JP2021138766A - Treatment of addiction and impulse-control disorders using pde7 inhibitors - Google Patents

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 24D

Description

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The sequence listings accompanying the present application are provided in text form instead of paper copies and are incorporated herein by reference. The name of the text file containing the sequence listing is NE_1_0172_SequenceListingFinal_ST25; it has been submitted via EFS-Web with the submission of this specification.

I. INDUSTRIAL APPLICABILITY The present disclosure relates to the prevention and treatment of substance addiction and behavioral addiction using a phosphodiesterase 7 (PDE7) inhibitor alone or in combination with other therapeutic agents or addictive agents.

II. Background of the Invention The World Health Organization (WHO) defines substance addiction as being aware of harmful effects and using the substance repeatedly despite the effects occurring. Substance addiction is characterized by uncontrollable drug overuse, compulsive drug demand and craving for the substance, persistent use despite negative effects, and physical and / or psychological dependence on the substance. It is a chronic and recurrent disease. Material addiction typically follows the course of tolerance, withdrawal, compulsive drug ingestion, drug demanding, addictive behavior, and recurrence. Excessive substance intake and addiction are public health issues that have a significant social and economic impact on both addiction and society by contributing significantly to the transmission of violent crime and infectious diseases. Addictions include alcohol, caffeine, nicotine, cannabis (marijuana) and cannabis derivatives, amphetamines and other morphine-like opioid agonists (such as heroines, phencyclidines and phencyclidine-like compounds), hypnotic stimulants (benzodiazepine and Barbiturate, etc.) and psychostimulants (such as cocaine, amphetamine and amphetamine-related drugs, such as dextroamphetamine and methylamphetamine).

Alcohol is one of the most commonly overdose substances at the world level. In addition, alcoholism leads to severe liver and cardiovascular disease, which results in severe mental illness, social problems and adverse consequences, such as family division, disastrous accidents and diminished functioning. Alcohol consumption accounts for 20-30% of the causes of esophageal and liver cancer, cirrhosis, murder, epilepsy and car accidents worldwide, according to the WHO. Globally, excessive alcohol consumption kills about 1.8 million people each year. Compulsive behavior towards alcohol consumption is a core symptom of the disorder. In recent years, several approaches have been sought to control not only alcohol consumption but also alcohol craving and recurrence in order to relieve alcoholics (Non-Patent Document 1; Non-Patent Document 2; and Non-Patent Document 3).

Drugs such as naltrexone, acamprosate, ondansetron, disulfiram, gamma-hydroxybutyric acid (GHB), and topiramate tested for their potential therapeutic effects on excessive alcohol intake belong to several types (non-patented). Document 2; Non-Patent Document 3). Some of these medicines, such as naltrexone, acamprosate and disulfiram, have proven to be useful to some extent and have been approved for the treatment of alcohol dependence. Of these drugs, the non-selective opioid antagonist naltrexone is currently considered the best pharmacological option. However, despite some promising outcomes, none of these drugs, including naltrexone, are sufficiently effective in alcoholism and the prognosis remains poor.

Nicotine is also one of the most widely used addictive drugs, and excessive nicotine intake is the most common form of excessive substance intake. The WHO estimates that there are 1.25 billion smokers worldwide, which is one-third of the world's population above the age of 15. In addition, the WHO estimates that smoking causes 5 million deaths each year directly from smoking, and excessive nicotine intake is the world's largest preventable single cause of death. There is. In developed countries, 70-90% of lung cancers, 56-80% of chronic respiratory illnesses, and 22% of cardiovascular illnesses are due to nicotine addiction. Smoking is associated with 430,000 deaths each year in the United States alone, with an estimated national health care cost of $ 80 billion annually. Smoking is responsible for one-third of all cancers (eg, lung, mouth, pharynx, larynx, esophagus, neck, kidney, ureter and bladder). The overall mortality rate from cancer is twice as high in smokers as in nonsmokers. Smoking also causes lung diseases such as chronic bronchitis and emphysema; exacerbates asthma symptoms; increases the risk of heart disease (eg, stroke, heart attack, vascular disease, and aneurysms). An estimated 20% of deaths from heart disease are due to smoking. Pregnant smoking women are at greater risk of preterm birth, spontaneous abortion, and infant underweight at birth than nonsmokers.

Nicotine use results in increased levels of the neurotransmitter dopamine, which regulates hedonic emotions and activates reward pathways that mediate desire for nicotine consumption. Symptoms associated with nicotine withdrawal include craving, irritability, anger, hostility, aggression, malaise, depression and cognitive impairment, which in turn lead to a demand for excessive nicotine intake. Environmental conditioning factors and exposure to psychological stress are additional factors that stimulate nicotine use in smokers. Repeated use of nicotine results in the development of tolerance and requires higher doses of nicotine to obtain the same stimuli as in the early stages.

Most treatments developed for nicotine addiction have shown moderately good results in preventing recurrence and have a high unsuccessful rate in attempts to quit smoking. Treatments include the use of nicotine substitutes, antidepressants, anti-hypersensitivity, and behavioral therapy.

It is estimated by the National Institute of Drug Damage that 72 million Americans, about one-third of the population, have tried marijuana. Acute effects of marijuana use include memory and learning problems, distorted cognition, problem-solving difficulties, coordination disorders, and increased heart rate. Long-term overdose causes the same respiratory problems observed in smokers, such as daily coughing, sputum production, increased risk of lung infection, and cancer of the head, neck and lungs. Increased likelihood of occurrence can be triggered. Depression, anxiety, and work-related problems are also associated with marijuana use. Long-term use of marijuana can result in addiction with obsessive-compulsive use that interferes with daily activities. Craving and withdrawal symptoms, such as irritability, increased aggression, insomnia and anxiety, make it difficult for addicts to stop using marijuana. No medicinal treatments are available to treat marijuana addiction and recurrence.

Globally, an estimated 13 million people, including 9 million heroin addicts, are overdose of opioids, according to the WHO. More than 25% of overdose opioids become addicted to suicide, homicide or infectious diseases (such as HIV and hepatitis) and die within 10 to 20 years. Tolerance and physical dependence can develop within 2-3 days. Excessive intake and addiction to opioid drugs are known phenomena, but in recent years this problem has been found to be exacerbated (Non-Patent Documents 4 and 5). An epidemiological study of young people in the United States in 2003 showed that opioid analgesics are the most frequently overdose of illicit drugs among middle and high school students (12th grade) after marijuana (12th grade). Non-Patent Document 6). Moreover, in the United States, there has been a marked increase in opioid drug use over the last few years, further increasing the problems associated with such use. This increase in use and problems is of particular concern as it is likely to extend the path to opioid addiction (Non-Patent Document 7).

According to recent epidemiological data, in 2002, 4.7% (ie, 11 million) of U.S. residents over the age of 12 were overdose of opioid drugs, 13 of these. 2.7% (ie, 1.5 million people) meet the criteria for DSM-IV opioid use disorder (Non-Patent Document 8; Non-Patent Document 9). As recently outlined by Compton and Volkow, the annual incidence of excessive opioid analgesic intake increased from 628,000 new cases in 1990 to 2.4 million in 2001 (Non-Patent Document 10). Non-Patent Document 11). One of the reasons for promoting the spread of opioid addiction is the increased use of prescription analgesics. Short-term use of opioid drugs is rarely associated with addiction. Conversely, long-term use with this drug is associated with the development of addiction in up to 18% of patients.

The purpose of treating opiate addiction is to discontinue opioid use, minimize painful withdrawal symptoms, and prevent recurrence, as in other types of substance addiction. Current treatment involves replacing addictive drugs with opioid receptor agonists or mixed agonist / antagonist substitutes. The alternative approach consists of the use of opioid receptor antagonists that block the effects of the agonist. Antagonists do not provide relief of pain or other withdrawal symptoms; on the contrary, withdrawal symptoms may be promoted, and their therapeutic use is associated with increased accidental overdose and increased mortality of opioid agonists. Was there. The use of agonists with low affinity for the receptor rarely results in severe withdrawal symptoms, but can result in dependence on alternative opium. Also, many alternative therapies are taken for 3 to 6 months, a period during which the addict can stop treatment prematurely.

Psychostimulants such as cocaine and amphetamines cause temporary euphoria, increased alertness, and increased physical fitness in humans. This substance initially increases dopamine transmission, but long-term use of the drug results in decreased dopamine activity, leading to dysregulation and dysphoria of the brain's reward system. According to the WHO, it is estimated that 33 million people worldwide are overdose of amphetamines.

Chronic excessive cocaine intake can result in hyperstimulation, tachycardia, hypertension, mydriasis, muscle spasms, insomnia, extreme nervousness, hallucinations, paranoia, aggressive behavior, and depression. Overdose of cocaine can result in tremors, convulsions, delirium, and death due to cardiac arrhythmias and cardiovascular insufficiency. Desipramine, amantadine and bromocriptine have been shown to reduce cocaine withdrawal symptoms.

Withdrawal symptoms of amphetamines include changes in EEG, malaise, and mental depression. Tolerance develops over time and may be associated with tachycardia, hallucinations and hallucinations, delusions, anxiety reactions, delusional psychosis, extreme fatigue, confusion, memory loss, and long-term depression with suicidal tendencies. Currently used treatments for amphetamine addiction include phenothiazine, haloperidol, and chlorpromazine (for hallucinations), but potential side effects of these drugs include postural hypotension and severe extrapyramidal movements. There are obstacles. Subjects who are addicted to psychostimulants may experience psychological and physiological withdrawal, increasing the likelihood of recurrence.

Until now, the treatment of substance addiction has been centered on behavior therapy, but it is difficult to break the dependence on many of these highly addictive substances. In particular, addiction to alcohol, cocaine and heroin is considered a recurrent chronic disorder. In addition, it is common to excessively ingest many kinds of substances such as nicotine, heroin, cocaine and alcohol in parallel.

The long-lasting, chronic nature of many addictions and the high rate of addictive offenses pose significant challenges in treating drug and alcohol addiction, so understanding the neurobiological basis of recurrence is a study of addiction. Has emerged as a central issue of. Among them, emotional and environmental factors (conditioning stimuli) were cited as the main causes of recurrence. For example, certain stress conditions (such as unemployment and financial difficulties) or stimuli that predict the presence of alcohol reminiscent of previous use (such as an environment such as a bottle of favorite wine and a bar) are alcohols that have recovered from addiction. It is known that it may strongly promote recurrence in those who have experienced dependence.

Increasing rates of obesity in the United States, Europe and other Western countries also indicate an epidemic of food addiction-like behavior. As distinguished from normal eating behavior, food addiction is a maladaptation that worsens rather than improves people who eat in response to addiction rather than hunger. Binge eating, a food addiction, is also the daily consumption of persistent, habitual, excess foods, and often excessive amounts of unhealthy foods. Food addiction can not only lead to obesity, but, paradoxically, malnutrition. There are some similarities between food addiction and substance abuse, including mood effects, external cues that cause the addictive behavior, anticipation, suppression, ambivalence and attribution.

There are two main theoretical claims, the homeostatic hypothesis and the conditioning hypothesis, to explain the permanence and relapse susceptibility of addictive behavior associated with drug and alcohol addiction.

The homeostasis hypothesis associates the risk of recurrence with neuroadaptive changes and disruption of neuroendocrine homeostasis, which causes physical symptoms associated with anxiety, mood dysregulation and acute withdrawal. It is believed that it can last for a fairly long period of time, called the "long-term withdrawal" period. Therefore, this view suggests mitigation of discomfort and negative effects as a motivational basis for recurrence.

The conditioning hypothesis is based on the observation that recurrence is often associated with exposure to drug-related environmental stimuli. The view is that certain environmental stimuli that have been associated with the rewarding effects of drugs by classical conditioning can induce a subjective state that induces resumption of drug use. The homeostasis hypothesis and the conditioning hypothesis are not mutually exclusive. In fact, homeostatic and conditioning factors appear to have an additive effect in that the likelihood of recurrence caused by homeostatic disturbances can be increased by exposure to drug-related environmental stimuli. ..

Clearly, there is a need for new methods in the art to treat and prevent recurrent use of addictive and addictive drugs. The present invention meets this need by providing methods and concomitant medications useful for the treatment and prevention of addictive and addictive offenses.

Monti et al., J Studio Alcohol 54: 235-45 (1993) Volpicelli et al., Arch Gen Psychiatry 49: 876-880 (1992) O'Brien Science 278: 66-70 (1997) Compton and Volkow, Drug Alcohol Depend 83 Suppl 1: S4-7 (2006A) Compton and Volkow, Drug Alcohol Depend 81 (2): 103-7 (2006B) Delva et al., Am J Public Health 95 (4): 696-702 (2005) Siegal et al., Am Fam Physician 67: 942-945 (2003) American Psychiatric Association, Digital and Static Manual of Mental Disorders, 4th Edition (1994) Substance Abuse and Mental Health Services Addistation, Mortality Data from the Drug Abuse Warning Network, 2002 (2004) Substance Abuse and Mental Health Services Administration, Overview of Findings from the 2002 National Survey on Drug Use and Health, (2003) Substation Abuse and Mental Health Services ADministration, Emergency Department Trends From the Drug Abuse Warning Network, Final Estem2, Final Estemate

III. Outline of the Invention The present invention determines that a subject has an addiction or is at risk of developing an addiction, and then provides the subject with a phosphodiesterase 7 (PDE7) inhibitor that is effective in treating or preventing the addiction. Provided is a method of treating or preventing addiction by administration.

In one aspect of the invention, the subject is addictive to the addictive drug. Examples of addictive agents 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 agents are opioids such as morphine, metadon, fentanyl, sufentanil, codeine, oxycodeine, and heroin. In a further embodiment, the addictive agent is a psychostimulant, such as cocaine, amphetamine or an amphetamine derivative. In another embodiment, the addictive drug is cocaine.

In one aspect of the invention, the subject is addictive to addictive or compulsive behavior, or suffers from impulse control disorder. In another aspect of the invention, the subject is a primary impulse control disorder, i.e. a non-disordered primary disorder that is either iatrogenic (secondary to medical procedure) or secondary to another primary disease or disorder. Suffering from impulse control disorder, a sexual disorder. Addiction or obsessive-compulsive behaviors that are primary impulse control disorders include: overeating, morbid gambling, morbid use of electronic devices, morbid use of video electronic games, morbid use of electronic communication devices, mobile phones Disease use, pornography dependence, sexual dependence, obsessive-compulsive consumption behavior, loss of appetite, obsessive-compulsive disorder, intermittent explosive disorder, stealing habits, burning habits, hair loss habits, obsessive-compulsive overexercise, and obsessive-compulsive overwork. In another embodiment, the addictive or obsessive-compulsive behavior is food addiction. In another embodiment, the addictive or compulsive behavior is binge eating. In another aspect of the invention, an addictive or obsessive-compulsive disorder is an obsessive-compulsive disorder.

In one aspect of the invention, PDE7 inhibitors for the treatment of habits include 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.

In one aspect of the present invention, PDE7 inhibitor has an _{IC 50} of less than about 1μM for inhibition of PDE7A and / or PDE7B activity. In one embodiment, PDE7 inhibitor has an _{IC 50} of less than about 100nM for inhibition of PDE7A and / or PDE7B activity. In another embodiment, PDE7 inhibitor has an _{IC 50} for inhibition of the smaller 5-fold greater than PDE1B activity of _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity. In another embodiment, PDE7 inhibitor has an _{IC 50} and PDE7B _{IC 50} for inhibition of the smaller 5-fold greater than PDE10 activity of _{IC 50} for inhibition of the activity for the inhibition of PDE7A activity. In a further embodiment, PDE7 inhibitor has an _{IC 50} for inhibition of the smaller 10-fold greater than the PDE3 activity of _{IC 50} for inhibition of _{IC 50} and / or PDE7B activity for the inhibition of PDE7A activity. In another embodiment, PDE7 inhibitor has an _{IC 50} and PDE7B _{IC 50} for inhibition of the smaller 10-fold greater than the PDE3 and PDE4 activity of _{IC 50} for inhibition of the activity for the inhibition of PDE7A activity. In a further embodiment, PDE7 inhibitor has an _{IC 50} and PDE7B _{IC 50} for inhibition of the smaller 10-fold greater than the PDE4 and PDE8 activity of _{IC 50} for inhibition of the activity for the inhibition of PDE7A activity. In another embodiment, the PDE7 agent relates to inhibition of PDE1, PDE2, PDE3, PDE4, PDE8, PDE10 and PDE11 activity, which is 10 times greater than the smaller _{IC 50 for inhibition of PDE7A activity and IC 50 for inhibition of PDE7B activity.} It has an IC ₅₀ . In a further embodiment, PDE7 inhibitors, smaller _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity of any other PDE enzyme activity from PDE1~6 and PDE8~11 enzyme family is less than one selective PDE7 inhibitors of 10 minutes _{an IC 50} having the dosage for inhibition. In another embodiment, PDE7 inhibitors, smaller _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity, any other PDE enzyme activity from PDE1~6 and PDE8~11 enzyme family is less than one highly selective PDE7 inhibitors of 50 minutes _{an IC 50} having the dosage for inhibition of. In a further embodiment, the PDE7 inhibitor has a molecular weight of less than about 450 g / mol. In another embodiment, the PDE7 inhibitor can cross the blood-brain barrier.

The present invention provides a method of treating or preventing an addiction by determining that the subject has or is at risk of developing the addiction and then administering a chemical compound that inhibits PDE7 activity. The chemical compounds of the following characteristics: (i) PDE7A and / or PDE7B activity of about 1μM below _{IC 50} for inhibiting; and (ii) PDE7A the _{IC 50} for inhibition of _{IC 50} and / or PDE7B activity for inhibition of the activity those having an _{IC 50} for inhibition of the smaller 10-fold greater than PDE3.

In one embodiment, the chemical compound has an _{IC 50} of less than about 100nM for inhibition of PDE7A and / or PDE7B activity. In another embodiment, PDE7 inhibitor has an _{IC 50} for inhibition of the smaller 5-fold greater than PDE1B activity of _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity. In another embodiment, PDE7 inhibitor has an _{IC 50} and PDE7B _{IC 50} for inhibition of the smaller 5-fold greater than PDE10 activity of _{IC 50} for inhibition of the activity for the inhibition of PDE7A activity. In another embodiment, PDE7 inhibitor has an _{IC 50} and PDE7B _{IC 50} for inhibition of the smaller 10-fold greater than the PDE4 activity of _{IC 50} for inhibition of the activity for the inhibition of PDE7A activity. In a further embodiment, PDE7 inhibitor has an _{IC 50} and PDE7B _{IC 50} for inhibition of the smaller 10-fold greater than PDE8 activity of _{IC 50} for inhibition of the activity for the inhibition of PDE7A activity. In another embodiment, the PDE7 agent relates to inhibition of PDE1, PDE2, PDE3, PDE4, PDE8, PDE10 and PDE11 activity, which is 10 times greater than the smaller _{IC 50 for inhibition of PDE7A activity and IC 50 for inhibition of PDE7B activity.} It has an IC ₅₀ . In a further embodiment, PDE7 inhibitors, smaller _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity of any other PDE enzyme activity from PDE1~6 and PDE8~11 enzyme family is less than one selective PDE7 inhibitors of 10 minutes _{an IC 50} having the dosage for inhibition. In another embodiment, PDE7 inhibitors, smaller _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity, any other PDE enzyme activity from PDE1~6 and PDE8~11 enzyme family is less than one highly selective PDE7 inhibitors of 50 minutes _{an IC 50} having the dosage for inhibition of. In a further embodiment, the PDE7 inhibitor has a molecular weight of less than about 450 g / mol. In another embodiment, the PDE7 inhibitor can cross the blood-brain barrier.

In one aspect of the invention, the subject is addictive to the addictive drug. Examples of addictive agents 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 agents are opioids such as morphine, methadone, fentanyl, sufentanil and heroin. In a further embodiment, the addictive agent is a psychostimulant, such as cocaine, amphetamine or an amphetamine derivative. In another embodiment, the addictive drug is cocaine.

In one aspect of the invention, a subject treated with a PDE7 inhibitor is addictive to addictive or compulsive behavior or suffers from impulse control disorders. In another aspect of the invention, the subject is a primary impulse control disorder, i.e. a non-disordered primary disorder that is either iatrogenic (secondary to medical procedure) or secondary to another primary disease or disorder. Suffering from impulse control disorder, a sexual disorder. Addiction or obsessive-compulsive behaviors that are primary impulse control disorders include: overeating, morbid gambling, morbid use of electronic devices, morbid use of video electronic games, morbid use of electronic communication devices, carrying Diseased use of the phone, porn dependence, sexual dependence, obsessive-compulsive consumption behavior, loss of appetite, macrophagia, intermittent explosive disorder, theft, burning habits, hair loss habits, obsessive-compulsive overexercise, and obsessive-compulsive overwork. .. In another embodiment, the subject suffers from food addiction. In another embodiment, the addictive or compulsive behavior is binge eating. In another aspect of the invention, the subject treated according to the invention has obsessive-compulsive disorder.

The present invention is also a method for treating or preventing an addiction, which comprises giving a subject having an addiction a phosphodiesterase 7 (PDE7) inhibitor and a further therapeutic agent, wherein the PDE7 inhibitor and the additional therapeutic agent are used. Each provides a method that contributes to the effective treatment or prevention of addiction. Further therapeutic agents include, for example, opioid antagonists, mixed opioid partial agonists / antagonists, antidepressants, antiemetics, antiemetics, corticotropin-releasing factor-1 (corticotropin-releasing factor-1). CRF-1) receptor antagonists, selective serotonin-3 (5-HT3) antagonists, 5-HT2A / 2C antagonists, cannabinoid-1 (CB1) receptor antagonists, and dopamine receptor agonists or other dopaminergic agents Can be mentioned.

Exemplary opioid antagonists include naltrexone and nalmefene. Exemplary antidepressants include fluoxetine, mirtazapine and bupropion. Exemplary antiepileptic drugs include topiramate, levetiracetam and gabapentin. Antalalmin 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 tanarabant. Buprenorphine is an exemplary mixed opioid agonist / antagonist. Exemplary opioid agonists include morphine, methadone, fentanyl, sufentanil and heroin.

Exemplary dopaminergic agents include, for example, levodopa (also referred to as "L-dopa"), carbidopa, and dopamine receptor agonists, and precursors (eg, bromocryptin, pergolide, pramipexol, ropinirole, cabergolin, apomorphin, etc. Lislide, rotigotine and quinagolide), and phenordopam, which is selective for dopamine receptor D1.

In one aspect, the subject is addictive to addictive agents such as alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates and psychostimulants. In one embodiment, the addictive agent is alcohol and the additional therapeutic agent 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, amphetamines, amphetamine derivatives or metaamphetamines) and additional therapeutic agents are antidepressants (such as bupropion). In a further embodiment, the subject is addictive to nicotine and an additional therapeutic agent is an antidepressant (such as bupropion).

In another embodiment, the subject is addictive or obsessive-compulsive (such as primary impulse control disorder), eg, morbid gambling, overeating, morbid use of electronic devices, morbid use of television electronic games, telecommunications devices. Pathological use, morbid use of mobile phones, pornography dependence, sexual dependence, obsessive-compulsive consumption behavior, loss of appetite, macrophagia, intermittent explosive disorder, theft, pyromania, hair loss, obsessive-compulsive exercise, and compulsion It is addictive to sexual overwork. In one embodiment, the addictive or obsessive-compulsive behavior is binge eating, and a further therapeutic agent is topiramate. In another aspect of the invention, the subject treated according to the invention has obsessive-compulsive disorder.

The present invention treats a subject who is in a state of addictive drug or addictive or obsessive-compulsive behavior, or in a state of restricted or reduced use thereof, by administering the PDE7 inhibitor to the subject. Thereby, a method for preventing recurrent use of an addictive drug or execution of addictive or compulsive behavior is provided. The present invention also applies PDE7 inhibitors to subjects who are in a state of remission of addictive or compulsive behavior associated with primary impulse control disorder or restricted or reduced performance of such behavior. Provided is a method of preventing the recurrence of addictive or compulsive behavior associated with primary impulse control disorder by treatment by administration to. The present invention also administers a PDE7 inhibitor to a subject who is in a state of remission of addictive or compulsive behavior associated with obsessive-compulsive disorder or restricted or reduced performance of the behavior. Provided is a method of preventing the recurrence of addictive or compulsive behavior associated with obsessive-compulsive disorder by treating by doing so. Additional therapeutic agents that contribute to the preventive effect of recurrence may be administered with the PDE7 inhibitor. The therapeutic agent may be administered to a subject who has previously been treated with a different anti-addiction treatment but is no longer in use.

In one aspect, recurrent use of addictive agents such as alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates, and psychostimulants is prevented by administration of PDE7 inhibitors. In a preferred embodiment, recurrent use of cocaine, amphetamine or metaamphetamine is prevented.

In another embodiment, the recurrence of addictive or compulsive behavior, particularly addictive or compulsive behavior associated with primary impulse control disorder, is prevented by administration of the PDE7 inhibitor. In a preferred embodiment, the following actions: bulimia, morbid gambling, morbid use of electronic devices, morbid use of video electronic games, morbid use of electronic communication devices, morbid use of mobile phones, porn dependence, sexual dependence , Obsessive-compulsive consumption behavior, loss of appetite, bulimia nervosa, intermittent explosive disorder, stealing habits, pyromania, hair loss habits, obsessive-compulsive overexercise, and recurrence of obsessive-compulsive overwork are prevented. In one embodiment, addictive or obsessive-compulsive behavior is stress-induced binge eating. In another embodiment, the subject is treated to prevent the recurrence of addictive or compulsive behavior associated with obsessive-compulsive disorder.

The present invention provides a pharmaceutical composition 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 pharmaceutical compositions.

In one aspect of the invention, the subject is addictive to the 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 agents are opioids such as morphine, methadone, fentanyl, sufentanil and heroin. In a further embodiment, the addictive agent is a psychostimulant, such as cocaine, amphetamine or an amphetamine derivative. In a preferred embodiment, the addictive agent is cocaine.

In one aspect of the invention, the subject is addictive to addictive or compulsive behavior, or suffers from impulse control disorder. In another aspect of the invention, the subject is a primary impulse control disorder, i.e. a non-disordered primary disorder that is either iatrogenic (secondary to medical procedure) or secondary to another primary disease or disorder. Suffering from impulse control disorder, a sexual disorder. Addiction or obsessive-compulsive behaviors that are primary impulse control disorders include: overeating, morbid gambling, morbid use of electronic devices, morbid use of video electronic games, morbid use of electronic communication devices, mobile phones Disease use, pornography dependence, sexual dependence, obsessive-compulsive consumption behavior, loss of appetite, obsessive-compulsive disorder, intermittent explosive disorder, stealing habits, burning habits, hair loss habits, obsessive-compulsive overexercise, and obsessive-compulsive overwork. In a preferred embodiment, the addictive or obsessive-compulsive behavior is binge eating. In another aspect of the invention, the subject treated according to the invention has obsessive-compulsive disorder.

In one embodiment, the additional therapeutic agent of the pharmaceutical composition is an opioid antagonist, a mixed opioid partial agonist / antagonist, antidepressants, antidepressants, antiemetics, corticostimulatory hormone releasing factor-1 (CRF-1) receptors. It is a body antagonist, a selective serotonin-3 (5-HT3) antagonist, a 5-HT2A / 2C antagonist, or a cannabinoid-1 (CB1) receptor antagonist.

Exemplary opioid antagonists include naltrexone or nalmefene. Exemplary antidepressants include fluoxetine, mirtazapine or bupropion. Exemplary antiepileptic drugs include topiramate, levetiracetam and gabapentin. Antalalmin 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.

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

The present invention provides a kit for the treatment or prevention of addiction. The kit includes a first container containing the PDE7 inhibitor and a second container containing additional therapeutic agents. Both PDE7 inhibitors and additional therapeutic agents contribute to the effective treatment or prevention of addiction.

In one embodiment, the additional therapeutic agent of the pharmaceutical composition is an opioid antagonist, a mixed opioid partial agonist / antagonist, antidepressants, antidepressants, antiemetics, corticostimulatory hormone releasing factor-1 (CRF-1) receptors. It is a body antagonist, a selective serotonin-3 (5-HT3) antagonist, a 5-HT2A / 2C antagonist, or a cannabinoid-1 (CB1) receptor antagonist.

Exemplary opioid antagonists include naltrexone and nalmefene. Exemplary antidepressants include fluoxetine, mirtazapine and bupropion. Exemplary antiepileptic drugs include topiramate, levetiracetam and gabapentin. Antalalmin 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 taranaban. Buprenorphine is an exemplary mixed opioid agonist / antagonist.

In one aspect, the subject is addictive to addictive agents such as alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates and psychostimulants. In one embodiment, the addictive agent is alcohol and the additional therapeutic agent 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, amphetamines, amphetamine derivatives or metaamphetamines) and additional therapeutic agents are antidepressants (such as bupropion). In a further embodiment, the subject is addictive to nicotine and an additional therapeutic agent is an antidepressant (such as bupropion). In another embodiment, the subject is addictive to more than one addictive drug, and additional therapeutic agents are opioid antagonists (such as naltrexone) or mixed opioid antagonists / partial agonists (such as buprenorphine). ..

In another aspect of the invention, the addictive substance is administered in combination with a PDE7 inhibitor to a subject at risk of addiction to the addictive substance. For example, a subject to whom an opioid agonist is administered for the relief of acute or chronic pain is administered the opioid agonist in combination with a PDE7 inhibitor to result in non-addictive or hypo-addictive painlessness. Examples of addictive agents that can be administered in combination with a fixed dose or in combination with a PDE7 inhibitor in the kit include benzodiazepine, barbiturate, and analgesics such as alfentanyl, allylprozine, alphaprozine, anirelidine benzylmorphine. , Vegitramide, Buprenorfin, Butorphanol, Chronitazen, Codein, Cyclazocin, Desomorphine, Dextromoramide, Dezosin, Diampromide, Dihydrocodein, Dihydromorphine, Dimenoxador, Dimefeptanol, Dimethylthiambutene, Dioxafetylbutyrate Eptazosin, etoheptidine, ethylmethylthiambutene, ethylmorphine, etnitazen fentanyl, heroine, hydrocodone, hydromorphone, hydroxypethidine, isometadon, ketobemidone, levallorphan, levorphanol, levofenacylmorphan, lofenitanil, lofenitanil, meperidine Metazosin, Metadon, Metopon, Morphine, Milophine, Narbufin, Narcene, Nicomorphine, Norrevorphanol, Normetadon, Narolfin, Normorphine, Norpipanone, Achen, Oxycodone, OXYCONTIN®, Oxymorphone, Papabelletum, Pentazocin, Phenadoxone Examples include phenazocin, phenoperidine, pimidine, pyritramide, propeptazine, promedol, properidine, propyram, propoxyphensfentanil, tramadol, tyridine, salts thereof, any mixture of those mentioned above, and mixed μ-agonists / antagonists. Be done.

In some embodiments, for any method and composition described herein, the following PDE7 inhibitor 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 is used.

In another embodiment of the invention, the PDE7 inhibitor is addictive or addictive to the addictive substance in order to reduce the motivation for the subject to request or acquire the addictive substance. Provided to subjects at risk of becoming.
In one embodiment, for example, the following items are provided.
(Item 1)
A method of treating an addiction to an addictive substance or the performance of compulsive behavior associated with primary impulse control disorder or obsessive-compulsive disorder.
Determining that a subject has or is at risk of developing an addiction; and comprising administering to the subject a certain amount of a phosphodiesterase 7 (PDE7) inhibitor and a dopaminergic agent.
Where the PDE7 inhibitor and the dopaminergic agent are effective in treating or reducing the use of addictive agents or the performance of the compulsive behavior.
(Item 2)
The method of item 1, wherein the subject is addictive to an addictive drug.
(Item 3)
The method of item 2, wherein the subject is addictive to an addictive drug selected from the group consisting of alcohol, nicotine, marijuana, marijuana derivatives, opioid agonists, benzodiazepines, barbiturates and psychostimulants.
(Item 4)
The method of item 1, wherein the addiction is an obsessive-compulsive behavior associated with a primary impulse control disorder or obsessive-compulsive disorder.
(Item 5)
The primary impulse control disorder is overeating, food addiction, morbid gambling, morbid use of electronic devices, morbid use of video electronic games, morbid use of electronic communication devices, morbid use of mobile phones, pornography dependence. , Sexual dependence, obsessive-compulsive consumption behavior, loss of appetite, major eating illness, intermittent explosive disorder, theft, pyromania, hair loss habit, obsessive-compulsive overexercise, and obsessive-compulsive overwork. The method described.
(Item 6)
5. The method of item 5, wherein the primary impulse control disorder is binge eating or food addiction.
(Item 7)
The dopaminergic agents are dopamine precursors, dopamine cofactors, inhibitors of enzymes that metabolize dopamine, dopamine receptor agonists, precursor compounds that are metabolized to dopamine receptor agonists, dopamine reuptake inhibitors and dopamine release. The method according to item 1, which is selected from the promoting factors.
(Item 8)
The method of item 1, wherein the dopaminergic agent is selected from levodopa, carbidopa, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, lislide, rotigotine and quinagolide, and phenoldpam.
(Item 9)
The method of item 1, wherein the dopaminergic agent is selective for the dopamine receptor D1.
(Item 10)
9. The method of item 9, wherein the dopaminergic agent is a dopamine agonist.
(Item 11)
The PDE7 inhibitor has an _{IC 50} of less than about 1μM for inhibition of PDE7A and / or PDE7B activity The method of claim 1.
(Item 12)
The method of item 1, _{wherein the PDE7 inhibitor has an IC 50} of less than about 100 nM with respect to inhibition of PDE7A and / or PDE7B activity.
(Item 13)
Dosage the PDE7 inhibitor is, smaller _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity for inhibition of any other PDE enzyme activity from PDE1~6 and PDE8~11 enzyme family is less than one selective PDE7 inhibitors of 10 minutes _{an IC 50} with the method of claim 1.
(Item 14)
The PDE7 inhibitors are such as 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 The method of item 1, wherein the member is selected from the group consisting of 6C, formula 6D, formula 6E, formula 6F, formula 6G, formula 6H, formula 16A, compound 1, compound 2, compound 3 and compound 4.
(Item 15)
The method of item 1, wherein the PDE7 inhibitor can cross the blood-brain barrier.
(Item 16)
The subject is in a state of being absent from performing the addictive drug or addictive or compulsive behavior, or a state in which its use is restricted or reduced, and the PDE7 inhibitor and the dopaminergic drug are said to be said. The method of item 1, which is effective for reducing the recurrent use of addictive practice.
(Item 17)
A pharmaceutical composition comprising a phosphodiesterase 7 (PDE7) inhibitor and a dopaminergic agent, wherein each of the PDE7 inhibitor and the dopaminergic agent is an effective treatment of the use of an addictive agent or the execution of compulsive behavior. A pharmaceutical composition that contributes to reduction.
(Item 18)
The dopaminergic agents are dopamine precursors, dopamine cofactors, inhibitors of enzymes that metabolize dopamine, dopamine receptor agonists, precursor compounds that are metabolized to dopamine receptor agonists, dopamine reuptake inhibitors and dopamine release. The pharmaceutical composition according to item 17, which is selected from the promoting factors.
(Item 19)
The pharmaceutical composition according to item 17, wherein the dopaminergic agent is selected from levodopa, carbidopa, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphin, lislide, rotigotine and quinagolide, and phenoldpam.
(Item 20)
The pharmaceutical composition according to item 17, wherein the dopaminergic agent is selective for the dopamine receptor D1.
(Item 21)
The method of item 20, wherein the dopaminergic agent is a dopamine agonist.
(Item 22)
The PDE7 inhibitors are 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 The pharmaceutical composition according to item 17, which is a member selected from the group consisting of 6C, formula 6D, formula 6E, formula 6F, formula 6G, formula 6H, formula 16A, compound 1, compound 2, compound 3 and compound 4. ..
(Item 23)
A useful kit for the treatment of addiction, the kit comprises a first container containing a phosphodiesterase 7 (PDE7) inhibitor; and a second container containing a dopaminergic agent, wherein the PDE7 inhibitor and the dopamine. Each of the active agents contributes to the effective treatment or reduction of the use of addictive agents or the execution of compulsive behavior, kits.
(Item 24)
A way to treat food addiction
Determining that a subject has or is at risk of developing food addiction; and includes administering to the subject a certain amount of a phosphodiesterase 7 (PDE7) inhibitor and a dopaminergic agent. ,
A method, wherein the PDE7 inhibitor and the dopaminergic agent are effective in treating or reducing the performance of food addiction.

IV. Brief Description of Drawings Next, the present invention will be described in more detail with reference to the accompanying drawings as an example. In the figure:
FIG. 1 shows the effect of the PDE7 inhibitor OMS182056 on cocaine self-administration by rats. FIG. 2 shows the effect of the PDE7 inhibitor OMS181869 on cocaine self-administration by rats. FIG. 3 shows the effect of the PDE7 inhibitor OMS182401 on cocaine self-administration by rats. FIG. 4 shows the effect of the dopamine D1 agonist SKF82958 on cocaine self-administration by rats. FIG. 5 shows the effect of the PDE7 inhibitor OMS182056 on the non-enhanced lever press response by rats. FIG. 6 shows the effect of the dopamine D1 agonist SKF82958 on the non-enhanced lever pressing response by rats. FIG. 7 shows the chronic effect of the PDE7 inhibitor OMS182401 on cocaine self-administration in rats. FIG. 8 shows the effect of the PDE7 inhibitor OMS182056 on the lever press response by rats on the first day of elimination after cocaine addiction. FIG. 9 shows the effect of the PDE7 inhibitor OMS182056 on yohimbine-induced recurrence of cocaine demand by rats. FIG. 10 shows the effect of the PDE7 inhibitor OMS182401 on yohimbine-induced recurrence of cocaine demand by rats. FIG. 11 shows the effect of the PDE7 inhibitor OMS182056 on cue-induced recurrence of cocaine demand by rats. FIG. 12 shows the effect of the PDE7 inhibitor OMS182401 on cue-induced recurrence of cocaine demand by rats. FIG. 13 shows the effect of the PDE7 inhibitor OMS182056 on cocaine initial stimulation-induced recurrence in rats. FIG. 14 shows the effect of the dopamine D1 agonist SKF82958 on cocaine initial stimulation-induced recurrence in rats. FIG. 15 shows the effect of the PDE7 inhibitor OMS182401 on nicotine self-administration in rats using a short-term access model. FIG. 16 shows the effect of the PDE7 inhibitor OMS182401 on nicotine self-administration in rats using a long-term access model. FIG. 17 shows the effect of the PDE7 inhibitor OMS182399 on nicotine self-administration in rats using a short-term access model. 18A and 18B show that the PDE7 inhibitors OMS182399 and OMS182401 have no effect on food self-administration, respectively. 18A and 18B show that the PDE7 inhibitors OMS182399 and OMS182401 have no effect on food self-administration, respectively. 19A-19C show the effect of the PDE7 inhibitor OMS182401 on the motivation of nicotine-addicted mice to acquire nicotine in a self-administered progressive ratio study. FIG. 20 shows the effect of the PDE7 inhibitor OMS182401 on the first day of elimination of nicotine self-administration. FIG. 21 shows the effect of the PDE7 inhibitor OMS182401 on cue-induced reinstatement of nicotine demanding behavior. FIG. 22 shows the effect of the PDE7 inhibitor OMS182401 on the yohimbine-induced resurrection of nicotine demanding behavior. 23A-23D show the effect of the PDE7 inhibitor OMS182401 on stress-induced binge eating by rats. FIG. 23A shows the results in control animals that were not stressed and were not subject to dietary restrictions. FIG. 23B shows the results in experimental animals that were not stressed and were subject to dietary restrictions. FIG. 23C shows the results in experimental animals that were stressed and not subject to dietary restrictions. FIG. 23D shows the results in experimental animals stressed and subject to dietary restrictions. 23A-23D show the effect of the PDE7 inhibitor OMS182401 on stress-induced binge eating by rats. FIG. 23A shows the results in control animals that were not stressed and were not subject to dietary restrictions. FIG. 23B shows the results in experimental animals that were not stressed and were subject to dietary restrictions. FIG. 23C shows the results in experimental animals that were stressed and not subject to dietary restrictions. FIG. 23D shows the results in experimental animals stressed and subject to dietary restrictions. 23A-23D show the effect of the PDE7 inhibitor OMS182401 on stress-induced binge eating by rats. FIG. 23A shows the results in control animals that were not stressed and were not subject to dietary restrictions. FIG. 23B shows the results in experimental animals that were not stressed and were subject to dietary restrictions. FIG. 23C shows the results in experimental animals that were stressed and not subject to dietary restrictions. FIG. 23D shows the results in experimental animals stressed and subject to dietary restrictions. 23A-23D show the effect of the PDE7 inhibitor OMS182401 on stress-induced binge eating by rats. FIG. 23A shows the results in control animals that were not stressed and were not subject to dietary restrictions. FIG. 23B shows the results in experimental animals that were not stressed and were subject to dietary restrictions. FIG. 23C shows the results in experimental animals that were stressed and not subject to dietary restrictions. FIG. 23D shows the results in experimental animals stressed and subject to dietary restrictions. Figures 24A-24D show the effect of the PDE7 inhibitor OMS182056 on stress-induced binge eating in rats. FIG. 24A shows the results in control animals that were not stressed and were not subject to dietary restrictions. FIG. 24B shows the results in laboratory animals that were not stressed and were subject to dietary restrictions. FIG. 24C shows the results in laboratory animals that were stressed and not subject to dietary restrictions. FIG. 24D shows the results in experimental animals stressed and subject to dietary restrictions. Figures 24A-24D show the effect of the PDE7 inhibitor OMS182056 on stress-induced binge eating in rats. FIG. 24A shows the results in control animals that were not stressed and were not subject to dietary restrictions. FIG. 24B shows the results in laboratory animals that were not stressed and were subject to dietary restrictions. FIG. 24C shows the results in laboratory animals that were stressed and not subject to dietary restrictions. FIG. 24D shows the results in experimental animals stressed and subject to dietary restrictions. Figures 24A-24D show the effect of the PDE7 inhibitor OMS182056 on stress-induced binge eating in rats. FIG. 24A shows the results in control animals that were not stressed and were not subject to dietary restrictions. FIG. 24B shows the results in laboratory animals that were not stressed and were subject to dietary restrictions. FIG. 24C shows the results in laboratory animals that were stressed and not subject to dietary restrictions. FIG. 24D shows the results in experimental animals stressed and subject to dietary restrictions. Figures 24A-24D show the effect of the PDE7 inhibitor OMS182056 on stress-induced binge eating in rats. FIG. 24A shows the results in control animals that were not stressed and were not subject to dietary restrictions. FIG. 24B shows the results in laboratory animals that were not stressed and were subject to dietary restrictions. FIG. 24C shows the results in laboratory animals that were stressed and not subject to dietary restrictions. FIG. 24D shows the results in experimental animals stressed and subject to dietary restrictions. 25A-25D show the effect of topiramate as a comparator on stress-induced binge eating by rats. FIG. 25A shows the results in control animals that were not stressed and were not subject to dietary restrictions. FIG. 25B shows the results in experimental animals that were not stressed and were subject to dietary restrictions. FIG. 25C shows the results in laboratory animals that were stressed and not subject to dietary restrictions. FIG. 25D shows the results in experimental animals stressed and subject to dietary restrictions. 25A-25D show the effect of topiramate as a comparator on stress-induced binge eating by rats. FIG. 25A shows the results in control animals that were not stressed and were not subject to dietary restrictions. FIG. 25B shows the results in experimental animals that were not stressed and were subject to dietary restrictions. FIG. 25C shows the results in laboratory animals that were stressed and not subject to dietary restrictions. FIG. 25D shows the results in experimental animals stressed and subject to dietary restrictions. 25A-25D show the effect of topiramate as a comparator on stress-induced binge eating by rats. FIG. 25A shows the results in control animals that were not stressed and were not subject to dietary restrictions. FIG. 25B shows the results in experimental animals that were not stressed and were subject to dietary restrictions. FIG. 25C shows the results in laboratory animals that were stressed and not subject to dietary restrictions. FIG. 25D shows the results in experimental animals stressed and subject to dietary restrictions. 25A-25D show the effect of topiramate as a comparator on stress-induced binge eating by rats. FIG. 25A shows the results in control animals that were not stressed and were not subject to dietary restrictions. FIG. 25B shows the results in experimental animals that were not stressed and were subject to dietary restrictions. FIG. 25C shows the results in laboratory animals that were stressed and not subject to dietary restrictions. FIG. 25D shows the results in experimental animals stressed and subject to dietary restrictions. FIG. 26 shows the effect of the PDE7 inhibitor OMS182399 on yohimbine-induced recurrence on food demand in a food addiction model. 27 and 28 show the effect of the PDE7 inhibitor OMS182399 on dopamine release in the nucleus and nucleus accumbens of Wistar rats by basal and nicotine-induced in vivo microdialysis studies, respectively. 27 and 28 show the effect of the PDE7 inhibitor OMS182399 on dopamine release in the nucleus and nucleus accumbens of Wistar rats by basal and nicotine-induced in vivo microdialysis studies, respectively. Figures 29A-29B show that the PDE7 inhibitor OMS182401 inhibits the spontaneous activity of dopaminergic ventral tegmental area (VTA) neurons and enhances the inhibitory effect of the dopamine D1 agonist SKF82958. Figures 29A-29B show that the PDE7 inhibitor OMS182401 inhibits the spontaneous activity of dopaminergic ventral tegmental area (VTA) neurons and enhances the inhibitory effect of the dopamine D1 agonist SKF82958. FIG. 30 shows the effect of the PDE7 inhibitor OMS182401 on VTA GABA release. FIG. 31 shows that the PDE7 inhibitor OMS182401 inhibits the activation of dopaminergic VTA neurons by nicotine and acts synergistically with the dopamine D1 agonist SKF82958. FIG. 32 shows the effect of direct administration of the PDE7 inhibitor OMS182401 to rat VTA. FIG. 33 shows that the PDE7 inhibitor OMS182399 blocks morphine-induced excitement of VTA dopamine cells in a dose-dependent manner. FIG. 34 shows that acute application of the PDE7 inhibitor OMS182399 blocks ethanol-induced arousal of VTA dopamine cells in a dose-dependent manner. FIG. 35 shows that acute application of the PDE7 inhibitor OMS182399 reverts cocaine-induced excitement of VTA dopamine cells in a dose-dependent manner. FIG. 36 shows that the PDE7 inhibitor OMS182401 enhances the activity of the dopamine D1 agonist SKF82958 in an open field activity model.

