally replaced by O, S, SO, SO, NH, NR, NHCO, NRCO, NHCOO, or NRCOO. A and A' are both alternatively alkylene having 3 to 7 carbon atoms, wherein one or two CH groups are optionally replaced by CHR, CHR, O, S, SO, SO, NH, NR, NHCO, NRCO, NHCOO, or NRCOO. B is phenyl or Het, each of which is unsubstituted or mono- or polysubstituted by R1 and / or R2; Het is an aromatic 5- or 6-membered heterocycle having 1 to 3 N, O and / or S atoms, which is unsubstituted or mono-, di- or tri-substituted by A"; Hal or CF3; R7 and R8 are each, independently of one another, branched or unbranched alkyl or alkenyl having up to 5 carbon atoms, which alkyl or alkenyl may be substituted with 1 to 5 F and / or Cl atoms, and / or in which one or more CH2 groups may be replaced by O, S, SO, SO2 or NH; A" is an alkyl having 1 to 6 carbon atoms; Hal is F, Cl, Br or I; and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all proportions.

[0454] In related embodiments, PDE7 inhibitors useful in the methods of the present invention include compounds of the formula above (wherein R5 is OH), and also include compounds of the formula:

[0455] [ka] These may also be in the form of their tautomers:

[0456] Regarding the above-mentioned compounds, the PDE7 inhibitors useful in the method of the present invention include optically active forms (stereoisomers), optical isomers, racemates, diastereomers and the hydrates and solvates of these compounds.The term solvate of compound means that the adduct of inert solvent molecules to said compound occurs due to their mutual attractive force.Solvate is for example monohydrate, dihydrate or alcoholate.

[0457] With respect to the above compounds, the term "pharmaceutically usable derivatives" refers to, for example, salts of the above compounds and so-called prodrug compounds. The term "prodrug derivatives" refers to, for example, the above compounds modified with, for example, alkyl or acyl groups, sugars, or oligopeptides, which are quickly degraded in living organisms to release the active compound. These also include biodegradable polymer derivatives of the above compounds, as described, for example, in Int. J. Pharm. 115, 61-67 (1995).

[0458] With respect to the compounds described above, the meanings of all radicals occurring more than once are independent of one another on each occasion.

[0459] A and A' are preferably alkyl, more preferably alkyl substituted with 1 to 5 fluorine and / or chlorine atoms, and even more preferably alkenyl.

[0460] In the above formula, alkyl is preferably unbranched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms, and is preferably methyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, more preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or n-hexyl. Methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, n-pentyl, n-hexyl or n-decyl are particularly preferred.

[0461] A" is preferably alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl or propyl, more preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or n-hexyl. Methyl, ethyl, propyl, isopropyl or butyl are particularly preferred.

[0462] Cycloalkyl preferably has 3 to 7 carbon atoms and is preferably cyclopropyl or cyclobutyl, more preferably cyclopentyl or cyclohexyl, and even cycloheptyl; cyclopentyl is particularly preferred.

[0463] Alkenyl is preferably vinyl, allyl, 2- or 3-butenyl, isobutenyl or sec-butenyl; furthermore, 4-pentenyl, isopentenyl or 5-hexenyl are preferred.

[0464] Alkylene is preferably unbranched and is preferably methylene or ethylene, more preferably propylene or butylene.

[0465] Hal is preferably F, Cl or Br, but also I.

[0466] The R1 and R2 groups may be the same or different and are preferably located at the 2- or 4-position of the phenyl ring. They may, for example, be independently A or Hal, or both may be methylenedioxy.

[0467] However, they are preferably respectively methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, but also fluoromethoxy, difluoromethoxy or trifluoromethoxy or 1-fluoroethoxy, 2-fluoroethoxy, 1,2-difluoroethoxy, 2,2-difluoroethoxy, 1,2,2-trifluoroethoxy or 2,2,2-trifluoroethoxy, and also fluorine or chlorine.

[0468] R1 is particularly preferably fluorine, chlorine, methyl, ethyl or propyl.