V. Detailed Description of Preferred Embodiments The present invention is based on the surprising finding by the present inventions that selective inhibitors of type 7 cyclic nucleotide phosphodiesterase (PDE7) result in a marked reduction in the recurrence of addiction. Using a rat model, this reduction was demonstrated in subjects who were addictive to addictive drugs and who showed compulsive behavior.

A. Addiction Treatment and Prevention Methods Using PDE7 Inhibitors (One or More) Thus, the present invention presents one or more PDE7 inhibitors to a subject who has or is at risk of developing addiction. Includes methods of treating or preventing addiction, including administration. In various embodiments, the subject is addictive to any addictive drug or action, such as, but not limited to, any of the addictive drugs or actions described herein. The subject may be physically or physiologically dependent on the substance or action; the subject may be psychologically dependent; the subject may be physically and psychologically dependent. It may be dependent on both. The subject may be addictive to one type of addictive drug or action, or may be addictive to more than one type of addictive drug or action.

As used herein, "treat" and similar language (eg, "treatment," "treating," etc.) are informative or, unless the context makes it clear. An approach for obtaining the desired outcome (eg, preferably clinical outcome). Treatment is optionally accompanied by either reduction or amelioration of the disease or condition (eg, addiction or recurrent use or behavior) or delay in the progression of the disease or condition (eg, addiction or recurrent use or behavior). It can be a thing.

As used herein, "prevent" and similar terms (eg, "prevention", "preventing", etc.) are diseases or medical conditions (eg, "preventing", "preventing", etc.) unless it is clear from the context that this is not the case. For example, to prevent the onset or recurrence of addiction or recurrent use or behavior), or to prevent the onset or recurrence of symptoms of the disease or condition, or optionally, delay the onset or recurrence of the disease or condition. It is an approach to prevent or delay the onset or recurrence of symptoms of the disease or condition.

As used herein, the term "PDE7" is used to generally refer to any translation product encoded in a transcript of either or both of these two genes: PDE7A and / or PDE7B.

As used herein, the term "PDE7 inhibitor" or "inhibitor of PDE7" is a chemical compound, peptide or compound that directly or indirectly inhibits or blocks the phosphodiesterase activity of PDE7A, PDE7B, or PDE7A and PDE7B. A drug such as a nucleic acid molecule. In some cases, the agent may be one that directly binds or interacts with the PDE7 protein. The agent that binds to PDE7 may serve to inhibit or block PDE7 activation by any suitable means, such as by inhibiting the binding of cAMP or substrate ligand to PDE7. In other cases, the PDE7 inhibitor may indirectly inhibit PDE7 activity, such as by reducing the expression of the PDE7 protein. In other cases, the PDE7 inhibitor can inhibit PDE7 activity by altering the cellular distribution of PDE7, for example by interfering with association between PDE7 and intracellular anchoring proteins.

As used herein, the term "dopaminergic agent" is an agent that functions to enhance or replicate the effects mediated by dopamine in the central nervous system (dopamine (a clinically effective delivery method has been developed). Metabolized to dopamine precursors (eg, levodopa (L-dopa), dopamine cofactors, inhibitors of dopamine-metabolizing enzymes, other dopamine receptor agonists and dopamine receptor agonists) Precursor compounds, as well as dopamine reuptake inhibitors and dopamine release promoters).

As used herein, the term "dopamine receptor agonist" refers to any molecule that causes activation of one or more of the subtypes of the dopamine receptor protein family.

As used herein, the term "mammalian subject" refers to all mammals, such as, but not limited to, humans, non-human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs and Includes rodents.

Generally, the subject is given an effective amount of PDE7 inhibitor. As used herein, a "effective amount" or "therapeutically effective amount" of a substance, eg, a PDE7 inhibitor, provides the desired biological or psychological effect (such as beneficial outcomes (eg, clinical outcomes)). Enough amount for. For example, in the context of the treatment of addiction using the methods of the invention, the effective amount of PDE7 inhibitor is sufficient for the subject to reduce or discontinue use of the addictive drug. In the case of addictive sexual activity, the effective amount of PDE7 inhibitor is sufficient for the subject to reduce or discontinue addictive sexual activity.

In one embodiment, the therapeutically effective dose is an amount of PDE7 inhibitor sufficient to inhibit PDE7 enzyme activity in nerve cells. In another embodiment of the method of the invention, the therapeutically effective dose is the amount of PDE7 inhibitor sufficient to inhibit PDE7 enzyme activity within the striatal neuron or nucleus accumbens. Determining the effective dose of a PDE7 inhibitor sufficient to cross the cell membrane and inhibit PDE7 enzyme activity intracellularly is determined by Smith S. et al. J. Et al., PDE7 inhibition cell assays, such as those described in Molecular Pharmacology 66 (6): 1679-1689 (2004) (incorporated herein by reference). To determine the effective dose of a PDE7 inhibitor sufficient to inhibit PDE7 enzyme activity in the striatum, see Siucik J. et al. A. Et al., Neuropharmacology 51: 386-396 (2006) (incorporated herein by reference), using an assay to measure the effect of PDE inhibitors on cAMP levels in the striatum. obtain.

According to some specific embodiments of the invention, the subject is given the PDE7 inhibitor alone, while in other embodiments the subject is given the PDE7 inhibitor in combination with additional therapeutic agents. It will be appreciated that the effective amounts of PDE7 inhibitors and / or additional therapeutic agents may differ depending on whether they are given alone or in combination. For example, if the PDE7 inhibitor and the additional therapeutic agent act synergistically, the amount of PDE7 inhibitor required to achieve the same therapeutic effect that either the PDE7 inhibitor or the additional therapeutic agent alone could provide. The amount of the PDE7 inhibitor or the additional therapeutic agent may be reduced, or the amount of the additional therapeutic agent may be reduced. In other embodiments, the same amount of PDE7 inhibitor and additional therapeutic agent is used to provide an improved therapeutic effect compared to the therapeutic effect provided by either the PDE7 inhibitor or the additional therapeutic agent alone.

According to some specific embodiments of the present invention, the subject is given a PDE7 inhibitor in combination with an addictive therapeutic agent and the dosage of the addictive therapeutic agent is determined to provide the desired therapeutic effect. The dosage of the PDE7 inhibitor is determined so that the possibility of addiction to the addictive therapeutic agent is eliminated or reduced.

The subject can be any animal, such as a mammal, especially a human.

In one aspect of the invention, a subject is first determined or diagnosed as having or at risk of developing an addiction by diagnostic testing, observation or analysis by a healthcare provider. An effective amount of PDE7 inhibitor, or an effective amount of PDE7 inhibitor and one additional therapeutic agent, is then given to the subject for the treatment or prevention of addiction. In another aspect of the invention, a subject is first determined or diagnosed as having or at risk of developing an addiction by diagnostic testing, observation or analysis by a healthcare provider, said subject. Not diagnosed or determined to have diabetes or other insulin disorders. An effective amount of PDE7 inhibitor, or an effective amount of PDE7 inhibitor and one additional therapeutic agent, is then given to the subject for the treatment or prevention of addiction. The dosage of PDE7 inhibitor, or PDE7 inhibitor and one additional therapeutic agent, may be specifically determined by a healthcare professional in the treatment or prevention of addiction rather than any other disorder or disease.

In certain embodiments, the subject suffers from or is at risk for any physical addictive agent or addictive or compulsive behavior, such as one of those described below. Is. In certain embodiments, the subject is addicted to alcohol, cocaine, nicotine, marijuana, opium or other opioid agonists or metaamphetamines or other psychostimulants, or phencyclidines 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 is a subject who has a history of repeated diets and is at risk of binge eating.

In certain embodiments, the subject has an addiction to the use of the addictive drug or the performance of the addictive behavior if the subject was previously addictive to the same or different addictive drug or addictive or compulsive behavior. Subjects who are considered at risk of recurrence. In some particular embodiments, a subject is addicted to an addictive drug or an addictive or compulsive behavior, even if he is no longer physically addictive. Subjects who are considered at risk of addiction or recurrence to the use of sex drugs or the performance of addictive behavior. In one embodiment, the subject suffers from food addiction. In other embodiments, the addictive act is binge eating. Subjects at risk of overeating typically have a history of: repeated dietary restrictions or yo-yo diets, eating in response to environmental stress, a preference for a very tasty high-calorie diet, and a feeling of fullness. Also have at least one of eating, and eating until uncomfortable. In another embodiment, the subject is a subject suffering from primary impulse control disorder.

In some specific embodiments, the subject is addicted to a therapeutic agent (eg, an analgesic) given to the patient to treat the disease or disorder, or is addicted to the therapeutic agent. A subject at risk of becoming a target. In a related embodiment, the subject may be a subject at risk of abusing an addictive therapeutic agent such as an analgesic. It should be understood that abuse of an addictive therapeutic agent indicates, in some particular embodiments, the use of the agent for a reason different from or in addition to the prescribed usage. In such situations, the subject may be given both an addictive therapeutic agent and a PDE7 inhibitor, alone or in combination with additional therapeutic agents. For example, a subject suffering from or at risk of pain may be given an opioid agonist and a PDE7 inhibitor to provide painlessness and prevent or treat addiction to the opioid agonist.

In various embodiments, the subject is given a PDE7 inhibitor at the same time that the subject is using the addictive drug, after the subject has stopped using the addictive drug, or the subject is addictive. Given before starting the use of sex drugs.

Addiction Drugs and Impulse Control Disorders The term "addiction" refers to recurrent obsessions in which an individual engages in some particular activity, despite adverse consequences for the individual's health, mental state or social life. It is used for. The term is often used for drug addiction, but also applies to other compulsions of problems such as gambling and binge eating. Factors suggested to cause addiction include genetic, biological / pharmacological and social factors.

In the medical community, there is now a theoretically cautious distinction between physical or physiological dependence (characterized by withdrawal symptoms) and psychological dependence (sometimes simply referred to as addiction). Addiction is now narrowly defined as "uncontrollable obsessive-compulsive use." This can be clinically considered obsessive if there is no harm to the patient or a third party, but it does not fall into the definition of "addiction" for some people. In fact, the two types of addiction (physiological and psychological dependence) are not always easily distinguished. Addiction often has both physical and psychological components.

"Physical dependence" (or "drug dependence") is a condition caused by regular drug use that causes negative physical withdrawal symptoms when stopped suddenly. Examples of addictive agents in which the user may develop physical dependence include nicotine, opioids, barbiturates, benzodiazepines, alcohols such as ethyl alcohol, GHB, and methaqualone.

Types of drugs, such as cocaine or amphetamines, which are generally overdose stimulants, are not believed to cause significant physical dependence. However, since it can be extremely psychologically addictive, the user may end up using a physically harmful amount, but no life-threatening withdrawal effect has been observed.

As used herein, "addictive agent (s)" includes any agent that can make a subject addictive, either physically or psychologically, or both. As described above, addiction includes addiction to chemical substances (for example, drugs) and addiction to actions such as in impulse control disorder.

Examples of addictive drugs include addictive recreational drugs and addictive drugs. Examples of addictive agents include, but are not limited to, alcohols such as ethyl alcohol, γ-hydroxybutyric acid (GHB), caffeine, nicotine, cannabis (marijuana) and cannabis derivatives, amphetamines and other morphine-like opioid agonists (heroines, Fencyclidine and fencyclidine-like compounds, hypnotic sedatives (benzodiazepine, metacarone, mecrocaron, etakalon and barbiturate, etc.) and psychostimulants (cocaine, amphetamine and amphetamine-related drugs, such as dextroamphetamine and methylamphetamine) Can be mentioned. Other examples include LSD, psilocibine, ecstasy and other hallucinogenic drugs. Examples of addictive medications include, for example, benzodiazepine, barbiturate, and analgesics, such as alfentanyl, allylprozine, alphaprozine, anileridine benzylmorphine, vegitramide, buprenorfin, butorphanol, chronitazen, codeine, cyclazosin, desomorphine, dexstromol. Amido, Dezosin, Diampromide, Dihydrocodein, Dihydromorphine, Dimenoxador, Dimefeptanol, Dimethylthiambutene, Dioxafetylbutyrate, Dipipanone, Eptazocin, Etoheptidine, Ethylmethylthiambutene, Ethylmorphine, Etonitazen fentanyl, Heroine, Hydrocodone, Hydromorphone, Hydropethidine, Isomethadone, Ketobemidone, Levallorphan, Levorfanol, Levofenacylmorphan, Lophenitanyl, Meperidine, Meptazinol, Metazosin, Metadon, Metopon, Morphine, Milophine, Narbufin, Narcene, Nicomorphine, Norrevorphanol , Narolphine, normorphine, norpipanone, achen, oxycodone, OXYCONTIN®, oxymorphone, papaveretum, pentazocin, phenadoxone, phenomorphan, phenazocin, phenoperidine, piminodin, pyritramide, propeptazine, promedol, properidine, propylum Included are fentanyl, tramadol, tilidine, salts thereof, any mixture of those mentioned above, mixed μ-agonists / antagonists and the like.

In some specific embodiments, the subject can be an opioid agonist-addictive subject. The terms "opioid agonist," "opioid," and "opium" are used interchangeably herein to indicate a group of drugs of varying degrees of opium-like or morphine-like properties. .. Its main use is pain relief. Such agents work primarily by binding to opioid receptors found in the central nervous system and gastrointestinal tract. Opium is also an addictive drug. Ahen includes alfentanyl, allylprozine, alphaprodine, anileridine, apomorphine, benzylmorphine, β-hydroxy3-methylfentanyl, vegitramide, calfentanyl, chronitazen, codeine, desomorphine, dextromorphine, diacetylmorphine (heroine), Diampromide, dihydrocodein, dihydroethurphin, dihydromorphine, dimenoxador, dimefeptanol, dimethylthiambutene, dioxafetylbutyrate, dipipanone, eptazocin, etoheptazine, ethylmethylthiumbutene, ethylmorphine, etnitazen, etolphin, fentanyl , Hydrocodon, hydromorphone, hydroxypetidine, isometadon, ketobemidone, LMM, levorphanol, levofenacilmorphan, lofentanyl, meperidine, metapon, metazocin, metadon, metazil acetate, metopon, morphine, Milophine, nalcein, nicomorphine, norlevorphanol, normetadon, normorphine, norpipanone, achen, oxycodon, oxymorphone, papaverin, phenadoxone, phenomorphan, phenoperidine, piminodin, pyritranide, propeptazine, promedol, properidine, propoxyphene, remifentanyl, Included are sfentanyl, tevaine, tilydin, and tramadol.

Natural opium includes codeine, morphine, noscapine, papaverine, and thebaine. Semi-synthetic opioids include diacetylmorphine, hydrocodone, hydromorphone, levorphanol, metapon, nalophine, naloxone, naltrexone, oxycodone, oxymorphone, and tramadol. Synthetic opioids include ethoheptazine, fentanyl, levorphanol, meperidine, methadone, phenazocine, propoxyphene and sufentanil.

Opium is roughly classified into three types: phenanthrene, phenylheptylamine, and phenylpiperidine. Examples of phenanthrene include codeine, etorphine, hydrocodone, hydromorphone, morphine, oxycodone, and oxymorphone. Examples of phenylheptylamines include dimeheptanol, dimenoxador, dipipanone, isomethadone, methadone, metazil acetate, and propoxyphene. Examples of phenylpiperidine include alfentanil, alphaprodin, β-promedol, carfentanil, fentanyl, lofentanil, meperidine, properidine, and sufentanil.

Specific psychostimulants include, for example, amphetamine, cocaine, dextroamphetamine, metaamphetamine, pemoline, ritalin, adderall and methylenedioxymethamphetamine.

As mentioned above, addictions include behavioral addictions (eg, food addiction, obsessive-compulsive disorder, morbid gambling, morbid use of electronic devices (eg, Blackberry®), and morbidity of video electronic games. Use, morbid use of electronic communication devices, morbid use of mobile phones, porn addiction, sexual dependence, obsessive-compulsive disorder, obsessive-compulsive consumption behavior, intermittent explosive disorder, theft, burning habit, hair loss habit, obsessive-compulsive hyperexercise , And addiction to obsessive-compulsive overwork.

In one aspect of the invention, subjects treated with PDE7 inhibitors suffer from food addiction or binge eating disorders and often have secondary health problems (eg, obesity due to overconsumption of food, and / Or with malnutrition due to overeating of foods high in fat and / or sugar and low in vitamins and minerals).

As used herein, "hypereating disorder" or "hypereating" refers to the following temporary symptoms: eating large amounts of food, eating even when full, eating fast, feelings of uncontrollable eating behavior, not hunger. Includes at least one of eating a significant amount of food, perhaps a frequent diet that has not lost weight, eating alone, feeling depressed or aversive about eating habits, and eating in response to stress. Binge eating disorders are distinguished from other types of eating disorders, including food addiction, bulimia nervosa and polyphagic vomiting syndrome. Unlike bulimia nervosa and polyphagic vomiting syndrome, subjects suffering from bulimia nervosa and food addiction-like behavior relieve excessive calorie consumption by subjects suffering from bulimia nervosa and food addiction-like behavior. Do not take compensatory actions for this.

Numerous scientific literature hypothesizes that binge eating and chronic binge eating share many characteristics with addictive behavior (eg, loss of control, continued use despite negative consequences). It is in the process of being established to support the characterization of certain types of eating behavior that are problematic as addictions. Despite their similarities, binge eating and food addiction can represent unique but overlapping conditions. Gearhard, A. et al. N. , Et al. , Binge Eating Disorderer and Food Addiction, Curr. Drug Abuse Rev, 4: 201-207 (2011).

As used herein, the term "food addiction" also refers to craving and demanding high-calorie foods, overeating in response to stimuli other than hunger, impaired control over food consumption, and negative consequences. A pattern of daily, persistent and habitual binge eating, characterized by the inability to reduce or stop consuming excess food, nevertheless. Food addiction is typically a chronically recurrent disorder that follows a course of binge eating, tolerance, discontinuation, demanding behavior of high-calorie foods and recurrence (beginning of binge eating after a period of suppression).

The natural preference for very tasty foods high in fats and carbohydrates arises for evolutionary reasons due to the high calorie support associated with such foods. It is undeniable that eating behavior is regulated by homeostatic mechanisms, but eating and binge eating are also regulated by emotional, emotional and learning processes. Polyvy, et al. , "Food Restriction and binge eating: a study of a former principal of war," J Abnorm Psychol 103: 409-411 (1994). In this regard, there are some commonalities between overeating and substance abuse (reward, enhancement, mood effects, external cue-desire control, stress-induced motivation). Evidence is accumulating that excessive intake of certain foods under certain conditions results in addictive-like brain behavior and changes. Gold, et al. , "Overeating, binge eating, and eating disorders as additions," Psychiatrist Ann 33: 112-116 (2003); Kenny, et al. , "Common cellular and molecular mechanisms in obesity and drug addiction," Nat Rev Neurosci 12: 638-651 (2011); Perchat, et al. , "Images of food: food-craving activation fMRI," Neuroimage 23: 1486-1493 (2004); Avena, et al. , "Evidence for sugar addiction: behavioral and neurochemical effects of intake," neuroscii Biobehav. , "Refined food addiction: a classic substance use disorder," Med Hyperses 72: 518-526 (2009); Gearhard, et al. , "Food Addiction: an addiction of the diagnotic criteria for defense," J Addiction Med 3: 1-7 (2011).

Drug addiction can be characterized by progressive gradual expansion in drug use, tolerated expression, their use and suppression after abrupt cessation of repeated recurrences, and similar phenomena have been described for high sucrose and high fat diets. rice field. For example, rats fed a very tasty sucrose solution experience opiate-like withdrawal symptoms after sucrose removal. Cross-sensitization between sucrose and drugs of abuse has also been described. Avena, et al. , "Evidence for sugar addiction: behavioral and neurochemical effects of intake," neuroscii Biobehav. , "Dysregulation of brain reward systems in eating disorders: Neurochemical information from animal models of binge eating, bulimia nervosa, and anorexia nervosa," Neuropharmacology (Epub ahead of print) (Nov.27,2011). Moreover, it has been well documented that psychological stress and unpleasant mood play a major role in promoting binge eating and overdrug use, contributing to the high addiction rates typical of both disorders. Corwin, et al. , "Feeling and word: perceptive from modes of binge eating," Physiol Behav 104: 87-97 (2011); Ghitza, et al. , "The anxiogenic drug yohimbine reinstates palatable food seeding in a rat relapse model: a roll of CRF1 receptors: a roll of CRF1 receptors: a roll of CRF1 receptors," Neuropsicho. , "Bulimia: A review of it symptomatology and treatment," Adv. Behave. Res. The. 7: 91-142 (1985); Crowther, et al. , "The roll of daily hassles in binge eating," Int J Eat Disord 29: 449-454 (2001); Herman, et al. , "Anxiety, restore, and eating behavior," JA Abnorm Psychol 84: 66-72 (1975).

Exposure to environmental conditioned stimuli has also been shown to play an important role in inducing drug craving in addictive individuals, as well as food craving in obese patients who meet the criteria for food addiction. Gearhard, et al. , "Food Addiction: an addiction of the diagnotic criteria for defense," J Addiction Med 3: 1-7 (2011). Consistent with studies in humans, in laboratory animals, exposure to environmental conditioning factors and stress (ie, yohimbine) resulted in reinstatement behavior against substances of abuse and on very tasty feeds. It has been shown to be equally effective in inducing. Cifani, et al. , "Preclinical model of binge-eating elicited by yo-yo dieting and stress full exposure to food: effective of sibutramine, fluoxetine, topiramate" , "Pre-exposure to environmental cures predictive of food availability elicits hypothalamic-pituitary-adrenal axis activation and deficiency 14 (4): 397-407 (Sept. 2009); Pickens, et al. , "Effective of phenfluramine on reinstatement of food seeding in female and male lats: implications for the predicates for the predicate (2) It has been proposed that the nervous system, which motivates and enhances substance abuse, also underlies compulsive food demands and behaviors associated with excessive food intake. Johnson, et al. , "Dopamine D2 addiction-like reward dysfunction and comprehensive eating in obesity," Nat Neurosci 13: 635-641 (2010); , "Brain neurotransmitters in food and drug review," Am J Clin Nutr 42 (5 Suppl): 1133-1150 (1985); Volkow, et al. , "How can drug addiction help understand obesity?" Nat Neurosci 8: 555-560 (2005); Corwin, et al. , "Feeling and word: perceptive from modes of binge eating," Physiol Behav 104: 87-97 (2011); Gearhard, et al. , "Neural correlates of food addiction," Arch Gen Psychiatry 68: 808-816 (2011); Wang, et al. , "Advanced striatal dopamine release dancing food stimulation daring binge eating disorder," Obesity 19 (8): 1601-1608 (Aug. 2011). For example, studies suggest that altered regulation of striatal dopamine (DA) may be present in patients with bulimia nervosa, as in drug addiction.

Concerns in the concept of food addiction have gained more attention in recent years, largely due to the similarities between addiction and binge eating disorder (BED) behavioral indicators. The episode of binge eating in humans is characterized by the obsessive and non-homeostatic consumption of an unusually large amount of very tasty food in a short period of time. Even if they are not hungry, subjects eat faster than usual until they feel uncomfortable and full. As described by DMS-IV-TR (American Psychiatric Association, "Diagnostic and Statistical manual of mental disorders," Washington, DC. (2000)), these episodes are referred to as dietary control. Associated with eating alone from pain, aversion, depression, guilt for overeating, and embarrassment.

BED was first described by Stunkard, "Eating Patterns and Obesity," Psychiatry Q 33: 284-295 (1959) and is perhaps the most common eating disorder. Hudson, et al. , "The prevalence and correlates of eating disorders in the National Comorbidity Replication Replication," Biol Psychiatry 61: 348-58 (2007). It is characterized by repeated binge eating episodes in the absence of compensatory actions to avoid weight gain. Diagnostic criteria for BED in DSM-IV-TR include assuming that binge eating episodes occur for at least 2 days per week during 6 months. BED is associated with serious medical and psychological comorbidities. Javaras, et al. , "Co-occurrence of binge eating disorder with psychiatric and medical disorders," J Clin Psychiatry 269: 266-273 (2008); Grucza, et al. , "Prevalence and psychiatry of binge eating disorder in a community sample," Compr Psychiatry 48: 124-131 (2007). Overeating afflicts about 5% of the American adult population sometime while they are alive (Foolds, et al., "The biology of binge eating," Appetite 52: 545-553 (2009)), obesity and It is predicted to contribute to the exacerbation of related medical conditions. Hudson, et al. , "The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication," Biol Psychiatry 61: 348-58 (2007); Yanovski, "Binge eating disorder and obesity in 2003: could treating an eating disorder have a positive effect on the obesity epidemic? "Int J Eat Disorder 34 Suppl: S117-S1120 (2003).

Numerous evidence suggests that diet, stress and negative emotional conditions represent significant triggers of binge eating in patients suffering from BED or bulimia nervosa. Wardle, et al. , "Stress, dietary restaurant and food industry," J Psychosom Res 48: 195-202 (2000); Freeman, et al. , "Daily stress, coping, and dietary restaurant in binge eating," Int J Eat Disord 36: 204-212 (2004). In fact, while dieting is common to binge eating careers, hunger itself does not appear to be sufficient to induce binge eating in the absence of stress and negative emotional conditions. Polyvy, et al. , "Food Restriction and binge eating: a study of former prisoner of war," J Abnorm Psychol 103: 409-411 (1994); Waters, et al. , "Internal and external antecedents of binge eating episodes in a group of women with bulimia nervosa," Int J Eat Disord 29: 17-22 (200). From considerable evidence, binge eating can be caused by a unique interaction between diet and stress; therefore, a history of environmental stress and periodic dietary restrictions can be responsible for its promotion and persistence. Is suggested. Stice, et al. "Subtyping binge eating-disordered women along dieting and negative affect dimensions," Int J Eat Disord 30: 11-27 (2001); Crowther, et al. , "The roll of daily hass in binge eating," Int J Eat Disord 29: 449-454 (2001). Thus, recurring food restrictions are consistently the strongest predictors of stress-responsive binge eating. Wardle, et al. , "Stress, dietary restaurant and food industry," J Psychosom Res 48: 195-202 (2000).

The subject may be a single addictive drug or action addictive subject, but frequently, the subject is addictive to more than one addictive drug or action. An addiction to two or more addictive drugs or addictive sexual activity is referred to as multiple addiction.

B. Methods for Treatment and Prevention of Addiction and Impulse Control Disorders Using PDE7 Inhibitors (One or More) in Combination with Other Therapeutic Agents PDE7 Inhibitors can be used in combination with one or more additional therapeutic agents for addiction, For example, it can be effectively used to treat or prevent one or more of the addictive agents described herein and addictions to obsessive-compulsive or addictive behavior. Accordingly, the present invention is a method of treating or preventing addiction, comprising administering one or more PDE7 inhibitors and one or more additional therapeutic agents to a subject who is addicted to an addictive drug. Each of the PDE7 inhibitor (s) and the additional therapeutic agent (s) includes methods that contribute 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 addictive to two or more addictive agents.

The PDE7 inhibitor and additional therapeutic agent may be administered simultaneously (ie, in parallel) or before any other (ie, sequentially). In general, both PDE7 inhibitors and additional therapeutic agents are at a time and level sufficient to simultaneously bring therapeutic benefit to the subject in the subject, ie, the treatment or prevention of addiction or the addictive agent or obsessive-compulsive disorder. Or it exists in the prevention of recurrent use (or resurrection) of addictive behavior. The PDE7 inhibitor and additional therapeutic agents may be administered on the same route of administration or on different routes of administration. Typically, the PDE7 inhibitor and additional therapeutic agent are each given to the subject according to standard routes of administration of over-the-counter or other pharmaceutical compositions. In one embodiment, the PDE7 inhibitor and additional therapeutic agent are co-administered with a composition comprising both agents.

Further therapeutic agents provided in combination with the PDE7 inhibitor can be any therapeutic agent that contributes to an effective treatment or prevention aspect of addiction. For example, additional therapeutic agents may be drugs used to treat addiction, or drugs used to alleviate the side effects associated with the physiological withdrawal of addictive agents. Further therapeutic agents include any drug that affects serotonin neurotransmission in the brain, such as selective serotonin reuptake inhibitors (SSRIs), and tricyclic and tetracyclic serotonin and norepinephrine reuptake inhibitors ( SNRIs) (discussed below), as well as serotonin agonists (such as sumatriptan, ergonobin, dihydroergotamine and buspyron). In some specific embodiments, additional therapeutic agents are opioid antagonists, such as mixed opioid partial agonists / antagonists, antidepressants, antiemetics, antiemetics, dopaminergic agents (eg, dopamine D1 receptor agonists). , Adrenal cortex stimulating hormone release factor-1 (CRF-1) receptor antagonist, selective serotonin-3 (5-HT3) antagonist, 5-HT2A / 2C antagonist (such as myanserin, miltazapine and ketanserin), or cannabinoid-1 ( CB1) Receptor antagonists (eg, but not limited to, therapeutic agents specifically described herein).

In one embodiment, the addictive agent is an 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.

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

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

In one embodiment, the addictive agent is cocaine and an additional therapeutic agent is buprenorphine.

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

In one embodiment, the addictive act is binge eating and the additional therapeutic agent is an antidepressant or antiepileptic drug. In one particular embodiment, the antidepressant is sibutramine. In another particular embodiment, the antidepressant is fluoxetine. In one particular embodiment, the antiepileptic drug is topiramate.

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

In one embodiment, the subject is addictive to two or more addictive agents, 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.

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

In the treatment of alcohol addiction, 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 are administered in combination according to the present invention. , PDE7 inhibitor and acamprosate, and PDE7 inhibitor and disulfiram.

In the treatment of addiction to psychostimulants, combinations administered according to the present invention include, for example, PDE7 inhibitors and antidepressants or PDE7 inhibitors and partial opioid agonists / antagonists (eg, buprenorphine).

In the treatment of nicotine addiction, the combinations administered according to the present invention include, for example, PDE7 inhibitor and antidepressant, PDE7 inhibitor and nicotine (as an alternative, orally, transdermally or in other conventional formulations), PDE7 inhibitor and opioid. Included are antagonists, PDE7 inhibitors and CB1 receptor antagonists / inverse agonists, and PDE7 inhibitors and varenicline. In one embodiment, an addictive agent (such as nicotine) and a PDE7 inhibitor are administered together using a transdermal patch delivery system. In another aspect of the invention, a kit comprising a large number of transdermal patches containing a tapering level dose of nicotine and a dose of either a constant level or a tapering level of PDE7 inhibitor is an nicotine-addictive test. Provided for continuous use by the body to disengage the subject from nicotine addiction.

In the treatment of multi-substance addiction, combinations administered according to the present invention include, for example, PDE7 inhibitors and opioid agonists or mixed opioid antagonists / partial antagonists.

In the treatment of gambling addiction, combinations administered according to the present invention include, for example, PDE7 inhibitors and antidepressants or PDE7 inhibitors and agents that affect dopamine neurotransmission (eg, direct or indirect dopamine antagonists).

Effective amounts of either or both of the PDE7 inhibitor and additional therapeutic agents may be less when administered in combination than when given either alone. For example, when a PDE7 inhibitor and an additional therapeutic agent act additively or synergistically, PDE7 is required to obtain the same therapeutic effect that either the PDE7 inhibitor or the additional therapeutic agent alone can provide. The amount of inhibitor may be low, the amount of additional therapeutic agent may be low, or the amount of both PDE7 inhibitor or additional therapeutic agent may be low.

1. 1. Opioid antagonists Opioid antagonists act on one or more opioid receptors. At least three types of opioid receptors, μ, κ, and δ opioid receptors have been reported, and opioid antagonists are generally classified by their effect on opioid receptors. Opioid antagonists can antagonize central, peripheral, or both receptors. 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. This effectively blocks the receptor and prevents the body from responding to opium and endorphins.

Many opioid antagonists are not only purely antagonists, but also provide some weak opioid partial agonist effects, which can be analgesic when administered at high doses to opioid-inexperienced individuals. Examples of such compounds include nalorphine and levallorphan. However, the analgesic effect of such drugs is limited and tends to be accompanied by dysphoria (probably due to their action on kappa opioid receptors). Such drugs are considered antagonists because they induce opioid withdrawal effects in those who are taking complete opioid agonists or who have previously used them.

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

Specific examples of opioid antagonists that can be used in accordance with the present invention include albimopan, vinyltorphimin, buprenorphine, cyclazocine, cyclolphan, cypridime, dinicotinate, β-funaltrexone, levallorphan, methylnaltrexone, nalphine, Included are nalide, nalmephene, nalmexone, nalorphine, nalorphine ginicotinate, naloxone, naloxoneazine, naltrexone, naltrexone, naltrixone, oxylorphan, and pentazocine.

2. Antidepressants Antidepressants are drugs used to treat depression. The three neurotransmitters believed to be involved in depression are serotonin, dopamine and norepinephrine. Certain types of antidepressants increase their levels in the brain by blocking the reabsorption of one or more of these neurotransmitters.

Several different types of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), tricyclic and tetracyclic serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine reuptake inhibitors (NRIs), Norepinephrine and dopamine reuptake inhibitors (NDRIs), azaspirones, monoamine oxidase inhibitors (MAOIs), and atypical antidepressants have been identified.

SSRIs include, for example, seripramine, citalopram, chromipramine, cyanodothiepine, dapoxetine, duroxetine, escitalopram, femoxetine, fluoxetine, fluboxamine, ihoxetine, imipramine, indalpine, inderoxetine, imipramine, indalpine, inderoxazine, ritoxetine, lofeplaminen. Examples include nortryptrin, paroxetine, sertraline, citalopram, tomoxetine, trazodone, benrafaxin, and dimerzine.

Amitriptyline, Amoxapine, Butriptiline, Chromipramine, Demexiptiline, Desipramine, Dibenzepin, Dimethacrine, Dotiepin, Doxepin, Imipramine, Iprindor, Lofepramine, Maprotyline, Melitracen, Metaplamine, Mianserin, Miltazapine, Metaplamine, Mianserin, Miltazapine, Nortriptyline , And trimipramine are all tricyclic and tetracyclic antidepressants.

SNRIs include, for example, amoxapine, atomoxetine, bicifadine, desipramine, desvenlafaxine, duloxetine, maprotiline, milnacipran, nephazodon, reboxetine, sibutramine, and venlafaxine.

Nisoxetine, nortriptyline, reboxetine, tarsplum, and tomoxetine are all examples of NRI.

NDRIs include, for example, bupropion, hydroxybupropion, and tesofencin.

Examples of azaspirone include buspirone, gepirone, ipsapirone, tandospirone, and tiaspirone. Buspirone is an anxiolytic (partial agonist at 5-HT1 autoreceptors) that can be provided with antidepressants such as SSRIs.

Specific MAOIs include, for example, amifluamine, brophalomine, chlordiline, α-ethyltryptamine, iproclodide, iproniazid, isocarboxazid, mevanazine, moclobemide, nearlamide, purgerin, phenelzine, pheniprazine, pirlindole, safradine, selegiline, toloxatone, etc. And tranylcypromine.

Atypical antidepressants include, for example, amesergide, amineeptine, benactidine, bupropion, clozapine, fezolamin, levoprotin, lithium, medifoxamine, mianserin, minapurine, olanzapine, oxafrosan, oxytriptan, loliplum, teniloxazine, tophenoxazine, tophenoxazine, tophenoxazine, and trazodone. Can be mentioned.

3. 3. Antiepileptic drugs Antispasmodics, also called antiepileptic drugs (AEDs), are a group of diverse drugs used to prevent the development of seizures and bipolar disorder. AEDs suppress rapid and excessive neuronal firing, which initiates seizures and / or suppresses the spread of seizures in the brain, and may have excitotoxic effects that may be due to brain damage. Provides sexual protection. Many antispasmodics block sodium channels, calcium channels, AMPA receptors or NMDA receptors.

Antiepileptic agents include, but are not limited to, benzodiazepines, barbituate, valproate, GABA agents, iminostilibene, hydantoin, NMDA antagonists, sodium channel blockers and succinamides.

Benzodiazepines include, for example, alprazolam, chlordiazepoxide, chlorazepam, clobazam, clonazepam, diazepam, halazapam, lorazepam, oxazepam, and prazepam.

Barbiturates used as anticonvulsants include, for example, amobarbital, mepobarbital, methylphenobarbital, pentobarbital, phenobarbital, and primidone.

Valproates used as antiepileptic drugs include, for example, sodium valproate, valproic acid, semisodium valproate, and valpromid.

Anti-epileptic GABA agents include, for example, gabapentin, rosigamon, pregabalin, retigabin, rufinamide, and vigabatrin.

Carbamazepine and oxcarbazepine are examples of iminostilbene.

Hydantoin includes, for example, sodium phosphenytoin, mephenytoin, and sodium phenytoin.

NMDA antagonists such as harkoceramide are used as antiepileptic drugs.

Sodium channel blockers such as lamotridin are also antiepileptic agents.

Examples of succinimide include ethosuximide, mesuximide, and fensuximide.

Other antiepileptic drugs include acetazolamide, briveracetam, CBD cannabis derivative, clomthiazole editilate, divalproex sodium, felbamate, isovaleramide, isovaleramide, lacosamide, lacosamide. Examples include talampanel, tiagabine, topiramate, saffinamide, levetiracetam, isovaleramide, stiripentol, sulfium, barrosemide, and zonisamide.

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

The classification of antiemetics includes, for example, 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, histamine receptor antagonist, dopamine receptor antagonist, muscarinic receptor antagonist, acetylcholine receptor antagonist, cannabinoid receptor antagonist, and side. Marginal inhibitors, NK-1 receptor antagonists, corticosteroids, takikinin antagonists, GABA agonists, cannabinoids, benzodiazepines, anticholinergic agents, and substance P inhibitors.

Examples of 5-HT3 receptor antagonists include alosetron, azasetron, bemesetron, silanecetron, dolasetron, granisetron, indicetron, itacetron, ondansetron, paronosetron, propisetron, ramosetron, lenzapride, tropisetron, and zatocetron. Be done.

Corticosteroid antiemetics include dexamethasone and methylprednisolone.

Limbic inhibitors include alprazolam, lorazepam, and midazolam.

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

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

Thiethylperazine is a type of histamine receptor antagonist.

Cannabinoid receptor antagonists or agonists used as antiemetics include dronabinol, nabilone, rimonabant, taranabout, and tetrahydrocanavinol.

Examples of other antiemetics include acetylleucine, monoethanolamine, alysapride, benzamide, vietanautine, bromopride, buclizine, chlorpromazine, cleboprid, cyclizine, dimenhydrinate, dipheniodol, domperidone, domperidone, domperidone ), Meclizine, metaltal, metopimazine, oxypendyl, pipamadin, piperinhydrinate, scopolamine, thioproperzine, and trimetbenzamide.

5. Cannabinoid Receptor Antagonists Cannabinoid receptors are a type of G-protein-coupled receptor superfamily. The ligand is known as a cannabinoid. Currently, there are two known subtypes, CB1 which is expressed mainly in the brain but also in the lungs, liver and kidneys, and CB2 which is mainly expressed in the immune system and hematopoietic cells. It is also believed that novel cannabinoid receptors, namely non-CB1 and non-CB2, are present and are expressed in endothelial cells and CNS. Cannabinoid receptor antagonists can be selective for either CB1 or CB2 receptors. The present invention envisions the use of either or both of CB1 receptor antagonists and CB2 receptor antagonists.

Addiction drugs (eg alcohol, opium, delta (9) -tetrahydrocannabinol (delta (9) -THC) and psychostimulants such as nicotine) by interacting with endogenous neural pathways in the brain. Induces a variety of chronic recurrent disorders. In particular, the drug shares the shared property of activating the mesolimbic dopamine brain reward system, and overdose drugs effectively all raise dopamine levels within the nucleus accumbens. Raise. Cannabinoid-1 (CB1) receptors are expressed in this brain reward circuit and modulate the dopamine-releasing effects of delta (9) -THC and nicotine.

Rimonabant (SR141716) is a CB1 receptor antagonist that blocks both the dopamine-releasing and discriminative reward effects of delta (9) -THC in animals. Blockade of CB1 receptors is generally not effective in reducing cocaine self-administration in rodents and primates, a condition in which the resurrection of disappeared cocaine demanding behavior is associated with cocaine. Reduces the consequences of irritation and initial cocaine stimulation injections. Similarly, blockade of CB1 receptors is effective in reducing nicotine demanding behavior induced by re-exposure to nicotine-related stimuli. In human clinical trials, rimonabant has been shown to block the subjective effects of delta (9) -THC in humans and suppress the resumption of smoking in those who have smoked.

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

6. Dopaminergic Drugs Drug addiction is characterized by loss of control over drug use, compulsive drug demand and substance craving, persistent use despite negative consequences, and physical and / or psychological dependence on the above substances. It is a chronic recurrent disease. Dopamine has been attributed to its basic role in the pathogenesis of addiction. Dopamine is, in fact, a natural drug addiction at all levels, from its involvement in forming individual responses to fragility factors (ie, genetic properties, environment and stress) to its role in the mechanism of action of substances of abuse. It was widespread in history.

The midbrain cortex dopamine system begins in the ventral tegmental area (VTA) and projects prominently into the nucleus accumbens (NAc) and prefrontal cortex (PFC). It is a clear commonality of all addictive drugs that, at least first, they stimulate dopamine transmission in the terminal area of the mesolimbic system, especially in the nucleus accumbens shell. Nestler, E.I. J. , "Is there a community molecular pathway for addiction?" Nat Neurosci 8: 1445-1449 (2005); Pierce, R. et al. C. , Et al. , "The mesolimbic dopamine system: The final common pastway for the reinforcement effect of drugs of abuse?" Neuroscii Biob. Brain imaging studies have extended these observations to humans. Drevets, W. et al. C. , Et al. , "Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria," Biol Psychiatry 49: 81-96 (2001); L. , Et al. , "Smoking-induced ventral striatum dopamine release," Am J Psychiatry 161: 1211-1218 (2004). Release of dopamine from these projections is thought to play an important role in mediating drug reward, reinforcement, and in inducing obsessive-compulsive addictive behavior. Dopamine is involved in predisposition and in the early stages of drug addiction development, a condition that, once established, is associated with long-term changes associated with chronic exposure to the drug itself.

These changes are collectively referred to as "nerve adaptation" and are considered to be a substrate for behavioral sensitization, a long-lasting increase in susceptibility to the behavioral stimulating properties of the drug, and a baseline change in hedonic state (pleasure allostasis). Be done. Berrydge K. C. , Et al. , "What is the roll of dopamine in reward: Hedonic impact, reward learning, or incident salience?" Brain Res Rev 28: 309-369 (1998); Koob, G. et al. F. , Et al. , "Neurobiological mechanisms for opponent motivation processes in addiction," Philos Trans R Soc Land B Biol Sci. 363: 3113-3123 (2008). Neural adaptation also occurs at the level of the dopamine system, where there is a relative decrease in basal levels of dopamine transmission activity in the ventral striatum region, demonstrating a decrease in dopamine D2 receptor levels. Volkow, N.M. D. , Et al. , "Dopamine in drug and addiction: results from imagining studies and treatment implications," Mol Psychiatry 9: 557-569 (2004); Vol. D. , Et al. , "Dopamine in drug abuse and addiction: results from imagining studies and treatment implications," Arch Neurol 64: 1575-1579 (2007); Fehr, C.I. , Et al. , "Association of low strike dopamine d2 receptor availability with nicotine dependence simillar to that seen with psychiatum 5

The most common mechanism by which drugs of abuse result in dopamine neurotransmission is through the regulation of presynaptic γ-aminobutyric acid (GABA) activity. Luescher, C.I. , Et al. , "The mechanical classicization of adaptive drugs," PLos Med 3: e437 (2006). In VTA, GABA neurons act as locally inhibitory interneurons that provide tension control over cortical midbrain limbic dopamine cells. Decreased GABA neurotransmission results in net disinhibition of dopamine neurons, as well as increased dopamine release in terminal regions such as NAc and PFC.

A basic example of this mechanism is demonstrated by achen, with prominent GABAergic neurotransmission resulting in desuppression of VTA dopaminergic cells after activation of μ-opioid receptors located on presynaptic GABA cells. Inhibition is brought about. Johnson, S.A. W. , Et al. , "Opioids excite dopamine neurons by hyperpolarization of local interneurons," J Neurosci 12: 483-488 (1992). Cannabis derivatives appear to increase the frequency of VTA dopamine firing by a similar mechanism, except through selective activation of cannabinoid receptor 1 (CB1R) located in presynaptic GABA neurons. Nicotine also increases dopamine neurotransmission, except through complex interactions of nicotine receptor action on GABA and on glutamatergic inputs to dopamine neurons. Luescher C, et al. , The mechanical classicization of additive drugs. , PLoS Med. 3 (11): e437 (2006). In fact, β2-containing nAChR-mediated nicotine reduces presynaptic GABA release, resulting in long-term disinhibition of dopamine and at the same time acting on homomer α7-containing nAChR. They are primarily expressed at synaptic terminals of excitatory glutamate-operated afferent pathways to dopamine neurons in VTA and promote glutamate release. This effect can also contribute to nicotine-induced dopamine release. In addition, recent evidence suggests that nicotine directly regulates dopamine release in NAc. Ethanol and benzodiazepines also appear to stimulate VTA dopamine neurotransmission through inhibition of presynaptic GABA activity through regulation of specific GABA-A receptor subunits.

Psychostimulants such as amphetamine derivatives and cocaine are the only addictive drugs that act directly on dopaminergic endings by inhibiting dopamine reuptake mechanisms or by promoting dopamine release from synapses. Construct a class. Through these mechanisms, they increase extracellular dopamine levels in the terminal regions of the brain dopamine system (ie, NAc and MPF). However, most notably, dopamine terminals also express D1-like and D2-like receptors on dopaminergic cell bodies (autoreceptors), and on glutamatergic and GABAergic presynaptic neurons. Exists in the VTA to be. Direct application of cocaine in VTA produces effects that can be potentially mediated by reduced dopamine firing frequency (dose-dependent), presynaptic GABA and D1 receptors located on glutamate cells, respectively. Thus, presynaptic regulation of VTA DA activity may play a role in the regulation of psychostimulant addictive traits. Brodie, M. et al. S. , Et al. , "Cocaine effects in the ventral tegmental area: Evidence for an indicator dopaminergic mechanism of action," Naunyn SchmiedebergsArch , Et al. , "Increased probability of GABA release withdrawal from morphine," J Neuroscii 17: 796-803 (1997).

Thus, in one embodiment of the invention, a further therapeutic agent administered simultaneously or sequentially in combination with a PDE7 inhibitor is a dopaminergic agent for treating a patient suffering from addiction or obsessive-compulsive disorder. .. In another embodiment of the invention, the PDE7 inhibitor is administered simultaneously or sequentially in combination with a dopamine receptor agonist to treat a patient suffering from addiction or impulse control disorder. In another embodiment of the invention, the PDE7 inhibitor is combined with a dopamine D1 receptor agonist (ie, a dopamine subtype D1 receptor agonist) to treat a patient suffering from addiction or impulse control disorder. Administered simultaneously or consecutively.

Exemplary dopaminergic agents suitable for administration in combination with PDE7 inhibitors include, for example, levodopa (also referred to as "L-dopa"), carvidopa, and dopamine receptor agonists as well as bromocryptin, pergolide, pramipexole, ropinirole. , Progenitors such as cabergolin, apomorphin, lislide, rotigotine and quinagolide, and phenordopam, which is selective for the dopamine receptor D1.

The dose of D1 receptor agonist suitable for administration in association with the PDE7 inhibitor in accordance with the present invention can be determined by the physician, eg, 0.1 mg to 1 mg per day or twice a week (biweekly). It can be in the range of 000 mg, or 0.25 mg to 100 mg per day or twice a week.

C. Treatment and Prevention of Recurrence Recurrent use or resurrection is the use of alcohol or another addictive drug after a period of inactivity or restricted or reduced addictive activity. The process of returning to the execution of addictive sexual activity. In certain situations, recurrent use of an addictive drug refers to a subject who has been physically withdrawn from the addictive drug returning to use of the addictive drug. Typically, the subject is a subject who will experience physical withdrawal of the addictive drug during periods of non-use or restricted or reduced use of the addictive drug. In one embodiment, recurrent use has previously received a treatment regimen with an effective amount of anti-addictive agent to reduce or eliminate the use of the addictive agent, but no longer uses an effective amount of anti-addictive agent. Occurs in non-subjects. Anti-addiction agents include any agent used to treat or prevent addiction or withdrawal symptoms.

Alcoholism, like many other addictions, is a recurrent chronic disorder characterized by a high addictive crime rate. Two major factors inducing recurrence are stress and environmental conditioning experience (O'Brien et al. 1997; Monti et al. 1993; Shaham et al. 1995), which probably facilitate recurrence to alcohol demand by different brain mechanisms. do. For example, activation of the mesolimbic dopamine system by an opioid-dependent mechanism (or by direct modification of dopamine transmission in the basolateral nucleus of the amygdala) appears to mediate the effects of drug-related queues (Liu). And Wiess 2002; Ciccocoippo et al. 2001), Stria terminalis and extrathalamic CRF in the amygdala of the medial limbic nucleus probably mediate the resurgence of stress-induced drug demanding behavior (Erb et al. 1998; Shaham et al. 1995). Le et al. 2000).

Several sets of evidence suggest that the molecular mechanisms underlying recurrence of addiction are common to overdose of various types of drugs. Decreased control over drug intake with drug craving and recurrence is under the direct influence of stress and environmental conditioning stimuli; two key factors influencing resumption of drug use.

Chronic excessive drug intake results in neuroadaptive changes not only in the system involved in the acute enhancing effect of ethanol, but also in other motivational systems, notably in the brain stress regulation mechanism. Stress has an established role in the initiation and maintenance of excessive drug intake and is a major determinant of recurrence in abstinent individuals (Brown et al., J Studios Alcohol 56: 538 (1995); Marlatt, Relapse presentation: introduction and overview of the model, in Relapse Prevention:. Maintenance Strategies in the Treatment of Addictive Behaviours, Guilford, London, (1985); McKay et al., Drug Alcohol Dep, 38,35, (1995); and Wallace, J Subst Abuse Treat, 6:95, (1989)). Also, the importance of stress in drug demanding behavior is well documented in the animal literature. Physical, social and emotional stress can facilitate the acquisition or increase of self-administration of cocaine, heroin and ethanol in rodents and non-human 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); Stewart, Psychopharmacology 119: 334 (1995); Nash and Mackel, Prog Neuropsychopharmacology Biol Psychopharmacology, 12, 653, (1988); Mollenauer et al. Biochem. Behave. 28,437, (1987) and Higley et al., Proc. Natl. Acad. Sci. USA, 88, 7261, (1991)). Overstress stimulation has also been shown to induce a resurgence of cocaine, heroin and ethanol demanding behavior in drug-free animals after elimination, and such findings are supported by experiments on the role of stress in recurrence. (Ahmed and Koob (1997); Shaham, Psychopharmacology, 111, 477, (1993); and Shaham and Stress (1995)).

Traditionally, stress-related drug demanding behavior has been thought to be mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. However, evidence suggests that the non-neuroendocrine adrenocorticotropic hormone-releasing factor (CRF) system within the central nucleus of the amygdala (CeA) may play a major independent role in the regulation of stress-related addictive behavior. Is increasing. CeA is rich in CRF immunoreactive cell bodies, terminals and receptors, and this neuronal CRF system is involved in mediating behavioral and emotional responses to overstress 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 CeA, but intra-CeA injection of the CRF receptor antagonist α-helix CRF9-41 is a sign of anxiety caused by social and environmental stressors. Reduced (Merali et al., J. Neurosci., 18, 4758, (1998); Mello 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 syndrome. Given the evidence for the role of CRF neurons in CeA in regulating the emotional and anxiety-inducing effects of stress, anxiety-inducing and stress-like outcomes of withdrawal from excessive drug intake are similarly CRF systems within CeA. May be mediated by.

Changes in the regulation of CRF system activity within CeA may represent a critical neuroadaptive mechanism that contributes to the development of addictive and obsessive-compulsive drug demanding behavior.

The data discussed above confirm neuroadaptive changes in brain circuits and disruption of the stress system as important factors in obsessive-compulsive drug demanding behavior and dependence. Excessive Drug Intake Another important factor in the potential for long-lasting addiction is the conditioning of rewarding effects by specific environmental stimuli. Environmental cues that are repetitively associated with the subjective effects of excessive drug intake (eg, alcohol) can evoke drug cravings that can eventually lead to recurrence or induce automatic action responses (Miller and Gold 1994). Tiffany and Carter 1998) (Childress et al., Conditioned craving and cocaine addition: A preliminary report, in NIDA Research Monograph, in NIDA Research Monograph 81, (1988); Alcohol 54: 235-45 (1993); Pommerleau et al., Addiction. Behav., 8, 1, (1983); Stormark et al., Addiction. Behav., 20, 571 (1995); Miller and Gold Ann. Clin. , 6,99, (1994); and Tiffany and Carter, JP Psychopharmacology. 12, 23, (1998)). Therefore, the learning response to drug-related stimuli can make a decisive contribution to the high rate of recurrence associated with cocaine and other drug addictions.

Data from an operant response-resurrection model developed to study drug demanding behavior associated with exposure to drug-related environmental queues in rats are discriminative stimuli that predict cocaine, ethanol, or heroin availability. , Has been shown to reliably induce a strong recovery of eliminated drug demanding behavior without 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. .. The response-restoring effect of such stimuli is markedly resistant to elimination by repeated exposure, and in the case of cocaine, it can still be observed even after a state of forced extinction for several months. In addition, with ethanol, the drug demanding behavior evoked by ethanol predictive discriminative stimuli is enhanced in alcohol-loving P-rats as compared to alcohol-free (NP) and non-selective Wistar rats. Was found (Weiss and Ciccocoippo, Soc. Neurosci. Abstr., 25, 1081, (1999)). This observation is that the genetic predisposition to high levels of ethanol intake is also reflected in the greater susceptibility to the motivational effects of ethanol cues (ie, drug demand under conditions where behavior is not directly enhanced by ethanol itself. Improvement) is shown. Taken together, these findings strongly support the hypothesis that learning responses to drug-related stimuli are a significant factor in long-lasting recurrence susceptibility.

In humans, the risk of recurrence is probably associated with a number of interacting determinants. For example, exposure to drug cues can increase the likelihood of recurrence conferred by long-term withdrawal symptoms due to neuroadaptive changes in dependent individuals. Also, interaction effects that exacerbate the risk of recurrence may exist between the motivational effects of stress and drug-related cues. Recent studies addressing these challenges have demonstrated an additive interaction between ethanol-related cues and stress response recovery effects, confirming that this effect is higher in rats with a history of ethanol dependence. (Liu and Weiss, Soc. Neurosci. Abstr. 26, 786 (2000)).

In the laboratory, administration of yohimbine, an α-2 adrenergic receptor antagonist that increases cell firing and release of noradrenaline in the brain and acts as a pharmacological stress factor, revived drug demand. Both foot shock stress and yohimbine-induced resurrection of drug-demanding behavior are valid experimental models for studying stress-induced alcohol recurrence (Lee et al., Neuropsychopharmacology 29: 686-93 (2004) and Le et al., Psychopharmacology. 150: 317-24 (2000)).

As shown in the attached Examples, the PDE7 inhibitor significantly reduces the recurrent use of stress-induced addictive agents (Example 1). Therefore, this data indicates that the PDE7 inhibitor has anti-recurrence properties.

Interestingly, according to various reports, the non-selective achen receptor antagonist naltrexone reduced the urge to drink induced by the presentation of alcohol queues in human alcohol dependence (Monti et al., 1993, supra), rat. Has been shown to reduce the effectiveness of alcohol cues in resurrecting the erased response in previous drug pair levers (Katner et al. 1999, supra). However, naltrexone does not reduce stress-induced recurrence ((Le AD Psychopharmacology 1998).

In a related embodiment, the invention has previously reduced or eliminated the use of addictive agents or the performance of addictive or compulsive behavior in response to exposure to an effective amount of another anti-addictive treatment, and is no longer an effective amount of said. Includes methods of treating or preventing recurrent use of addictive agents or the performance of addictive or compulsive behavior, including administration of effective doses of PDE7 inhibitors to subjects not exposed to anti-addictive treatment. The anti-addiction treatment may be an anti-addiction drug or a non-pharmacological therapy (such as counseling, psychotherapy or hypnosis). Recurrent use may be stress-induced.

In some specific embodiments, the subject becomes tolerant of the anti-addiction agent and is no longer effective because the plasma concentration of the anti-addiction agent, which was previously effective in treating addiction, is no longer effective. A subject who has not been exposed to the anti-addiction agent. In another embodiment, the subject is no longer exposed to an effective amount of the anti-addiction agent because the subject is currently exposed to a low plasma concentration of the anti-addiction agent and this low plasma concentration is no longer effective. The body.

In some specific embodiments of the methods of the invention, the subject is in a state of discontinuing or restricted or reduced use of addictive agents or performing addictive or compulsive behavior. The period of discontinuation or restricted or reduced use is, 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 It can be 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.

In another embodiment, the invention provides a method of treating or preventing recurrent use of an addictive drug, comprising giving a PDE7 inhibitor and an opioid antagonist to a subject who is in a physiological withdrawal state from the addictive drug. include.

In a further embodiment, the invention comprises administering to a subject who is in a physiological withdrawal state from an addictive drug a PDE7 inhibitor and a CB1 antagonist, such as disulfiram, topiramate, levetiracetam, SSRI, or ondansetron. , Includes methods of treating or preventing recurrent use of addictive drugs.

In certain embodiments, recurrent use is induced by stress, environmental conditioning factors, or both.

Although the method of the present invention can be carried out on a subject who is addicted to a single addictive drug, it may be used on a subject who is addicted to two or more kinds of addictive drugs. Similarly, this method can be used to prevent recurrent use of addictive drugs in which the subject is in a withdrawal state, but with recurrent use or in which the subject is in a physiological withdrawal state. May be adapted to prevent the initiation of use of different addictive agents.

D. Pharmaceutical Compositions, Routes of Administration, Unit Dosages, Kits According to the invention, PDE7 inhibitors can be combined with one or more additional therapeutic agents, such as opioid antagonists, antidepressants, antiepileptic agents, antiemetics, and CB1 receptor antagonists. The effectiveness of using the combined combination was established. Accordingly, the present invention further comprises one or more PDE7 inhibitors and one or more additional therapeutic agents such as opioid antagonists, mixed opioid antagonists / partial agonists, antidepressants, antidepressants, antiemetics, CRF1 receptors. Includes compositions containing body antagonists and CB1 receptor antagonists.

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, additional therapeutic agents are antiepileptic drugs, antiemetics, or opioid antagonists or mixed opioid partial agonists / antagonists.

The composition of the present invention can be administered to a subject as a pharmaceutical composition or formulation. In certain embodiments, the pharmaceutical composition of the invention can be any form in which the composition can be administered to a subject. For example, the composition can be in the form of a solid, liquid or gas (aerosol). Typical routes of administration include, but are not limited to, oral, transsurface, parenteral, sublingual, transrectal, transvaginal, and intranasal. The term parenteral, as used herein, includes subcutaneous injection, intravenous, intramuscular, epidural, intrasynovial injection or infusion techniques.

Pharmaceutical compositions used in accordance with the present invention include PDE7 inhibitors, other therapeutic agents, and pharmaceutically acceptable diluents, excipients, or carriers. "Pharmaceutically acceptable carriers" for therapeutic use are well known in the pharmaceutical arts and are described, for example, in Remingtons Pharmaceutical Sciences, Mac Publishing Co., Ltd. (A.R. Gennaro ed., 1985). For example, sterile saline and phosphate buffered saline of physiological pH can be used. It may be included in preservatives, stabilizers, dyes, and even flavoring pharmaceutical compositions. For example, esters of sodium benzoate, sorbic acid and p-hydroxybenzoic acid can be added as preservatives. (Same as above, p. 1449). Also, antioxidants and suspending agents may be used (ibid.).

The pharmaceutical composition of the present invention is generally formulated so that when the composition is administered to a subject, the encapsulated active ingredient can become bioavailable. The composition administered to the subject can be in the form of one or more dosing units, in which case, for example, a tablet, capsule or cachet can be a single dosing unit and the agent in the form of an aerosol according to the invention. The container containing the combination of may contain a plurality of dosing units.

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

The present invention further includes a unit dosage form of a pharmaceutical composition comprising a PDE7 inhibitor and another therapeutic agent. Each unit dosage form comprises a therapeutically effective amount of the pharmaceutical composition of the invention and is used in the recommended amount when used. For example, a unit dosage form may include a therapeutically effective amount in a single tablet, and a unit dosage form may be therapeutically effective in two or more tablets such that the prescribed amount constitutes a therapeutically effective amount. It may include an amount.

In certain embodiments, the PDE7 inhibitor is given 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 given to the patient at about 30 mg / day.

Certain combinations of PDE7 inhibitors and other therapeutic agents may not be readily compatible with co-formulations. For example, one drug may be more suitable for intravenous administration, while another drug may be more suitable for oral administration. Alternatively, the serum half-life of the two drugs may be such that one must be administered more frequently than the other. Therefore, in the present invention, one or more unit dosage forms of PDE7 inhibitor and one or more unit dosage forms of another therapeutic agent are provided to the subject in a manner in which the two unit dosage forms are therapeutically effective. A kit is envisioned to include as possible.

In one embodiment, the invention includes a kit comprising a unit dosage form of PDE7 inhibitor and a unit dosage form of nicotine. In one embodiment, the unit dosage form of nicotine is composed of a plurality of different unit dosage forms of nicotine, the different dosage forms of nicotine being tapering, overcoming addiction and withdrawal from nicotine. It can be taken sequentially over time to be achieved. The unit dosage form of nicotine may be present, for example, in the form of a transdermal patch, gum or lozenge.

E. PDE7 protein and PDE7 inhibitor Cyclic nucleotide phosphodiesterase type 7 (PDE7) has been identified as a unique family based on enzymatic activity that differs from its primary amino acid sequence. The PDE gene identified as PDE7 (PDE7A and PDE7B) encodes a cAMP-specific PDE. The biochemical and pharmacological properties of PDE7 show a high affinity cAMP-specific PDE (Km = 0.2 μM) that is unaffected by cGMP or selective inhibitors of other PDEs. The PDE7 enzyme selectively degrades cAMP and is characterized as an enzyme that is not inhibited by rolipram, a selective inhibitor of the different cAMP-specific PDE family PDE4. In the PDE7 family, two subtypes, PDE7A (Michael, T. et al., J Biol. Chem. 268 (17): 12925-2932, 1993; Han, P. et al., J Biol. Chem. 272 (26):: 16152-16157 (1997) and PDE7B (US Pat. No. 6,146,876; Gardner, C. et al., Biochem. Biophyss. Res. Commun. 272 (1): 186-192, 2000; and Sasaki, T. et al., Biochem. Biophys. Res. Chemun. 271 (3): 575-583, 2000) have been identified. The products of these two genes show 70% identity in their C-terminal catalytic domain (Hetman JM et al., PNAS 97 (1): 472-476 (2000).

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

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

The PDE7A protein has a region of about 270 amino acids at the carboxy terminus that shows significant similarity (about 23% homology) to other cAMP hydrolyzable PDE-like regions. This region serves as a catalytic domain. The amino-terminal region of this protein, unlike that of other PDEs, probably mediates different regulatory properties inherent in this enzyme family.

The protein sequence of human PDE7B is available in public databases under accession number NM_018945 and is shown as SEQ ID NO: 6 (encoded in SEQ ID NO: 5). Three splicing variants PDE7B1, PDE7B2 and PDE7B3 have been reported for PDE7B. PDE7B is published in WO01 / 62904, US Pat. No. 6,146,876.

Both PDE7B2 and PDE7B3 have a unique N-terminal sequence. The human PDE7B gene product has an apparent molecular weight of 53-55 kDa on reduced SDS-PAGE (Sasaki, T., Kotera, J., Omori, K., Biochemical J. 361: 211-220, 2002). As with PDE7A, PDE7B has a significantly conserved region of about 270 amino acids shared by all PDEs at the carboxy terminus, which functions as a catalytic domain. Like the PDE7A protein, the amino-terminal region of the PDE7B protein is unique and probably explains the different regulatory properties that are unique to the individual PDE family. The PDE7B protein shows homology with other cAMP-dependent PDEs in the catalytic domain (23%). The PDE7B polypeptide is 61% homologous to PDE7A, according to WO2004 / 044196.

In addition, PDE7 is uniquely localized in mammalian subjects as compared to other PDE families. PDE7A expression has been detected in most of the tissues analyzed, 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 populations (Miro et al., Synapse 40: 201, 2001). The widespread expression of PDE7A in the brain (eg, basal ganglia and substantia nigra) provides a rationale for the role of PDE7A in brain function.

In the practice of the method of the present invention, as a typical PDE7 inhibitor that inhibits the phosphodiesterase activity of PDE7, a molecule that binds to PDE7 and inhibits the enzymatic activity of PDE7 (a small molecule that binds to PDE7 and reduces the enzymatic activity). Inhibitors or block peptides), as well as molecules that reduce PDE7 expression at transcriptional and / or translational levels (such as PDE7 antisense nucleic acid molecules, PDE7-specific RNAi molecules and PDE7 ribozymes), thereby causing PDE7 to cAMP. Prevents disconnection. PDE7 inhibitors are used as the main therapeutic agent alone or in combination with other therapeutic agents (such as dopamine receptor agonists) as adjunctive therapeutic agents to enhance the therapeutic benefits as described above. obtain.

Inhibition of PDE7 results in the following changes resulting from administration of the PDE7 inhibitor by the method of the invention: 5'-adenosin monophosphate (5') by PDE7-dependent enzymatic cleavage of the 3'-phosphodiester bond within cAMP. At least one of inhibition of -AMP) formation, decreased expression level of PDE7 gene or protein (eg, measured by gene expression analysis (eg, RT-PCR analysis) or protein analysis (eg, Western blot)). It is characterized by.

In some embodiments, the PDE7 inhibitor is intracellular corresponding to a molecule or composition that inhibits the expression of PDE7A, PDE7B, or both PDE7A and PDE7B, eg, the gene (s) of the target PDE7. It specifically hybridizes mRNA and / or genomic DNA with an antisense or small inhibitory nucleotide (eg, siRNA) that specifically hybridizes to inhibit its transcription and / or translation, or mRNA of target PDE7. Ribozyme to cut, etc.

In effect one embodiment of PDE7 inhibitors, PDE7 inhibitors useful in the methods of the present invention, _{IC 50} ≦ 1μM, preferably _{an IC 50} of about 0.1μM or less, PDE7 (PDE7A, PDE7B or PDE7A and PDE7B,) It is a compound that is sufficiently effective to inhibit the enzymatic activity of. In one embodiment, PDE7 inhibitors are those with sufficiently potent to inhibit the enzymatic activity of an _{IC 50} of about 0.1 to about 500 nM PDE7 (PDE7A, PDE7B or PDE7A and PDE7B,). In one embodiment, PDE7 inhibitors are those that are potent to inhibit the enzymatic activity of an _{IC 50} of about 1 to about 100 nM PDE7 (PDE7A, PDE7B or PDE7A and PDE7B,).

PDE7 representative method for determining the _{IC 50} for (PDE7A or PDE7B) inhibitors, Bardelle et, Anal Biochem 15: 275 (2 ): 148-55 disclosed (1999) a Scintillation Proximity Assay (SPA) It is well known in the technical field.

PDE7A or PDE7B Selective Inhibitor In one embodiment, a PDE7 inhibitor useful for the methods of the invention is a PDE7A inhibitor. In one embodiment, PDE7A inhibitors are those that are potent to inhibit the enzymatic activity of PDE7A with _{an IC 50} of about 0.1 to about 500 nM. In one embodiment, PDE7A inhibitor has an _{IC 50} of about 1 to about 100 nM. Suitable assays for determining the _{IC 50} of PDE7A inhibitors are those using recombinant human PDE7A2 enzyme was expressed in a baculovirus system. This assay is a variant of the SPA assay reported by Bardelle et al. (Supra).

In some embodiments, the PDE7 inhibitor exhibits isozyme-selective activity against PDE7A. PDE7A selective inhibitors reduce PDE7A activity by at least 2-fold greater than PDE7B activity, more preferably by at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold. In some embodiments, the PDE7A inhibitor is at least 10-fold (eg, at least 20-fold) with respect to the inhibition of PDE7A activity over the enzymatic activity of any other PDE (PDE1-6, 7B, and 8-11). , Or at least 50-fold, or at least 100-fold) selective inhibitor.

In one embodiment, PDE7B inhibitor has an _{IC 50} of about 0.1 to about 500 nM. In one embodiment, PDE7B inhibitor is one that is sufficiently potent in inhibiting about 0.1 to about enzymatic activity of PDE7B with _{an IC 50} of 500 nM. In one embodiment, PDE7B inhibitor has an _{IC 50} of about 1 to about 100 nM. Method of measuring the _{IC 50} of PDE7B inhibitors, such assays disclosed Bardelle et al (supra), are well known in the art.

In some embodiments, the PDE7 inhibitor exhibits isozyme-selective activity against PDE7B. PDE7B selective inhibitors reduce PDE7B activity by at least 2-fold greater than PDE7A activity, more preferably by at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold. In some embodiments, the PDE7B inhibitor is at least 10-fold (eg, at least 20-fold) with respect to the inhibition of PDE7B activity over the enzymatic activity of any other PDE (PDE1-6, 7A, and 8-11). , Or at least 50-fold, or at least 100-fold) selective inhibitor.

In certain embodiments of PDE7-selective part compared to other PDE, PDE7 inhibitors, smaller 5 times larger than the _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity (e.g., at least 10 fold, it has an _{IC 50} for inhibition of at least 20 fold, or at least 50 fold, or at least 100-fold) PDE1B activity. In other words, PDE7 inhibitors in inhibiting the activity of PDE7A or PDE7B (the isozyme of PDE7A or PDE7B where the PDE7 inhibitor is most effective) than in inhibiting the activity of PDE1B (5-fold, 10-fold, 20 times, 50 times or 100 times) Greater efficacy. In the interpretation of the present specification, as an example, this property is even more simply that the PDE7 inhibitor in inhibiting the activity of PDE7 is 5 times, 10 times, 20 times, 50 times or 100 times more than the inhibition of the activity of PDE1B. Double) Can be described as having great efficacy.

Double inhibition of both PDE7 and PDE1B may confer additional benefits in the treatment of movement disorders. This is based on reports that deletion of the PDE1B gene in mice stimulated dopamine metabolism and animals were sensitized to the effects of dopaminergic agonists (Siuciak et al., Neuropharmacology 53 (1): 113-23 (2007). Year)).

In some embodiments, PDE7 inhibitor is smaller 5 times larger than the _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity (e.g., at least 10 fold, or at least 20 fold, or at least 50-fold, or an _{IC 50} for inhibition of at least 100-fold) PDElO activity. Double inhibition of PDE7 and PDE10 may provide additional benefits in the treatment of movement disorders. This is based on reports that selective inhibitors of PDE10 cause increased levels of cAMP in the streaks (Siucik JA et al., Neuropharmacology 51 (2): 386-96 (2006)).

In some embodiments, PDE7 inhibitor is smaller 10-fold greater than the _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity (e.g., at least 20 fold, at least 50 fold, or at least 100 an _{IC 50} for inhibition of times) PDE3 activity. This is because administration of selective PDE3 inhibitors to patients with heart failure has been shown to increase mortality (Packker M. et al., N Engl J Med. 325 (21): 1468-75 (1991)).

In some embodiments, PDE7 inhibitor is smaller 10-fold greater than the _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity (e.g., at least 20 fold, at least 50 fold, or at least 100 an _{IC 50} for inhibition of times) PDE4 activity. This is because the deletion of one PDE4 gene in mice has been shown to result in cardiomyopathy (Lehnart S.E. et al., Cell 123 (1): 25-35 (2005)).

In some embodiments, the PDE7 inhibitor is used in an in vivo assay for PDE4 inhibition (eg, sedation or inhibition of TNFα levels after endotoxin treatment) for in vivo assays for PDE7A and PDE7B inhibition (eg, cocaine addiction or other psychiatric). _{It has a semi-maximum effective amount (“ED 50} ”) greater than 10-fold (eg, at least 20-fold, at least 50-fold, or at least 100-fold) of the smaller _{of ED 50} in (preventing recurrence of stimulant addiction). According to such embodiments, some compounds with dual PDE4 / PDE7 inhibitory activity are more than against PDE4 in vivo compared to the PDE4 / PDE7 selectivity of the compound as measured in an in vitro assay. It is measured to have selectivity for large PDE7.

In some embodiments, PDE7 inhibitor is smaller 10-fold greater than the _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity (e.g., at least 20 fold, at least 50 fold, or at least 100 an _{IC 50} for inhibition of times) PDE3 activity and PDE4 activity.

In some embodiments, PDE7 inhibitor is smaller 10-fold greater than the _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity (e.g., at least 20 fold, at least 50 fold, or at least 100 an _{IC 50} for inhibition of times) PDE8 activity.

In some embodiments, PDE7 inhibitor is smaller 10-fold greater than the _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity (e.g., at least 20 fold, at least 50 fold, or at least 100 an _{IC 50} for inhibition of times) PDE4 activity and PDE8 activity. According to this embodiment, it can be seen that the PDE family that specifically / preferentially hydrolyzes cAMP includes PDE4, PDE7 and PDE8.

In some embodiments, PDE7 inhibitor, _{IC 50} and PDE7B 10 times larger than the smaller _{IC 50} for inhibition of the activity PDE1 for inhibition of PDE7A activity, PDE2, PDE3, the PDE4 and PDE8, PDElO and PDE11 an _{IC 50} for inhibition of activity. According to this embodiment, the PDE family that specifically / preferentially hydrolyzes cAMP comprises PDE4, PDE7 and PDE8, and the PDE1, PDE2, PDE3, PDE10 and PDE11 families are relative to both cAMP and cGMP. It can be seen that it exhibits considerable activity.

In some embodiments, PDE inhibitors, smaller _{IC 50} for inhibition _{IC 50} of the PDE7B activity for inhibition of PDE7A activity, any other PDE enzymes from PDE1~6 and PDE8~11 enzyme family less than one-tenth _{an IC 50} that the drug has for inhibition of (e.g., one-twentieth of 1,50 minutes, or 1 to 100 minutes) is a selective PDE7 inhibitor.

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 other PDE family PDE enzymes. .. 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 50} inhibition of PDE7 (i.e., higher sensitivity of PDE7A or PDE7B) each PDE (1 to 6 and 8 to 11) the ratio _{IC 50} of inhibition of isozyme relative to the standard in vitro, in vivo or ex vivo assay (the It can be measured by (such as those described in the specification).

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

Types of PDE7 Inhibitors PDE7 inhibitors can be any type of agent, such as, but not limited to, chemical compounds, proteins or polypeptides, peptide mimetics, nucleic acid molecules, or ribozymes. In some embodiments, PDE7 inhibitors are small molecule inhibitors (including natural and synthetic) with small molecular weights (ie, less than about 450 g / mol), such as peptides, peptidomimetics and non-peptides. Inhibitors (chemical compounds, etc.).

Chemical compound:
PDE7 inhibitors useful in the methods of the invention are administered into the bloodstream by conventional routes (eg, oral, intramuscular, subcutaneous, transdermal, via oral, intravenous, etc.) and ultimately in the vasculature. Drugs that are transported into the brain via the blood-brain barrier and inhibit PDE7 are included. Therefore, for such a method of administration, the PDE7 inhibitor can cross the blood-brain barrier. The following PDE inhibitors capable of crossing the blood-brain barrier (eg, those having a molecular weight of less than about 450 g / mol and being sufficiently lipophilic) are ultimately transported to the brain in the bloodstream. When administered by the route, it is useful for the method of the present invention.

The following is a description of exemplary PDE7 inhibitors useful in the methods of the invention.

In one embodiment, PDE7 inhibitors useful for the methods of the invention are generally or specifically disclosed in EP1454897, WO2003 / 053975, and US20050148604, each of which is expressly incorporated herein by reference in its entirety. It is selected from the compounds selected. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

A represents N or CR _4,
B represents a hydrogen atom or a halogen atom,
R ₁ represents optionally substituted C _3-7 cycloalkyl or tert-butyl.
R ₂ represents hydrogen, methyl, or ethyl,
R ₃ is hydrogen, nitro, cyano or halogen atom, NR ₅ R ₆ , C (= X) R ₇ , SO ₂ NR ₅ R ₆ , OR ₈ , NR ₈ CONR ₅ R ₆ , NR ₈ SO ₂ R ₉ , NR ₈ CO ₂ R ₉ , heteroaryl groups, optionally substituted C _1-3 alkyl, optionally substituted C _{1 to 6} alkenyl, or optionally substituted saturated or unsaturated Represents heterocycloalkyl,
R ₄ represents _{C 1-3} alkoxy substituted with hydrogen, or optionally one or more fluorine atoms.
R ₅ and R ₆ are the same or different, hydrogen atom, optionally substituted C _1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted acyl. Azetidinyl, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino, piperazinyl, or homopiperazinyl (each of which is optionally substituted C _{1-). 4} Alkoxy, OH, C _1-3 alkoxy, CO ₂ H, NR ₅ R ₆ , oxo group, NR ₉ COR ₇ , or optionally substituted with C (= O) R ₇₎ And
R ₇ represents optionally substituted C _1-6 alkyl, OH, OR ₈ , or NR ₅ R ₆ .
R ₈ represents hydrogen, optionally substituted C _1-6 alkyl groups, or optionally substituted heterocycloalkyl.
R ₉ represents an optionally substituted C _1-6 alkyl group.
X represents O, S or NH.

For the above compounds, "optionally substituted" means an optionally substituted linear, branched or cyclic alkyl group (such as methyl, ethyl, propyl or cyclohexyl); hydroxyl group; Cyan group; alkoxy group (such as methoxy or ethoxy); optionally substituted amino group (such as amino, methylamino or dimethylamino); optionally substituted acyl group (such as acetyl or propionyl); carboxyl group Optionally substituted aryl group (such as phenyl or naphthyl); Optionally substituted heteroaryl group (such as pyridinyl, thiazolyl, imidazolyl, or pyrazil); optionally substituted saturated or unsaturated Heterocycloalkyl groups (such as piperazinyl or morphonyl); optionally substituted carbamoyl groups; optionally substituted amide groups; halogen atoms (such as chlorine, fluorine or bromine); nitro groups; optionally substituted Substituent sulfone group; optionally substituted sulfonylamide group; oxo group; urea group; and optionally substituted linear, branched or cyclic alkenyl group (ethenyl, propenyl or cyclo) Hexenil, etc.).

An example of a heteroaryl group as R ³ is a 5- to 7-membered monocyclic compound having 2 to 8 carbon atoms and containing 1 to 4 heteroatoms consisting of an oxygen atom, a nitrogen atom or a sulfur atom. Heteroaryl groups and polycyclic heteroaryl groups containing the same or different two or more such monocyclic compounds condensed with each other are mentioned, and examples of the monocyclic and polycyclic heteroaryl groups are pyrrol. , Frill, thienyl, imidazolyl, thiazolyl, pyridyl, pyrazil, indrill, quinolyl, isoquinolyl, and tetrazolyl.

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

Have.

In some other embodiments, PDE7 inhibitors useful in the methods of the invention are of the formula:

Have.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

In other embodiments, PDE7 inhibitors useful in the methods of the invention are of the formula:

Have.

Preparations of the above compounds are described in EP1454897, WO2003 / 053975, and US20050148604.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are US2002 / 0198198, WO2002 / 076953, WO2002 / 074754, WO2006 / 092691, Bioorganic & Medicinal Chemistry Letters 14 (2004) 4623-4626, and Bioorganic & Medicinal Chemical Letters 14 (2004) 4623-4626. It is selected from the compounds generally or specifically disclosed in Chemistry Letters 14 (2004) 4627-4331, each of which is expressly incorporated herein by reference in its entirety. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

(A) X ₁ , X ₂ , X ₃ and X ₄ are the same or different.
N (provided that _{no more than two of the X 1} , X ₂ , X ₃ and X ₄ groups represent nitrogen atoms at the same time) or CR ₁
In the formula, R ₁ is selected from
Q 1 or lower alkyl, lower alkenyl or lower alkynyl, _(these groups is unsubstituted, or those substituted with one or several Q ₂ 'group);
X _5- R ₅ selected from 5 units, in the formula X ₅ is selected from:
Single bond,
Lower alkylene, lower alkenylene, or lower alkynylene (optionally partitioned by one or two heteroatoms selected from O, S, S (= O), SO _{2 or N, of these groups} The carbon atom was unsubstituted or substituted with one or several identical or different groups selected from _{SR 6} , OR ₆ , NR ₆ R ₇ , = O, = S, or = NR _{6. R 6} and R ₇ are the same or different in the formula and are selected from hydrogen or lower alkyl.
R ₅ is optionally 1, 2 or 3 heteroatoms selected from aryl, heteroaryl, cycloalkyl (C (= O) or O, S, S (= O), SO _{2 or N).} Divided), cycloalkenyl (C (= O) or optionally partitioned by 1, 2 or 3 heteroatoms selected from _{O, S, S (= O), SO 2 or N} ones), or is selected from the bicyclic group, these groups is unsubstituted, or Q _3, 1 or is heteroaryl or lower alkyl optionally substituted with Q ₃ or Substituted with a few groups,
_Here, Q 1, _{Q 2} and _{Q 3} are are the same or different,
Hydrogen, halogen, CN, NO ₂ , SO ₃ H, P (= O) (OH) ₂ , OR ₂ , OC (= O) R ₂ , C (= O) OR ₂ , SR ₂ , S (= O) It is selected from R ₂ , NR ₃ R ₄ , QR ₂ , Q-NR ₃ R ₄ , NR _2- Q-NR ₃ R ₄ , or NR _3- Q-R ₂ , where Q is C (in the formula). = NR), C (= O), C (= S), or SO ₂ , R is selected from hydrogen or lower alkyl, R ₂ , R ₃ and R ₄ are the same or different. ,
Hydrogen, lower alkyl optionally partitioned by C (= O), (CH ₂ ) _n -aryl, (CH ₂ ) _n -heteroaryl, (CH ₂ ) _n -cycloalkyl (C (= O)) , Or optionally divided by one or two heteroatoms selected from O, S, S (= O), SO ₂ or N, where n is 0, 1, (An integer selected from 2, 3 or 4), selected from
These groups are unsubstituted or lower alkyl, halogen, CN, CH ₃ , SO ₃ H, SO ₂ CH ₃ , CF ₃ , C (= O) NHSO ₂ CH ₃ , OR ₆ , COOR ₆ , C (= O) R ₆ , NR ₆ R ₇ , C (= O) NR ₆ R ₇ , or SO ₂ NR ₆ R ₇ substituted with one or several groups selected from the formula. Among them, R ₆ and R ₇ are the same or different and are selected from hydrogen or lower alkyl, which lower alkyl is optional with one or two groups selected from _{OR, COOR or NRR 8.} Substituted with, in the formula, R and R ₈ are hydrogen or lower alkyl,
R ₆ and R ₇ and / or R ₃ and R ₄ may form a 4- to 8-membered heterocycle with the nitrogen atom to which they are attached, the heterocycle being O, S, It may contain one or two heteroatoms selected from S (= O), SO _{2 or N, or may be substituted with:}
A 4- to 8-membered heterocycle, the heterocycle may contain one or two heteroatoms selected from O, S or N, may be substituted with a lower alkyl, or may be substituted.
Lower alkyl, the lower alkyl is optionally substituted with OR', NR'R', C (= O) NR'R' or COOR', and R'and R'are the same in the formula. Or different, selected from H, lower alkyl, the lower alkyl being optionally substituted with OR or COOR, where R is hydrogen or lower alkyl and R'. And R "may form a 4- to 8-membered heterocycle with the nitrogen atom to which they are attached, the heterocycle being one or two selected from O, S or N. It may contain heteroatoms of;
(B) X is O, S or NR ₉ , where in the formula R ₉ is selected from hydrogen, CN, OH, NH ₂ , lower alkyl, lower alkenyl, or lower alkynyl, these groups are non-. Cycloalkyls that are substituted or optionally partitioned by one or two heteroatoms selected from O, S, S (= O), SO _{2 or N, or O, S, S.} (= O), cycloalkenyl optionally partitioned by one or two heteroatoms selected from _{SO 2} or N, or substituted with _{aryl, heteroaryl, OR 10} , or NR ₁₀ R _11. In the formula, R ₁₀ and R ₁₁ are the same or different and are selected from hydrogen or lower alkyl;
(C) Y is selected from O, S or N-R ₁₂ , where in the formula R ₁₂ is selected from hydrogen, CN, OH, NH ₂ , lower alkyl, lower alkenyl, or lower alkynyl, these groups. Is an unsubstituted or cycloalkyl optionally partitioned by one or two heteroatoms selected from O, S, S (= O), SO _{2 or N, or O,} Cycloalkenyl optionally partitioned by one or two heteroatoms selected from S, S (= O), SO _{2 or N, or aryl, heteroaryl, OR 10} , or NR ₁₀ R ₁₁ Substituted with, in the formula, R ₁₀ and R ₁₁ are the same or different and are selected from hydrogen or lower alkyl;
(D) Z is selected from CH-NO ₂ , O, S or NR ₁₃ , where R ₁₃ is hydrogen, CN, OH, NH ₂ , aryl, heteroaryl, or O, S, S ( = O), _{cycloalkyl optionally partitioned by one or several heteroatoms selected from SO 2} or N, or selected from O, S, S (= O), SO ₂ or N Selected from cycloalkenyl optionally partitioned by one or several heteroatoms, or C (= O) R ₁₄ , C (= O) NR ₁₄ R ₁₅ , OR ₁₄ , or lower alkyl. lower alkyl are those unsubstituted or equal to or is selected from _{oR 14} or _NR 14 _{R 15,} or substituted with a different one or several groups, _{R 14} and _{R 15,} Independently selected from hydrogen or lower alkyl, R ₁₄ and R ₁₅ may form a 4- to 8-membered heterocycle with the nitrogen atom to which they are attached, said hetero. The ring can contain one or two heteroatoms selected from O, S or N and may be substituted with a lower alkyl;
(E) Z ₁ is selected from H, CH ₃ , or NR ₁₆ R ₁₇ , where R ₁₆ and R ₁₇ are the same or different in the formula, hydrogen, CN, aryl, heteroaryl, or O. , S, S (= O), SO ₂ or cycloalkyl optionally partitioned by one or several heteroatoms selected from N, or O, S, S (= O), SO ₂ Alternatively, cycloalkenyl optionally partitioned by one or several heteroatoms selected from N, or C (= O) R ₁₄ , C (= O) NR ₁₄ R ₁₅ , OR ₁₄ , or lower. Selected from alkyl, the lower alkyl is either unsubstituted or substituted with one or several groups selected from _{OR 14} or NR ₁₄ R _15.
R ₁₄ and R ₁₅ are selected from hydrogen or lower alkyl, and R ₁₄ and R ₁₅ and / or R ₁₆ and R ₁₇ form a 4- to 8-membered heterocycle with the nitrogen atom to which they are attached. The heterocycle may contain one or two heteroatoms selected from O, S or N and may be substituted with a lower alkyl;
(F) A is

It is a ring selected from
In the formula, A ₁ , A ₂ , A ₃ , A ₄ , A ₅ and A ₆ are the same or different and can be selected from O, S, C, C (= O), SO, SO ₂ or NR _18. In the formula, R ₁₈ is optionally divided by one or several heteroatoms selected from hydrogen, aryl, heteroaryl, or O, S, S (= O), SO _{2 or N.} Cycloalkyl, or cycloalkenyl optionally partitioned by one or several heteroatoms selected from O, S, S (= O), SO _{2 or N, or lower alkyl} The lower alkyl is unsubstituted or optionally selected with one or several heteroatoms selected from aryl, heteroaryl, or O, S, S (= O), SO _{2 or N.} Cycloalkyl, or cycloalkenyl, optionally partitioned by one or several heteroatoms selected from O, S, S (= O), SO _{2 or N, or CN.} , NR ₁₉ R ₂₀ , C (= O) NR ₁₉ R ₂₀ , OR ₁₉ , C (= O) R ₁₉ or C (= O) OR ₁₉ , substituted with R ₁₉ and R _{20 in the equation.} Are the same or different and are selected from hydrogen or lower alkyl;
* Represents a carbon atom shared by the main skeleton ring containing rings A and X and / or Y;
Each carbon atom of ring A is unsubstituted or lower alkyl ( _{arbitrarily substituted with OR 21} , NR ₂₁ R ₂₂ , COOR ₂₁ , or CONR ₂₁ R ₂₂ ), lower haloalkyl, CN, One selected from F, = O, SO ₂ NR ₁₉ R ₂₀ , OR ₁₉ , SR ₁₉ , C (= O) OR ₁₉ , C (= O) NR ₁₉ R ₂₀ , or NR ₁₉ R ₂₀ Alternatively, it is substituted with two groups, in which R ₁₉ and R ₂₀ are the same or different and are selected from hydrogen or lower alkyl, the lower alkyl being OR ₂₁ , NR ₂₁ R _22. , COOR ₂₁ or CONR ₂₁ R ₂₂ optionally substituted, in which 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 with the nitrogen atom to which they are attached;
The two atoms of the non-adjacent ring A can be linked by a chain of 2, 3 or 4 carbon atoms, the chain being one heteroatom selected from O, S or N. However, no more than _{two of the A 1} , A 2, A ₃ , A ₄ , A ₅ and A ₆ groups may represent heteroatoms at the same time; and their tautomers. It is a body form, its racemic form, its isomer, and its pharmaceutically acceptable derivative.