[0469] R2 is particularly preferably fluorine, chlorine, methyl, ethyl or propyl.

[0470] X is preferably a phenyl group monosubstituted with R1 or unsubstituted Het.

[0471] X is particularly preferably 2-chlorophenyl, 2-fluorophenyl, 4-methylphenyl, 3-chlorophenyl or 4-chlorophenyl.

[0472] Het is preferably, for example, unsubstituted 2-furyl or 3-furyl, 2-thienyl or 3-thienyl, 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl or 5-imidazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl, more preferably 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl or 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl or 1,2,4-triazol-5-yl, 1,2,3-oxadiazol-4-yl or 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl or 1,3,4-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl or 1,2,4-thiadiazol-5-yl, or 1,2,3-thia-diazol-4-yl or 1,2,3-thia-diazol-5-yl.

[0473] R3 is preferably, for example, COOA" or COOH.

[0474] R4 is preferably unbranched or branched alkyl, for example having 1, 2, 3, 4, 5 or 6 carbon atoms, which may be substituted with 1 to 5 F or Cl atoms, preferably methyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, more preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but may also be substituted with n-pentyl, neopentyl, isopentyl or n-hexyl. Methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, n-pentyl, n-hexyl or n-decyl are particularly preferred.

[0475] R5 is preferably Cl or OH.

[0476] R6 is preferably H.

[0477] For the above compounds, at least one of said groups has one of the preferred meanings indicated above.

[0478] In related embodiments, PDE7 inhibitors useful in the methods of the invention include the following compounds (wherein X is a phenyl group monosubstituted with R1 or is unsubstituted Het; R1 is A or Hal; R3 is COOA" or COOH; R4 is unbranched or branched alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms, which may be substituted with 1 to 5 F or Cl atoms; R5 is Cl or OH; and R6 is H); In other related embodiments, PDE7 inhibitors useful in the methods of the present invention include the following compounds: (wherein X is a phenyl group monosubstituted with R1 or is unsubstituted Het; R1 is A or Hal; R3 is COOA" or COOH; R4 is unbranched or branched alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms, which alkyl may be substituted with 1 to 5 F or Cl atoms; R5 is Cl or OH; R6 is H; Het is furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, or pyrimidinyl; A and A" are each, independently of the other, unbranched or branched alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms, which may be substituted with 1 to 5 F or Cl atoms; and Hal is F, Cl, or Br), as well as pharmaceutically acceptable derivatives, solvates, and stereoisomers thereof, including mixtures thereof in all proportions.

[0479] The preparation of the above-mentioned compounds and the starting materials for their preparation are described in the literature (for example in standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart) and are carried out under known and suitable reaction conditions for the reactions described above. Method variants, which are known per se, can also be used here, although they are not mentioned in more detail here.

[0480] In another related embodiment, PDE7 inhibitors useful in the methods of the present invention include: Ethyl 5-isopropyl-4-oxo-7-p-tolyl-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidine-6-carboxylate, Ethyl 5-methyl-4-oxo-7-(3-chlorophenyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylate, Ethyl 5-methyl-4-oxo-7-(2-chlorophenyl)-4,7-dihydro-3H-pyrrolo[ 2,3-d]pyrimidine-6-carboxylate, ethyl 5-methyl-4-oxo-7-(2-fluorophenyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylate, ethyl 5-propyl-4-oxo-7-(2-chlorophenyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylate, ethyl 5-methyl-4-oxo-7-(4 -chlorophenyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylate, ethyl 5-methyl-4-oxo-7-p-tolyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylate, methyl 5-methyl-4-oxo-7-(2-chlorophenyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylate , methyl 5-methyl-4-oxo-7-phenyl-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidine-6-carboxylate, methyl 5-methyl-4-oxo-7-(2-thienyl)-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidine-6-carboxylate, and pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all proportions. Examples include:

[0481] The preparation of the above compounds is described in US Pat. No. 7,498,334 and WO 2003 / 055882.