With respect to the above compounds, halogens include fluoro, chloro, bromo, and iodine. Preferred halogens are F and Cl. Examples of the lower alkyl 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 alkenyl includes straight and branched hydrocarbon groups having 2 to 6 carbon atoms and at least one double bond. Examples of such alkenyl groups are ethynyl, 3-butyne-1-yl, 2-ethenylbutyl, and 3-hexene-1-yl. Lower alkynyls include straight and branched hydrocarbon groups having 2 to 6 carbon atoms and at least one triple bond. Examples of such alkynyl groups are ethynyl, 3-butyne-1-yl, propynyl, 2-butyne-1-yl, and 3-pentyne-1-yl. Examples of the lower haloalkyl include the lower alkyls specified above, which are substituted with one or several halogens. An example of haloalkyl is trifluoromethyl. Aryl should be understood as an aromatic carbocycle containing 6 to 10 carbon atoms. An example of an aryl group is phenyl. Examples of the heteroaryl include aromatic rings having 5 to 10 intra-ring atoms, of which 1 to 4 are independently selected from the group consisting of O, S and N. A typical heteroaryl group has one, two, three or four heteroatoms in a 5- or 6-membered aromatic ring. Examples of such groups are tetrazole, pyridyl, and thienyl. A typical cycloalkyl contains 3 to 8 carbon atoms. Examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "divided" means that in the backbone, a carbon atom is replaced with a heteroatom or a group defined herein. For example, in "cycloalkyl or cycloalkenyl arbitrarily partitioned by one heteroatom selected from C (= O) or O, S, S (= O), SO _{2 or N", the term.} "Divided" means that a C (= O) or heteroatom can be present in place of the carbon atom of the ring. Examples of such groups are morpholine or piperazine. Cycloalkenyl includes 3-10 membered cycloalkyls containing at least one double bond. As the heterocycle, the above-mentioned specified heteroaryl and the above-mentioned specified cycloalkyl or cyclo divided by 1, 2 or 3 heteroatoms selected from O, S, S (= O), SO _{2 or N.} Alkenyl can be mentioned. A bicyclic substituent refers to two rings selected from aryl, heterocycle, cycloalkyl or cycloalkenyl that are condensed with each other to form the bicyclic substituent. An example of a bicyclic substituent is indrill.

In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

In other embodiments, PDE7 inhibitors useful in the methods of the invention are of the formula:

Have.

The preparations of the above compounds were made in US 2002/0198198, WO 2002/076953, WO 2002/074754, WO 2006/092691, Bioorganic & Medicinal Chemistry Letters 14 (2004) 4623-4626, and Bioorganic & Medic Have been described.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are EP1193261, WO2002 / 28847, US20030045557, US Pat. No. 7,122,565, Bioorganic & Medicinal Chemistry Letters 14 (2004) 4607-4613, and Bio. & Medical Chemistry Letters 14 (2004) 4615-4621, each of which is selected from the compounds commonly or specifically disclosed in the present specification in its entirety by reference. In one embodiment, PDE7 inhibitors useful for the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

Y is S or O;
R ₁ is a C _{1 to} C ₁₀ alkyl, C _{2 to} C ₁₀ alkenyl, C _{2 to} C ₁₀ alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, or polycyclic group; each is one or more. are optionally substituted by identical or different several _X 1 -R ₄ group, wherein, _{X 1} is a single bond, lower _alkylene, C 2 -C ₆ alkenylene, cycloalkylene, arylene or divalent, a heterocycle, _{R 4} are the following (1) to (3):
(1) H, = O, NO ₂ , CN, halogen, lower haloalkyl, lower alkyl, carboxylic acid bioisostar;
(2) COOR ₅ , C (= O) R ₅ , C (= S) R ₅ , SO ₂ R ₅ , SOR ₅ , SO ₃ R ₅ , SR ₅ , OR ₅ ;
(3) C (= O) NR ₇ R ₈ , C (= S) NR ₇ R ₈ , C (= CH-NO ₂ ) NR ₇ R ₈ , C (= N-CN) NR ₇ R ₈ , C ( = N-SO ₂ NH ₂ ) NR ₇ R ₈ , C (= NR ₇ ) NHR ₈ , C (= NR ₇ ) R ₈ , C (= NR ₉ ) NHR ₈ , C (= NR ₉ ) R ₈ , SO ₂ NR ₇ R ₈ or NR ₇ R ₈ , in the formula, R ₇ and R ₈ are the same or different, OH, R ₅ , R ₆ , C (= O) NR ₅ R ₆ , C (= O) R ₅ , SO ₂ R ₅ , C (= NR ₉ ) NHR ₁₀ , C (= NR ₉ ) R ₁₀ , C (= CH-NO ₂ ) NR ₉ R ₁₀ , C (= N-SO ₂ NH ₂₎ ) NR ₉ R ₁₀ , C (= N-CN) NR ₉ R ₁₀ , or C (= S) NR ₉ R ₁₀ ;
R ₂ is a lower alkyl, C _{2 to} C ₁₀ alkynyl, C _{2 to} C ₁₀ alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl; each is selected from (1) to (3) below. Arbitrarily substituted with one or several groups of the same or different:
(1) H, carboxylic acid bioisostar, lower haloalkyl, halogen,
(2) COOR ₅ , OR ₅ , SO ₂ R ₅ ,
(3) SO ₂ NR ₁₁ R ₁₂ , C (= O) NR ₁₁ R ₁₂ , NR ₁₁ R ₁₂ , in the formula, R ₁₁ and R ₁₂ are the same or different, OH, R ₅ , R ₆ , C (= O) NR ₅ R ₆ , C (= O) R ₅ , SO ₂ R ₅ , C (= S) NR ₉ R ₁₀ , C (= CH-NO ₂ ) NR ₉ R ₁₀ , C (= N) -CN) NR ₉ R ₁₀ , C (= N-SO ₂ NH ₂ ) NR ₉ R ₁₀ , C (= NR ₉ ) NHR ₁₀ , or C (= NR ₉ ) R ₁₀ ;
R _{3 is X} 2 -R _'3, wherein, _{X 2} is a single bond or _C 1 -C _{4 alkylene,} C 2 -C _{6 alkenylene,} is selected from C 2 -C ₆ alkynylene Each group is optionally substituted with one, the same or several different groups selected from (1)-(3) below:
(1) H, C _{1 to} C ₃ alkyl, C _{3 to} C ₄ cycloalkyl, aryl, heterocycle, = O, CN,
(2) OR ₅ , = NR ₅ ; or (3) NR ₁₃ R ₁₄ , in the formula, R ₁₃ and R ₁₄ are the same or different, R ₅ , R ₆ , C (= O) NR ₅ R ₆ , C (= O) R ₅ , SO ₂ R ₅ , C (= S) NR ₉ R ₁₀ , C (= CH-NO ₂ ) NR ₉ R ₁₀ , C (= NR ₉ ) NHR ₁₀ , or C ( = NR ₉ ) Selected from _{R 10;}
R _'3 is cycloalkyl, cycloalkenyl, aryl, and heterocyclic or polycyclic group; each of which is optionally substituted with one or several X ₃ -R ₁₇ group, wherein Among them, X ₃ is a single bond, lower alkylene, C _{2 to} C ₆ alkenylene, C _{2 to} C ₆ alkinylene, cycloalkylene, arylene, divalent heterocyclic or divalent polycyclic group, and R ₁₇ is , The following (1) to (4):
(1) H, = O, NO ₂ , CN, lower haloalkyl, halogen, carboxylic acid bioisostar, cycloalkyl,
(2) COOR ₅ , C (= O) R ₅ , C (= S) R ₅ , SO ₂ R ₅ , SOR ₅ , SO ₃ R ₅ , SR ₅ , OR ₅ ;
(3) C (= O) NR ₁₅ R ₁₆ , C (= S) NR ₁₅ R ₁₆ , C (= N-CN) NR ₁₅ R ₁₆ , C (= N-SO ₂ NH ₂ ) NR ₁₅ R ₁₆ , C (= CH-NO ₂ ) NR ₁₅ R ₁₆ , SO ₂ NR ₁₅ R ₁₆ , C (= NR ₁₅ ) NHR ₁₆ , C (= NR ₁₅ ) R ₁₆ , C (= NR ₉ ) NHR ₁₆ , C (= NR ₉ ) R ₁₆ or NR ₁₅ R ₁₆ , in the formula, R ₁₅ and R ₁₆ are the same or different, OH, R ₅ , R ₆ , C (= O) NR ₅ R ₆ , C (=) O) R ₅ , SO ₂ R ₅ , C (= S) NR ₉ R ₁₀ , C (= CH-NO ₂ ) NR ₉ R ₁₀ , C (= N-CN) NR ₉ R ₁₀ , C (= N-) SO ₂ NH ₂ ) NR ₉ R ₁₀ , C (= NR ₉ ) NHR ₁₀ or C (= NR ₉ ) R ₁₀ selected from,
(4) optionally substituted heterocycle with one or several R ₅ groups;
In the formula, R ₅ and R ₆ are the same or different, H, lower alkyl, C _2- C ₆ alkenyl, C _2- C ₆ alkynyl, X ₄ -cycloalkyl, X ₄ -cycloalkenyl, X ₄ - aryl, _{X 4} - heterocycle or _{X 4} - is selected from polycyclic group, wherein, _{X 4} is a single bond, is a lower alkylene or _C 2 -C ₆ alkenylene; each, halogen, = O , COOR ₂₀ , CN, OR ₂₀ , OR ₂₀ optionally substituted O-lower alkyl, C (= O) -lower alkyl, lower haloalkyl,

(In the formula, X ₅ 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);
Optional with one or several groups selected from X ₆ -heterocycle, X ₆ -aryl, X ₆ -cycloalkyl, X ₆ -cycloalkenyl, or X _{6-polycyclic groups} In the formula, X ₆ is a single bond or lower alkylene, and these groups are selected from halogen, COOR ₂₁ , OR ₂₁ or (CH ₂ ) _n NR ₂₁ R _22. Are optionally substituted with one or several identical or different groups, where n is 0, 1, or 2 and R ₂₁ and R ₂₂ are the same or different. And selected from H or lower alkyl;
R ₉ is H, CN, OH, lower alkyl, O-lower alkyl, aryl, heterocycle, SO ₂ NH ₂ , or

(In the formula, X ₅ 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.

With respect to the above compounds, aryl refers to unsaturated carbon rings containing only carbon atoms in the cyclic structure and having 5 to 10 carbon atoms, and examples thereof include phenyl, naphthyl, and tetrahydronaphthyl. The heterocycle contains 1 to 7 carbon atoms in the cyclic structure and is selected from at least one heteroatom such as nitrogen, oxygen or sulfur, preferably nitrogen, sulfur and oxygen atoms in the cyclic structure. Refers to an unsaturated or saturated monocycle containing 1 to 4 heteroatoms that are the same or different. 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. The polycyclic group comprises at least two identical or different rings selected from aryl, heterocyclic, cycloalkyl, cycloalkenyl groups and condensed with each other to the polycyclic groups (2- and 3-benzothienyl, 2- and 3-benzofuranyl, 2-indrill, 2- and 3-quinolinyl, acridinyl, quinazolinyl, indolylbenzo [1,3] dioxolyl, and 9-thioxanthanyl, etc.) are formed. A bicyclic group is one in which two identical or different rings selected from aryl, heterocyclic, cycloalkyl or cycloalkenyl are fused together to form the bicyclic group. Halogen refers to fluorine, chlorine, bromine, or iodine. Lower alkyl refers to a 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. Alkinyl 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 alkynyl haloalkyl groups include perhaloalkyl groups (such as _{CF 3).} Cycloalkyl refers to a saturated monocyclic carbon ring containing 3 to 10 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkenyl refers to an unsaturated monocyclic carbon ring containing 3 to 10 carbon atoms. Examples of suitable cycloalkenes are 3-cyclohexene and 3-cycloheptene. Carboxylic acid bioisostars have a classical meaning, common carboxylic acid bioisostars are tetrazole-5-yl, C (= O) N (H) OH, isoxasol-3-yl, Hydroxythia zolyl, sulfonamide, sulfonylcarboxamide, phosphonic acid, phosphonamide, phosphinic acid, sulfonic acid, acylsulfonamide, mercaptoazole, acylcyanamide.

In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

In other embodiments, PDE7 inhibitors useful in the methods of the invention are of the formula:

Have.

Preparations of the above compounds were made in EP1193261, WO02 / 28847, US20030045557, US Pat. No. 7,122,565, Bioorganic & Medicinal Chemistry Letters 14 (2004) 4607-4613, and Bioorganic & Medicinal14. 4621.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are generally or specifically in WO2004 / 111054, US20060128728, and US20070270419, each of which is expressly incorporated herein by reference in its entirety. It is selected from the disclosed compounds. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ is a substituted or unsubstituted C _3-8 cycloalkyl group or tert-butyl group;
R ₂ is a hydrogen atom or a C _1-3 alkyl group;
R ₃ is NR ₅ R ₆ , C (= O) R ₇ , or S (O) _0-2 R ₈ units;
R ₄ is a hydrogen atom, or unsubstituted or one or more C _{1 to 3} alkoxy group substituted with a fluorine atom;
R ₅ and R ₆ are the same or different from each other, with hydrogen atoms, substituted or unsubstituted C _1-6 alkyl groups, substituted or unsubstituted acyl groups, substituted or unsubstituted heterocycloalkyl groups, and substitutions. or unsubstituted heterocycloalkyl ring (R ₅ and form together with the nitrogen atom attached to R _6);
R ₇ is OR ₉ or NR ₅ R ₆ units;
R ₈ is a hydrogen atom, a halogen atom, an NR ₅ R ₆ group, a substituted or unsubstituted C _1-6 alkyl group, or a substituted or unsubstituted aryl group;
R ₉ is a hydrogen atom or a substituted or unsubstituted C _1-6 alkyl group;
Alternatively, it is a pharmaceutically acceptable salt or solvate thereof.

With respect to the above compounds, the term "C ₁ -C ₃ alkyl group" includes straight or branched chain alkyl radical having 1-3 carbon atoms. The term "C _{3 to} C ₈ cycloalkyl groups" includes cycloalkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. The term "heterocycloalkyl group" is a 3- to 7-membered heterocyclic group containing the same or different 1 to 4 heteroatoms (oxygen, nitrogen or sulfur atoms), for example pyrrolidinyl, piperidinyl, piperazinyl. , Homopiperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl and azetidinyl. The term "C _{1 to} C ₃ alkoxy group" means an alkoxy group having 1 to 3 carbon atoms. The term "acyl group" means an acyl group having 1 to 8 carbon atoms. The term "aryl group" is a phenyl, naphthyl, biphenyl group having 6-12 carbon atoms and the term "heteroaryl group" is the same or different from 1 to 4 carbon atoms. It is a 5- to 7-membered monocyclic group containing a hetero atom (oxygen, nitrogen, sulfur atom) or a polycyclic group thereof. Examples include pyrrole, frills, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl pyridadinyl and pyrimidinyl. Examples of suitable substituents of the "substituted or unsubstituted C _{1 to} C ₆ alkyl groups" include hydroxyl groups and halogen atoms, and examples of suitable substituents of the "substituted or unsubstituted acyl group" include. Examples include halogen atoms and nitro groups. Further, examples of suitable substituent of "substituted or unsubstituted aryl group", C ₁ -C ₃ alkyl, halogen atom, an amino group, an acyl group, an amide group, a hydroxyl group, an acylamino group, a carboxyl group and sulfonyl The group is mentioned. Examples of suitable substituent of "substituted or unsubstituted C ₃ -C ₈ cycloalkyl group" is a C ₁ -C ₃ alkyl, hydroxyl and oxo group, "substituted or unsubstituted heterocycloalkyl group" Examples of suitable substituents of the above are carboxy group, acyl group, alkoxy group, amino group, alkylamino group, acylamino group, hydroxyl group, oxo group, ethylenedioxy group, methyl group, ethyl group and hydroxyethyl group. Can be mentioned.

In other embodiments, PDE7 inhibitors useful in the methods of the invention are of the formula:

Have.

Preparations of the above compounds are described in WO2004 / 111054, US20060128728, and US20070270419.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are U.S. Pat. No. 6,903,109, US2004082578, WO2003 / 088963, and US20060159499 (each expressly herein in its entirety by reference). It is selected from the compounds generally or specifically disclosed in (Incorporated). In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

(A) R ₁ is selected from the group consisting of the following (i) to (vi):
(I) COR ₅ , in the formula, R ₅ is H, optionally substituted C _1-8 linear or branched alkyl, optionally substituted aryl, and optionally substituted. The substituents on the alkyl, aryl and arylalkyl groups are C _1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkyl, or NR. is selected from the ₂₀ R _{21, wherein, R 20} and _{R 21} are independently _{hydrogen, C 1 to 8} straight or branched chain _{alkyl, C 3 to 7} cycloalkyl, from the group consisting of benzyl or aryl, Selected;
(Ii) COOR ₆ , in the formula, R ₆ is H, optionally substituted C _1-8 linear or branched alkyl, optionally substituted aryl, and optionally substituted. The substituents on the alkyl, aryl and arylalkyl groups are C _1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkyl, or NR. is selected from the ₂₀ R _{21, wherein, R 20} and _{R 21} are independently _{hydrogen, C 1 to 8} straight or branched chain _{alkyl, C 3 to 7} cycloalkyl, from the group consisting of benzyl or aryl, Selected;
(Iii) Cyano;
(Iv) a lactone or lactam formed with _{R 4;}
(V) CONR ₇ R ₈ , in the formula, R ₇ and R ₈ are independently H, C _1-8 linear or branched alkyl, C _3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy. , Aryl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl, and heterocyclyl; the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl, and heterocyclyl groups are: It 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, R ₇ and R ₈ combine with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl group;
(Vi) Carboxylic acid ester or carboxylic acid bioisostar containing optionally substituted heteroaryl groups;
(B) R ₂ is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C _3-7 cycloalkyl, optionally. Selected from the group consisting of selectively substituted heterocyclyls, the heterocyclyls are 1,3-dioxolane or furan, or R ₂ is

Is;
(C) R ₃ is 1 to 4 groups independently selected from the group consisting of the following (i) to (iii):
(I) Hydrogen, halo, C _1-8 linear or branched alkyl, arylalkyl, C _3-7 cycloalkyl, C _1-8 alkoxy, cyano, C _1-4 carboalkoxy, trifluoromethyl, C _{1 ~ 8} Alkoxysulfonyls, halogens, nitros, hydroxys, trifluoromethoxys, C _1-8 carboxylates, aryls, heteroaryls, and heterocyclyls;
(Ii) NR ₁₀ R ₁₁ , in the formula, R ₁₀ and R ₁₁ are independently H, C _1-8 linear or branched chain alkyl, arylalkyl, C _3-7 cycloalkyl, carboxyalkyl, aryl. , Heteroaryl, or heterocyclyl, or R ₁₀ and R ₁₁ form a heterocyclyl or heteroaryl group together with the nitrogen to which they are attached;
(Iii) NR ₁₂ COR ₁₃ , in the formula, R ₁₂ is selected from hydrogen or alkyl, R ₁₃ is hydrogen, alkyl, substituted alkyl, C _1-3 alkoxyls, carboxyalkyl, R ₃₀ R ₃₁ N (CH _2). ) _P , R ₃₀ R ₃₁ NCO (CH ₂ ) _p , aryl, arylalkyl, heteroaryl, or heterocyclyl, or R ₁₂ and R ₁₃ combined with a carbonyl group to form a carbonyl-containing heterocyclyl group. Forming, in the formula, R ₃₀ and R ₃₁ are independently selected from H, OH, alkyl and alkoxy, p is an integer of 1-6, and the alkyl group is carboxyl, alkyl, aryl. , Substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy, or arylalkyl;
(D) R ₄ is (i) hydrogen, (ii) C _1-3 linear or branched alkyl, (iii) benzyl, and (iv) NR ₁₃ R ₁₄ (in the formula, R ₁₃ and R ₁₄ are , Independently selected from hydrogen and C _1-6 alkyl); the C _1-3 alkyl and benzyl groups are C _3-7 cycloalkyl, C _1-8 alkoxy, cyano, Select from C _1-4 carboalkoxy, trifluoromethyl, C _1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C _1-8 carboxylate, amino, NR ₁₃ R ₁₄ , aryl, and heteroaryl It is optionally substituted with one or more groups to be; and (e) X is selected from S and O;
And its pharmaceutically acceptable salts, esters and prodrug forms.

In one alternative embodiment, R ₁ , R ₃ and R ₄ are as described above, R ₂ is NR ₁₅ R ₁₆ , and in the formula, R ₁₅ and R ₁₆ are independently hydrogen. , C _1-8 straight chain or branched chain alkyl, aryl alkyl, C _3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R ₁₅ and R ₁₆ are bound to them. Together with nitrogen, it forms a heterocyclyl or heteroaryl group.

With respect to the above compounds, "alkyl" refers to straight-chain, cyclic and branched-chain alkyls. Alkoxy groups may be optionally substituted with one or more groups, the one or more groups being halogen, OH, CN, mercapto, nitro, amino, C _{1 to} C ₈ alkyl, C ₁ to. C _{8 alkoxyl,} C 1 -C _{8 alkylthio,} C 1 -C ₈ alkyl - amino, di _(C 1 -C ₈ alkyl) amino, (mono -, di -, tri -, and perfluoroalkyl -) haloalkyl, formyl, carboxy , Alkoxycarbonyl, C _{1 to} C ₈ alkyl-CO-O-, C _{1 to} C ₈ alkyl-CO-NH-, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl, aryl (C _{1 to} C ₈ ) Alkoxy, heterocyclyl, and heteroaryl and the like. The term "bioisostar" is defined as "a group or molecule having chemical and physical properties that results in a wide range of similar biological properties"(Burger's Medicinal Chemistry and Drug Discovery, ME Wolff). Hen, 5th Edition, Volume 1, 1995, p. 785). The term "acyl", as used herein, whether used alone or as part of a group of substituents, is derived from 2 to 6 carbon atoms derived by removing a hydroxyl group from an organic acid. Means an organic group (branched chain or straight chain) having. "Aryl" or "Ar" is a carbocyclic aromatic group, whether used alone or as part of a group of substituents, including, but not limited to, phenyl, 1- or 2-naphthyl, and the like. Be done. Carbocyclic aromatic groups, by 1-5 independent replacement of a hydrogen atom on said halogen, OH, CN, mercapto, nitro, _amino, C 1 -C _{8 alkyl,} C 1 -C ₈ Alkoxyl, C _{1 to} C ₈ alkylthio, C _{1 to} C ₈ alkyl-amino, di (C _{1 to} C ₈ alkyl) amino, (mono-, di-, tri-, and per-) haloalkyl, formyl, carboxy, alkoxy It may be substituted with carbonyl, C _{1 to} C ₈ alkyl-CO-O-, C _{1 to} C ₈ alkyl-CO-NH-, or carboxamide. Examples of aryl groups include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl. , Methoxyethyl phenyl, acetamide phenyl, trill, xylyl, dimethylcarbamylphenyl and the like. The term "heteroaryl" is a cyclic fully unsaturated group with 5-10 intracyclic atoms, one of which is selected from S, O and N; within 0-2 rings. An additional heteroatom in which the atom is independently selected from S, O and N; the remaining intraring atom is carbon. The group may be linked to the rest of the molecule via any intracyclical atom. The terms "heterocycle", "heterocyclic" and "heterocycle" are optionally substituted fully or partially saturated cyclic groups such as 4- to 7-membered monocyclic, 7 to 11-membered. A bicyclic or 10-15 membered tricyclic ring system having at least one heteroatom in a ring containing at least one carbon atom. Each ring of the heterocyclic group containing a heteroatom can have one, two or three heteroatoms selected from nitrogen, oxygen and sulfur atoms, and the nitrogen and sulfur heteroatoms are It may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocyclic group may be bonded at any heteroatom or carbon atom.

In other embodiments, PDE7 inhibitors useful in the methods of the invention are of the formula:

Have.

Preparations of the above compounds are described in US Pat. No. 6,903,109, US2004082578, WO2003 / 088963, and US20060159499.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are US Pat. No. 6,958,328, WO2002 / 085894, and US20030212089, each of which is expressly incorporated herein by reference in its entirety. ) Is selected from the compounds generally or specifically disclosed. These PDE7 inhibitors, except that _{R 1} is not a carboxylic acid ester or carboxylic acid bioisostere has the same formula as those described above (e.g., U.S. Pat. No. 6,903,109). The preparation of such compounds is described in US Pat. No. 6,958,328, US20030212089, and WO2002 / 085894.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are generally or specifically disclosed in WO2006 / 00440 and EP1775298, each of which is expressly incorporated herein by reference in its entirety. It is selected from compounds. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ is a substituted or unsubstituted C _3-8 alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group (eg, cyclohexyl, cycloheptyl, or tetrahydropyranyl). ;
R ₂ is a hydrogen atom or a substituted or unsubstituted C _1-3 alkyl group (eg, methyl);
R ₃ is a hydrogen atom, a substituted or unsubstituted C _1-3 alkyl group, or a halogen atom; and R ₄ is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or CONR ₅ R ₆ or CO ₂ R ₇ units,
In the formula, R ₅ and R ₆ are the same or different from each other and are hydrogen atom; C _1-6 alkyl group optionally substituted with halogen atom, substituted or unsubstituted aryl group, substituted or unsubstituted hetero. Aryl groups, substituted or unsubstituted heterocycloalkyl groups, substituted or unsubstituted cycloalkyl groups, NR ₇ COR ₈ , COR ₈ , NR ₉ R ₁₀ groups; substituted or unsubstituted cycloalkyl groups; substituted or unsubstituted cycloalkyl groups heterocycloalkyl group; a substituted or unsubstituted aryl group; a substituted or unsubstituted heteroaryl group; or ring, R ₅ and substituted or unsubstituted with R ₆ and is formed with a nitrogen atom linked Substituted heterocycloalkyl group;
In the formula, R ₇ is a hydrogen atom or a substituted or unsubstituted C _1-3 alkyl group;
In the formula, R ₈ is a substituted or unsubstituted heterocycloalkyl group, or OH group, OR ₇ , or NR ₉ R ₁₀ ;
In the formula, R ₉ and R ₁₀ are the same or different from each other and are hydrogen atoms; substituted or unsubstituted C _1-3 alkyl groups, substituted or unsubstituted heterocycloalkyl groups; substituted or unsubstituted acyls; SO ₂ R ₇ groups, or rings, are substituted or unsubstituted heterocycloalkyl groups formed with a nitrogen atom bonding _{R 5} and R _6;
Alternatively, it is a pharmaceutically acceptable salt or solvate thereof.

With respect to the above compounds, the term "cycloalkyl group" means a cycloalkyl group having 3-8 carbon atoms. The term "heterocycloalkyl group" can be a 3- to 7-membered monocyclic or polycyclic heterocyclic group containing the same or different 1 to 4 heteroatoms (oxygen, nitrogen or sulfur atoms). Examples include piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, azetidinyl, imidazolidinyl, oxazolidinyl, hexahydropyrrolidinyl, octahydroindridinyl, octahydroquinolidinyl, octahydroindrill and theirs. Oxo derivatives can be mentioned. The term "aryl group" is derived from a single benzene ring, or an aromatic hydrocarbon group consisting of a bonded or condensed benzene ring (eg, phenyl, naphthyl, biphenyl, etc.); and a benzene ring fused to a cycloalkyl or heterocycle. Can be a bicyclic or tricyclic group (eg, 1,2,3,4-tetrahydronaphthalene, 2,3-dihydroindene, indolin, kumaron, etc.). The term "heteroaryl group" is a 5- to 7-membered monocyclic or polycyclic heteroaryl group with 2 to 8 carbon atoms and 1 to 4 heteroatoms (oxygen, nitrogen, The polycyclic heteroaryl group may have a sulfur atom), the polycyclic heteroaryl group may have a fused ring system with the same or different monocyclic heteroaryl or benzene rings, or the polycyclic group may be cycloalkyl or It consists of a heteroaryl group fused with a heterocycloalkyl ring. Examples of suitable substituents of the present invention, straight-chain, branched or cyclic C ₁ -C ₈ alkyl group (which may comprise one or more methyl, ethyl, propyl, isopropyl, n- butyl, t- butyl, cyclohexyl, cycloheptyl, methoxymethyl, hydroxymethyl, trifluoromethyl, C ₁ -C ₃ alkoxy group, may be substituted with a halogen atom, and a hydroxyl group); a hydroxyl group; a cyano group; a substituted or unsubstituted alkoxy groups (methoxy, an ethoxy group); an amino group (which may, C ₁ -C ₆ alkyl group or an acyl group (amino, methylamino, ethylamino, dimethylamino, may be substituted by acylamino, etc.)); carboxylic Acid group; substituted or unsubstituted ester group; phosphate group; sulfonic acid group; substituted or unsubstituted aryl group; substituted or unsubstituted heteroaryl group; saturated or unsaturated heterocycloalkyl group (even if substituted) Good); substituted or unsubstituted carbamoyl group; substituted or unsubstituted amide group; substituted or unsubstituted thioamide group; halogen atom; nitro group; substituted or unsubstituted sulfone group; substituted or unsubstituted sulfonylamide group; Oxo groups; substituted or unsubstituted urea groups; linear, branched or cyclic alkenyl groups (ethenyl, propenyl, cyclohexenyl, etc.) and the like can be mentioned.

In other embodiments, PDE7 inhibitors useful in the methods of the invention are of the formula:

Have.

Preparations of the above compounds are described in EP1775298 and WO2006 / 00440.

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

Have.

Substituents for the above compounds are defined as follows.

A is N or CR ₄ ;
B is N or CH;
R ₁ is a substituted or unsubstituted C _3-8 cycloalkyl group or tert-butyl group;
R ₂ is a hydrogen atom or a C _1-6 alkyl group;
R ₃ 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; a substituted or unsubstituted C _2-6 alkenyl group; a substituted or unsubstituted saturated Alternatively, unsaturated heterocycloalkyl groups; NR ₅ R ₆ , C (O) R ₇ , SO ₂ R ₇ , OR ₈ , NR ₈ COR ₇ , NR ₈ SO ₂ R ₇ groups;
R ₄ is a hydrogen atom, or unsubstituted or one or more C _{1 to 3} alkoxy group substituted with a fluorine atom;
R ₅ and R ₆ are the same or different from each other and are hydrogen atoms; substituted or unsubstituted C _1-6 alkyl groups; substituted or unsubstituted acyl groups; or substituted or unsubstituted heterocycloalkyl groups. ;
R ₇ is a hydrogen atom; a substituted or unsubstituted C _1-6 alkyl group; a substituted or unsubstituted heterocycloalkyl group; OH; OR ₈ or NR ₅ R ₆ ;
R ₈ is a hydrogen atom, a substituted or unsubstituted C _1-6 alkyl group; or a substituted or unsubstituted heterocycloalkyl group;
Alternatively, it is a pharmaceutically acceptable salt or solvate thereof.

With respect to the above compounds, the term "C _1- C ₆ alkyl group" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, and the term "C _{2 to} C ₆ alkenyl group" is used. A straight or branched 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" is a 3- to 7-membered heterocyclic group containing the same or different 1 to 4 heteroatoms (oxygen, nitrogen or sulfur atoms), for example piperidinyl, pyrrolidinyl, piperazinyl. , Tetrahydrofuryl, tetrahydropyranyl, morpholinyl, azetidinyl, and homopiperazinyl. The term "heteroaryl group" is a 5- to 7-membered monocyclic or polycyclic containing 2 to 8 carbon atoms and the same or different 1 to 4 heteroatoms (oxygen, nitrogen or sulfur atoms). It is the basis of the formula. Examples include pyrrole, frills, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl, pyridadinyl, and pyrimidinyl. Examples of the "halogen atom" include fluorine, chlorine, bromine and iodine. "Substituted or unsubstituted C _{1 to} C ₆ alkyl groups", "substituted or unsubstituted C _{3 to} C ₈ cycloalkyl groups", "substituted or unsubstituted alkenyl groups", "substituted or unsubstituted heterocycloalkyl groups" Examples of suitable substituents for "groups" and "substituted or unsubstituted acyl groups" are linear or branched or substituted or unsubstituted alkyl groups (methyl, ethyl, propyl, isopropyl, n-butyl). , Tart-butyl, etc.), Substituent or unsubstituted cycloalkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl); hydroxyl groups; cyano groups; alkoxy groups (such as methoxy and ethoxy); 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 group; substituted or unsubstituted carbamoyl group; substituted or unsubstituted amide group; halogen atom; nitro group; substituted or unsubstituted sulfone group; oxo group; urea group Included substituted or unsubstituted linear or branched or cyclic alkenyl groups (such as ethenyl, propenyl, and cyclohexenyl).

In other embodiments, PDE7 inhibitors useful in the methods of the invention are of the formula:

Have.

Preparations of the above compounds are described in US 20060128707 and WO 2004/111053.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are U.S. Pat. Nos. 6,617,357, US20020156064, and Molecular Pharmacology, 66: 1679-1689, 2004, all of which are specified by reference in their entirety. Of the compounds generally or specifically disclosed in (incorporated herein). In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ is NR _a R _b , in which _Ra and R _b are independently H or C _1-6 alkyl, or are selected from carbon or carbon and O, N or S. Represents a 5-7 membered ring composed of one or more additional heteroatoms;
R ₂ 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, the Ar being a substituted or unsubstituted phenyl;
R ₃ is NO ₂ , halo, CN, C (O) OR ₇ , COR ₁ , or NR _a R _b , where R _a and R _b are independently H or C _1-6 alkyl. be;
R ₄ is H, OC _1-6 alkyl, halo, C (O) NR _a R _b , C (O) OR ₇ , C _1-8 alkyl, OCHF ₂ , CH ₂ OR ₈ , OC _1-3 alkyl- Ar, or CH ₂ NHC (O) CH ₃ ;
R ₅ is a H, halo or alkyl;
R ₆ is C _1-8 alkyl, OC _1-4 alkyl, or halo;
R ₇ is a hydrogen or ester or amide forming group;
R ₈ is hydrogen or C _1-6 alkyl;
Alternatively, it is a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Preparations of the above compounds are described in US Pat. No. 6,617,357, US20020156064, and Molecular Pharmacology, 66: 1679-1689, 2004.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are U.S. Pat. No. 6,852,720, EP1348433, and WO2003 / 082277, each of which is expressly incorporated herein by reference in its entirety. ) Is selected from the compounds generally or specifically disclosed. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ is a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and these groups are independent of each other, halogen, trifluoromethyl, nitro, cyano, oxo, NR ₄ R ₅ , One of the same or different selected from CO ₂ R ₄ , CONR ₄ R ₅ , OR ₄ , S (O) _n R ₄ , S (O) _n NR ₄ R ₅ , tetrazolyl and (C _1- C _{6) alkyl} Arbitrarily substituted with the above groups, the (C _1- C ₆ ) alkyls are the same or different _{, independently selected from OR 4} , NR ₄ R ₅ and CO ₂ R _4. It is optionally substituted with 1 to 3 groups; in the formula, n is an integer from 0 to 2 (including both ends), and R ₄ and R ₅ are the same or different. , independently of one another, a group of a hydrogen atom or the formula _X 1 -R _a, wherein, _{X 1} is a single bond or a _(C 1 _{~C 6)} alkylene group, _{R a} is _(C 1 ~ C ₆ ) A group selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
R ₂ is a group selected from (C _{1-2 to} C ₆ ) alkyl, (C _{2 to} C ₆ ) alkenyl, (C _{2 to} C ₆ ) alkynyl, aryl, and cycloalkyl.
R ₃ is a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups are independently from each other, halogen, nitro, cyano, trifluoromethyl, oxo, (C ₁ -C ₆ ) Alkyl, OR ₆ , NR ₆ R ₇ , COR ₆ , CO ₂ R ₆ , CONHOH, CONR ₆ R ₇ , S (O) _m R ₆ , S (O) _m NR ₆ R ₇ , NR ₆ COR ₇ , NR ₆ SO ₂ R ₇ , N (SO ₂ R ₇ ) ₂ , NR ₆ CONR ₇ R ₈ , C (= NCN) NR ₆ R ₇ , NR ₈ C (= NCN) NR ₆ R ₇ , and tetrazolyl ((C)) _{1 to} C ₄ ) One or more groups of the same or different selected from (optionally substituted with alkyl), optionally substituted, where m is 0 to 2 (both ends). R ₆ and R ₇ are the same or different, independent of each other, a hydrogen atom or a group of _{formula X 2} R _{b , where X 2} is a single bond or (C _{1 to} C ₆ ) alkylene groups, R _b are (C _{1 to} C ₆ ) alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl (these groups are independent of each other, hydroxy, (C 1 to C 6). C _{1 to} C ₆ ) alkoxy, (C _{1 to} C ₆ ) alkyl, amino, mono (C _{1 to} C ₆ ) alkyl amino, di (C _{1 to} C ₆ ) alkyl amino (each alkyl amino is the same or is or independently are different from each other), carboxy, selected from (C 1 _{-C 6)} alkoxycarbonyl, and in which is optionally substituted by the same or different 1 to 3 groups selected from benzyl) is a group, _{R 8} represents a hydrogen atom or a _(C 1 _{~C 6)} alkyl group;
Its racemic form, its isomers, its N-oxides, or its pharmaceutically acceptable acid salts or base salts.

Preparations of the above compounds are described in US Pat. No. 6,852,720, EP1348433, and WO2003 / 082277.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are U.S. Pat. No. 6,753,340, US20030191167, EP1348701, and WO2003 / 082839 (each expressly herein in its entirety by reference). It is selected from the compounds generally or specifically disclosed in (Incorporated). In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R _1a is _hydrogen, a group selected from _(C 1 _{~C 6)} alkyl and aryl _(C 1 _{~C 6)} alkyl,
R _1b is a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and these groups are independent of each other, halogen, trifluoromethyl, nitro, cyano, oxo, NR ₄ R ₅ , Same or different 1 selected from CO ₂ R ₄ , CONR ₄ R ₅ , OR ₄ , S (O) _n R ₄ , S (O) _n NR ₄ R ₅ , tetrazolyl, and (C _1- C _{6) alkyl} Arbitrarily substituted with one or more groups, the (C _1- C ₆ ) alkyls are the same or selected from _{OR 4} , NR ₄ R ₅ and CO ₂ R ₄ independently of each other. It is optionally substituted with 1 to 3 different groups, where n is an integer from 0 to 2 (including both ends) and R ₄ and R ₅ are the same or different. cage, independently of one another, a group of a hydrogen atom or the formula _X 1 -R _a, wherein, _{X 1} is a single bond or a _(C 1 _{~C 6)} alkylene group, _{R a} is _{(C 1} ~ C ₆ ) A group selected from alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
R ₂ is a group selected from (C _{1-2 to} C ₆ ) alkyl, (C _{2 to} C ₆ ) alkenyl, (C _{2 to} C ₆ ) alkynyl, aryl and cycloalkyl.
R ₃ is a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, these groups are independently from each other, halogen, nitro, cyano, trifluoromethyl, oxo, (C ₁ -C ₆ ) Alkyl, OR ₆ , NR ₆ R ₇ , COR ₆ , CO ₂ R ₆ , CONHOH, CONR ₆ R ₇ , S (O) _m R ₆ , S (O) _m NR ₆ R ₇ , NR ₆ COR ₇ , NR ₆ SO ₂ R ₇ , N (SO ₂ R ₇ ) ₂ , NR ₆ CONR ₇ R ₈ , C (= N-CN) NR ₆ R ₇ , NR ₈ C (= N-CN) NR ₆ R ₇ , and tetrazolyl are those which are optionally substituted by the same or different one or more groups selected from ((C 1 _{-C 4)} optionally substituted as alkyl), wherein, m is 0-2 is an integer of (inclusive), _{R 6} and _{R 7} are the same or different, independently of one another, a group of a hydrogen atom or the formula _X 2 -R _b, wherein, X ₂ is a single bond or (C _{1 to} C ₆ ) alkylene group, and R _b is (C _{1 to} C ₆ ) alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl (these groups are independent of each other). Then, hydroxy, (C _{1 to} C ₆ ) alkoxy, (C _{1 to} C ₆ ) alkyl, amino, mono (C _{1 to} C ₆ ) alkyl amino, di (C _{1 to} C ₆ ) alkyl amino (each alkyl amino). are different from each other identical or independently), carboxy, it is optionally substituted by the same or different 1 to 3 groups selected from (C 1 _{-C 6)} alkoxycarbonyl, and benzyl a group selected from the a) one, R ₈ is hydrogen atom or (C 1 _{-C 6)} alkyl group, or a racemic forms, isomers thereof, the N- oxide or a pharmaceutically acceptable The acid salt or base salt that can be used.

Preparations for such compounds are described in US Pat. No. 6,753,340, US20030191167, EP1348701, and WO2003 / 082839.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are U.S. Pat. Nos. 6,849,638, US2003011982, and WO2002 / 088138, each of which is expressly incorporated herein by reference in its entirety. ) Is selected from the compounds generally or specifically disclosed. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ and R ₂ are independently hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, and 3 to 7 carbon atoms. Cycloalkyl, selected from the group consisting of 2-6 carbon atoms and a fully saturated heterocycle of 1-2 heteroatoms selected from NH, S and O, and aryl of 6-12 carbon atoms. These are alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, halogen, 1 to 6 Heteroatoms of carbon atoms and heteroatoms up to the perhalo level, haloalkoxy of 1-6 carbon atoms and halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms or 4-11 carbon atoms Replaced with 1 or 2 heteroatom heteroaryls selected from N, S and O, 4 to 11 carbon atoms and 1-2 heteroatom heteroaryls selected from N, S and O 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 with 1 to 6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy with 1 to 6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl or 4 with 6 to 12 carbon atoms It may be replaced with ~ 11 carbon atoms and a heteroaryl of 1-2 heteroatoms selected from N, S and O, with R _4- R ₅ or R ₁ and R ₂ bonded together. They form a 5- to 7-membered saturated ring with the attached nitrogen atom, which is one or two additional _{rings selected from the group consisting of NH, NR 8, S and O.} It may contain heteroatoms, or R _4- R ₅ or R ₁ and R ₂ are attached to form a 5- to 7-membered unsaturated ring with the attached nitrogen atom. The unsaturated ring may contain one or two additional heteroatoms selected from the group consisting of N, S and O.
The saturated or unsaturated ring is 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. , 2-6 carbon atoms and a fully saturated heterocycle of 1-2 heteroatoms selected from NH, S and O, halogens, 1-2 carbon atoms and haloalkyl of a number of halogen atoms up to the perhalo level , 1 to 6 carbon atom alkoxy, 1 to 6 carbon atom and haloalkoxy of halogen atoms up to the perhalo level, and 1 to 2 substituents selected from the group consisting of _{R 9-} R _10. Alternatively; R ₁ and R ₂ are bonded to form an 8- to 10-membered bicyclic saturated ring with the bonded nitrogen atom;
R ₃ is selected from the group consisting of NH, S, S (= O) _{2 and O;}
R ₄ is 1-8 alkyl carbon atoms, 2-8 alkenyl carbon atoms, 2 to 8 carbon atoms alkynyl, C (= C), S (= O) 2, and C ( = O) Selected from O;
R ₅ is 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, 6 to Selected from 12 carbon atom aryls, these are 1-6 carbon atom alkyl, 2-6 carbon atom alkenyl, 2-6 carbon atom alkynyl, 1-6 carbon Atomic alkoxy, halogen, haloalkyl of 1 to 6 carbon atoms and number of halogen atoms up to perhalo level, haloalkyl of 1 to 6 carbon atoms and number of halogen atoms up to perhalo level, 6 to 12 carbon atoms Heteroaryl and 1 to 2 heteroatoms selected from 4 to 11 carbon atoms and N, S and O Heteroaryl and 1 to 2 selected from 4 to 11 carbon atoms and N, S and O It may be substituted with a heteroaryl of 1 heteroatom, the substituents being an alkyl of 1 to 6 carbon atoms, an alkenyl of 2 to 6 carbon atoms, an alkynyl of 2 to 6 carbon atoms, 1 ~ 6 carbon atoms alkoxy, halogen, 1-6 carbon atoms and a number of halogen atoms haloalkyl up to the perhalo level, 1-6 carbon atoms and a number of halogen atoms haloalkoxy up to the perhalo level, 6 ~ 12 carbon atom aryl and 4-11 carbon atom and 1-2 heteroatom heteroaryl selected from N, S and O, 3-7 carbon atom cycloalkyl, 2-6 It may be replaced with a fully saturated heterocycle of 1 or 2 heteroatoms selected from 1 carbon atom and NH, S and O, as well as NR ₆ R _7.
R ₆ and R ₇ 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 ₆ and R ₇ are bonded to form a 5- to 7-membered unsaturated ring with the attached nitrogen atom, which is selected from N, S and O. It may contain one or two additional heteroatoms, or R ₆ and R ₇ are attached to form a 5- to 7-membered saturated ring, which is NH. , S and O may contain one or two additional heteroatoms selected from;
R ₈ is an alkyl of 1 to 8 carbon atoms, an alkenyl of 2 to 8 carbon atoms, an alkynyl of 2 to 8 carbon atoms, an R _11- R ₁₂ , a cycloalkyl of 3 to 7 carbon atoms. , 2-6 carbon atoms and a fully saturated heterocycle of 1-2 heteroatoms selected from NH, S and O, selected from 6-12 carbon atoms aryl, these are 1-6 Alkyl of 1 carbon atom, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, 1 to 6 carbon atoms and up to perhalo level From a number of halogen atoms haloalkyl, 1 to 6 carbon atoms and a number of halogen atoms haloalkoxy up to the perhalo level, 6 to 12 carbon atom aryls or 4 to 11 carbon atoms and N, S and O Heteroaryl of 1-2 heteroatoms selected may be substituted with 4-11 carbon atoms and heteroaryl of 1-2 heteroatoms selected from N, S and O, said substitution. The groups are alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, halogen, and 1 to 6 carbon atoms. With carbon atoms and haloalkyl of halogen atoms up to the perhalo level, haloalkoxy of 1 to 6 carbon atoms and halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms or 4-11 carbon atoms It may be replaced with a heteroaryl of one or two heteroatoms selected from N, S and O;
R ₉ is selected from 1 to 8 carbon atom alkyl, 2 to 8 carbon atom alkenyl, and 2 to 8 carbon atom alkynyl.
R ₁₀ is selected from OH, an aryl of 6 to 12 carbon atoms, which are alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, of 2 to 6 carbon atoms. Alkinyl, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and number of halogen atoms up to perhalo level, haloalkoxy of 1 to 6 carbon atoms and number of halogen atoms up to perhalo level , 6-12 carbon atoms aryl or 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and 4-11 carbon atoms and N, They may be substituted with 1 to 2 heteroatom heteroaryls selected from S and O, which are 1 to 6 carbon atom alkyls, 2 to 6 carbon atom alkenyls, 2 to 6 carbon atoms. Alkinyl of 1 carbon atom, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and number of halogen atoms up to perhalo level, number of 1 to 6 carbon atoms and number of perhalo level It may be replaced with haloalkoxy, a halogen atom, aryl of 6-12 carbon atoms or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O;
R ₁₁ is selected from 1 to 8 carbon atom alkyl, 2 to 8 carbon atom alkenyl, and 2 to 8 carbon atom alkynyl; and R ₁₂ is 3 to 7 carbon atoms. Selected from atomic cycloalkyl, fully saturated heterocycles of 2 to 6 carbon atoms and 1-2 heteroatoms selected from NH, S and O, aryls of 6 to 12 carbon atoms, these are , 1 to 6 carbon atom alkyl, 2 to 6 carbon atom alkenyl, 2 to 6 carbon atom alkynyl, 1 to 6 carbon atom alkoxy, halogen, 1 to 6 carbon atom And haloalkyl of a number of halogen atoms up to the perhalo level, haloalkoxy of 1 to 6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms or 4-11 carbon atoms and N, Replaced with 1-2 heteroatoms selected from S and O, and 4 to 11 carbon atoms and 1-2 heteroatoms selected from N, S and O. 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, etc. Haloalkyl with 1 to 6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy with 1 to 6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl with 6 to 12 carbon atoms or 4 to 11 It may be replaced with a carbon atom and a heteroaryl of 1-2 heteroatoms selected from N, S and O;
And its pharmaceutically acceptable salt.

Preparations of such compounds are described in US Pat. No. 6,849,638, US2003011982, and WO2002 / 088138.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are generally or specifically disclosed in US2000222138 and WO2003 / 064389, each of which is expressly incorporated herein by reference in its entirety. It is selected from compounds. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ and R ₂ are independently (1) hydrogen atoms or (2) C _1-8 alkyls, or R ₁ and R ₂ are combined with the carbon atom to which they are attached. Cyc1 may be formed
In the formula, R ₁ and R ₂ cannot be hydrogen atoms at the same time;
Z is (1) CR ₃ R ₄ , (2) O, (3) S, or (4) binding;
R ₃ and R ₄ are independently either (1) hydrogen atom, (2) C _1-8 alkyl, (3) C _1-8 alkoxy, or (4) hydroxy, or R ₃ and R. ₄ may form Cyc1 or C (O) together with the carbon atoms to which they are attached;
R ₅ and R ₆ are independently (1) hydrogen atoms or (2) C _1-8 alkyls, or R ₅ and R ₆ are combined with the carbon atom to which they are attached. May form Cyc1;
Cyc1 is represented by _{R 1} and _R 2, _{R 3} and _R 4, _{R 5} and _{R 6,} each independently selected from _{(1) C 3 to 10} cycloalkyl, or (2), oxygen, nitrogen and sulfur a monocyclic heterocycle having 3 to 10-membered containing 1-2 heteroatoms, Cyc1 may be substituted with _{R 10;}
R ₁₀ is (1) C _1-8 alkyl, (2) C _1-8 alkoxy, (3) hydroxy, (4) COOR ₁₁ , (5) oxo, (6) SO ₂ R ₁₂ or (7). COR ₁₃ ;
R ₁₁ is a hydrogen atom or C _1-8 alkyl;
R ₁₂ and R _{13 are phenyls} that may be substituted with (1) C 1-8 alkyl or (2) C _{1-8 alkyl;}
R ₇ and R ₈ are independently (1) hydrogen atom, (2) C _1-8 alkyl, (3) C _1-8 alkoxy, (4) hydroxy, (5) cyano, (6) halogen. Atoms, (7) COOR ₁₄ , (8) CONR ₁₅ R ₁₆ , (9) Cyc2, (10) C _2-8 alkoxy, (11) C _2-8 alkoxyl, (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 _{C 1-8} alkyl substituted with _{NR 53-} Cyc2, ( 17) NR ₅₄ COR ₅₅ , (18) NR ₅₆ SO ₂ R ₅₇ , (19) SO ₂ NR ₅₈ R ₅₉ , (20) _{C 2-8} alkoxy substituted with _{COOR 14} , (21) CH = N-OH _{, (22) C} 1~8 alkylene _-NR 60 - _{(C 1~8 alkylene) -R 61, (23) C} 1~8 _alkylthio, (24) _C 1~ substituted with 1 to 3 halogen atoms ₈ alkyl, (25) C _1-8 alkoxy substituted with 1-3 halogen atoms, (26) C _1-8 alkoxy substituted with Cyc2, (27) O-Cyc2, (28) OSO ₂ R ₆₅ , or (29) CH = N-OR ₁₃₇ ;
R ₁₄ is a hydrogen atom or C _1-8 alkyl;
R ₁₅ and R ₁₆ are each independently a hydrogen atom or C _1-8 alkyl;
R ₅₁ and R ₅₂ , R ₅₈ and R ₅₉ are independently hydrogen atoms or C _1-8 alkyl;
R ₅₃ , R ₅₄ , R ₅₆ and R ₆₀ are each independently a hydrogen atom or C _1-8 alkyl;
R ₅₅ is a hydrogen atom, C _1-8 alkyl or C _1-8 alkoxy;
R ₅₇ is C _1-8 alkyl;
R ₆₁ is NR ₆₂ R ₆₃ or hydroxy;
R ₆₂ and R ₆₃ are independently hydrogen atoms or C _1-8 alkyl;
R ₆₅ is C _1-8 alkyl;
R ₁₃₇ is C _1-8 alkyl;

(Hereinafter abbreviated as a ring in the present specification) is Cyc2 in which the group bonded to the carbonyl is carbon;
Cyc2, represented by R _{7, R 8} and ring are each independently, _{(1) C 3 to 15} monocyclic, bicyclic or tricyclic (fused or spiro) carbocyclic ring or (2) A 3- to 15-membered monocyclic, bicyclic or tricyclic (condensed or spiro) heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur;
Cyc2 may be replaced with 1 to 5 R _17s or R _17';
R ₁₇ is, ₍₁₎ C _{1 ~ 8} alkyl, _{(2) C 2 to 8} alkenyl, _{(3) C 2 to 8} alkynyl, _{(4) C 1 to 8} alkoxy, _{(5) C 1 to 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, it may be substituted with 1-5 _{R 20, (15) C 1~8 alkyl, C 2 to 8 alkenyl, C 1 to 8} alkoxy or _{C 1 to 8} alkylthio, these, 1 May be replaced with ~ 5 R _21s , (16) OCOR ₂₂ , (17) CONR ₂₃ R ₂₄ , (18) SO ₂ NR ₂₅ R ₂₆ (19) COOR ₂₇ , (20) COCOOR ₂₈ , (21) _{) COR 29, (22) COCOR} 30, (23) NR 31 COR 32, is _{(24) SO2R 33, (25} ) NR 34 SO 2 R 35 or (26) _{SOR 64,;}
R ₁₈ and R ₁₉ , R ₃₁ and R ₃₄ are each independently a hydrogen atom or C _1-8 alkyl;
R ₂₀ and R ₂₁ are C _1-8 alkyl, C _1-8 alkoxy, hydroxy, halogen atoms, nitro, or COOR ₃₆ ;
R ₂₂ and R ₆₄ are each independently C _1-8 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 are (1) C _1-8 alkyl, (2) C _2-8 alkenyl, and (3) 1-5 R _37. in substituted _{C 1 to 8} alkyl, (4) diphenylmethyl, (5) triphenylmethyl, (6) Cyc3, (7 ) C 1~8 substituted with CYC3 alkyl or _{C 2 to 8} alkenyl, (8 ) is O-Cyc3, S-Cyc3 or _{C 1 to 8} alkyl substituted with _SO 2 -Cyc3;
R ₃₆ is a hydrogen atom or C _1-8 alkyl;
R ₃₇ is C _1-8 alkoxy, C _1-8 alkylthio, benzyloxy, halogen atom, nitro or COOR ₃₈ ;
R ₃₈ is a hydrogen atom, C _1-8 alkyl or C _2-8 alkenyl;
Cyc3 is composed of (1) C _3-15 monocyclic, bicyclic or tricyclic (condensation or spiro) carbocycles, or (2) 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. A 3- to 15-membered monocyclic, bicyclic or tricyclic (condensed or spiro) heterocycle containing.
Cyc3 may be substituted with 1-5 _{R 39;}
R ₃₉ is composed of (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, (5) 6) hydroxy, (7) a halogen atom, (8) nitro, (9) oxo, (10) cyano, (11) benzyl, (12) benzyloxy, substituted with (13) 1-5 _{R 40} C _1-8 alkyl, C _1-8 alkoxy or C _1-8 alkylthio, (14) phenyl, phenoxy, phenylthio, phenylsulfonyl or benzoyl, which may be substituted with _{1-5 R 41s, (14).} 15) OCOR ₄₂ , (16) SO ₂ R ₄₃ , (17) NR ₄₄ COR ₄₅ , (18) SO ₂ NR ₄₆ R ₄₇ , (19) COOR ₄₈ , or (20) NR ₄₉ R ₅₀ ;
R ₄₀ is a halogen atom;
R ₄₁ is C _1-8 alkyl, C _1-8 alkoxy, halogen atom, or nitro;
R ₄₂ , R ₄₃ and R ₄₅ are C _1-8 alkyl;
R ₄₄ and R ₄₈ are hydrogen atoms or C _1-8 alkyl;
R ₄₆ and R ₄₇ , R ₄₉ and R ₅₀ are independently hydrogen atoms or C _1-8 alkyl;
R _{17 'is, (1) SH, (2} ) NR 66 CHO, (3) Cyc5, (4) C 1~8 alkyl substituted with _{CYC5, C 2 to 8} alkenyl or _{C 2 to 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) SO ₂ NR ₉₁ R ₉₂ , (19) COOR ₉₃ , (20) COCOOR ₉₄ , (21) COR ₉₅ , (22) COCOR ₉₆ , (23) NR ₉₇ COR ₉₈ , (24) SO ₂ R ₉₉ , (25) NR ₁₀₀ SO ₂ R ₁₀₁ , or (26) NR ₁₀₂ R ₁₀₃ ;
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 , R ₁₀₀ and R ₁₀₂ are hydrogen atoms or C _1-8 alkyl;
R ₆₇ and R ₆₈ , R ₇₀ and R ₇₁ are each independently a hydrogen atom or C _1-8 alkyl;
R ₈₉ and R ₉₁ are (1) hydrogen atoms, (2) C _1-8 alkyls, (3) phenyls, or (4) cyano-substituted C _1-8 alkyls or C _1-8 alkoxys;
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) _{C 1-8} alkyl substituted with _{1-5 R 104s} , (6) diphenylmethyl, (6) 7) triphenylmethyl, (8) Cyc6, substituted with ₍₉₎ Cyc6 _C 1~8 alkyl or _{C 2 to 8} alkenyl substituted with or (10,) O-Cyc6, S-Cyc6 or _SO 2 -Cyc6 C _1-8 alkyl;
R ₁₀₄ is composed of (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) N ₁₀₈ COR ₁₀₉ , (10) hydroxy, (H) SH, (12) SO ₃ H, (13) S (O) OH, (14) OSO ₃ H, ( 15) C _2-8 alkoxyoxy, (16) C _2-8 alkynyloxy, (17) COR ₁₁₀ , (18) SO ₂ R ₁₁₁ , or (19) hydroxy-substituted C _1-8 alkoxy or C _{1 ~ 8} Alkoxythio;
R ₁₀₅ is a hydrogen atom, C _1-8 alkyl, or C _2-8 alkenyl;
R ₁₀₆ and R ₁₀₇ are each independently a hydrogen atom or C _1-8 alkyl;
R ₁₀₈ is a hydrogen atom or C _1-8 alkyl;
R ₁₀₉ and R ₁₁₁ are C _1-8 alkyl;
R ₁₁₀ is a C _1-8 alkyl or halogen atom;
R ₉₃ , R ₉₄ , R ₉₅ , R ₉₆ , R ₉₈ , R ₉₉ and R ₁₀₁ are replaced by (1) C _2-8 alkylyl and (2) _{R 128} which may be replaced by _{1 to 4 R 29.} Substituted C _1-8 alkyl, (3) Cyc _{8, (4) C 1-8} alkyl substituted with Cyc 8 or C _2-8 alkoxy, or (5) O-Cyc 8, S-Cyc 8 or SO _2- Cyc 8 _{C 1-8} alkyl substituted with; R ₁₂₈ is (1) cyano, (2) NR ₁₀₆ R ₁₀₇ , (3) NR ₁₀₈ COR ₁₀₉ , (4) hydroxy, (5) SH, (6). SO ₃ H, (7) S (O) OH, (8) OSO ₃ H, (9) C _2-8 alkoxyoxy, (10) C _2-8 alkynyloxy, (11) COR ₁₁₀ , (12) SO ₂ R ₁₁₁ , or (13) hydroxy-substituted C _1-8 alkoxy or C _1-8 alkyl thios;
R ₁₂₉ has the same meaning as _{R 104;}
Cyc5 and Cyc6 may be replaced with _{1-5 R 112s;}
R ₁₁₂ contains (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, (5) 6) Hydroxy, (7) Halogen atom, (8) Nitro, (9) Oxo, (10) Cyano, (11) Benzyl, (12) Benzyloxy, (13) Substituted with _{1-5 R 113s} C _{1 to 8 alkyl, C 1 to 8} alkoxy or _{C 1 to 8} alkylthio, (14) phenyl, phenoxy, phenylthio or benzoyl, which may be substituted with 1-5 _{R 114,} (15) COR ₁₁₅ , (16) SO ₂ R ₁₁₆ , (17) NR ₁₁₇ COR ₁₁₈ , (18) SO ₂ NR ₁₁₉ R ₁₂₀ , (19) COOR ₁₂₁ , (20) NR ₁₂₂ R ₁₂₃ , (21) COR ₁₂₄ , (22) ) CONR ₁₂₅ R ₁₂₆ , (23) SH, (24) hydroxy or _{C 1-8} alkyl substituted with _{NR 127} -benzoyl, or (25) Cyc 7;
R ₁₁₃ is a halogen atom;
R ₁₁₄ is C _1-8 alkyl, C _1-8 alkoxy, halogen atom, or nitro;
R ₁₁₅ , R ₁₁₆ and R ₁₁₈ are C _1-8 alkyl;
R ₁₁₇ , R ₁₂₁ , R ₁₂₄ and R ₁₂₇ are hydrogen atoms or C _1-8 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 alkyl;
Cyc7 may be substituted with 1-5 groups selected from (1) C _1-8 alkyl, (2) C _1-8 alkoxy, (3) halogen atoms, or (4) nitro;
Cyc8 may _{be substituted with R 130} and may be further substituted with _{1 to 4 R 131s;}
R _{130 is C 1-8} alkyl substituted with (1) COR ₁₂₄ , (2) CONR ₁₂₅ R ₁₂₆ , (3) SH, (4) hydroxy or NR ₁₂₇ -benzoyl, or (5) Cyc 7;
R ₁₃₁ has the same meaning as _{R 112;}
Cyc5, Cyc6, Cyc7 and Cyc8 are (1) C _3-15 monocyclic, bicyclic or tricyclic (condensed or spiro) carbocycles, or (2) 1 to 4 oxygen, nitrogen or sulfur. A 3- to 15-membered monocyclic, bicyclic or tricyclic (condensed or spiro) heterocycle containing 1 to 4 heteroatoms selected from;
Here, when _{R 17 'is} CYC5, CYC5 _is 1-5 selected _{C 1 to 8 alkyl, C 1 to 8} alkoxy, hydroxy, halogen atom, nitro, a COOH or COO _{(C 1 to 8} alkyl) Not a phenyl that may be replaced by an individual;
Here, Cyc7 is not phenyl;
_{Cyc4 is a 5-7} membered monocyclic heterocycle containing (1) C 5-7 monocyclic carbocycles or (2) 1-2 heteroatoms selected from oxygen, nitrogen and sulfur. (Hereinafter abbreviated as dotted line a) and (hereinafter abbreviated as dotted line b in this specification) are (1) a bond or (2) a double bond;
R ₉ is either (1) absent or (2) a hydrogen atom;
here,
(1) When the dotted line a is a bond, the dotted line b is a double bond and R ₉ is absent.
(2) When the dotted line a is a double bond, the dotted line b is a bond, R ₉ is a hydrogen atom, R ₆ is absent, and (3) 2- (3,3-dimethyl-3,4). -Dihydro- (2H) -isoquinoline-1-iriden) -1-phenylethane-1-one is excluded, or a pharmacologically acceptable salt thereof.

Preparations of such compounds are described in US2000222138 and WO2003 / 064389.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are selected from compounds commonly or specifically disclosed in WO2003 / 057149, which is expressly incorporated herein by reference in its entirety. It is a thing. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

(1) X is selected from _{halogen and NR 1} R _2.
(2) Y is _{selected from NR 3} , S and O, where when X is Cl, Y is not S.
(3) R ₁ and R ₂ are independently hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, 3 to 7 of them. Carbon atom cycloalkyl, 5-9 carbon atom polycycloalkyl, 2-6 carbon atoms and 1-2 heteroatom heterocycloalkyl selected from NH, S and O, 6 ~ Selected from 12 carbon atom aryls, these are 1-6 carbon atom alkyl, 2-6 carbon atom alkenyl, 2-6 carbon atom alkynyl, 1-6 carbon Atomic alkoxy, halogen, haloalkyl of 1 to 6 carbon atoms and number of halogen atoms up to perhalo level, haloalkoxy of 1 to 6 carbon atoms and number of halogen atoms up to perhalo level, 6 to 12 carbon atoms Of the aryl, or a heteroaryl of 1-2 heteroatoms selected from 4 to 11 carbon atoms and N, S and O, and 1 selected from 4 to 11 carbon atoms and N, S and O It may be substituted with a heteroaryl of ~ 2 heteroatoms, the substituents being an alkyl of 1-6 carbon atoms, an alkenyl of 2-6 carbon atoms, an alkynyl of 2-6 carbon atoms. , 1 to 6 carbon atoms alkoxy, halogen, 1 to 6 carbon atoms and a number of halogen atoms haloalkyl up to the perhalo level, 1 to 6 carbon atoms and a number of halogen atoms haloalkoxy up to the perhalo level, It may be replaced with an aryl of 6 to 12 carbon atoms, or a heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S and O, R ₄ R ₅ or R ₁ and R ₂ are bonded to form a 5- to 7-membered monocyclic saturated ring together with the nitrogen atom to which they are bonded, and the saturated ring is optionally NH. It contains one or two additional heteroatoms selected from the group consisting of _{NR 6 , S and O, or R 4} R ₅ or R ₁ and R ₂ are attached and these are attached nitrogen atoms. A 6- to 10-membered fused polycyclic saturated ring is formed together with the saturated ring, and the saturated ring is optionally selected from the group consisting of _{NH, NR 6, S and O.} It contains additional heteroatoms, or R ₄ R ₅ or R ₁ and R ₂ are attached to form a 5- to 7-membered unsaturated ring with the attached nitrogen atom. The unsaturated ring is optionally N, S. It comprises one or two additional heteroatoms selected from the group consisting of and O, wherein the monocyclic saturated ring, polycyclic saturated ring or unsaturated ring is OH, 1 to 6 carbons. Atomic alkyl, 2-6 carbon atom alkoxy, 2-6 carbon atom alkynyl, 3-7 carbon atom cycloalkyl, 2-6 carbon atoms and NH, S and O Heterocycloalkyls of 1-2 heteroatoms, halogens, haloalkyls of 1-2 carbon atoms and halogen atoms up to the perhalo level, alkoxy of 1-6 carbon atoms, 1-6 carbons It may be substituted with haloalkoxy of atoms and halogen atoms up to the perhalo level, as well as 1-2 substituents selected from the group consisting of _{R 7} R _8.
(4) R ₃ is 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 selected from 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S and O, these are 1 to 6 carbon atom alkyls, 2 to 6 carbon atoms. Alkenyl of 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 number of halogen atoms up to perhalo level, 1 to 6 Haloalkoxy of a number of halogen atoms up to the carbon atom and perhalo level, aryl of 6-12 carbon atoms, or of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O May be replaced with heteroaryl,
(5) R ₄ is an alkyl of 1 to 8 carbon atoms, an alkenyl of 2 to 8 carbon atoms, an alkynyl of 2 to 8 carbon atoms, C (= O), S (= O) ₂ , And C (= O) O, selected from
(6) R ₅ is 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. , 1-8 carbon atom thioxy, 6-12 carbon atom aryl, these are 1-6 carbon atom alkyl, 2-6 carbon atom alkenyl, 2-6 Alkinyl of 1 carbon atom, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and number of halogen atoms up to perhalo level, number of 1 to 6 carbon atoms and number of perhalo level Haloalkoxy of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 1 to 2 heteroatoms selected from 4 to 11 carbon atoms and N, S and O, 4 to 11 It may be substituted with a carbon atom and a heteroaryl of 1 to 2 heteroatoms selected from N, S and O, the substituent being an alkyl of 1 to 6 carbon atoms, 2 to 6 carbons. Atomic alkenyl, 2 to 6 carbon atoms alkynyl, 1 to 6 carbon atom alkoxy, halogen, 1 to 6 carbon atoms and a number of halogen atoms haloalkyl up to the perhalo level, 1 to 6 carbon atoms And haloalkoxy of halogen atoms up to the perhalo level, aryl of 6-12 carbon atoms, or heteroaryl of 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O Substituted with 3, 7 carbon atoms of cycloalkyl, 2 to 6 carbon atoms and 1-2 heteroatom heterocycloalkyls selected from NH, S and O, and NR ₉ R _10. Good,
(7) R ₆ and R ₇ are independently selected from 1 to 8 carbon atom alkyl, 2 to 8 carbon atom alkenyl, and 2 to 8 carbon atom alkynyl.
(8) R ₈ is selected from OH, an aryl of 6 to 12 carbon atoms, which are an alkyl of 1 to 6 carbon atoms, an alkenyl of 2 to 6 carbon atoms, and 2 to 6 carbon atoms. Alkinyl of carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and number of halogen atoms up to perhalo level, halogen atoms of 1 to 6 carbon atoms and number of halogen atoms up to perhalo level Haloalkoxy, 6-12 carbon atom aryls or 4-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, and 4-11 carbon atoms And may be substituted with a heteroaryl of 1 to 2 heteroatoms selected from N, S and O, the substituent being an alkyl of 1 to 6 carbon atoms, of 2 to 6 carbon atoms. Alkenyl, alkynyl with 2 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, halogen, haloalkyl with 1 to 6 carbon atoms and a number of halogen atoms up to the perhalo level, 6 to 12 carbon atoms It may be replaced with an aryl or a heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S and O;
(9) R ₉ 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 ₉ and R ₁₀ are bonded to form a 5- to 7-membered unsaturated ring together with the nitrogen atom to which they are bonded, and the unsaturated ring is derived from N, S and O. It may contain one or two additional heteroatoms of choice, or it may be 5-7 member saturated with the nitrogen atoms to which _{R 9} and R _{10 are attached and to which they are attached.} Forming a ring, the saturated ring may contain one or two additional heteroatoms selected from _{NH, NR 11, S and O;}
(10) R ₁ is selected from 1 to 8 carbon atom alkyl, 2 to 8 carbon atom alkenyl, and 2 to 8 carbon atom alkynyl, and is pharmaceutically acceptable thereof. It is salt.

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

In another embodiment, PDE7 inhibitors useful in the methods of the invention are US 20030092721, US Pat. No. 7,022,849, WO2002 / 102315, and US2006116516, respectively, expressly herein in their entirety. It is selected from the compounds generally or specifically disclosed in (Incorporated). In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ is H or alkyl;
R ₂ is, (a) heteroaryl, or heterocyclo, these may be optionally substituted either with 1-3 T1, T2, T3 group; or (b) a heteroaryl or heterocyclo ring It is a fused aryl, where the bound ring system may be optionally substituted with 1-3 T1, T2, T3 groups;
L is (a) OR ₄ , C (O) R ₄ , C (O) OR ₄ , SR ₄ , NR ₃ R ₄ , C (O) NR ₃ R ₄ , NR ₃ SO ₂ R _4b , halogen, nitro. , Or haloalkyl; or (b) alkyl, aryl, heteroaryl, heterocyclo, or cycloalkyl, all optionally substituted with 1-3 T1a, T2a and / or T3a groups. May;
Y _l , Y ₂ and Y ₃ are independently (a) hydrogen, halo, or -OR _4a ; or (b) alkyl, alkenyl, or alkynyl, each of which is 1-3. It may be optionally substituted with T1b, T2b and / or T3b groups;
R ₃ and R ₄ are independently H, alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyclo, or (heterocyclo) alkyl. There, they are both 1-3 T1a, may be optionally substituted with T2a and / or T3a group; or R ₃ and R ₄ are joined together with the nitrogen atom to which they are attached Thus, a 4- to 8-membered heterocyclo ring optionally substituted with 1 to 3 T1a, T2a and / or T3a groups may be formed;
R _4a is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl) alkyl, (heteroaryl) alkyl, heterocyclo, (heterocyclo) alkyl, cycloalkyl, or (cycloalkyl) alkyl, all of which are 1 It may be optionally substituted with ~ 3 groups T1b, T2b and / or T3b;
R _4b is alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyclo, or (heterocyclo) alkyl, all of which are 1-3. It may be optionally substituted with T1a, T2a and / or T3a groups;
Z is N or CH;
T1 to 1b, T2 to 2b, and T3 to 3b are independent of each other.
(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) itself is substituted with one or more of the same or different (i) groups (i). (I) or (iii) independently substituted with one or more of the following groups (i)-(13) as defined in T1-1b, T2-2b, and T3-3b. Is the basis of (ii);
(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) -SO ₃ H, -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;
T4 and T5 are independently single-bonded, TllS (O) _t T12-, T11C (O) T12-, T11C (S) T12, T11OT12, T11ST12, T11OC (O) T12, T11C (O) OT12, respectively. TllC (= NT9a) T12, or T11C (O) C (O) T12;
T7, T8, T9, T9a and T10 are
(1) each independently, the groups shown in the definition of hydrogen or T6, or (2) T7 and T8 together can be alkylene or alkenylene, 3 to together with the atoms to which they are attached. An 8-membered saturated or unsaturated ring has been completed, which is unsubstituted or substituted with one or more groups listed in the description of T1-1b, T2-2b, and T3-3b. Or (3) T7 or T8, together with T9, can be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached. The ring is unsubstituted or substituted with one or more groups listed in the description of T1-1b, T2-2b, and T3-3b, or (4) T7 and T8. Alternatively, T9 and T10 may be bonded together with the nitrogen atom to which they are bonded to form an N = CT13T14 group, in which T13 and T14 are independently defined as H or T6, respectively. And T11 and T12 are independently single-bonded, alkylene, alkenylene, or alkynylene, respectively.
Is.

Preparations of such compounds are described in US 20030092721, US Pat. No. 7,022,849, WO2002 / 102315, and US2006116516.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are described in US Pat. No. 6,838,559, U.S.A. S. It is selected from the compounds generally or specifically disclosed in 200300100571 and WO2002 / 102314, each of which is expressly incorporated herein by reference in its entirety. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

and

Have.

Substituents for the above compounds are defined as follows.

R ₁ is H or alkyl;
R ₂ is, (a) heteroaryl, or heterocyclo, these may be optionally substituted with any 1-3 T1, T2, T3 group; (b) a 1-3 T1, T2 , T3 substituted aryl, provided that at least one of T1, T2, T3 is other than H; or (c) an aryl fused to a heteroaryl or heterocyclo ring, wherein the bond is made. The 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, all of which are optional with 1 to 3 T1a, T2a, T3a groups. May be selectively replaced;
J is (a) hydrogen, halo, or OR ₄ , or (b) alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, or cycloalkyl, all of which are 1-3 T1b, T2b, It may be optionally substituted with a T3b group;
Z is (a) OR ₄ , SR ₄ , NR ₃ R ₄ , NR ₃ SO ₂ R _4a halogen, nitro, haloalkyl; or (b) alkyl, aryl, heteroaryl, heterocyclo, or cycloalkyl, which are All may be optionally substituted with 1-3 T1c, T2c, T3c groups;
R ₃ is H, alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyclo or (heterocyclo) alkyl, all of which are atoms. If the valence is acceptable, they may be independently optionally substituted with 1-3 T1c, T2c, T3c groups;
R ₄ is alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyclo or (heterocyclo) alkyl, any of which valence Where permitted, they may be independently optionally substituted with 1-3 d, T2d, or T3d groups; or R ₃ and R ₄ together with the nitrogen atom to which they are attached. They may be combined to form a 4- to 8-membered heterocyclo ring optionally substituted with 1-3 T1c, T2c, or T3c groups;
R _4a is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl) alkyl, (heteroaryl) alkyl, heterocyclo, (heterocyclo) alkyl, cycloalkyl, or (cycloalkyl) alkyl, all of which are 1 It may be optionally substituted with ~ 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 T1-1d, T2-2d, and T3-3d in the present specification. Are independently the following (1) to (13),
(1) Hydrogen or T6, in the formula, T6 is the following (a) to (c).
(A) Alkyl, (Hydroxy) Alkoxy, (Alkoxy) Alkoxy, Alkenyl, Alkynyl, Cycloalkyl, (Cycloalkyl) Alkyl, Cycloalkenyl, (Cycloalkenyl) Alkyl, Aryl, (aryl) Alkyl, Heterocyclo, (Herocyclo) Alkyl , Heteroaryl, or (heteroaryl) alkyl;
(B) A group of (a) that itself is substituted with one or more of the same or different (a) groups; or (c) independently, definitions of T1-1d, T2-2d and T3-3d. The group of (a) or (b) substituted with one or more (preferably 1 to 3) of the following groups (2) to (13).
(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) Haro,
(7) Cyano,
(8) Nitro,
(9) T4NT7T8,
(10) T4N (T9) -T5NT7T8,
(11) T4N (T10) -T5-T6,
(12) T4N (T10) -T5H,
(13) Oxo,
T4 and T5 are independently single-bonded, 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 the following (1) to (4).
(1) each independently, the groups shown in the definition of hydrogen or T6, or (2) T7 and T8 together can be alkylene or alkenylene, 3 to together with the atoms to which they are attached. An 8-membered saturated or unsaturated ring has been completed, which is unsubstituted or substituted with one or more groups listed in the description of T1-1d, T2-2d, and T3-3d. Or (3) T7 or T8, together with T9, can be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached. The ring is unsaturated or substituted with one or more of the groups listed in the description of T1-1d, T2-2d and T3-3d, or (4) T7 and T8 or T9 and T10 may be bonded together with the nitrogen atom to which they are bonded to form an N = CT13T14 group.
T13 and T14 are independently the groups shown in the definition of H or T6; and T11 and T12 are each independently single bond, alkylene, alkenylene, or alkynylene.

The preparation of such compounds is described in US Pat. No. 6,838,559, U.S.A. S. 20030100571 and WO2002 / 102314.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are described in US Pat. No. 7,087,614, U.S.A. S. It is selected from the compounds generally or specifically disclosed in 20030162802, and WO2002 / 102313, each of which is expressly incorporated herein by reference in its entirety. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are described below.

In a related embodiment, PDE7 inhibitors useful for the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R _1a is hydrogen or alkyl; R _2a is

And W is S; X ₁ is alkoxy; X ₂ is alkyl;
Z ^* is halogen, haloalkyl, oxazolyl, NR _3a R _4a , C (O) -N (H) -alkylene-COOH, or phenyl, which phenyl is unsubstituted or heteroaryl, CO _t. Substituted with H or CO _{t T6;}
R _3a is 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, the aryl group being 1 Substituted with one or two T1 and / or T2 groups, and / or further substituted with T3 groups; or R _3a and R _4a together with the nitrogen atom to which they are attached. Combined to form an unsubstituted or substituted heterocyclo 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. those substituted with T3 group; or R5 _a and R _6a are joined together with the nitrogen atom to which they are attached, is obtained by forming a heterocyclo ring unsubstituted or substituted; R _6a is is hydrogen or alkyl; ^{J *} is a certain hydrogen or alkyl; T1 and T2, independently, alkoxy, alkoxycarbonyl, heteroaryl, _SO 3 H or _SO 2 _{R 8a,,} wherein, R _8a is alkyl, amino, alkylamino or dialkylamino; or T1 and T2 are combined together with the aryl ring to which they are attached 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.

Preparation of such compounds is described in US Pat. No. 7,087,614, U.S. Pat. S. 20130162802, and WO2002 / 102313.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are general or specific to US20030104974, WO2002 / 088800, and WO2002 / 088079, each of which is expressly incorporated herein by reference in its entirety. It is selected from the compounds disclosed above. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ is H or alkyl; R ₂ is optionally substituted heteroaryl, or 4-substituted aryl; R ₃ is hydrogen or alkyl; R ₄ is alkyl, optionally substituted. Are optionally substituted (aryl) alkyl, optionally substituted (heteroaryl) alkyl, optionally substituted heterocyclo, or optionally substituted (heterocyclo) alkyl; or R ₃ And R ₄ may be attached together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclo ring; R ₅ is an alkyl, optionally substituted. (aryl) is alkyl or optionally substituted, is (heteroaryl) alkyl; and R ₆ is hydrogen or alkyl.

In a related embodiment, PDE7 inhibitors useful for the methods of the invention are:

Have.

In the formula, R _1a is H or alkyl; R _2a is an optionally substituted heteroaryl; Z is halogen, alkyl, substituted alkyl, haloalkyl, or NR _3a R _4a ; R _3a is hydrogen or alkyl; _R4a is alkyl, optionally substituted (heteroaryl) alkyl, optionally substituted heterocyclo, optionally substituted (heterocyclo) alkyl, or It is an (aryl) alkyl, the aryl group being substituted with one or two T1 and T2 groups and further optionally substituted with a T3 group; or R _3a and R _4a are these. May be attached together with the nitrogen atom to which is attached to form an optionally substituted heterocyclo ring; R _5a is an (aryl) alkyl and the aryl group is one or two. Substituted with T1 and T2 groups, and optionally with T3 groups; R _6a is hydrogen or alkyl; R _7a is hydrogen or alkyl; T1 and T2 are Independently, they are alkoxy, alkoxycarbonyl, heteroaryl or SO ₂ R _8a , where in the formula R _8a is alkyl, amino, alkyl amino or dialkyl amino; or T1 and T2 are these bonded. It may be attached together with the atom to form a ring (eg, benzodioxol); T3 is H, alkyl, halo, haloalkyl or cyano.

In another related embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

In the formula, R _1b is H or alkyl; R _2b is an optionally substituted heteroaryl; R _3b is H or alkyl; R _4b is optionally substituted. (Aryl) alkyl; R _5b is H, alkyl, or C (O) (CH ₂ ) _v OYR _6b , where Y is a bond or C (O) and R _6b is hydrogen. Or alkyl, where v is an integer between 0 _{and 2 ; J 1} and J 2 are independently, optionally substituted C _1-13 alkylene, where J ₁ and J ₂ are. , Both shall not be greater than _{C 2 alkylene; X 4} and X ₅ are optional substituents attached to any available carbon atom of one or both of _{J 1} and J _2. Independently selected from hydrogen, OR ₇ , NR ₈ R ₉ , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl. R ₇ 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, it is heterocycloalkyl and heteroaryl; and R ₈ and R ₉ are independently 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) O alkyl, C (O) O substituted alkyl, C ( O) Heterocycloalkyl, C (O) Heteroaryl, S (O) _2- alkyl, S (O) _2- substituted alkyl, S (O) _2- cycloalkyl, S (O) _2- substituted cycloalkyl, S ( _{O) 2} aryl, S _{(O) 2-substituted} aryl, S _{(O) 2} heterocycloalkyl, S _{(O) 2} heteroaryl, aryl, substituted aryl, is selected from the group consisting of heterocycloalkyl, and heteroaryl, or R ₈ and R ₉ together with the nitrogen atom to which they are attached complete an optionally substituted heterocycloalkyl or heteroaryl ring.

In a further related embodiment, PDE7 inhibitors useful for the methods of the invention are:

Have.

In the formula, R _1c is H or alkyl; R _2C is an optionally substituted heteroaryl; R _3c is H or alkyl; R _4c is optionally substituted. (aryl) is alkyl; and X ₄ and X ₅ are optional substituents attached to one or both any available carbon atom of J ₁ and J _2, independently, hydrogen, It is selected from OR ₇ , NR ₈ R ₉ , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl.

Preparations for such compounds are described in US20030104974, WO2002 / 088080, and WO2002 / 088079.

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

Have.

Substituents for the above compounds are defined as follows.

R ₁ is hydrogen or alkyl;
R ₂ is, (a) heteroaryl, or heterocyclo, these may be optionally substituted with any 1-3 T1, T2, T3 group; (b) a 1-3 T1, T2 , T3 substituted aryl, provided that at least one of T1, T2, T3 is other than H; or (c) an aryl fused to a heteroaryl or heterocyclo ring, wherein the bond is made. The ring system may be optionally substituted with 1-3 T1, T2, T3 groups;
Z is NR ₃ R ₄ , NR ₃ SO ₂ R _4a , OR ₄ , SR ₄ , haloalkyl, or halogen;
R ₃ and R ₄ are independently H, alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyclo or (heterocyclo) alkyl. , Each of which may be optionally optionally substituted with 1-3 T1a, T2a, or T3a groups, where valences are acceptable; or R ₃ and R ₄ are these. Together with the attached nitrogen atom, if the valence is acceptable, it independently forms a heterocyclo or heteroaryl ring optionally substituted with 1-3 T1a, T2a, or T3a groups. May be;
R _4a is alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyclo or (heterocyclo) alkyl, all of which have valences. Where permitted, they may be independently optionally substituted with 1-3 T1a, T2a, or T3a groups;
R _3b and R _4b are independently H, alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyclo or (heterocyclo) alkyl. ;
R ₅ 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, all of which are atoms. If the valence is acceptable, they may be optionally substituted with 1-3 T1b, T2b, or T3b groups independently; or (3) C (O) R ₆ , C (O) OR ₆ , C (O) -C (O) OR, or SO ₂ R _6a ;
R ₆ 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, both of which may be independently optionally substituted with 1-3 T1b, T2b, or T3b groups if valences are acceptable;
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, all of which may be independently optionally substituted with 1-3 T1b, T2b, or T3b groups if valences are acceptable;
J ₁ and J ₂ are independently and optionally substituted C _1-3 alkylene, except that both _{J 1} and J _{2 are no greater than C 2} alkylene; and T1. ~ 1b, T2 ~ 2b, and T3 ~ 3b are independently the following (1) to (13), respectively.
(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) itself is substituted with one or more of the same or different (i) groups (i). Groups; or (iii) independently at one or more (preferably 1-3) of the following groups (2)-(13) as defined in T1-1b, T2-2b, and T3-3b. Which is the base of the substituted (i) or (ii),
(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) SO ₃ H, S (O) _t T6, or S (O) _t N (T9) T6,
(6) Haro,
(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 are independently (1) 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 the following (1) to (4).
(1) each independently is a group as shown in the definition of hydrogen or T6, or (2) T7 and T8 together can be alkylene or alkenylene, together with the atom to which they are bonded. A 3- to 8-membered saturated or unsaturated ring has been completed, the ring being unsubstituted or with one or more groups listed in the description of T1-1b, T2-2b, and T3-3b. Substituted, or (3) T7 or T8, together with T9, can be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached. The ring is unsubstituted or substituted with one or more groups listed in the description 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 bonded to form an N = CT13T14 group, in which T13 and T14 are independently H or T6, respectively. And T11 and T12 are independently single bonds, alkylenes, alkenylenes, or alkynylenes, respectively.