[0482] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 6,884,800 and WO 01 / 36425 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0483] [ka] It has.

[0484] The substituents for the above compounds are defined as follows:

[0485] R1 and R2, independently of one another, each represent A1, OA1, SA1 or Hal, where A1 represents H, A, alkenyl, cycloalkyl or alkylenecycloalkyl, A represents alkyl having 1 to 10 carbon atoms, Hal represents F, Cl, Br or I, and x represents O, S, SO or SO2, as well as physiologically acceptable salts and / or solvates thereof.

[0486] In the above compounds, A represents alkyl having 1 to 10 carbon atoms, preferably methyl, ethyl, or propyl, more preferably isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, but also n-pentyl, neopentyl, isopentyl, or hexyl. In these groups, 1 to 7 H atoms may be replaced by F and / or Cl. Thus, A may also represent, for example, trifluoromethyl or pentafluoroethyl. Cycloalkyl represents 3 to 9 carbon atoms, preferably cyclopentyl or cyclohexyl. Alkenyl represents 2 to 10 carbon atoms, linear or branched, preferably vinyl, propenyl, or butenyl. Alkylenecycloalkyl represents 4 to 10 carbon atoms, preferably methylenecyclopentyl, ethylenecyclopentyl, methylenecyclohexyl, or ethylenecyclohexyl. R1 and R2 preferably denote, in each case independently of one another, H, fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, cyclopentyl or cyclohexyl.

[0487] In related embodiments, PDE7 inhibitors useful in the methods of the present invention include the following compounds: X is S; X is S and R1 is H; X is S and R1 is F or Cl; X is S and R2 is H; X is S and R2 is F or Cl; X is S, R1 is H, and R2 is F or Cl; X is S, R1 is F or Cl, and R2 is H; X is S; A1 is H or A, where A is alkyl having 1, 2, 3 or 4 carbon atoms; X is S, R1 and R2, independently of one another, each represent A1 or Hal, where A1 is H or A, A is alkyl having 1, 2, 3 or 4 carbon atoms, and Hal is F or Cl. and physiologically acceptable salts and solvates thereof.

[0488] In another related embodiment, PDE7 inhibitors useful in the methods of the present invention include the following compounds: 10-chloro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 4-chloro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 10-methoxy-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine Thiazine, 10-propoxy-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 10-methylthio-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 10-fluoro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3, 2,1-kl]phenothiazine, 4,10-dichloro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 10-trifluoromethyl-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 4-cyclopentoxy-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 10-chloro-3-imidazol-1-yl-2,3-dihydro-1H-7-oxa-11b-azabenzo[de]-anthracene and 10-chloro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine 7,7-dioxide.

[0489] The preparation of such compounds is described in US Pat. No. 6,884,800 and WO 01 / 36425.

[0490] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 6,531,498 and WO 01 / 32175 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound having the formula:

[0491] [ka] It has.

[0492] The substituents for the above compounds are defined as follows:

[0493] R1, R2, R3, R4 are each independently Hal, OA1, SA1, A, H, COOA1, CN or CONA1A2; R5 is COOA1, CN or CONA1A2; A1, A2 are each independently H, A, alkenyl, cycloalkyl or alkylenecycloalkyl; A is alkyl having 1 to 10 C atoms, Hal is F, Cl, Br or I; and physiologically acceptable salts and / or solvates thereof.

[0494] In the above compounds, A is alkyl having 1 to 10 carbon atoms, preferably methyl, ethyl or propyl, and more preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl. 1 to 7 H atoms in the group may be replaced by F and / or Cl. Thus, A can also be, for example, trifluoromethyl or pentafluoroethyl.

[0495] Cycloalkyl has 3 to 9 carbon atoms and is preferably, for example, cyclopentyl or cyclohexyl. Alkenyl has 2 to 10 carbon atoms and is linear or branched, preferably vinyl, propenyl or butenyl.

[0496] Alkylenecycloalkyl has 4 to 10 C ato...

Claims

[Claim 1] A kit or method as described in the specification.

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