Preparations of such compounds are described in US20030092908 and WO2002/087513.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are generally or specifically disclosed in US200401727707 and WO2002/085906, each of which is expressly incorporated herein by reference in its entirety. It is selected from compounds. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ is 1-2 C alkoxy or 1-2 C alkoxy, which is completely or largely substituted with fluorine.
R ₂ is fluorine, bromine, or chlorine,
R ₃ and R ₄ are both hydrogen or together form additional bonds,
R ₅ is R ₆ , C _m H _2m- R ₇ , C _n H _2n- C (O) R ₈ , CH (R ₉ ) ₂ , C _p H _2p- Y-aryl ₁ , R ₁₂ or R ₂₆ . can be,
During the ceremony
R ₆ is 1-8C alkyl, 3-10C cycloalkyl, 3-7C cycloalkylmethyl, 3-7C alkoxy, 3-7C alkoxyl, phenyl-3-4C-alkoxy, 7-10C polycycloalkyl, naphthyl, pyridyl. , Pyrazineyl, pyridadinyl, 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] pyridine-6-yl, 3-thiophen-2-yl [1,2,4] thiazazole-5-yl , 1,1-dioxide-tetrahydrothiophene-3-yl, 1-oxo-1,3-dihydro-isobenzofuran-5-yl, 4- (4-yl-buta-1-oxy) benzoic acid, or unsubstituted Or a phenyl group substituted with _{R 61} and / or R _{62 , in which R 61} is hydroxyl, 1-4C alkyl, 1-4C alkoxy, nitro, cyano, halogen, carboxyl, hydroxycarbonyl-1 to 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-methylphenylsulfonamide, imidazolyl; tetrazole-5-yl, 2- (1-4C-alkyl) tetrazol-5-yl or 2-benzyl it is a tetrazol-5-yl, and R ₆₂ are 1-4C alkyl, 1-4C alkoxy, nitro or halogen,
R ₇ is hydroxyl, halogen, cyano, nitro, nitroxy (O-NO ₂ ), carboxyl, carboxyphenyloxy, phenoxy, 1-4C alkoxy, 3-7C cycloalkoxy, 3-7C cycloalkylmethoxy, 1-4C alkyl. Carbonyl, 1-4C alkylcarbonyloxy, 1-4C alkylcarbonylamino, 1-4C alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, amino, mono- or di-1-4C-alkyl Amino, or unsubstituted or R ₇₁ and / or R ₇₂ substituted piperidyl, piperazinyl, pyrrolidinyl or morpholinyl groups, in the formula,
R ₇₁ is a hydroxyl, 1-4C alkyl, hydroxy-1 to 4C-alkyl or 1 to 4C alkoxycarbonyl, and R ₇₂ is a 1 to 4C alkyl, carboxyl, aminocarbonyl or 1 to 4C alkoxycarbonyl.
R ₈ is a phenyl, naphthyl, phenanthrenyl or anthracenyl group unsubstituted or substituted with R ₈₁ and / or R _{82, and in the formula,}
R ₈₁ is hydroxyl, halogen, cyano, 1-4C alkyl, 1-4C alkoxy, carboxyl, aminocarbonyl, mono- or di-1 to 4C-alkylaminocarbonyl, 1-4C alkylcarbonyloxy, 1-4C alkoxycarbonyl. , Amino, mono- or di-1 to 4C-alkylamino, 1 to 4C alkylcarbonylamino, or 1 to 4C alkoxy, completely or largely substituted with fluorine, and R ₈₂ is hydroxyl, Halogen, 1-4C alkyl, 1-4C alkoxy or 1-4C alkoxy, completely or largely substituted with fluorine.
R ₉ is C _q H _2q -phenyl,
Y is a bond or O (oxygen),
Aryl ₁ is unsubstituted phenyl, naphthyl, pyridyl, pyrazinyl, pyridadinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl, isoquinolyl, quinolyl, coumarinyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, N-benzosuccin. thiazole-4-yl group or a phenyl group substituted by _{R 10} and / or _{R 11,,} - Imijiru, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, furyl, thienyl, pyrrolyl, 2-(1-4C-alkyl) During the ceremony
R ₁₀ is hydroxyl, halogen, nitro, cyano, 1-4C alkyl, trifluoromethyl, 1-4C alkoxy, carboxyl, hydroxycarbonyl-1 to 4C-alkyl, 1-4C alkylcarbonyloxy, 1-4C alkoxycarbonyl, Amino, mono- or di-1 to 4C-alkylamino, 1-4C alkylcarbonylamino, aminocarbonyl, mono- or di-1 to 4C-alkylamino-carbonyl, imidazolyl or tetrazolyl, where 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 given by the formula (a).

Is the basis of
_{Wherein, R} 13 _{is, S (O) 2 -R 14} , S (O) 2 - (CH 2) r -R15, (CH 2) S -S (O) 2 R16, C (O) R 17, _{C (O) - (CH 2} ) r -R 18, (CH 2) s -C (O) -R 19, hetaryl _{(hetaryl) 1,} aryl ₂ or aryl ₃ -1～4C- _{alkyl, R 14} Is a phenyl substituted with 1-4C alkyl, 5-dimethylaminonaphthalin-1-yl, N (R ₂₀ ) R ₂₁ , phenyl or R ₂₂ and / or R _{23 , and R 15} is N (R _20). ) R ₂₁ and R ₁₆ is N (R ₂₀ ) R ₂₁ .
R ₁₇ is 1 to 4C alkyl, hydroxycarbonyl-1 to 4C-alkyl, phenyl, pyridyl, 4-ethyl-piperazin-2,3-dione-1-yl, 2-oxo-imidazolidine-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 . Substituted phenyl, R ₂₀ and R ₂₁ are independent of each other, hydrogen, 1-7C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl methyl or phenyl, or R ₂₀ and R ₂₁ are , 4-morpholinyl ring, 1-pyrrolidinyl ring, 1-piperidinyl ring, 1-hexahydroazepino ring or formula (b) together, including the nitrogen atom to which they are attached.

1-piperazinyl ring of
_{Wherein, R 25} is pyrid-4-yl, pyrid-4-ylmethyl, 1-4C-alkyl - dimethylamino, dimethylaminocarbonyl methyl, N- methyl - piperidin-4-yl, 4-morpholino - ethyl or tetrahydrofuran- - 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- alkyl Amino, aminocarbonyl 1-4C alkylcarbonyl Amino or mono- or di-1-4C-alkylaminocarbonyl, R ₂₃ is halogen, amino, nitro, 1-4C alkyl or 1-4C alkoxy, R ₂₄ Is halogen,
Hetaryl ₁ is pyrimidine-2-yl, thieno- [2,3-d] pyrimidin-4-yl, 1-methyl-1H-pyrazolo- [3,4-d] pyrimidin-4-yl, thiazolyl, imidazolyl or Furanyl, aryl ₂ is pyridyl, phenyl or phenyl _{substituted with R 22} and / or R ₂₃ , and aryl ₃ is phenyl substituted with pyrimidine, phenyl, R ₂₂ and / or R ₂₃ , 2- Oxo-2H-chromen-7-yl or 4- (1,2,3-thiadiazol-4-yl) phenyl,
r is an integer of 1 to 4, and s is an integer of 1 to 4.
R ₂₆ is given by the formula (c).

Is the basis of
In the formula, R ₂₇ is C (O) R ₂₈ , (CH ₂ ) _t- C (O) R ₂₉ , (CH ₂ ) _u R ₃₀ , aryl ₄ , hetaryl ₂ , phenylpropa-1-en-3-. Il or 1-methylpiperidin-4-yl, where R ₂₈ is hydrogen, 1-4C alkyl, OR ₃₁ , furanyl, indolyl, phenyl, pyridyl, R ₃₄ and / or R ₃₅ substituted phenyl or R _36. And / or pyridyl substituted with _{R 37 , R 29} is N (R ₃₂ ) R ₃₃ , R ₃₀ is N (R ₃₂ ) R ₃₃ , tetrahydrofuranyl or pyridinyl, and R ₃₁ is 1 to 4C alkyl, R ₃₂ is hydrogen, 1 to 4C alkyl, 3 to 7C cycloalkyl or 3-7C-cycloalkylmethyl, R ₃₃ is hydrogen, 1 to 4C alkyl, 3 to 7C cycloalkyl. or 3-7C- cycloalkyl-methyl or R ₃₂ and _{R 33,} may together including the nitrogen atom to which they are attached, 4-morpholinyl -, 1-pyrrolidinyl -, 1-piperidinyl - or 1- Forming a hexahydroazepinyl ring,
Aryl ₄ is phenyl, pyridyl, pyrimidinyl, R ₃₄ and / or R ₃₅ substituted phenyl, R ₃₆ and / or R ₃₇ substituted pyridyl, where R ₃₄ is halogen, nitro, 1-4C alkyl. , Trifluoromethyl or 1-4C alkoxy, R ₃₅ is halogen or 1-4C alkyl, R ₃₆ is halogen, nitro, 1-4C alkyl, trifluoromethyl or 1-4C alkoxy, R ₃₇ is halogen or 1-4C alkyl,
Hetaryl ₂ contains indole-4-yl, 2-methyl-quinoline-4-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazine-4-yl, 3-phenyl-1, 2,4-Thiadiazole-5-yl or 3-o-tolyl-1,2,4-thiadiazole-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.

Preparations for such compounds are described in US200401727707 and WO2002 / 085906.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are U.S. Pat. Nos. 6,818,651, US20040044212, and WO2002 / 040450, each of which is expressly incorporated herein by reference in its entirety. ) Is selected from the compounds generally or specifically disclosed. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ represents hydrogen and R ₂ represents fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or R ₁ represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and R ₂ is either for hydrogen, R'and R'both represent hydrogen, or together represent a bond, where Ar is the formula IIa, IIb, or IIc.

Represents the phenyl group of
In the formula, R ₃ is hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C alkoxy, trifluoromethoxy, 1-4C alkoxycarbonyl or mono- or di-1 to 4C-alkylaminocarbonyl R ₄ , 1-4C alkyl, naphthalenyl, 5-dimethylaminonaphthalene-1-yl, phenylethen-2-yl, 3,5-dimethylisoxazole-4-yl, 5-chloro-3-methylbenzo [b] thiophene- 2-yl, 6-chloro-imidazole [2,1b] -thiazole-5-yl, or a phenyl or thiophene group unsubstituted or substituted with one or more of the same or different groups, said substituent. Are halogen, cyano, 1-4C alkyl, trifluoromethyl, 1-4C alkoxy completely or primarily substituted with fluorine, 1-4C alkoxy, 1-4C alkylcarbonylamino, 1-4C alkoxycarbonyl, phenylsulfonyl or A hydrate, solvate, salt, hydrate of a salt, or solvate of a salt, selected from the group of isoxazolyls.

Preparations of such compounds are described in US Pat. No. 6,818,651, US20040044212, and WO2002 / 04450.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are selected from compounds commonly or specifically disclosed in WO2002 / 040449, which is expressly incorporated herein by reference in its entirety. It is a thing. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ represents hydrogen and R ₂ represents fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or R ₁ represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and R ₂ represents either hydrogen,
R'and R'both represent hydrogen or together represent a bond,
R ₃ represents hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C alkoxy, trifluoromethoxy, 1-4C alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl, where R ₄ is. , C (O) -X-R ₅ , N (H) -C (O) -R ₆ or N (H) -C (O) -N (H) -R ₂ , in the formula,
X represents O or N (H),
R ₅ is hydrogen, 1-4C alkyl, 3-7C cycloalkylmethyl, 6,6-dimethylbicyclo [3,3,I] hepta-2-yl, 3-7C alkynyl, 1-4C alkylcarbonyl-1-1 4C-alkyl, aminocarbonyl-1 to 4C-alkyl, furan-2-ylmethyl, 2-pyridine-2-yleta-1-yl, 2-pyridine-3-ylmethyl, N-methylpiperidin-3-yl, 1- Benzylpiperidin-4-yl, morpholin-4-yl-eth-2-yl, morpholin-4-yl-eta-1-yl, 2-benzo [1,3] dioxolu-4-yl-eta-1-yl , Chroman-4-yl, 1-methoxycarbonyl-2-indole-3-yl-eta-1-yl, 1,3-bis-methoxycarbonylpropa-1-yl, 1-methoxycarbonyl-3-methylsulfanyl- Represents eta-1-yl, 1-methoxycarbonyl-2-thiazole-2-yl-eta-1-yl, or 4-methylthiazole-5-yl-eta-2-yl, or unsubstituted or one. Represents a benzyl-, phenyl-eta-1-yl or 1-methoxycarbonyl-2-phenyl-eta-2-yl group substituted with the above groups, the substituents being in the group of halogen, trifluoromethyl and phenyl. Selected from,
R ₆ represents 2,4-dichlorophenoxymethyl, 2-tert-butoxycarbonylamino-eta-1-yl, 1-acetylpiperidin-4-yl, Ar1 or Ar2-CH = CH-.
In the formula, Ar1 is 3-chlorophenyl, 4-trifluoromethoxyphenyl, 3-phenoxyphenyl, indol 5-yl, 2-methylpyridine-5-yl, quinoline-6-yl or 2-benzothiazole-6-yl. Ar2 represents furan-2-yl, furan-3-yl, thiophen-2-yl, indol-3-yl, 3-trifluoromethylphenyl, 3-methoxyphenyl or pyridine-3-yl.
R ₇ is 1 to 4C alkyl, 3 to 7C alkenyl, 3 to 7C cycloalkyl, 1-ethoxycarbonyl-2-phenyl-eta-1-yl, thiophen-2-yleta-1-yl or unsubstituted or one. Represents a phenyl group substituted with the above groups, the substituents being halogen, cyano, 1-4C alkyl, trifluoromethyl, 1-4C alkylthio, 1-4C alkoxy, complete or predominantly fluorine substituted 1 Selected from the group ~ 4C Alkoxy, 1-4C Alkylcarbonyl and Phenoxy,
Or its salt.

The preparation of such compounds is described in WO 2002/040449.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are selected from compounds commonly or specifically disclosed in WO2001 / 098744, which is expressly incorporated herein by reference in its entirety. It is a thing. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

W, X, Y and Z may be the same or different, respectively, with a nitrogen atom or C (R ⁵ ) group [in the formula, R ₅ is a hydrogen or halogen atom or alkyl, haloalkyl, alkoxy, Halokoxy, hydroxy, -NO ₂ or -CN group], provided that two or more of W, X, Y and Z are C (R ₅ ) groups;
R ₁ , R ₂ and R ₃ may be the same or different, respectively, and are atoms or -L ₁ (Alk ₁ ) _r- L ₂ (R ₆ ) _s groups, respectively, L _{1 in the formula.} And L ₂ may be the same or different, respectively, being a covalent bond or a linker atom or a linker group, r being zero or an integer 1, and Alk ₁ being an aliphatic or heteroaliphatic chain. , S is an integer of 1, 2 or 3, R6 is a hydrogen or halogen atom, or alkyl, −OR ₇ [in the formula, R ₇ is a hydrogen atom or an optionally substituted alkyl. Group], -SR ₇ , NR ₇ R ₈ [In the formula, R ₈ is as _{specified for R 7} , and may be the same or different], -NO ₂ , CN, CO ₂ R _{7 , SO 3 H, S (O} ) R 7, SO 2 R 7, OCO 2 R 7, CONR 7 R 8, OCONR 7 R 8, CSNR 7 R 8, OCR 7, OCOR 7, N (R 7) COR 8 , N (R ₇ ) CSR ₈ , S (O) NR ₇ R ₈ , SO ₂ NR ₇ R ₈ , N (R ₇ ) SO ₂ R ₈ , N (R ₇ ) CON (R ₈ ) (R ₉ ) [ In the formula, R ₉ is a hydrogen atom or an optionally substituted alkyl group], N (R ₇ ) CSN (R ₈ ) (R ₉ ), N (R ₇ ) SO ₂ N (R ₈ ). (R ₉ ), C (R ₇ ) = NO (R ₈ ), cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group]; however, of R ₁ , R ₂ or R ₃ Suppose one or more are substituents other than hydrogen atoms;
R ₄ is optionally substituted phenyl, 1- or 2-naphthyl, pyridyl, pyrimidinyl, pyridazinyl or an pyrazinyl group; a and the salts, solvates, hydrates and N- oxides.

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

In another embodiment, PDE7 inhibitors useful for the methods of the invention are selected from compounds commonly or specifically disclosed in WO2001 / 074786, which is incorporated herein by reference in its entirety. It is a thing. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ represents an aryl or heteroaryl group;
A, B, P and E may be the same or different, respectively, with a nitrogen atom or C (R ₂ ) group [in the formula, R ₂ is a hydrogen or halogen atom or alkyl, haloalkyl, alkoxy, Haloalkoxy, hydroxy, -NO ₂ or -CN group], provided that two or more of A, B, D and E are C (R ₂ ) groups; X is oxygen or sulfur. Represents an atom or N (R ₃ ) group, where R ₃ is a hydrogen atom or alkyl group in the formula;
Q, R, S and T may be the same or different, respectively, and each is a nitrogen atom or C (R ₄ ) group [in the formula, R ₄ is an atom or -L ₁ (Alk ₁ ) rL ₂ It is a (R ₅ ) group, in which L ₁ and L ₂ may be the same or different, respectively, a covalent bond or a linker atom or a linker group, where r is zero or integer 1. Yes, Alky1 is an aliphatic or heteroaliphatic chain, s is an integer of 1, 2 or 3, R ₅ is a hydrogen or halogen atom, or alkyl, OR ₆ [in the formula, R ₆ is Hydrogen atom or optionally substituted alkyl group], SR ₆ , NR ₆ R ₇ [In the formula, R ₇ is as _{specified for R 6} and may be the same or different. _{], NO 2, CN, CO} 2 R 6, SO 3 H, S (O) R 6, SO 2 R 6, OCO 2 R 6, CONR 6 R 7, OCONR 6 R 7, CSNR 7 R 7, OCR 6 , OCOR ₆ , N (R ₆ ) COR ₇ , N (R ₆ ) CSR ₇ , S (O) NR ₆ R ₇ , SO ₂ NR ₆ R ₇ , N (R ₆ ) SO ₂ R ₇ ; N (R ₆₎ ) CON (R ₇ ) (R ₈ ) [In the formula, R ₈ is a hydrogen atom or an optionally substituted alkyl group], N (R ₆ ) CSN (R ₇ ) (R ₈ ), N (R ₆ ) SO ₂ N (R ₇ ) (R ₈ ), C (R ₆ ) = NO (R ₇ ) cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group]. However, it is assumed that two or more of Q, R, S and T are C (R ₄ ) groups; and their salts, solvates, hydrates and N-oxides.

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

In another embodiment, PDE7 inhibitors useful in the methods of the invention are selected from compounds commonly or specifically disclosed in WO2000 / 068230, which is expressly incorporated herein by reference in its entirety. It is a thing. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

XYZ represents NR _4- C = N or N = C-NR ₄ ;
R ₁ represents H, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
R ₂ represents OR ₈ , NR ₈ R ₉ , SR ₁₃ , alkyl or CF ₃ ;
R ₃ represents halogen, alkyl, CF ₃ or OR ₈ ;
R ₄ is one that can be coupled to either the X or Z,

Residues selected from,
During the ceremony
Binding is due to any position on the saturated ring, where binding is intended not located adjacent to V, the saturated ring may be any position may be substituted by one or more R ₆ May;
A, B, D and E are the same or different _{, representing Cl n} R ₅ , N or NO, respectively;
V represents O, S, NR ₇ or C (L ¹ _m R ₁₄ ) (L ² _n R ₁₄ );
Q and W are the same or different _{, representing CL n} R ₅ or N, respectively;
T represents O, S or NR ₇ ;
L ¹ and L ² are the same or different, respectively, representing _{C (R 15} ) _2;
m and n are the same or different, representing 0, 1, 2, 3, 4 or 5, respectively;
R ₅ is the same or different, H, halogen, alkyl, cycloalkyl, OR ₈ , NR ₈ R ₉ , CO ₂ R ₁₀ , CONR ₁₁ R ₁₂ , CONHOH, SO ₂ NR ₁₁ R ₁₂ , SON, respectively. _{Represents 11} R ₁₂ , COR ₁₃ , SO ₂ R ₁₃ , SOR ₁₃ , SR ₁₃ , CF ₃ , NO ₂ or CN;
R ₆ is H, alkyl, cycloalkyl, OR ₈ , NR ₈ R ₉ , CO ₂ R ₁₀ , CONR ₁₁ R ₁₂ , SO ₂ NR ₁₁ R ₁₂ , SON ₁₁ R ₁₂ , COR ₁₃ , SO ₂ R ₁₃ , SOR. _{Represents 13} , SR ₁₃ , CF ₃ , CN or = O;
R ₇ represents H or alkyl;
R ₈ represents H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl;
R ₉ is R ₈ or alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, cycloalkylsulfonyl, cycloalkylalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkylsulfonyl, arylcarbonyl, arylsulfonyl, hetero Arylcarbonyl, Heteroarylsulfonyl, Heterocyclocarbonyl, Heterocyclosulfonyl, Arylalkylcarbonyl, Arylalkoxycarbonyl, Arylalkylsulfonyl, Heteroarylalkylcarbonyl, Heteroarylalkoxycarbonyl, Heteroarylsulfonyl, Heterocycloalkylcarbonyl, Heterocycloalkoxycarbonyl Or represents a heterocycloalkylsulfonyl; or NR ₈ R ₉ represents a heterocycle such as morpholin;
R ₁₀ represents H, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
R ₁₁ and R ₁₂ are the same or different, respectively, R ₈ 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 is the same or different, H, alkyl, cycloalkyl, OR ₈ , NR ₈ R ₉ , CO ₂ R ₁₀ , CONR ₁₁ R ₁₂ , CONHOH, SO ₂ NR ₁₁ R ₁₂ , SON ₁₁ R, respectively. ₁₂ , COR ₁₃ , SO ₂ R ₁₃ , SOR ₁₃ , SR ₁₃ , CF ₃ , NO ₂ and CN, where when m and n both represent 0, one R ₁₄ is OR ₈ , NR ₈ If it is R ₉ or SR ₁₃ , the other shall _{not be OR 8} , NR ₈ R ₉ or SR ₁₃ ; and R ₁₅ represents H, alkyl or F; or in a pharmaceutically acceptable salt thereof. be.

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

In another embodiment, PDE7 inhibitors useful for the methods of the invention are general or specifically in US20040106631, EP1400244, and WO2004 / 026818, each of which is expressly incorporated herein by reference in its entirety. It is selected from the disclosed compounds. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

m is 1, 2 or 3; R ₁ is methyl, chloro, bromo or fluoro; R ₂ is −Q ¹ −Q ² −Q ³ −Q ⁴ or (C _{1 to} C ₆ ) alkyl The (C _{1 to} C ₆ ) alkyl is 1 to 3 OR ₄ , COOR ₄ , NR ₄ R ₅ , NRC (= O) R ₄ , C (= O) NR ₄ R ₅ or SO _2. It was replaced with NR ₄ R _5;
R ₄ is 1 to 3 F, CN, S (= O) R ₆ , SO ₃ H, SO ₂ R ₆ , SR ₇ , C (= O) -NH-SO _2- CH ₃ , C (=). O) R ₇ , NR'C (= O) R ₇ , NR'SO ₂ R ₆ , C (= O) NR ₇ R ₈ , OC (= O) NR ₇ R ₈ or SO ₂ NR ₇ R ₈ in it is substituted _(C 1 _{~C 6)} alkyl;
R ₅ is H, or 1-3 F, CN, S (= O) R ₆ , SO ₃ H, SO ₂ R ₆ , SR ₇ , C (= O) -NH-SO _2- CH ₃ , C (= O) R ₇ , NR'C (= O) R ₇ , NR'SO ₂ R ₆ , C (= O) NR ₇ R ₈ , OC (= O) NR ₇ R ₈ or The _{(C 1 to} C ₆ ) alkyl optionally substituted with _{SO 2} NR ₇ R ₈ ; or the (C _{1 to} C ₆ ) alkyl described above are (1) and (2) below.
(1) 1-3 OC (= O) R _4a , SR _4a , S (= O) R ₃ , C (= NR ₉ ) R _4a , C (= NR ₉ ) -NR _4a R _5a , NR- C (= NR ₉ ) -NR _4a R _5a , NRCOOR _4a , NR-C (= O) NR _4a R _5a , NR-SO _2- NR _4a R _5a , NR-C (= NR ₉ ) -R _4a or NR -SO _2- R ₃ substituted; and (2) one or two OR _4a , COOR _4a , C (= O) -R _4a , NR _4a R _5a , NRC (= O) R _4a , Optionally substituted with C (= O) NR ₄ R _5a or SO ₂ NR _4a R _5a;
R _{9 is, H, CN, OH, OCH} 3, SO 2 CH 3, SO 2 NH 2 or _(C 1 _{~C 6)} is alkyl; and _{R 3} is 1-3 F, CN, S ( = O) R ₆ , SO ₃ H, SO ₂ R ₆ , C (= O) -NH-SO _2- CH ₃ , OR ₇ , SR ₇ , COOR ₇ , C (= O) R ₇ , OC ( = O) NR ₇ R ₈ , NR ₇ R ₈ , NR'C (= O) R ₇ , NR'SO ₂ R ₆ , C (= O) NR ₇ R ₈ or SO ₂ NR ₇ R ₈ substituted a is _(C 1 _{~C 6)} alkyl;
R _4a and R _5a are the same or different and are H or 1-3 F, CN, S (= O) R ₆ , SO ₃ H, SO ₂ R ₆ , C (= O) ) -NH-SO _2- CH ₃ , OR ₇ , SR ₇ , COOR ₇ , C (= O) R ₇ , OC (= O) NR ₇ R ₈ , NR ₇ R ₈ , NR'C (= O) ) R ₇ , NR'SO ₂ R ₆ , C (= O) NR ₇ R ₈ or SO ₂ NR ₇ R ₈ optionally substituted (C _1- C ₆ ) alkyl;
Q ¹ is a single bond or (C _1- C ₆ ) alkylene; Q ² is a 4- to 6-membered saturated heterocyclyl containing one or two O or N; Q ³ is (C _1). -C ₆₎ is alkylene; ^{Q 4} is a 1-4 O, S, S (= O ), 4~8 -membered aromatic or non-aromatic heterocyclyl containing SO ₂ or N, said heterocyclyl is 1-3 oR, NRR ', - CN, or _((C 1 _{~C 6)} in which is optionally substituted with alkyl;
R is H or _(C 1 _{~C 6)} alkyl;
R ₆ is a 1 or is optionally substituted with 2 OR _'(C 1 ~C ₆₎ alkyl;
Or R ₇ and _{R 8} are the same, or different, or is H, or optionally substituted with one or two OR _'(C 1 ~C ₆₎ is alkyl;
R ₉ is a _{H, CN, OH, OCH 3} , SO 2 CH 3, SO 2 NH 2 or _(C 1 _{~C 6)} alkyl;
R'is H or (C _{1- C 6} ) alkyl; and R'is _{H or (C 1- C 6} ) alkyl;
However, it is assumed that (1) ^{the atom of Q 2 bonded to Q 1} is a carbon atom; and (2) ^{the atom of Q 4} bonded to ^{Q 3} is a carbon atom;
Or its racemic form, isomer, pharmaceutically acceptable derivative.

Preparations of such compounds are described in US200040106631, EP1400244, and WO2004 / 026818.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are commonly used in US Pat. No. 6,936,609 and US200402949148, each of which is expressly incorporated herein by reference in its entirety. It is selected from the specifically disclosed compounds. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ represents (C _{6 to} C ₁₀ ) -aryl, which is optionally substituted with the same or different groups, the groups being halogen, formyl, carbamoyl, cyano, hydroxyl. , Trifluoromethyl, trifluoromethoxy, nitro, selected from the group consisting of _{(C 1-} C ₆ ) -alkyl or (C _1- C ₆ ) -alkoxy, and optionally with _{6 groups of formula SO 2} NR ₅ R. In the formula, R ₅ and R ₆ represent hydrogen or (C _{1 to} C ₆ ) -alkyl independently of each other, or NR ₅ R ₆ is bonded by a nitrogen atom. Represents 4- to 8-membered heterocyclyls that are optionally substituted with the same or different groups, the groups being oxo, halogen, (C _1- C ₆ ) -alkyl and (C _1- C ₆ ). -Selected from the group consisting of acyl,
R ₂ represents a saturated or partially unsaturated hydrocarbon group having 1 to 10 carbon atoms.
R ₃ represents methyl or ethyl,
A represents O, S or NR ₇ , where R _{7 represents hydrogen or (C 1 to} C ₆ ) -alkyl optionally substituted with hydrogen or (C _{1 to} C _{3) -alkoxy.} ,
E is a bond or _(C 1 _{~C 3)} - represents alkanediyl,
R ₄ represents (C _{6 to} C ₁₀ ) -aryl or 5-10 membered heteroaryl, which aryl and heteroaryl are optionally substituted with groups to be the same or different and said. groups, halogen, formyl, carboxyl, carbamoyl, _-SO 3 H, aminosulfonyl, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, _{nitro, (C} 1 _{~C 6)} - _{alkyl, (C} 1 _~C 6) - alkoxy, 1,3-dioxa - _{propane-1,3-diyl, (C} 1 _{~C 6)} - _{alkylthio, (C} 1 _{~C 6)} - alkylsulfinyl and _(C 1 _{~C 6)} - alkyl - sulfonyl, Selected from the group consisting of −NR ₈ R ₉ and optionally methyl-substituted 5- to 6-membered heteroaryls or phenyls.
In the formula, R ₈ and R ₉ represent hydrogen, (C _{1 to} C ₆ ) -alkyl or (C _{1 to} C ₆ ) -acyl, or salts thereof, independently of each other.

The preparation of such compounds is described in US Pat. No. 6,936,609 and US200402949148.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are selected from compounds commonly or specifically disclosed in WO2006 / 092692, which is expressly incorporated herein by reference in its entirety. It is a thing. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

In the equation, n is an integer of 1 to 4, and if there are stereocenters, each center can be R or S independently.

The preparation of such compounds is described in WO 2006/092692.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are generally or specifically disclosed in US20022629306 and WO2004 / 065391, each of which is expressly incorporated herein by reference in its entirety. It is selected from compounds. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R ₁ and R ₂ 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, the alkyl, alkenyl and alkynyl groups are each independently optionally optionally substituted with one or more substituents and the substituents are , Halogen atom, hydroxy, alkoxy, aryloxy, alkylthio, hydroxycarbonyl, alkoxycarbonyl, mono- and di-alkylaminoacyl, oxo, amino, and mono- and di-alkylamino groups; or formula (c). (CH ₂ ) _{The group of n} −R ₆ in the formula, n is an integer from 0 to 4 and R ₆ represents a cycloalkyl or cycloalkenyl group;
(2) R ₁ and R ₂ form a 3- to 8-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur together with the nitrogen atom to which they are bonded. The ring is saturated or unsaturated and is optionally substituted with one or more substituents, the substituents being halogen atoms, alkyl, hydroxy, alkoxy, acyl, hydroxycarbonyl, Selected from alkoxycarbonyl, alkylenedioxy, amino, mono- and di-alkylamino, mono- and di-alkylaminoacyl, nitro, cyano and trifluoromethyl groups;
R ₃ is a group of the formula (CH ₂ ) _n−G , in which n is an integer from 0 to 4, and G is a monocyclic or bicyclic compound containing 0 to 4 heteroatoms. Representing an aryl or heteroaryl group, the group is optionally substituted with one or more substituents selected from (1)-(3) below.
(1) Halogen atom;
(2) Alkoxy and alkylene groups, each of which is independently optionally substituted with one or more substituents 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;
R ₄ represents a hydrogen atom, an alkyl or aryl group.

Preparations of such compounds are described in US20022629306 and WO2004 / 065391.

Other compounds useful in the method of the present invention include imidazole pyridine derivatives (WO2001 / 34601), dihydropurine derivatives (WO2000 / 68203), pyrrole derivatives (WO2001 / 32618), benzothiopyranoimidazolone derivatives (DE 19950647). , Heterocyclic compound (WO2002 / 87519), guanine derivative (Bioorg. Med. Chem. Lett. 11: 1081-1083, 2001), and benzothienothiasiazine derivative (Eur. J. Med. Chem. 36:). 333, 2001) can be mentioned. The disclosures of each of the above published patent applications and journal articles are expressly incorporated herein by reference in their entirety.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are selected from compounds commonly or specifically disclosed in WO2008 / 130619, which is incorporated herein by reference in its entirety. It is a thing. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

X is SO or SO ₂ and
R1 is H or alkyl
R2 is alkyl or halogen.

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

It is selected from.

In a related embodiment, PDE7 inhibitors useful for the methods of the invention are:

(During the ceremony,
R1 is alkyl
R2 is aryl or heteroaryl and is
R3 is alkyl, aryl, cycloalkyl or alkylaryl)
Have.

In a specific embodiment, R1 is methyl. In certain embodiments, R2 is flanyl 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

It is selected from.

In another related embodiment, PDE7 inhibitors useful in the methods of the invention are:

(During the ceremony,
R1 is a nitrile or alkyl carboxylate and
R2 is alkyl, aryl or heteroaryl)
Have.

In a specific embodiment, R1 is a nitrile or methyl carboxylate. In certain embodiments, R2 is a 5-membered heteroaryl. In a more specific embodiment, R2 is flanyl or thienyl. In other embodiments, R2 is a 6-membered aryl. In a more specific embodiment, R2 is a substituted phenyl.

In another related embodiment, PDE7 inhibitors useful in the methods of the invention are:

(During the ceremony,
R1 is an alkyl, alkenyl or alkylcarboxylic acid
R2 is a halogen)
Have.

In certain embodiments, R1 is butyl. In other embodiments, R1 is a terminal alkenyl. In a more specific embodiment, R1 is allyl or vinyl. In other embodiments, R1 is C _1-4 alkyl. In a specific embodiment, R1 is a methylcarboxylic acid. In certain embodiments, R2 is Cl or Br. In a more specific embodiment, the compound is

It is selected from.

In other related embodiments, PDE7 inhibitors useful for the methods of the invention are of the formula:

(During the ceremony,
R1 is a CO or alkyl alcohol, R2 is an alkyl, R3 is an alkoxy, and the C4 and C9 stereocenters are independently (R) or (S)).
Have.

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

It is selected from.

In another related embodiment, PDE7 inhibitors useful in the methods of the invention are:

(During the ceremony,
R1 is a hydrogen, hydroxyl, carbonyl or alkyl alcohol,
R2 and R3 are independently selected from hydrogen, alkyl, alkylcarboxylate 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))
Have.

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

It is selected from.

For the above compounds, the terms "alkyl", "alkenyl" and the prefix "alk-" include both straight-chain and branched-chain groups as well as cyclic groups (ie, cycloalkyl and cycloalkenyl). included. 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. The cyclic group may be monocyclic or polycyclic, and preferably has 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-" (eg, alkylcarboxylic acids, alkylalcohols, alkylcarboxylates, alkylaryls, etc.). Examples of suitable alkylcarboxylic acid groups are methylcarboxylic acid, ethylcarboxylic acid and the like. Examples of suitable alkyl alcohols are methyl alcohols, ethyl alcohols, isopropyl alcohols, 2-methylpropan-1-ol and the like. Examples of suitable alkyl carboxylates are methyl carboxylates, ethyl carboxylates and the like. Examples of suitable alkylaryl groups are benzyl, phenylpropyl and the like.

The term "aryl" as used herein includes a carbocyclic aromatic ring or ring system. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term "heteroaryl" includes an aromatic ring or ring system containing at least one ring heteroatom (eg, O, S, N). Suitable heteroaryl groups include frills, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindryl, thiazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl. , Benomidazolyl, quinoxalinyl, benzothiazolyl, naphthyldinyl, isooxazolyl, isothiazolyl, prynyl, quinazolinyl and the like.

Aryl and heteroaryl groups, even unsubstituted, are independently 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, alkenyl. Carbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, aryl Carbonyloxy, arylcarbonylthio, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino , Arylalkylcarbonylamino, arylcarbonylaminoalkyl, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, From the group consisting of heteroarylalkylsulfonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonylamino, heteroarylaminocarbonylamino, heteroarylalkylaminocarbonylamino and, in the case of heterocyclyl, oxo. It may be substituted with one or more substituents of choice. Where other groups are described as "substituted" or "optionally substituted," those groups may also be substituted with one or more of the substituents listed above.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are selected from compounds commonly or specifically disclosed in WO2008 / 142550, which is expressly incorporated herein by reference in its entirety. It is a thing. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

m is 0, 1 or 2, n is 0, 1, 2 or 3 and
X is O, S or N-CN,
R ¹ is halogen or CN and
A is a single bond, CH ₂ , O or S,
B is a single bond, CH ₂ or OCH ₂ , and R ² is an independent halogen, (optionally substituted with 1-3 fluorine atoms) (C _1-6 ) alkyl. OH, (C _1-6 ) alkylthio or CN,
R ³ is selected from the following groups (i)-(x):

R is H or (C _1-6 ) alkyl (optionally substituted with 1-3 fluorine atoms) and R'is (optionally substituted with 1-3 fluorine atoms). (C _1-6 ) Alkyl or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.

With respect to the above compounds, the term "alkyl" means 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, 3methylpentyl, 4-methylpentyl, 2-ethylbutyl and 2,2-dimethylbutyl. Preferred alkyl groups are particularly methyl and ethyl, especially methyl.

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 groups, difluoromethyl groups and trifluoromethyl groups (particularly trifluoromethyl groups) and monofluoroethyl groups, difluoroethyl groups and trifluoroethyl groups (particularly 2,2,2-trifluoroethyl groups) , Especially preferable.

The term "alkoxy" means "alkyl-O-" and "alkyl" is defined as described above, i.e. in its broadest or preferred embodiment. Preferred alkoxy groups are groups, especially methoxy and ethoxy. The term "alkylthio" means "alkyl-S-" and "alkyl" is defined as described 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 iodine. Preferred halogen groups are fluoro and chloro.

Preferably m is 0 or 1, more preferably 1.

Preferably n is 0 or 1, more preferably 0.

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

Preferably, R ¹ is F or Cl, more preferably Cl.

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

When B is OCH _2, the oxygen atom is bonded to the benzene ring, the methylene group is attached to the R ³ group.

Preferably, B is a single bond.

Preferably, R ² is F or Cl, more preferably F.

Preferably, ^{R 3} is, (i), (ii) , (iii), (iv), (v) or group (vi), more preferably (i) or (ii) group, in particular (ii) Is the basis of.

In one embodiment, the ^three -BR groups are located at the 2-position of the phenyl ring (the position of the A group is the 1-position). In other embodiments, the ^three -BRs are at the 3-position. In a further embodiment, the ^three -BRs are at the 4-position.

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

In a related embodiment, the following PDE7 inhibitors are useful for the methods of the invention:
5-[(8'-chloro-2'-oxo-2', 3'-dihydro-1'Η-spiro [cyclohexane-1,4'-quinazoline] -5'-yl)] -2-fluorobenzoic acid ,
3- (8'-Chloro-2-oxo-2', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazoline] -5'-ylbenzoic acid,
5-[(8'-chloro-2'-oxo-2', 3'-dihydro-1'Η-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)- On, [3- (8'-chloro-2'-oxo-2', 3'-dihydro-1'Η-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} benzoin acid,
3-Chloro-2-{(8'-fluoro-2'-oxo-2', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazoline] -5'-yl) oxy} benzoin acid,
8'-Chloro-5'-[2-Fluoro-6- (2H-Tetrazole-5-yl) Phenoxy] -1'H-Spiro [Cyclohexane-1,4'-Quinazoline] -2'(3'H) -On,
8'-Chloro-5'-[4-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazoline] -2'(3'H) -On, 8'-chloro-5'-[6-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazoline] -2'(3) 'H) -On,
8'-Chloro-5'-[4-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazoline] -2'(3'H ) -On,
8'-Chloro-5'-[6-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazoline] -2'(3'H ) -On,
8'-Chloro-5'-[6-chloro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazoline] -2'(3'H ) -On,
8'-Chloro-5'-[2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazoline] -2'(3'H) -on,
8'-Chloro-5'-[2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazoline] -2'(3'H) -on,
8'-Chloro-5'-[2-Fluoro-6- (5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) phenoxy] -1'H-spiro [cyclohexane -1,4'-quinazoline] -2'(3'H) -on,
8'-Chloro-5'-[2-Fluoro-6- (5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-yl) phenoxy] -1'H-spiro [cyclohexane] -1,4'-quinazoline] -2'(3'H) -on,
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-fluoro Phenyl} 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'-quinazoline-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-fluoro Benzoart,
And their pharmaceutically acceptable salts, solvates and prodrugs.

In another related embodiment, the following PDE7 inhibitors are useful in the methods of the invention:
8'-Chloro-5'-[2-Fluoro-6- (2H-Tetrazole-5-yl) Phenoxy] -1'H-Spirocyclohexane-1,4'-Quinazoline] -2'(3'H)- on,
8'-Chloro-5'-[4-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazoline] -2'(3'H) -On,
8'-Chloro-5'-[6-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'Η-spiro [cyclohexane-1,4'-quinazoline] -2'(3'H) -On,
8'-Chloro-5'-[4-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazoline] -2'(3'H ) -On,
8'-Chloro-5'-[6-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazoline] -2'(3'H ) -On,
8'-Chloro-5'-[6-chloro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazoline] -2'(3'H ) -On,
8'-Chloro-5'-[2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazoline] -2'(3'H) -on,
8'-Chloro-5'-[2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazoline] -2'(3'H) -on,
And their pharmaceutically acceptable salts, solvates and prodrugs.

The following compounds are most preferred:
8'-Chloro-5'-[2-Fluoro-6- (2H-Tetrazole-5-yl) Phenoxy] -1'H-Spiro [Cyclohexane-1,4'-Quinazoline] -2'(3'H) -On,
8'-Chloro-5'-[4-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazoline] -2'(3'H) -On,
8'-Chloro-5'-[6-fluoro-2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclopentane-1,4'-quinazoline] -2'(3'H ) -On,
8'-Chloro-5'-[2- (1H-tetrazol-5-yl) phenoxy] -1'H-spiro [cyclohexane-1,4'-quinazoline] -2'(3'H) -on,
And their pharmaceutically acceptable salts, solvates and prodrugs.

The preparation of such compounds is described in WO 2008/142550.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are generally found in US Pat. No. 7,499,334, US2005 / 0059686 and WO2003 / 055882, each of which is expressly incorporated herein by reference in its entirety. It is selected from the compounds disclosed specifically or specifically. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

X is phenyl or Het, each of which is unsubstituted or mono- or poly-substituted with R1 and / or R2, where R1 and R2 are independent of each other and A. , OH, OA, SA, SOA, SO2A, SO2NH2, SO2NHA, SO2AA', CN, NO2, NH2, NHA, NAA', NHCOA, NHCOOA, COOH, COOA, CONH2, CONHA, CONAA' or H, R' And R2 are both -OCH2O- 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, CONA' or H, and R4 is a branched or undivided chain having up to 10 carbon atoms. A branched alkyl or alkenyl, the alkyl or alkenyl may be substituted with 1 to 5 F and / or Cl atoms, and / or in the alkyl or alkenyl, one or more CH2 groups may be It may be replaced with O, S, SO, SO2, NH, NA, NHCO, NACO, NHCOO or NACOO, or cycloalkyl or cycloalkenyl having 3-7 carbon atoms, in said cycloalkyl or cycloalkenyl. One or two CH2 groups may be replaced with O, S, SO, SO2, SO2NH, SO2NA, NH, NHA, NHCONH, NACONH, NACONA, NHCO, NACO, NHCOO or NACOO, where R5 is OH, OA, SA, SOA, SO2A, SO2NH2, SO2NHA, SO2AA', CN, NO2, NH2, NHA, NAA', NHCOA, NHCOOA, COOH, COOA, CONH2, CONHA, CONAA'or Hall, where R6 is H, OH, OA, SA, SOA, SO2A, SO2NH2, SO2NHA, SO2AA', CN, NO2, NH2, NHA, NAA', NHCOA, NHCOOA, COOH, COOA, CONH2, CONHA, CONA' or H, A and A 'Is a branched or non-branched al, each independently of each other and having up to 10 carbon atoms. It is a kill or alkenyl, the alkyl or alkenyl may be substituted with 1-5 F and / or Cl atoms, and / or in the alkyl or alkenyl, one or more CH2 groups are O, S. , SO, SO2, NH, NR7, NHCO, NR7CO, NHCOO or NR7COO. A and A'are both alkylenes having 3 to 7 carbon atoms, and in the alkylene, one or two CH2 groups are CHR7, CHR7R8, O, S, SO, SO2. , NH, NR7, NHCO, NR7CO, NHCOO or NR7COO. B is phenyl or Het, each of which is unsubstituted or mono- or poly-substituted with R1 and / or R2, where Het is 1-3 N, O and / Or an aromatic 5- or 6-membered heterocycle with an S atom, which is unsubstituted or mono-, di- or tri-substituted with A ″, Hal or CF3, R7 and R8 is a branched or non-branched alkyl or alkenyl each independently having up to 5 carbon atoms, the alkyl or alkenyl being 1 to 5 F and / or Cl atoms. It may be substituted and / or in the alkyl or alkenyl, one or more CH2 groups may be substituted with O, S, SO, SO2 or NH, where A ″ is 1 to 6 carbon atoms. Alk of, Hall is F, Cl, Br or I, and their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions.

In a related embodiment, PDE7 inhibitors useful for the method of the present invention include compounds of the above formula (in the formula, R5 is OH), and formula:

It may be in the form of those tautomers of.

With respect to the above compounds, PDE7 inhibitors useful in the methods of the invention include optically activated forms (stereoisomers), optical isomers, racemic compounds, diastereomers and hydrates and solvates of these compounds. Can be mentioned. The term solvate of a compound means an adduct of an inert solvent molecule to the compound, which is produced by their mutual attraction. The solvate is, for example, monohydrate, dihydrate or alcoholate.

With respect to the above compounds, the term pharmaceutically usable derivative means, for example, salts of the above compounds and so-called prodrug compounds. The term prodrug derivative means, for example, the above compounds that are modified with, for example, alkyl or acyl groups, sugars or oligopeptides and rapidly degraded in an organism to release the active compound. These include, for example, Int. J. Pharm. As described in 115, 61-67 (1995), biodegradable polymer derivatives of the above compounds are also mentioned.

With respect to the above compounds, the meanings of all the groups that appear more than once are independent of each other each time.

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

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

A ″ is preferably an 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. Is also n-pentyl, neopentyl, isopentyl or n-hexyl. Methyl, ethyl, propyl, isopropyl or butyl are particularly preferred.

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

The alkenyl is preferably vinyl, allyl, 2-butenyl or 3-butenyl, isobutenyl or sec-butenyl; and even more preferably 4-pentenyl, isopentenyl or 5-hexenyl.

The alkylene is preferably a non-branched chain, preferably methylene or ethylene, more preferably propylene or butylene.

Hal is preferably F, Cl or Br, and is also I.

The R1 and R2 groups may be the same or different, preferably at the 2nd or 4th position of the phenyl ring. They are, for example, A or Hal, or both methylenedioxy, independent of each other.

However, they are preferably methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, respectively, but fluoromethoxy, difluoromethoxy or trifluoromethoxy or 1-fluoroethoxy, 2-fluoroethoxy, respectively. , 1,2-Difluoroethoxy, 2,2-difluoroethoxy, 1,2,2-trifluoroethoxy or 2,2,2-trifluoroethoxy, as well as fluorine or chlorine.

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

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

X is preferably a R1-substituted phenyl group or an unsubstituted Het.

X is particularly preferably 2-chlorophenyl, 2-fluorophenyl, 4-methyl-phenyl, 3-chlorophenyl or 4-chlorophenyl.

Het is preferably, for example, an unsubstituted 2-furyl or 3-furyl, 2-thienyl or 3-thienyl, 1-pyrrolyl, 2-pyrrolill or 3-pyrrolill, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl. Alternatively, 5-imidazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl, more preferably 1,2,3-triazole-1-yl, 1, 2,3-Triazole-4-yl or 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl or 1,2, 4-Triazole-5-yl, 1,2,3-oxadiazole-4-yl or 1,2,3-oxadiazole-5-yl, 1,2,4-oxadiazole-3-yl or 1,2,4-oxadiazole-5-yl, 1,3,4-thiazole-2-yl or 1,3,4-thiazole-5-yl, 1,2,4-thiazole-3-yl or 1,2,4-thiazidol-5-yl, or 1,2,3-thia-diazole-4-yl or 1,2,3-thia-diazole-5-yl.

R3 is preferably, for example, COOA ″ or COOH.

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

R5 is preferably Cl or OH.

R6 is preferably H.

With respect to the above compounds, at least one said group has one of the preferred meanings shown above.

In a related embodiment, PDE7 inhibitors useful for the methods of the invention are the following compounds (where X is a R1-substituted phenyl group or an unsubstituted Het; R1 is A or Hal; R3 is COOA ″ or COOH; R4 is a non-branched or branched chain alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms. May be substituted with 1-5 F or Cl atoms; R5 is Cl or OH; R6 is H);
In other related embodiments, PDE7 inhibitors useful for the methods of the invention include the following compounds, where X is a R1-substituted phenyl group or an unsubstituted Het, R1. Is A or H, R3 is COOA "or COOH, and R4 is a non-branched or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms. , This alkyl may be substituted with 1-5 F or Cl atoms, R5 is Cl or OH, R6 is H and Het is frill, thienyl, pyrrolyl, imidazolyl, pyridyl or Pyrimidinyl, A and A ″ are non-branched or branched alkyls having 1, 2, 3, 4, 5 or 6 carbon atoms, respectively, independent of each other, which is 1 May be substituted with ~ 5 F or Cl atoms, Hal is F, Cl or Br) and its pharmaceutically usable derivatives, solvates and sterics, including their mixture in all proportions. Examples include isomers.

Preparation of the above compounds and starting materials for their preparation are available in the literature (eg, Houben-Weil, Methodon der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart, etc. ), And is rigorous under reaction conditions known and suitable for the reaction. Although not mentioned in more detail here, a variant (the variant itself is known) can also be used here.

In another related embodiment, as a PDE7 inhibitor useful for the methods of the invention:
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-tryl-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-pyrimidine [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 all. Included are their pharmaceutically usable derivatives, solvates and steric isomers, including their mixtures in proportion.

Preparations of the above compounds are described in US Pat. No. 7,499,334 and WO 2003/055882.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are general or specific in US Pat. No. 6,884,800 and WO01 / 36425, each of which is expressly incorporated herein by reference in its entirety. It is selected from the compounds disclosed in. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R1 and R2 independently mean A1, OA1, SA1 or Hal, respectively, A1 means H, A, alkenyl, cycloalkyl or alkylenecycloalkyl, and A means 1-10. Alk with a carbon atom, H means F, Cl, Br or I, x means O, S, SO or SO2, and their physiologically acceptable salts and / or Solvation product.

With respect to the above compounds, A means alkyl having 1-10 carbon atoms, preferably 1,2,3,4,5,6,7,8,9 or 10 carbon atoms. Means 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, 1-7 H atoms may be replaced with F and / or Cl. Thus, A also means, for example, trifluoromethyl or pentafluoroethyl. Cycloalkyl has 3 to 9 carbon atoms and preferably means, for example, cyclopentyl or cyclohexyl. Alkenyl has 2 to 10 carbon atoms and is straight or branched, preferably meaning vinyl, propenyl or butenyl. The alkylenecycloalkyl has 4 to 10 carbon atoms and means, for example, methylenecyclopentyl, ethylenecyclopentyl, methylenecyclohexyl or ethylenecyclohexyl. R1 and R2 preferably mean H, fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, cyclopentyl or cyclohexyl, respectively, independently of each other.

In a related embodiment, the PDE7 inhibitor useful for the method of the present invention includes the following compounds (in the formula,
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 and A is an alkyl having 1, 2, 3 or 4 carbon atoms;
X is S, R1 and R2 are independent of each other, meaning A1 or H, respectively, A1 is H or A, and A is 1, 2, 3 or 4 carbon atoms. Alkyl having, Hal is F or Cl)
And the physiologically acceptable salts and solvates thereof.

In another related embodiment, PDE7 inhibitors useful for the methods of the 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, 10-propoxy- 3-Imidazole-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] 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- Imidazole-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- Imidazole-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.

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

In another embodiment, PDE7 inhibitors useful in the methods of the invention are generally found in US Pat. No. 6,531,498 and WO01 / 32175, each of which is expressly incorporated herein by reference in its entirety. It is selected from the compounds disclosed specifically or specifically. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R1, R2, R3, R4 are Hal, OA1, SA1, A, H, COOA1, CN or CONA1A2, respectively, independently of each other.
R5 is COOA1, CN or CONA1A2
A1 and A2 are H, A, alkenyl, cycloalkyl or alkylenecycloalkyl, respectively, independently of each other.
A is an alkyl having 1 to 10 C atoms.
Hal is F, Cl, Br or I,
And their physiologically acceptable salts and / or solvates.

With respect to the above compounds, A is an alkyl having 1-10 C atoms, having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, preferably. Methyl, ethyl or propyl, and preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl. The 1 to 7 H atoms in the group may be replaced with F and / or Cl. Therefore, A is also, for example, trifluoromethyl or pentafluoroethyl.

Cycloalkyl has 3 to 9 C atoms, preferably, for example, cyclopentyl or cyclohexyl. The alkenyl has 2 to 10 C atoms and is straight or branched, preferably vinyl, propenyl or butenyl.

The alkylenecycloalkyl has 4 to 10 C atoms and is, for example, methylenecyclopentyl, ethylenecyclopentyl, methylenecyclohexyl or ethylenecyclohexy.

In a related embodiment, the PDE7 inhibitor useful for the method of the present invention is a compound (in the formula,
R1 is H;
R1 and R2 are H;
R1 is H and R2 is F or Cl;
R1 and R2 are H or H, respectively, independent of each other;
R1 and R2 are independent of each other and are H or H, and A1 and A2 are independent of each other and are H or A;
A1 and A2 are H or A, respectively, independent of each other;
R1 and R2 are independent of each other and are H or H, A1 and A2 are independent of each other and are H or A, and A has 1, 2, 3 or 4 C atoms. Alkyl, H is F or Cl)
Can be mentioned.

In another related embodiment, the PDE7 inhibitor useful for the method of the invention is compound:
5- [2- (2-fluoro-4-hydroxyphenylamino) vinyl] -4-cyano-3-phenylisoxazole,
5- [2- (2,4-difluorophenylamino) vinyl] -4-cyano-3-phenylisoxazole,
5- [2- (3-Methylthiophenylamino) vinyl] -4-cyano-3-phenylisoxazole,
5- [2- (2,4-dimethoxyphenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isooxazole,
5- (2-Amino-2-phenylvinyl) -4-methylaminocarbonyl-3-phenylisoxazole,
5- (2-Phenylaminovinyl) -4-methoxycarbonyl-3-phenylisoxazole,
5- [2- (4-carboxyphenylamino) vinyl] -4-cyano-3-phenylisoxazole,
5- [2- (4-carboxyphenylamino) vinyl] -4-methoxycarbonyl-3-phenylisoxazole,
5- [2- (5-Chloro-2-hydroxyphenylamino) vinyl] -4-cyano-3-phenylisoxazole,
5- [2- (3,4-Dimethylphenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isooxazole,
5- [2- (4-chlorophenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isoxazole,
5- (2-Phenylaminovinyl) -4-cyano-3- (2-chlorophenyl) isoxazole,
5- [2- (4-Methoxyphenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isoxazole,
5- [2- (4-carboxyphenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isooxazole,
5- [2- (2-Fluoro-4-hydroxyphenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isooxazole,
5- [2- (4-fluorophenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isooxazole,
5- [2- (3,5-dichlorophenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isoxazole,
5- [2- (3-Chlorophenylamino) vinyl] -4-cyano-3- (2-chlorophenyl) isoxazole,
5- (2-Phenylaminovinyl) -4-cyano-3- (2,6-dichlorophenyl) isoxazole,
5- [2- (4-chlorophenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,
5- (2-Phenylaminovinyl) -4-methoxycarbonyl-3- (2,6-dichlorophenyl) isoxazole,
5- [2- (4-Chlorophenylamino) vinyl] -4-methoxycarbonyl-3- (2,6-dichlorophenyl) isoxazole,
5- [2- (4-carboxyphenylamino) vinyl] -4-methoxycarbonyl-3- (2,6-dichlorophenyl) isoxazole,
5- [2- (2,4-difluorophenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isooxazole,
5- [2- (2,4-dichlorophenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,
5- [2- (4-carboxyphenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,
5- [2- (3,5-dichlorophenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,
5- [2- (4-Methoxyphenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,
5- [2- (2,4-dimethoxyphenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,
5- [2- (2-Phenylphenylamino) Vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,
5- [2- (4-Methylphenylamino) vinyl] -4-cyano-3- (2,6-dichlorophenyl) isoxazole,
5- (2-Phenylaminovinyl) -4-cyano-3- (2-chloro-6-fluorophenyl) isoxazole,
5- [2- (4-carboxyphenylamino) vinyl] -4-cyano-3- (2-chloro-6-fluorophenyl) isooxazole,
5- [2- (4-Chlorophenylamino) vinyl] -4-cyano-3- (2-chloro-6-fluorophenyl) isooxazole,
5- [2- (3-Methoxyphenylamino) vinyl] -4-cyano-3- (2-chloro-6-fluorophenyl) isooxazole,
5- [2- (4-Chlorophenylamino) vinyl] -4-methoxycarbonyl-3- (2-chloro-6-fluorophenyl) isooxazole,
5- (2-Phenylaminovinyl) -4-methoxycarbonyl-3- (2-chloro-6-fluorophenyl) isooxazole,
5- [2- (2,4-dichlorophenylamino) vinyl] -4-methoxycarbonyl-3- (2-chloro-6-fluorophenyl) isooxazole,
5- (2-Phenylaminovinyl) -4-cyano-3-phenylisoxazole,
5- [2- (3-trifluoromethoxyphenylamino) vinyl] -4-cyano-3-phenylisoxazole,
5- [2- (4-Methoxyphenylamino) vinyl] -4-cyano-3-phenylisoxazole,
5- [2- (4-Methoxyphenylamino) vinyl] -4-methoxycarbonyl-3- (2-chloro-6-fluorophenyl) isooxazole,
5- [2- (3-Methylthiophenylamino) vinyl] -4-cyano-3-phenylisoxazole,
5- [2- (2,4-difluorophenylamino) vinyl] -4-cyano-3-phenylisoxazole,
Examples thereof include 5- [2- (2-fluoro-4-hydroxyphenylamino) vinyl] -4-cyano-3-phenylisoxazole.

The preparation of such compounds is described in US Pat. No. 6531498 and WO 01/32175.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are general or specific in US Pat. No. 7,491,742 and WO 2001/29049, each of which is expressly incorporated herein by reference in its entirety. It is selected from the compounds disclosed in. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R1 is H, A, benzyl, indane-5-yl, 1,2,3,4-tetrahydronaphthalene-5-yl, dibenzothien-2-yl, or unsubstituted, or Hal, A, A. -CO-NH, benzyloxy, alkoxy, COOH or COOA-substituted, di- or tri-substituted phenyls, R2 is H or A, X is O or S, Hal is F. , Cl, Br or I, where A is an alkyl having 1 to 6 C atoms, and physiologically acceptable salts and / or solvates thereof.

With respect to the above compounds, A is an alkyl having 1 to 6 C atoms, having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl or propyl, and preferably methyl, ethyl or propyl. Is isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but is also n-pentyl, neopentyl, isopentyl or hexyl. A is also a cycloalkyl such as cyclohexyl, for example. Alkoxy is preferably methoxy, ethoxy, propoxy or butoxy. Hal is preferably F or Cl. A-CO-NH is preferably acetamide.

In a related embodiment, PDE7 inhibitors useful for the methods of the invention are selected from the following compounds:
1-phenyl- [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1-benzyl- [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1-cyclohexyl- [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1-cyclopentyl- [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1-butyl- [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1-isopropyl- [1] benzopyrano [3,4-d] imidazol-4- (1H) -on, 1-propyl- [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1-ethyl- [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1-Methyl- [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 2-methyl- [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1-phenyl- [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1-benzyl- [1] Benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1-cyclohexyl- [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1-cyclopentyl- [1] Benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1-butyl- [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1-isopropyl- [1] Benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1-propyl- [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1-ethyl- [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1-methyl- [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -on, [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 2-methyl- [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1- (2-chlorophenyl- [ 1] Benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (4-methyl-phenyl)-[1] benzopyrano [3,4-d] imidazol-4- (1H) -one , 1- (4-fluorof) Enyl)-[1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1- (2,4-dimethyl-phenyl)-[1] benzopyrano [3,4-d] imidazole-4 -(1H) -one, 1- (3-chlorophenyl)-[1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (2,4-dichlorophenyl)-[1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (2,5-dichlorophenyl)-[1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (4-Acetamide-phenyl)-[1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1- (2-fluorophenyl)-[1] benzopyrano [3,4-d] imidazole -4- (1H) -one, 1- (3-fluorophenyl)-[1] benzopyrano [3,4-d] imidazole-4- (1H) -one, 1- (2-benzyloxy-phenyl)- [1] Benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (2,6-dimethyl-phenyl)-[1] benzopyrano [3,4-d] imidazol-4- (1H) ) -On, 1- (indan-5-yl)-[1] benzopyrano [3,4-d] imidazol-4- (1H) -on, 1- (2-methoxy-phenyl)-[1] benzopyrano [ 3,4-d] Imidazole-4- (1H) -one, 1- (2,3-dimethyl-phenyl)-[1] benzopyrano [3,4-d] imidazole- (1H) -4-one, 1 -(2,3-dichlorophenyl)-[1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (3-chloro-4-methyl-phenyl)-[1] benzopyrano [3] , 4-d] Imidazole-4- (1H) -one, 1- (2,5-dimethyl-phenyl)-[1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (4-Chlorophenyl)-[1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (1,2,3,4-tetrahydronaphthalene-5-yl)-[1] benzopyrano -[3,4-d] imidazol-4- (1-H) -one, 1- (dibenzothien-2-yl)-[1] benzopyrano [3,4-d] imidazol-4- (1H)- On, 1- (3-methoxy-phenyl)-[1] benzopyrano [3,4-d] imidazol-4- (1H) -on, 1- (4-carboxy-2-methyl-phenyl)-[1] benzopyrano [3,4-d] imidazol-4- (1H) -one and their physiologically acceptable salts and / or solvates thereof (Sovates).

In another embodiment, PDE7 inhibitors useful in the methods of the invention are commonly or commonly used in US Pat. No. 6,737,436 and WO01 / 32618, which are expressly incorporated herein by reference in their entirety. It is selected from the specifically disclosed compounds. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R1 and R2 independently mean H, A, OA, SA or H, respectively.
R3 means H or A
R4 means A or NH2
R5 means H, NH2, NHA or NA2,
A means alkyl, alkenyl, cycloalkyl or alkylenecycloalkyl having 1 to 10 carbon atoms.
Hal means F, Cl, Br or I, and physiologically acceptable salts and / or solvates thereof.

With respect to the above compounds, A means alkyl having 1-10 carbon atoms, preferably 1,2,3,4,5,6,7,8,9 or 10 carbon atoms. Means 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, 1-7 H atoms may be replaced with F and / or Cl. Thus, A also means, for example, trifluoromethyl or pentafluoroethyl.

A also means cycloalkyl having 3 to 8 carbon atoms, preferably, for example, cyclopentyl or cyclohexyl.

A also means alkenyl. Alkenyl has 2 to 10 carbon atoms and is straight or branched, meaning, for example, vinyl, propenyl or butenyl. A further means alkylene cycloalkyl. The alkylenecycloalkyl has 4 to 10 carbon atoms and preferably means, for example, methylenecyclopentyl, ethylenecyclopentyl, methylenecyclohexyl or ethylenecyclohexyl.

R1 and R2 are preferably independent of each other, H, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, S-methyl, S-ethyl, F. Or it means Cl.

R3 preferably means H, methyl or ethyl.

R4 preferably means methyl, ethyl, propyl, butyl or NH2.

R5 preferably means H, amino, methylamino, ethylamino, dimethylamino or diethylamino.

In a related embodiment, PDE7 inhibitors useful for the method of the present invention include the above formulas (in the formula, R1 and R2 are not both H, and if one of R1 or R2 is H, the other is CH3, Compounds (which cannot be OCH3 or Cl) can be mentioned.

In another related embodiment, the PDE7 inhibitor useful for the method of the invention is a compound (in the formula,
R1, R2, R3 and R5 are H and R4 is methyl;
R1 is 4-Cl, R2 is H, R3 is ethyl, R4 is amino, and R5 is H;
R1 and R2 are H, R3 is ethyl, R4 is methyl, and R5 is amino;
R1 and R2 are H, R3 is ethyl, R4 is amino, and R5 is H;
R1 and R2 are H, R3 is ethyl, R4 is H, and R5 is amino;
R1 is 3-Cl, R2 is 4-O-methyl, R3 is ethyl, R4 is amino, and R5 is H;
R1 is 3-Cl, R2 is 4-O-methyl, R3 is ethyl, R4 is methyl, and R5 is amino;
R1 is 4-OCF3, R2 is H, R3 is ethyl, R4 is amino, and R5 is H;
R1 is 3-Cl, R2 is 4-O-methyl, R3 is ethyl, R4 is amino, and R5 is H;
R1 is 3-Cl, R2 is 4-O-methyl, R3 is ethyl, R4 is methyl, and R5 is amino;
R1 is 4-OCF3, R2 is H, R3 is ethyl, R4 is amino, and R5 is H).
Can be mentioned.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are commonly used in US Pat. No. 6,613,778 and WO01 / 34601, which are expressly incorporated herein by reference in their entirety. It is selected from the specifically disclosed compounds. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R1 means CONR4R5
R2 means H or A
R4 and R5, independent of each other, mean H or A1, respectively.
R3 means Hal
Hal means F, Cl, Br or I,
A means an alkyl having 1 to 4 carbon atoms.
A1 means an alkyl having 1 to 10 carbon atoms.
X means an alkylene having 1 to 4 carbon atoms, in which the ethylene group may be replaced with a double or triple bond.
And their physiologically acceptable salts and / or solvates.

With respect to the above compounds, A means alkyl having 1 to 4 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms, preferably methyl, ethyl or propyl, more preferably isopropyl. It means butyl, isobutyl, sec-butyl or tert-butyl. The 1 to 7 H atoms in the group may be replaced with F and / or Cl. Thus, A also means, for example, trifluoromethyl or pentafluoroethyl.

A1 means alkyl having 1 to 10 carbon atoms, having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably methyl, ethyl or It means propyl, more preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl. The 1 to 7 H atoms in the group may be replaced with F and / or Cl. Thus, A1 also means, for example, trifluoromethyl or pentafluoroethyl.

X means an alkylene having 1 to 4 carbon atoms, preferably methylene, ethylene, propylene or butylene, in which one ethylene group may be replaced with a double or triple bond. Therefore, X is, for example,

Also means.

In a related embodiment, PDE7 inhibitors useful for the methods of the invention include the following compounds:
2- (3-Butyl-7-chloro-3H-imidazole [4,5-c] pyridin-4-ylsulfanyl) -N, N-dimethylacetamide

2- (3-Butyl-7-chloro-3H-imidazole [4,5-c] pyridin-4-ylsulfanyl) acetamide,
2- (3-Butyl-7-chloro-3H-imidazole [4,5-c] pyridin-4-ylsulfanyl) propionamide,
2- (3-Butyl-7-chloro-3H-imidazole [4,5-c] pyridin-4-ylsulfanyl) butyramide,
2- (3-Butyl-7-chloro-3H-imidazole [4,5-c] pyridin-4-ylsulfanyl) -N-hexylacetamide,
2- (3-Butyl-7-chloro-3H-imidazole [4,5-c] pyridin-4-ylsulfanyl) -N-octylacetamide,
4- (3-Butyl-7-chloro-3H-imidazole [4,5-c] pyridin-4-ylsulfanyl) -buta-2-enoic acid dimethylamide.

In another related embodiment, the PDE7 inhibitor useful for the method of the present invention includes the following compounds (in the formula,
R3 is Cl;
R3 is Cl and X is an alkylene having 1 to 4 carbon atoms;
R3 is Cl, X is an alkylene having 1, 2, 3 or 4 carbon atoms, and A1 is an alkyl having 1, 2, 3 or 4 carbon atoms).
Can be mentioned.

The preparation of such compounds is described in US Pat. No. 6,613,778 and WO 01/34601.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are generally or specifically disclosed in WO2008 / 113881 and ESP200700762, each of which is expressly incorporated herein by reference in its entirety. It is selected from compounds. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows:
A is a 5, 6 or 7-membered fused carbocyclo or heterocyclo, saturated or may be unsaturated; dotted lines independently represent single or double bonds; X and Y are independent. Then, it is selected from the group consisting of alkyl, hydrogen, = O, = S, -N (alkyl), -N (aryl), aryl, O-alkyl, O-aryl, alkyl-S and -S-aryl. R1 and R2 are independently hydrogen, halogen, alkyl, haloalkyl, aryl, cycloalkyl, (Z) _n -aryl, heteroaryl, -OR3; -C (O) OR3,-(Z) _n- C. (O) A pharmaceutically acceptable salt, derivative, prodrug, solvate or steric isomer of the compound selected from the group consisting of OR3 and —S (O).

Exception: X = O, Y = S if A is unsubstituted benzene, X = O, Y = O if A is unsubstituted benzene, and A is unsubstituted. If it is benzene, then X = O, Y = S-Me, if A is an unsubstituted thiophene, then X = O, Y = S, and if A is an unsubstituted benzothiophene. X = O and Y = S.

In a related embodiment, the compound comprises a therapeutically effective amount of the compound or a mixture of the compounds, salts, derivatives, prodrugs, solvates or pharmaceutically acceptable stereoisomers of the compound. Consists of a useful pharmaceutical composition for IV administration to a patient, including with an adjunct or a pharmaceutically acceptable vehicle.

In other related embodiments, PDE7 inhibitors useful for the methods of the invention include the following compounds: 4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline and selected from the following groups. Its derivatives to be:

6-Bromo-2,3,4-tetrahydroquinazoline, 6-bromo- (2,6-difluorophenyl) -4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline, 6-bromo- ( 2,3,4-Trifluorophenyl) -4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline, 6-bromo- (2-bromophenyl) -4-oxo-2-dioxo-1 , 2,3,4-tetrahydroquinazoline, 3- (2,6-difluorophenyl) -8-methyl-4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline, 3- (2,3) , 4-Trifluorophenyl) -8-methyl-4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline and 3- (2-bromophenyl) -8-methyl-4-oxo-2- Dioxo-1,2,3,4-tetrahydroquinazoline.

In a further related embodiment, PDE7 inhibitors useful for the methods of the invention include the following compounds: 2-methylthio-4-oxo-3,4-dihydroquinazoline and its derivatives selected from the following group:

6-Bromo- (2,6-difluorophenyl) -2-methylthio-4-oxo-3,4-dihydroquinazoline, 6-bromo- (2,3,4-trifluorophenyl) -2-methylthio-4- Oxo-3,4-dihydroquinazoline, 6-bromo- (2-bromophenyl) -2-methylthio-4-oxo-3,4-dihydroquinazoline, 3-phenyl-8-methyl-2-methylthio-4-oxo -3,4-dihydroquinazoline, 3- (2,6-difluorophenyl) -8-methyl-2-methylthio-4-oxo-3,4-dihydroquinazoline, 3- (2,3,4-trifluorophenyl) ) -8-Methyl-2-methylthio-4-oxo-3,4-dihydroquinazoline and 3- (2-bromophenyl) -8-methyl-2-methylthio-4-oxo-3,4-dihydroquinazoline.

In another related embodiment, PDE7 inhibitors useful for the methods of the invention include the following compounds: 2,4-dithioxo-1,2,3,4-tetrahydroquinazoline and selected from the following group. Its derivative:

3-Phenyl-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline, 3- (2,6-difluorophenyl) -2,4-dithioxo-1,2,3,4-tetrahydroquinazoline and 3 -(2,3,4-trifluorophenyl) -2,4-dithioxo-1,2,3,4-tetrahydroquinazoline.

In another related embodiment, PDE7 inhibitors useful for the methods of the invention include the following compounds: (2-methylthio-4-thioxo-3,4-dihydroquinazoline) and selected from the following groups: Its derivative:

3-Phenyl-2-methylthio-4-thioxo-3,4-dihydroquinazoline, 3- (2,6-difluorophenyl) -2-methylthio-4-thioxo-3,4-dihydroquinazoline, 3- (2, 3,4-Trifluorophenyl) -2-methylthio-4-thioxo-3,4-dihydroquinazoline and 3- (2-bromophenyl) -2-methylthio-4-thioxo-3,4-dihydroquinazoline.

Preparations of the above compounds are described in WO 2008/113881.

In a related embodiment, PDE7 inhibitors useful for the methods of the invention are those described in ESP200700762, which is expressly incorporated herein by reference in its entirety. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are described in US Pat. No. 7,214,676 and U.S.A. S. It is selected from the compounds generally or specifically disclosed in 2007/0049558, each of which is expressly incorporated herein by reference in its entirety. In one embodiment, PDE7 inhibitors useful for the methods of the invention include the following compounds:
Spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 6'-methoxyspiro [cyclohexane-1-4'-(3', 4') -Dihydro) quinazoline] -2'(1'H) -on, spiro [cycloheptane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 7' − , 4'-dihydro) quinazoline] -2'(1'H) -on, 8'-methoxyspiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H ) -On, 8'-chlorospiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 7'-chlorospiro [cyclohexane-1--4'- (3', 4'-dihydro) quinazoline] -2'(1'H) -on, 5'-chlorospiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1) 'H) -on, 8'-methylspiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 6'-chlorospiro [cyclohexane-1--4] '-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 8'-bromospiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 8'-fluorospiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 6'-methylspiro [cyclohexane- 1-4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 5', 8'-dichlorospiro [cyclohexane-1--4'-(3', 4'-) Dihydro) quinazoline] -2'(1'H) -on, 6', 7'-dichlorospiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -On, 5', 6'-dichlorospiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 6'-phenylspiro [cyclohexane-1] -4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 8'-iodospiro [cyclohexane-1-4'-(3', 4'-dihydro) quinazoline ] -2'(1'H) -on, 8'-bromospiro [cyclobutane-1--4-'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 8'-bromospiro [Cycloheptane-1-4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-bromo-4-methylspiro [Cyclohexane-1--4'-(3') , 4'-dihydro) quinazoline] -2'(1'H) -on, 8'-bromospiro [bicyclo [3,2,1] octane-2-4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 6', 8'-dichlorospiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 8 '-Chloro-6'-iodospiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-methoxyspiro [cyclohexane] -1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 8'-chloro-6'-phenylspiro [cycloheptane-1-4'-(3') , 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-phenylspiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2 '(1'H) -on, 8'-chloro-6'-methylspiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 8'-Chloro-6'-(3-pyridyl) spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'- (4-Pyridyl) spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 6'-(4-carboxyphenyl) -8'-chlorospiro [Cyclohexane-1- (3', 4'-dihydro) quinazoline] -2'(1'H) -one, 6'-(3-carboxyphenyl) -8'-chlorospiro (cyclohexane-1--4) '-(3', 4'-dihydro) -quinazoline] -2'(1'H) -on, 8'-chloro-6'-(1H-indole-5-yl) spiro [cyclohexane-1--4'- (3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-(2-pyridyl) spiro [cyclohexane-1--4'-(3', 4') -Dihydro) quinazoline] -2'(1'H ) -On, 8'-chloro-6'-(3-dimethylamino-propa-1-ynyl) spiro [cyclohexane-1--4'-(3', 4'-dihydro) -quinazoline] -2'(1) 'H) -on, 8'-chloro-6'-(3-methylamino-propa-1-ynyl) spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'( 1'H) -on, 8'-chloro-6'-[4- (4-methyl-piperazin-1-carbonyl) phenyl] spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline ] -2'(1'H) -on, 8'-chloro-6'-[4- (3-N-dimethylamino-propylcarboxamide) phenyl] -spiro- [cyclohexane-1--4'-(3') , 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-[4- (2-N-dimethylamino-ethylcarboxamide) phenyl] -spiro- [cyclohexane-1 -4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-[3- (3-N-dimethylamino-propylcarboxamide) phenyl] -Spiro- [cyclohexane-1--4-'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-[3- (4-methyl-piperazine) -1-carbonyl) -phenyl] spiro- [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-[3 -(2-N-Dimethylamino-ethylcarboxamide) phenyl] spiro- [cyclohexane-1--4-'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chlorospiro [Cyclohexane-1- (3', 4'-dihydro) quinazoline] -2'(1'H) -thione, 8'-chloro-2'-cyanoiminospiro [Cyclohexane-1--4'-( 3', 4'-dihydro) quinazoline, 8'-chloro-6'-[4- (4-pyrimidin-2-yl-piperazin-1-carbonyl) phenyl] spiro [-cyclohexane-1--4'-(3) ', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-[4- (4- (2-morpholin-4-yl-ethyl) -piperazin-1- Carbonyl) -phenyl] spiro [-cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -o , 8'-Chloro-6'-[4- (4- (2-morpholin-4-yl-2-oxo-ethyl) -piperazin-1-carbonyl) -phenyl] Spiro [-cyclohexane-1--4'-(3',4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-[4- (4- (2-hydroxy-ethoxy) -ethyl) -piperazin- 1-carbonyl) -phenyl] spiro [-cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, spiro [cyclohexane-1-9'-(8) ', 9'-dihydro) -pyrazolo [4', 3'-f] quinazoline] -7'(6'H) -on, 8'-chloro-5'-methoxyspiro [cyclohexane-1--4'-( 3', 4'-dihydro) quinazoline] -2'(1'H) -on, 5', 8'-difluorospiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2 '(1'H) -on, 8'-chloro-5'-methylspiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 8'-Chloro-6'-(morpholin-4-yl) methylspiro [cyclohexane-1--4-'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-5 '-Hydroxyspiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 8'-chloro-5'-hydroxy-6'-iodo-spiro [Cyclohexane-1- (3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-iodo-5'-methoxy-spiro [cyclohexane-1 -4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-cyano-5'-methoxy-spiro [cyclohexane-1--4'- (3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-5'-[2- (4-morpholino) ethoxy] spiro [cyclohexane-1--4'-( 3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-5'-[2-dimethylaminoethoxy] spiro [cyclohexane-1--4'-(3', 4''-Dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-5'-(2-aminoethoxy) -spiro [cyclohexane-1--4'-(3', 4'-dihydro) Quinazoline] -2'(1'H) -one, 8'-chloro-5'-[2- (methylamino) ethoxy] -spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline]- 2'(1'H) -on, 8'-chloro-5'-[2- (2-aminoethoxy) ethoxy] spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline]- 2'(1'H) -one, 8'-chloro-5'-[3-dimethylaminopropoxy] spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1) 'H) -on, 8'-chloro-5'-ethoxycarbonylmethoxyspiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 5'-Carboxymethoxy-8'-chloro-spiro[cyclohexane-1--4'-(3',4'-dihydro) quinazoline] -2'(1'H) -on, 5'-carboxypropoxy-8'-chloro -Spiro [cyclohexane-1-4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-5'-(3-sulfopropoxy) -spiro [cyclohexane] -1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 8'-chloro-5'-[2- (tetrahydro-piran-2-yloxy) -ethoxy ] -Spiro [Cyclohexane-1--4-'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 8'-chloro-5'-(2-hydroxy-ethoxy) -spiro [Cyclohexane-1- (3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-5'-(5-ethoxycarbonyl-furan-2-ylmethoxy) -Spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-5'-(5-carboxy-furan-2-ylmethoxy) ) -Spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-5'-cyanomethoxyspiro [cyclohexane-1--4] '-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-5'-(1H-tetrazol-5-ylmethoxy) -spiro [cyclohexane-1--4'-(3',4'-dihydro) quinazoline] -2'(1'H) -on, 8'-chloro-5'-(5-hydroxy- [1,2,4] ] Oxadiazole-3-ylmethoxy) -spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-iodoine -5'-[2-Dimethylamino-ethoxy] spiro [Cyclohexane-1--4'-(3', 3',
4'-dihydro) quinazoline] -2'(1'H) -one, 6'-(4-carboxyphenyl) -8'-chloro-5'-methoxyspiro [cyclohexane-1--4'-(3', 3', 4'-dihydro) quinazoline] -2'(1'H) -one, 6'-(3-carboxyphenyl) -8'-chloro-5'-methoxyspiro [cyclohexane-1--4'-(3', 3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-[2- (4-methyl-piperazin-1-carbonyl) phenyl] spiro [cyclohexane-1--4'-(3',4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-[2-methyl-4- (4-methyl-piperazin-1-carbonyl) phenyl ] Spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-[4- (piperazin-1-carbonyl) Phenyl] Spiro [Cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-[4-carbamoyl-phenyl] Spiro [ Cyclohexane-1- (3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-[4-((1-methyl-piperidine-4-) Il) -piperazin-1-carbonyl) phenyl] spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-5'- Methoxy-6- [4- (4-methyl-piperazin-1-carbonyl) phenyl] spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one , 8'-trifluoromethylspiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-6'-cyanomethylspiro [ Cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-5'-(3-dimethylamino-2-hydroxy-propoxy)- Spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro-5'-(3-methylamino-2-hydroxy-propoxy) ) -Spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -on, 8'-chloro-5' -[2- (ethoxycarbonylmethyl-amino) -ethoxy] -spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one, 8'-chloro -5'-[2- (carboxymethyl-amino) -ethoxy] -spiro [cyclohexane-1--4-'-(3', 4'-dihydro) quinazoline] -2'(1'H) -one hydrochloride, 8'-Chloro-5'-(2-methanesulfonylamino-2-oxo-ethoxy) -spiro [cyclohexane-1--4'-(3', 4'-dihydro) quinazoline] -2'(1'H) -On, 8'-chloro-5'-(2-[(5-methyl-isoxazole-3-ylmethyl) -amino] ethoxy) -spiro [cyclohexane-1--4'-(3', 4'-dihydro) ) Quinazoline] -2'(1'H) -on.

Preparation of such compounds is described in US Pat. No. 7,087,614, U.S. Pat. S. 2007/0049558 and WO2002/074754.

In another embodiment, PDE7 inhibitors and dual PDE4 / 7 inhibitors useful in the methods of the invention are U.S. Pat. No. 7,087,614, US2003 / 0162802 and WO2002 / 102313, all of which are specified by reference in their entirety. Of the compounds generally or specifically disclosed in (incorporated herein). In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

PDE7 inhibitors useful in the methods of the invention include optical isomers, diastereomers, tautomers and pharmaceutically acceptable salts, prodrugs and solvates of the compounds of the formula above.

Substituents for the above compounds are defined as follows.

R1 is H or alkyl;
R2 may be (a) heteroaryl or heterocyclo, each optionally substituted with 1-3 T1, T2, T3 groups; (b) 1-3 T1, T2, Aryl substituted with a T3 group, provided that at least one T1, T2, T3 is other than H; or (c) an aryl condensed into a heteroaryl or heterocyclo ring, wherein the attached ring. The system may be optionally substituted with 1-3 T1, T2, T3 groups;
Z is (a) -OR4, -C (O) R4, -C (O) OR4, -SR4, -NR3R4, -C (O) NR3R4, -NR3SO2R4c, halogen, nitro, haloalkyl; or (b) alkyl , Aryl, Heteroaryl, Heterocyclo, or Cycloalkyl, all of which may be optionally substituted with 1-3 T1a, T2a, T3a groups;
J is (a) hydrogen, halo, -OR4a, or (b) alkyl, alkenyl, or alkynyl, all of which may be optionally substituted with 1-3 T1b, T2b or T3b groups. good;
L is (a) hydrogen, -OR4b, -C (O) R4b, -C (O) OR4b, -SR4b, -NR5R6, -C (O) NR5R6, -NR5SO2R4d, halogen, haloalkyl, nitro, or (b). ) Alkyl, aryl, heteroaryl, heterocyclo, or cycloalkyl, all of which may be optionally substituted with 1-3 T1c, T2c or T3c groups;
R3 and R4 are independently H, alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyclo (heterocyclo), or (heterocyclo) alkyl. Any of these may be optionally substituted with 1-3 T1a, T2a or T3a groups;
Alternatively, R3 and R4 combine with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclo ring optionally substituted with 1-3 T1a, T2a or T3a groups. May be;
R4a is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl) alkyl, (heteroaryl) alkyl, heterocyclo, (heterocyclo) alkyl, cycloalkyl, or (cycloalkyl) alkyl. May be optionally substituted with 1-3 T1b, T2b or T3b groups;
R4b is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl) alkyl, (heteroaryl) alkyl, heterocyclo, (heterocyclo) alkyl, cycloalkyl, or (cycloalkyl) alkyl. May be optionally substituted with 1-3 T1c, T2c or T3c groups;
R4c and R4d are independently alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyclo (heterocyclo), or (heterocyclo) alkyl. , All of which may be optionally substituted with 1-3 T1a, T2a or T3a groups;
R5 and R6 are independently H, alkyl, alkenyl, aryl, (aryl) alkyl, heteroaryl, (heteroaryl) alkyl, cycloalkyl, (cycloalkyl) alkyl, heterocyclo, or (heterocyclo) alkyl. Any of these may be optionally substituted with 1-3 T1c, T2c or T3c groups independently if valences are acceptable;
Alternatively, R5 and R6 combine with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclo ring optionally substituted with 1-3 T1c, T2c or T3c groups. May be;
T1-1c, T2-2c and T3-3c are independent of (1) hydrogen or T6 (where T6 is (i) alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cyclo. Alkyl, (cycloalkyl) alkyl, cycloalkoxy, (cycloalkoxy) alkyl, aryl, (aryl) alkyl, heterocyclo, (heterocyclo) alkyl, heteroaryl, or (heteroaryl) alkyl; (ii) one or more of itself Groups of (i) substituted with the same or different (i) groups of; or (iii) independently, one or more (preferably 1-3), T1-1c, T2-2c and T3. It is a group of (i) or (ii) substituted with the following groups (2) to (13) in the definition of ~ 3c) (2) -OH or -OT6, (3) -SH or -ST6, (4) -C (O) tH, -C (O) tT6, or -O-C (O) T6, where t is 1 or 2; (5) -SO3H, -S (O) T6 , Or S (O) tN (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, (13) oxo.
T4 and T5 are independently (1) 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 each independently (1) a group as defined in the definition of hydrogen or T6, or (2) T7 and T8 together are alkylene or alkenylene. Obtained to complete a 3- to 8-membered saturated or unsaturated ring with the atoms to which they are attached, the ring being unsubstituted or T1-1c, T2-2c, and T3-. It has been substituted with one or more of the groups listed in the description of 3c, or (3) T7 or T8, together with T9, can be alkylene or alkenylene, together with the nitrogen atom to which they are attached. To complete a 3- to 8-membered saturated or unsaturated ring, which is unsubstituted or with one or more groups listed in the description of T1-1c, T2-2c and T3-3c. It may be substituted or (4) T7 and T8 or T9 and T10 may be bonded together with the nitrogen atom to which they are bound to form the -N = CT13T14 group, in the formula. , T13 and T14, respectively, are the groups shown in the definition of H or T6;
And T11 and T12 are each independently (1) single bond, (2) alkylene, (3) alkenylene, or (4) alquinylene.

In a related embodiment, the PDE7 inhibitor useful for the method of the present invention is the above compound (in the formula:
Z is (a) halogen, alkoxy, haloalkyl, -NR3R4, -C (O) OR4, -C (O) NR3R4; (b) aryl or heteroaryl, all of which are one or more T1a, T2a, T3a. (In particular, cyano, optionally substituted alkyl, (hydroxy) alkyl, -OH, -OT6, -ST6, -SOtT6, -COtH, -COtT6, -T4NT7T8 or -T4N (T10) -T5-T6) May be optionally substituted with; (c) (particularly one or more -OH, -COtH, -COtT6, -T4-NT7T8, -T4-N (T10) -T5-H or -T4- An optionally substituted alkyl (substituted with N (T10) -T5-T6);
J is (a) H, or (b) alkyl or alkenyl, both of which may be optionally substituted with one or more -OH, -OT6, -COtH or -COtT6. good;
L is (a) H; (b) halogen, alkoxy, haloalkyl, -NR5R6, -C (O) OR4b, -C (O) NR5R6; (c) aryl or heteroaryl, all of which are one or more. T1c, T2c, T3c (particularly cyano, optionally substituted alkyl, (hydroxy) alkyl, -OH, -OT6, -ST6, -SOtT6, -COtH, -COtT6, -T4NT7T8 or -T4N (T10) -T5-T6) may be optionally substituted; or (d) (particularly one or more -OH, -COtH, -COtT6, -T4-NT7T8, -T4-N (T10) -T5. -H or; optionally substituted alkyl substituted with -T4-N (T10) -T5-T6;
R1 is H or alkyl;
R2 is optionally substituted with (a) 1 to 3 T1, T2, T3 groups, preferably H, alkyl, haloalkyl, halo, heteroaryl, cyano, C (O) tT6, OT6, -T4NT7T8 and the like. Heteroaryl (more preferably thiazolyl or oxazolyl); (b) 1-3 T1, T2, T3 groups (preferably heteroaryl (preferably imidazolyl, oxazolyl, or thiazolyl), all of which are further Aryl substituted with (may be optionally substituted), cyano, C (O) tT6, S (O) tN (T9) T6, haloalkyl, and haloalkyl); or (c) fused to a heterocyclo ring. Aryl (eg, 2,3-dihydro-1H-indole attached to the aryl ring, quinolyl attached to the aryl ring (particularly quinol-6-yl), quinazolinyl attached to the aryl ring (particularly quinazoline-7-yl). ), Synolinyl attached to the aryl ring (particularly synnoline-6-yl), isoquinolinyl attached to the aryl ring (particularly isoquinol-6-yl), and phthalazinyl attached to the aryl ring (particularly phthalazine-6). -Il)), where the bound ring system consists of 1-3 T1, T2, T3 groups (particularly halo, OH, OT6, alkyl, -COtH, -COtT6, or -C (O). ) NT7T8) may be optionally replaced;
R3 is H or an optionally substituted alkyl (particularly substituted with one or more -OH or -OT6);
R4 is (a) hydrogen; (b) (aryl) alkyl, where the aryl group is one or more independently T1a, T2a, T3a groups (particularly optionally substituted alkyl, halo, Cyan, Nitro, (Hydroxy) Alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4NT7T8, -T4-N (T10)- It is optionally substituted with T5-T6, heterocyclo or heteroaryl); (c) (heteroaryl) alkyl, where the heteroaryl group is independently one or more T1a, T2a, T3a. Groups (particularly optionally substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4NT7T8, -T4-N (T10) -T5-T6, heterocyclo or heteroaryl); (d) (heterocyclo) alkyl, where the heterocyclo group is , Independently one or more T1a, T2a, T3a groups (particularly optionally substituted alkyl, halo, cyano, nitro, oxo, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH , -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4NT7T8, -T4-N (T10) -T5-T6, heterocyclo or heteroaryl). (E) Independently optional with one or more T1a, T2a, T3a groups (particularly -OH, -OT6, -COtH, -COtT6, -T4NTT8 or -T4-N (T10) -T5-T6). (F) Independently one or more T1a, T2a, T3a groups (particularly optionally substituted alkyl, optionally substituted aryl, optionally substituted) Heteroaryl, optionally substituted aralkyl, optionally substituted heterocyclo, cyano, -OH, -OT6, -COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4 Heterocyclos optionally substituted with −N (T10) -T5-T6 or −T4-NT2T8);
Alternatively, R3 and R4 are attached together with the nitrogen atom to which they are attached to form 1-3 T1a, T2a, T3a groups (particularly optionally substituted alkyl, optionally substituted). Aryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted heterocyclo, cyano, -OH, -OT6, -COtH, -COtT6, oxo, hydroxy ( 4- to 8-membered heterocyclocycles (particularly pyrrolidinyl, piperazinyl, piperazinyl, morpholinyl) optionally substituted with (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4-NT7T8). , Diazapanyl or 1,4-dioxa-8-azaspiro [4.5] decane-8-yl);
R5 is hydrogen or alkyl;
R6 is (a) hydrogen; (b) (aryl) alkyl, where the aryl group is one or more independently T1c, T2c, T3c groups (particularly optionally substituted alkyl, halo, Cyan, Nitro, (Hydroxy) Alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4-N (T10) -T5-T6 , Heterocyclo or heteroaryl); (c) (heteroaryl) alkyl, where the heteroaryl groups are independently one or more T1c, T2c, T3c groups (particularly). , Arbitrarily substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6) , -T4-N (T10) -T5-T6, heterocyclo or heteroaryl); (d) (heterocyclo) alkyl, where one heterocyclo group is independent. The above T1c, T2c, T3c groups (particularly, optionally substituted alkyl, halo, cyano, nitro, oxo, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H. , -SOtT6, -SOtN (T9) (T6), -T4-N (T10) -T5-T6, heterocyclo or heteroaryl); Alkyl optionally substituted with the above T1c, T2c, T3c groups (particularly -OH, -OT6, -COtH, -COtT6, -T4NT7T8 or -T4-N (T10) -T5-T6); ) Independently one or more T1c, T2c, T3c groups (particularly optionally optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted) Aralkyl, optionally substituted heterocyclo, cyano, -OH, -OT6, -COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 Alternatively, it is a heterocyclo optionally substituted with −T4-NT7T8);
Alternatively, R5 and R6 are attached together with the nitrogen atom to which they are attached to form 1-3 T1c, T2c, T3c groups (particularly optionally substituted alkyl, optionally substituted). Aryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted heterocyclo, cyano, -OH, -OT6, -COtH, -COtT6, oxo, hydroxy ( 4- to 8-membered heterocyclocycles (particularly pyrrolidinyl, piperazinyl, piperazinyl, morpholinyl) optionally substituted with (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4-NT7T8). , Diazapanyl or 1,4-dioxa-8-azaspiro [4.5] decane-8-yl)
Can be mentioned.

In another related embodiment, the PDE7 inhibitor useful for the method of the present invention is the above compound (in the formula:
Z is (a) halogen, alkoxy, haloalkyl, -NR3R4, -C (O) OR4, -C (O) NR3R4; (b) aryl or heteroaryl, all of which are optionally substituted with cyano. One or more T1a, T2a, selected from the alkyl, (hydroxy) alkyl, -OH, -OT6, -ST6, -SOtT6, -COtH, -COtT6, -T4NT7T8 or -T4N (T10) -T5-T6, It may be optionally substituted with T3a, where T4 is a bond or -C (O)-; T5 is -C (O)-or -C (O) O-; T6. Are alkyl or haloalkyl; T7 and T8 are independently H; alkyl optionally substituted with cycloalkyl, heteroaryl, hydroxy or -NT7T8 cycloalkyl; or optionally with halogen. Substituted aryls; or T7 and T8 combine with the nitrogen atom to which they are attached to form a heterocyclo ring optionally substituted with (hydroxy) alkyl, COtH or COtT6, T10. Is hydrogen; (c) at one or more -OH, -COtH, -COtT6, -T4-NT7T8, -T4-N (T10) -T5-H or T4-N (T10) -T5-T6. Arbitrarily substituted alkyl, where T4 is -C (O)-; T5 is -alkylene-O-; T6 is alkyl; T7 and T8 are independent. H, alkyl, cycloalkyl, aryl, (arbitrarily substituted as described in the definition of R4) (aryl) alkyl or (bonding to form a heterocyclo ring) of R3 and R4. Heterocyclo (optionally substituted as described in the definition); and T10 is H;
J is (a) H, or (b) alkyl or alkenyl, both of which may be optionally substituted with one or more -OH, -OT6, -COtH or -COtT6. And T6 is alkyl;
L is (a) H; (b) halogen, alkoxy, haloalkyl, -NR5R6, -C (O) OR4b, -C (O) NR5R6; (c) aryl or heteroaryl, all of which are cyano, ( In particular, optionally substituted alkyl, (hydroxy) alkyl, -OH, -OT6, -ST6, -SOtT6, -COtH, -COtT6, -T4NT7T8 or -T4N (T10) substituted with COtH or COtT6. It may be optionally substituted with one or more T1c, T2c, T3c selected from -T5-T6, where T4 is a binding or -C (O)-; T5 is -C. (O)-or -C (O) O-; T6 is alkyl or haloalkyl; T7 and T8 are H independently; optionally with cycloalkyl, heteroaryl, hydroxy or -NT7T8. Substituentally substituted alkyl; cycloalkyl; or optionally substituted aryl with halogen; or T7 and T8 are bonded together with the nitrogen atom to which they are attached to the (hydroxy) alkyl, COtH. Alternatively, a heterocyclo ring optionally substituted with COtT6 is formed; T10 is hydrogen; (d) one or more -OH, -COtH, -COtT6, -T4-NT7T8, -T4-N (T10). ) -T5-H or -T4-N (T10) -T5-T6 optionally substituted alkyl, where T4 is -C (O)-; T5 is -alkylene- O-; T6 is alkyl; T7 and T8 are independently H, alkyl, cycloalkyl, aryl, (optionally substituted as described in the definition of R4) ( Aryl) alkyl or heterocyclo (optionally substituted as described in the definitions of R3 and R4 that combine to form a heterocyclo ring); and T10 is H;
R1 is H or alkyl;
R2 is optionally substituted with (a) 1 to 3 T1, T2, T3 groups, preferably H, alkyl, haloalkyl, halo, heteroaryl, cyano, C (O) tT6, OT6, -T4NT7T8 and the like. Heteroaryl (more preferably thiazolyl or oxazolyl); (b) 1-3 T1, T2, T3 groups (preferably heteroaryl (preferably imidazolyl, oxazolyl or thiazolyl), all of which are further optional. Aryl substituted with (may be selectively substituted), cyano, C (O) tT6, S (O) tN (T9) T6, haloalkyl and haloalkyl, etc.; or (c) aryl fused to a heterocyclo ring. (For example, 2,3-dihydro-1H-indole bound to an aryl ring), wherein the bound ring system consists of 1 to 3 T1, T2, T3 groups (particularly, halo, -OH, -OT6, alkyl, -COtH, -COtT6 or -C (O) NT7T8) may be optionally substituted;
R3 is H or an optionally substituted alkyl (particularly substituted with one or more -OH or -OT6);
R4 is (a) hydrogen; (b) (aryl) alkyl, where the aryl group is an independently optionally optionally substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4NT7T8, -T4N (T10) -T5-T6, heterocyclo or heteroaryl) 1 It is optionally substituted with one or more T1a, T2a, T3a groups, where T4 is the binding, -SO2- or -C (O)-; T5 is -SO2- or-. Alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (c) (heteroaryl) alkyl Here, the heteroaryl group is an independently optionally substituted alkyl, halo, cyano, nitro, oxo, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, With one or more T1a, T2a, T3a groups selected from -SO3H, -SOtT6, -SOtN (T9) (T6), -T4NT7T8, -T4-N (T10) -T5-T6, heterocyclo or heteroaryl) It is optionally substituted, where T4 is the bond, -SO2- or -C (O)-; T5 is -SO2- or -alkylene-O-; T6 is. Alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (d) (heterocyclo) alkyl, where the heterocyclo group is independent. , Arbitrarily substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -T4NT7T8, -T4-N ( It is optionally substituted with one or more T1a, T2a, T3a groups selected from T10) -T5-T6, heterocyclo or heteroaryl), where T4 is the binding, -SO2- or -C (O)-; T5 is -SO2- or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; T9 and T10 are hydrogen; ( e) Independently optional with one or more T1a, T2a, T3a groups selected from -OH, -OT6, -COtH, -COtT6, -T4NT7T8 or -T4-N (T10) -T5-T6) Substituentally substituted alkyl, where T4 is a bond; T5 is -C (O)-; T6 is an alkyl; T7 and T8 are independently H or alkyl. And T10 is hydrogen; independently, optionally substituted alkyl (particularly substituted with -T4NT7T8), optionally substituted (particularly substituted with halogen or haloalkyl). 1 selected from aryl, cyano, -OH, -OT6, -COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4-NT7T8) Heterocyclo optionally substituted with one or more T1a, T2a, T3a groups, where T4 is bound or -C (O)-; T5 is -C (O)-, -SO2- or -Alkylene-C (O) O-; T6 is alkyl, alkoxy or heteroaryl; T7 and T8 are independently H, alkyl or cycloalkyl; or T7 and T8 are these. Combines with the nitrogen atom to which it is attached to form an optionally substituted heterocyclo ring;
Alternatively, R3 and R4 bind together with the nitrogen atom to which they are attached, pyrrolidinyl, piperazinyl, piperazinyl, morpholinyl, diazapanyl or 1,4-dioxa-8-azaspiro [4.5] decane-8-. Ill) formed heterocyclo rings selected from, all of which were independently substituted with optionally substituted alkyl (particularly substituted with -T4NT7T8), particularly with halogen or haloalkyl. ) Arbitrarily substituted aryl, cyano, -OH, -OT6, -COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4 It is optionally substituted with 1-3 T1a, T2a, T3a groups selected from −NT7T8), where T4 is bound or −C (O) −; T5 is -C (O)-, -SO2- or -alkylene-C (O) O-; T6 is alkyl, alkoxy or heteroaryl; T7 and T8 are independently H, alkyl or cycloalkyl. Alternatively, T7 and T8 combine with the nitrogen atom to which they are attached to form an optionally substituted heterocyclo ring;
R5 is hydrogen or alkyl;
R6 is (a) hydrogen; (b) (aryl) alkyl, where the aryl group is an independently optionally optionally substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -TNT7T8, -T4-N (T10) -T5-T6, heterocyclo or heteroaryl) Are optionally substituted with one or more T1c, T2c, T3c groups, where T4 is an attached, -SO2- or -C (O)-; T5 is -SO2-. Or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (c) (heteroaryl). ) Alkyl, where the heteroaryl group is an independently optionally substituted alkyl, halo, cyano, nitro, oxo, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH,- One or more T1c, T2c, T3c selected from COtT6, -SO3H, -SOtT6, -SOtN (T9) (T6), -T4NT7T8, -T4-N (T10) -T5-T6, heterocyclo or heteroaryl) It is optionally substituted with a group, where T4 is a bond, -SO2- or -C (O)-; T5 is -SO2- or -alkylene-O-; T6. Are alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (d) (heterocyclo) alkyl, where the heterocyclo group is independent. Then, optionally substituted alkyl, halo, cyano, nitro, (hydroxy) alkyl, -OH, -OT6, -ST6, -COtH, -COtT6, -SO3H, -SOtT6, -T4NT7T8, -T4- It is optionally substituted with one or more T1c, T2c, T3c groups selected from N (T10) -T5-T6, heterocyclo or heteroaryl), where T4 is bound, -SO2. -Or -C (O)-; T5 is -SO2- or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl. And T9 and T10 are hydrogens; e) Independently optional with one or more T1c, T2c, T3c groups selected from -OH, -OT6, -OCtH, -COtT6, -T4NT7T8 or -T4-N (T10) -T5-T6) Substituentally substituted alkyl, where T4 is a bond; T5 is -C (O)-; T6 is an alkyl; T7 and T8 are independently H or alkyl. And T10 is hydrogen; independently, optionally substituted alkyl (particularly substituted with -T4NT7T8), optionally substituted (particularly substituted with halogen or haloalkyl). One selected from aryl, cyano, -OH, -OT6, -COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4-NT7T8 Heterocyclos optionally substituted with the above T1c, T2c, T3c groups, where T4 is bound or -C (O)-; T5 is -C (O)-, -SO2- or- Alkylene-C (O) O-; T6 is alkyl, alkoxy or heteroaryl; T7 and T8 are independently H, alkyl or cycloalkyl; or T7 and T8 are these bonded. It combines with the nitrogen atom to form an optionally substituted heterocyclo ring;
Alternatively, R5 and R6 bind together with the nitrogen atom to which they are attached to pyrrolidinyl, piperazinyl, piperazinyl, morpholinyl, diazapanyl or 1,4 dioxo-8-azaspiro [4.5] decane-8-yl. ), All of which independently (particularly substituted with -T4NT7T8) optionally substituted alkyl, (particularly substituted with halogen or haloalkyl). Arbitrarily substituted aryl, cyano, -OH, -OT6, -COtH, -COtT6, oxo, hydroxy (alkyl), (alkoxy) alkyl, -T4-N (T10) -T5-T6 or -T4- It is optionally substituted with 1-3 T1a, T2a, T3a groups selected from NT7T8, where T4 is a bond or -C (O)-; 5 is -C. (O)-, -SO2- or -alkylene-C (O) O-; T6 is alkyl, alkoxy or heteroaryl; T7 and T8 are independently H, alkyl or cycloalkyl. Alternatively, T7 and T8 combine with the nitrogen atom to which they are attached to form an optionally substituted heterocyclo ring;
In a further related embodiment, PDE7 inhibitors useful for the methods of the invention include the following compounds:
2-[[4-[[[4- (Aminosulfonyl) phenyl] methyl (methy)] amino] -6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5- Thiazolcarboxylic acid ethyl ester; 2-[[4-[[(3,4-dimethoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid Acid ethyl ester trifluoroacetate; 2-[[4-[[[4- (aminosulfonyl) phenyl] methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5 -Thiazolcarboxylic acid ethyl ester; 4-methyl-2-[[4-[[[4- (methylsulfonyl) phenyl] methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -5- Ethyl thiozolcarboxylic acid ester; ethyl 2-[[4-[[(4-methoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazole carboxylic acid Ester; 2-[[4-[[(3-methoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [[4-[[(2-methoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-methyl-2- [[4- (1-piperazinyl) -6-[[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4 -[[(2-ethoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[( 2,5-Dimethoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[(3,3,3) 5-Dimethoxyphenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[(2,6--2,6-- Dimethylphenyl) Methyl] Amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[[4- (methoxycarbonyl) phenyl] methyl] amino] -6- (1-piperazinyl)- 2-Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[(3-bromophenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl) Amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[(1,3-benzodioxol-5-ylmethyl) amino] -6- (1-piperazinyl) -2-pyrimidinyl ] Amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-methyl-2-[[4- [methyl (3-pyridinylmethyl) amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -5-Thiazole Carboxylic Acid Ethylester; 4-Methyl-2-[[4- (1-piperazinyl) -6-[[[4- (1,2,3-thiazazole-4-yl) phenyl] methyl] methyl] amino ] -2-Pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[[3- (cyclopentyloxy) -4-methoxyphenyl] methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-methyl-2-[[4-[(phenylmethyl) amino] -6- (1-piperazinyl) -2-pyrimidinyl] Amino] -5-thiazole carboxylic acid ethyl ester; 4-methyl-2-[[4- (4-methyl-1-piperazinyl) -6-[[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4- (4-hydroxy-1-piperidinyl) -6-[[[4- (methylsulfonyl) phenyl] methyl] amino]- 2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-methyl-2-[[4-[[2- (1-methylethoxy) ethyl] amino] -6-[[[4 -(Methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3- (aminocarbonyl) -1-piperidinyl] -6-[[[ [4- (Methylsulfonyl) phenyl] methyl] amino]- 2-Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[(2- (1H-imidazol-4-yl) ethyl] amino] -6-[[[4 -(Methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-methyl-2-[[4-[[[4- (methylsulfonyl)) Phenyl] methyl] amino] -6-[[3- (4-morpholinyl) propyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4-[(2-methoxy-) 1-Methylethyl) amino] -6-[[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-methyl-2 -[[4-[[[4- (Methylsulfonyl) phenyl] methyl] amino] -6-[[(tetrahydro-2-furanyl) methyl] amino] -2-pyrimidinyl] amino] -ethyl 5-thiazole carboxylate ester;
2-[[4- [4- (2-Hydroxyethyl) -1-piperazinyl] -6-[[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl- 5-Thiazole Carboxylic Acid Ethylester; 2-[[4- [2- (Aminocarbonyl) -1-pyrrolidinyl] -6-[[[4- (Methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino ] -4-Methyl-5-thiazolecarboxylic acid ethyl ester; 4-methyl-2-[[4- [methyl (3-pyridinylmethyl) amino] -6-[[[4- (methylsulfonyl) phenyl] methyl] amino] ] -2-Pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4- (hydroxymethyl) -1-piperidinyl] -6-[[[4- (methylsulfonyl) phenyl] methyl ] Amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[2- (diethylamino) ethyl] methylamino] -6-[[[4- ( Methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-methyl-2-[[4-[[[4- (methylsulfonyl) phenyl]] Methyl] amino] -6-[[3- (2-oxo-1-pyrrolidinyl) propyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3- ( Hydroxymethyl) -1-piperidinyl] -6-[[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-methyl- 2-[[4- (4-Methyl-1-piperazinyl) -6-[[[(4- (Methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[2-[(Acetylamino) ethyl] amino] -6-[[[(4- (Methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl- 5-Thiazole carboxylic acid ethyl ester; 2-[[4- (4-ethyl-1-piperazinyl) -6-[[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4 -Methyl-5-thiazole carboxylate ethyl es Tel; 2-[[4- (4-acetyl-1-piperazinyl) -6-[[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazole Carboxylic acid ethyl ester; 2-[[4-[[2- (dimethylamino) ethyl] amino]-[[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl -5-thiazole carboxylic acid ethyl ester; 2-[[4- [3- (aminocarbonyl) -1-piperazinyl] -6-[[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] Amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- (3-hydroxy-1-pyrrolidinyl) -6-[[[4- (methylsulfonyl) phenyl] methyl] amino] -2 -Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[(4-hydroxybutyl) amino] -6-[[[4- (methylsulfonyl) phenyl] methyl] amino ] -2-Pyrimidinyl] Amino] -4-Methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[(2,3-dihydroxypropyl) amino] -6-[[[4- (methylsulfonyl)) Phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[(4-amino-1-piperidinyl) -6-[[[4- (Methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-hydroxy-3- (hydroxymethyl) -1-) Piperidinyl] -6-[[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- (4-dimethyl) Amino-1-piperidinyl) -6-[[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-] [[[4- (Aminosulfonyl) phenyl] methyl] amino] -6- (methylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4,6-bis -(4-Methyl-piperazin-1-a -Pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4- (4-hydroxy-piperidin-1-yl) -6- (4-methyl-piperazin-1) -Il) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4- (3-hydroxymethyl-piperidin-I-yl) -6- (4-methyl-piperazin) -1-yl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 4-methyl-2- [4- (4-methyl-piperazin-1-yl) -6-morpholin -4-Il-pyrimidine-2-ylamino] -thiazole-5-carboxylic acid ethyl ester; 2- [4- (4-amino-piperidin-1-yl) -6- (4-methyl-piperazin-1-yl) ) -Pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4,6-bis- (4-hydroxy-piperidine-1-yl) -pyrimidine-2-ylamino]- 4-Methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4- (4-oxo-piperidin-1-yl) -6- (4-methyl-piperazin-1-yl) -pyrimidine-2-ylamino] -4-Methyl-thiazole-5-carboxylic acid ethyl ester;
2- [4- (4-Methyl-4-hydroxy-piperidin-1-yl) -6- (4-methyl-piperazin-1-yl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5- Carboxylic acid ethyl ester; 2- [-(4-hydroxy-piperidine-1-yl) -6- (4-dimethylmethyl-piperazin-1-yl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5 -Carboxylic acid ethyl ester; 2- [4- (4-hydroxymethyl-piperidin-1-yl) -6- (4-dimethylmethyl-piperazin-1-yl) -pyrimidine-2-ylamino] -4-methyl- Thiazol-5-carboxylic acid ethyl ester; 2- [4- (3-hydroxymethyl-piperidin-1-yl) -6- (4-dimethylmethyl-piperazin-1-yl) -pyrimidine-2-ylamino] -4 -Methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4- (4-hydroxymethyl-piperidin-1-yl) -6- (4-hydroxy-piperazin-1-yl) -pyrimidine-2-ylamino] -4-Methyl-thiazole-5-carboxylic acid ethyl ester; 4-methyl-2- [4- (4-hydroxy-piperazin-1-yl) -6-morpholin-4-yl-pyrimidine-2-ylamino]- Thiazol-5-carboxylic acid ethyl ester; 2-[[(4-[[[4- (methylsulfonyl) phenyl] methyl] amino] -6-chloro-2-pyrimidinyl] amino] -4-methyl-5-thiazole Carboxylic acid ethyl ester; 2-[[4-[[[4- (aminosulfonyl) phenyl] methyl] amino] -6-chloro-2-pyrimidinyl] amino] -4-methyl-5-thiazole carboxylic acid ethyl ester; 2-[[4- [4- (Dimethylamino) -1-piperidinyl] -6-[[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl- 5-Thiazole Carboxylic Acid Ethyl Ester; 2-[[4- [1-piperidinyl] -6-methyl-6-[[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-Methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- (4-amino-1-piperidinyl) -6-[[[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl ] Amino] -4-methyl-5-thiazole carboxylate ethyl Ester; 2-[[4- [4-Hydroxy-1-piperidinyl] -6-methyl-6-[[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4 -Methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4- (hydroxymethyl) -1-piperidinyl] -6-methyl-6-[[(3,4,5-trimethoxyphenyl) methyl ] Amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- (4-hydroxypiperidine-1-yl) -6- (3-oxo-piperazin-1-yl) Il) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[[4- [3- (aminocarbonyl) -1-piperidinyl] -6-methyl-6-[[ (3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [1-morpholinyl] -6-methyl -6-[[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3-oxo3-oxo] -1-piperidinyl] -6-[[(1,1-dioxide-3-oxo-1,2-benzoisothiazole-2- (3H) -yl) methyl] amino] -2-pyrimidinyl] amino] -4 -Methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3-oxo-1-piperidinyl] -6-[[(4- (ethylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] Amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3-oxo-1-piperidinyl] -6-[[(4- (hydroxysulfonyl) phenyl) methyl] amino] -2 -Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- (4-hydroxypiperidine-1-yl) -6- (4-methyl-3-oxo-piperazin-1-yl) ) -Pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4- (4 (dimethylamino) -piperidin-1-yl) -6-(4-((1-(1-) Pyrrolidinyl) carbonylmethyl) piperazin-1-yl) -pyrimidine-2-ylamino] -4-methyl-thiazole -5-Carboxylic acid ethyl ester; 2-[[4- [3- (aminocarbonyl) -1-piperazinyl] -6-[[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl ] Amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- (4-amino-1-piperidinyl) -6-[[(3,4,5-trimethoxyphenyl) methyl] amino] ] -2-Pyrimidinyl] Amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4- (hydroxymethyl) -1-piperidinyl] -6- [4- [tetrazole-5-] Il] -4-hydroxypiperidine-1-yl] 2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-methyl-1-piperazinyl] -6- [ N-methyl-N-[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4] -Hydroxy-1-piperidinyl] -6-[[(4- (Hydroxysulfonyl) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4 -[[(4-Cyanophenyl) methyl] amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; trifluoroacetate (1: 1); 2-[[4-[[[4- (Aminosulfonyl) phenyl] methyl] amino] -6- (4-morpholinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester;
2-[[4- [4-Hydroxy-1-piperidinyl] -6-[(1-oxa-3,8-diazaspiro [4.5] decane-2,4, dione-8-yl] -2-pyrimidinyl] ] Amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- (2- (dimethylamino) ethyl) -piperazin-1-yl) -6- (4-methylpiperazin-1-yl) −Pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[[4- (4-hydroxy-1-piperidinyl) -6- [methyl (3-pyridinylmethyl) amino] -2 -Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-hydroxy-3-hydroxymethylpiperidin-1-yl] -6-[[(3,4,5 -Trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- (3,4-dihydro-6,7-dihydroxy-2) 1H) -isoquinolinyl) -6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester, trifluoroacetate 1: 1); 2-[[4 − [4-[(methoxyacetyl) amino] -1-piperidinyl] -6- [[4- (methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid Ethyl ester; 2-[[4-[[(3,4-dimethoxyphenyl) methyl] amino] -6- [4- (dimethylamino) -1-piperidinyl] -2-pyrimidinyl] amino] -4-methyl- Thiazolcarboxylic acid ethyl ester; 2-[[4- [4- (hydroxyethyl) piperidin-1-yl] -6- [4- (dimethylamino) -1-piperidinyl] -2-pyrimidinyl] amino] -4- Methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4- (dimethylamino) -1-piperidinyl] -6- [methyl (3-pyridinylmethyl) amino] -2-pyrimidinyl] amino] -4- Methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4- (hydroxy) piperidin-1-yl] -6- [4- (methoxycarbonyl) -1-piperidinyl] -2-pyrimidinyl] amino] -4-Methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4- (Hydroxy) piperidin-1-yl] -6- [4- (methyl) -4- (hydroxy) -1-piperidinyl] -2-pyrimidinyl] amino] -4-methyl- 5-Thiazole Carboxylic Acid Ethyl ester; 2- [4- (3-oxopiperazin-1-yl) -6- (4-methylpiperazin-1-yl) -pyrimidine-2-ylamino] -4-methyl-thiazole- 5-Carboxylic acid ethyl ester; 2-[[4-[[(4-cyanophenyl) methyl] amino] -6- [4-dimethylamino) -1-piperidinyl] -2-pyrimidinyl] amino] -4-methyl -5-Thiazole Carboxylic Acid Ethylester; 4-Methyl-2-[[4-[[(3-Nitrophenyl) Methyl] Amino] -6- (1-piperazinyl) -2-pyrimidinyl] Amino] -5-Thiazole Carboxylic acid ethyl ester, trifluoroacetate (1: 1); 2-[[4- (4-hydroxy-1-piperidinyl) -6-[[(3,4,5-trimethoxyphenyl) methyl] amino]- 2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- (dimethylamino) -piperazin-1-yl) -6- (4-methylpiperazin-1-yl) -pyrimidine -2-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4- (dimethylamino) -piperidin-1-yl) -6- (3- (aminocarbonyl) -1- Piperazinyl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4- (2-hydroxyethyl) -piperazin-1-yl) -6- (4-methyl-1) -Piperazinyl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[[4- [4- (aminocarbonyl) -1-piperidinyl] -6-[[[4- (Methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4- (hydroxymethyl) -1-piperidinyl] -6 -[N-methyl-N- (3-pyridinylmethyl) amino] -2-pyrimidinyl] amino] -4-methyl (methy) -5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-methylpiperazin-] 1-yl] -6-[[(3,4-dimethoxyphenyl) methyl] Amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [piperazin-1-yl] -6-[[(4-carboxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3-hydroxymethylpiperidine-1-yl] -6-[[N-[(3,4) 5-Trimethoxyphenyl) methyl]]-N- (methyl) amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- (4-hydroxypiperidine-1-) Il) -6- (4-carboxypiperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[[4- [piperazin-1-yl]- 6-[[(3,4-dimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- (4-formyl-1-piperazinyl) ) -6-[[[4- (Methylsulfonyl) phenyl] methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- (4-hydroxypiperidine-) 1-yl) -6- (4- (hydroxy) -4- (4-chlorophenyl) piperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 4- Methyl-2-[[4- [4-dimethylamino-1-piperidinyl] -6-[[(tetrahydro-2-furanyl) methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4- [Piperazine-1-yl] -6- [[N-methyl-N- (5-tetrazolylmethyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid Acid ethyl ester; 2-[[4- [4-morpholinyl] -6- [4- [tetrazol-5-yl] -4-hydroxypiperidin-1-yl] -2-pyrimidinyl] amino] -4-methyl- 5-Thiazole Carboxylic Acid Ethylester; 2-[[4- [4-Hydroxy-1-piperidinyl] -6-[[(1,1-dioxide-3-oxo-1,2-benzoisothiazole-2-) 3H) -yl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thi Azolcarboxylic acid ethyl ester; 2- [4- (4-hydroxypiperidine-1-yl) -6- (4- (1-methyl-1-hydroxyethyl) piperidin-1-yl) -pyrimidine-2-ylamino] -4-Methyl-thiazole-5-carboxylic acid ethyl ester; 2-[[4- [3- (aminocarbonyl) -1-piperidinyl] -6- [[N-methyl-N- (3-pyridinylmethyl)] amino ] -2-Pyrimidinyl] Amino] -4-Methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-Hydroxymethyl-1-piperidinyl] -6-[[(4- (ethylsulfonylamino)] Phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-hydroxy-1-piperidinyl] -6- [4- [tetrazole-] 5-yl] -4-hydroxypiperidine-1-yl] 2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-tertbutyloxycarbonylamino-1-] Piperidinyl] -6-[[N-[(3,4,5-trimethoxyphenyl) methyl]]-N- (methyl) amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazole carboxylate ethyl Ester; 2-[[4-[[(4-cyanophenyl) methyl] amino] -6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazole carboxylate ethyl Ester, trifluoroacetate (1: 1); 2-[[4- [4-[[(2-ethoxy-2-oxoethyl) amino] carbonyl] -1-piperazinyl] -6- [methyl (3-pyridinylmethyl)) Amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester, trifluoroacetate (1: 1); 2- [4- (4-hydroxypiperidine-1-yl) -6- ( 3-Hydroxypiperidine-1-yl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4- (4-hydroxypiperidine-1-yl) -6- (4) -Hydroxy-4-phenyl-1-piperidinyl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 4-methyl-2-[[4- [4-morpholinyl] -6- [[(Tetrahydro-2-fla Nyl) methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4-[(tetrahydro-2-furanyl) methyl] amino] -6-[[N-[(3) , 4,5-trimethoxyphenyl) methyl]]-N- (methyl) amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-morpholinyl) ] -6-[[(4- (Hydroxysulfonyl) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [bis-4,6- (4) -Cyano-1-piperidinyl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[[4- [4- (cyclopentylaminocarbonyl) -1-piperazinyl] -6- [N-methyl-N- (3-pyridinylmethyl) amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- (2-methoxyethyl) -piperazin-1- Il) -6- (4-methyl-1-piperazinyl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4- (4-hydroxypiperidine-1) -Il) -6- (3-carboxypiperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[[4- [4-methylpiperazin-1] -Il] -6- [3- (acetylamino) -1-pyrrolidinyl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3- (aminocarbonyl) ) -1-Piperadinyl] -6- [[N-methyl-N- (3-pyridinylmethyl)] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4 -[2-Methyl-3-oxol-piperidinyl] -6- [4-methyl-1-piperazinyl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3- (Aminocarbonyl) -1-piperazinyl] -6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3- (Aminocarbonyl) -1-piperidinyl] -6- (4-dimethylamino-1-piperidinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [1-piperazinyl]- 6-[[N-methyl-N- (2-furylmethyl)] amino] -2-
Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[(4-methoxycarbonylphenyl) methyl] amino] -6- (4-dimethyl-1-piperidinyl) -2 -Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester, trifluoroacetate (1: 1);
2-[[4- [3-oxo-1-piperazinyl] -6-[[(4- (methylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid Acid ethyl ester; 2-[[4- [3-oxo-1-piperazinyl] -6-[[(4- (propylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl- 5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3- (aminocarbonyl) -1-piperidinyl] -6-[[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl ] Amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [bis-4,6- (4-hydroxy-4-methyl-1-piperidinyl) -pyrimidine-2-ylamino] -4-methyl- Thiazol-5-carboxylic acid ethyl ester; 4-methyl-2-[[4- [4-dimethylamino-1-piperidinyl] -6-[[(2-oxo-1-pyrrolidinyl) propyl] amino] -2-] Pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3-oxo-1-piperazinyl] -6-[[(4- (iso-propylsulfonylamino) phenyl) methyl] amino]- 2-Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- (4-hydroxypiperidin-1-yl) -6- (3-hydroxymethyl-1-piperidinyl) -pyrimidine- 2-Ilamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 4-methyl-2-[[4- [4-hydroxy-1-piperidinyl] -6-[[(2- (4-morpholinyl)) Ethyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[[4- (ethylaminosulfonyl) phenyl] methyl] amino] -6-methoxy-2-pyrimidinyl ] Amino] -4-methyl-5-thiazole carboxylic acid methyl ester, trifluoroacetate (1: 1); 2-[[4- [4-morpholinyl] -6-[(1-oxa-3,8-diazaspiro) [4.5] Decane-2,4,dione-8-yl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-hydroxy-1-] Piperidinyl] -6-[[(4- (Ethylsulfonylamino)) Phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [tertbutyloxycarbonyl-1-piperazinyl] -6-[[(3,3) 4,5-Trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3- (aminocarbonyl) -1-piperidinyl]] -6-[[(3,4-dimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-ethoxycarbonyl-1] − Piperazinyl] -6- [[N-methyl-N- (5-tetrazolylmethyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3-oxo-1-piperidinyl] -6-[[(4- (cyclopropylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2 -[[4- [4-Hydroxymethyl-1-piperidinyl] -6-[[(4- (methylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid Acid ethyl ester; 2- [4- (4-dimethylamino-1-piperazinyl) -6- (4-tertbutyloxycarbonylamino-1-piperidinyl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5 -Carboxylic acid ethyl ester; 2- [4- (4-hydroxypiperidine-1-yl) -6- (4-methoxymethyl-1-piperidinyl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5- Carboxylic acid ethyl ester; 2- [4- (4-hydroxypiperidine-1-yl) -6- (4-hydroxyethyl-1-piperidinyl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic Acid ethyl ester; 2- [4- (4-hydroxypiperidine-1-yl) -6- (4- (hydroxy) -4- (3-trifluoromethylphenyl) piperidin-1-yl) -pyrimidine-2- Ilamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[[4- [4-morpholinyl] -6- [4- [1-methyl-1-hydroxyethyl] -1-piperidini] Le] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- (3-oxo-1-piperidinyl] -6-[[3-pyridyl] oxy] -2 -Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-methyl-1-piperazinyl] -6-[(1,4-dioxaspiro [4.5] decane- 8-yl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-morpholinyl] -6-[[(4- (methylsulfonylamino) phenyl)) Methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3-oxo-1-piperazinyl] -6-[(1-oxa-3,, 1-oxa-3,) 8-diazospiro [4.5] decane-2,4, dione-8-yl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-hydroxy -1-piperidinyl] -6-[[(4- (carboxy) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; Hydroxypiperidin-1-yl) -6- (4- (hydroxy) -4- (4-bromophenyl) piperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-ethyl carboxylate ester;
2-[[4- [4-morpholinyl] -6-[[(4-ethylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl] -5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3- (Aminocarbonyl) -1-piperazinyl] -6-[[(3,4-dimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazole Carboxylic acid ethyl ester; 2-[[4- [4-formyl-1-piperazinyl] -6-[[(3- (5- (1H) tetrazolyl) phenyl) methyl] amino] -2-pyrimidinyl] amino]- 4-Methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4- (hydroxymethyl) -1-piperidinyl] -6- [[N-methyl-N- (5-tetrazolylmethyl] amino ] -2-Pyrimidinyl] Amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-methyl-1-piperazinyl] -6-[[(2,5-dimethyl) phenyl)) Methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3- (2-oxo-1-pyrrolidinyl) propyl] amino] -6- [ N-methyl-N- (3-pyridinylmethyl) amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[(1-morpholinyl)]-6- [ [N-methyl-N- (5-tetrazolylmethyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-methyl-1-] Piperazinyl] -6- [4- [methylsulfonylamino] -1-piperidinyl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-hydroxy-1] -Piperidinyl] -6-[[(2,5-dimethyl) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-methyl-2-[[4] -(4-Morphorinyl) -6-[[(3,4,5-trimethoxyphenyl) methyl] amino-2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2- [4- (4-hydroxy) Piperidine-1-yl) -6- (3-hydroxy-1-piperidinyl) -pyrimidine-2-ylua Mino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 4-methyl-2-[[4- (4-methyl-1-piperazinyl) -6- [methyl (3-pyridinylmethyl) amino] -2-] Pyrimidinyl] amino] -5-thiazole carboxylic acid ethyl ester; 2-[[4- [3-oxo-1-piperazinyl] -6-[[(2- (5- (1H) tetrazolyl) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-4-thiazolecarboxylic acid ethyl ester; 2-[[4-[(2-furanylmethyl) amino] -6- (1-piperazinyl) -2-pyrimidinyl] amino]- 4-Methyl-5-thiazolecarboxylic acid ethyl ester, trifluoroacetate (1: 1); 2-[[4-[[(3,4-dimethoxyphenyl) methyl] amino] -6- (4-morpholinyl)- 2-Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-methyl-2-[[4- [methyl (3-pyridinylmethyl) amino] -6-[[(tetrahydro-2-furanyl)) Methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4-[(4-hydroxy-1-piperidinyl)]-6-[[N-methyl-N- (5) -Tetrazolylmethyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- (4-hydroxypiperidine-1-yl) -6-[(4-4-) (Hydroxy) -4- (phenylmethyl) piperidine-1-yl)] -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4- (4-dimethylamino-1) − Piperazinyl) -6- [[2- (1-morpholinyl) ethyl] amino] pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[[4- [4-hydroxy- 1-piperidinyl] -6-[[(3-pyridinylmethyl)] oxy] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3- (aminocarbonyl)) -1-piperidinyl] -6-[[(2,6-dimethylphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4] -Hydroxy-1-piperidinyl] -6-[[(4- (meperidinyl] Tylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-hydroxy-1-piperidinyl] -6-[[[ (4- (propylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3- (aminocarbonyl) -1-) Piperidinyl] -6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- (3,4-dihydro-6,7) -Dimethoxy-2 (1H) -isoquinolinyl) -6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4] -Formyl-1-piperazinyl] -6- [[N-methyl-N- (5-tetrazolylmethyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [[4-[[(4-carboxyphenyl) methyl] amino] -6- [4- (hydroxymethyl) -1-piperidinyl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester 2-[[4-[[(4-carboxyphenyl) methyl] amino] -6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester Monochloride;
4-Methyl-2-[[4- (4-Methyl-1-piperazinyl) -6-[[(Tetrahydro-2-furanyl) methyl] amino] -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester 2-[[4-[[(4-carboxyphenyl) methyl] amino] -6- [3- (hydroxymethyl) -1-piperidinyl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid Acid ethyl ester; 2-[[4-[[[4-[[(2-methoxyethyl) amino] carbonyl] phenyl] methyl] amino] -6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] Amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester, trifluoroacetate (1: 1); 2- [4,6-bis- (1-morpholinyl) -pyrimidine-2-ylamino] -4-methyl- Thiazol-5-carboxylic acid ethyl ester; 2-[[4- [3- (aminocarbonyl) -1-piperazinyl] -6- [[N-methyl-N- (5-tetrazolylmethyl] amino] -2] -Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-methyl-2-[[4- [-methyl (3-pyridinylmethyl) amino] -6- [4-morpholinyl] -2-pyridinylmethyl ] Amino] -5-thiazole carboxylic acid ethyl ester; 2-[[4- [3- (aminocarbonyl) -1-piperazinyl] -6-[[[4- (methoxycarbonyl) phenyl] methyl] amino] -2 -Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-chloro-6-[(1-oxa-3,8-diazaspiro [4.5] decane-2,4 Dione-8-yl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4- (hydroxymethyl) -1-piperidinyl] -6-[[( 3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3- (hydroxymethyl) -1-) Piperidinyl] -6-[[N-methyl-N- (5-tetrazolylmethyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4- [ 3- (Hydroxymethyl) -1-pyrrolidinyl] -6- [[N-methyl-N- (5-tet) Razolylmethyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-methyl-2-[[4- [methyl (phenylmethyl) amino] -6- (4-methyl-) 1-piperazinyl) -2-pyrimidinyl] amino] -5-thiazolecarboxylic acid ethyl ester; 2-[[4- (dimethylamino) -6-[[[4- (methylsulfonyl) phenyl] methyl] amino] -2 -Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-hydroxy-1-piperidinyl] -6-[[(3- (5- (1H) tetrazolyl) phenyl) ) Methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-hydroxymethyl-1-piperidinyl] -6-[[(4- (4-( Propylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-hydroxymethyl-1-piperidinyl] -6- [ [(4- (Cyclopropylsulfonylamino) phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [3- (hydroxymethyl)-) 1-Piperidinyl] -6-[[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-] [4-Tetrahydropyranyl] Oxy-6- [[N-[(3,4,5-trimethoxyphenyl) methyl]]-N- (methyl) amino] -2-pyrimidinyl] amino] -4-methyl- 5-Thiazole Carboxylic Acid Ethyl ester; 2-[[4- [4-methyl-1-piperazinyl] -6-[(4-methoxyphenyl) oxy] -2-pyrimidinyl] amino] -4-methyl-5-thiazole Carboxylic acid ethyl ester; 4-methyl-2- [4- (4-methyl-piperazin-1-yl) -6- [[[4- (aminosulfonyl) phenyl] methyl] amino] pyrimidin-2-ylamino]- Thiazol-5-carboxylic acid ethyl ester; 2- [4-isopropyl-6- (4-sulfamoyl-benzylamino) -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 4-methyl -2- [4- (4-Sulfamoyl-benzylamino) -6-methyl-pyrimidine-2-ylamino] -thiazole-5-carboxylic acid ethyl ester; 4-methyl-2- [4- (4-sulfamoyl-benzyl) Amino) -6-Hydroxymethyl-pyrimidine-2-ylamino] -thiazole-5-carboxylic acid ethyl ester; 4-methyl-2- [4- (4-methyl-piperazin-1-yl) -6- [4-yl) (1H-tetrazol-5-yl) -benzylamino] -pyrimidine-2-ylamino] -thiazole-5-carboxylic acid ethyl ester; 2- [4- (4-hydroxy-piperidin-1-yl) -6- [ 4- (1H-tetrazol-5-yl) -benzylamino] -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 4-methyl-2- [4-[(tetrahydro-furan) -2-Ilmethyl) -amino] -6- [4- (1H-tetrazol-5-yl) -benzylamino] -pyrimidine-2-ylamino] -thiazole-5-carboxylic acid ethyl ester; 4-methyl-2- [4-Morphorin-4-yl-6- [4- (1H-tetrazol-5-yl) -benzylamino] -pyrimidine-2-ylamino] -thiazole-5-carboxylic acid ethyl ester; 2- [4-( 3-Carbamoyl-piperidin-1-yl) -6- [4- (1H-tetrazol-5-yl) -benzylamino] -pyrimidine-2-ylamino]) -4-methyl-thiazole-5-carboxylic acid ethyl ester ;
2- [4- (4-Hydroxymethylpiperidin-1-yl) -6- [4- (1H-tetrazol-5-yl) -benzylamino] -pyrimidine-2-ylamino] -4-methyl-thiazole-5 -Carboxylic acid ethyl ester; 2- [4- (2-hydroxymethyl-1-pyrrolidinyl) -6- [4- (1H-tetrazol-5-yl) -benzylamino] -pyrimidine-2-ylamino] -4- Methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4- (3-N, N-diethylcarbamoyl-1-piperidinyl) -6- [4- (1H-tetrazol-5-yl) -benzylamino]- Pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4- (3-hydroxy-1-pyrrolidinyl) -6- [4- (1H-tetrazole-5-yl)- Benzylamino] -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 4-methyl-2-[[[2- [4-morpholin-4-yl] ethyl] amino-6- [4- (1H-tetrazol-5-yl) -benzylamino] pyrimidin-2-ylamino] -thiazole-5-carboxylic acid ethyl ester; 4-methyl-2-[[[4-hydroxyl] butyl] amino-6 -[4- (1H-tetrazol-5-yl) -benzylamino] -pyrimidine-2-ylamino] -thiazole-5-carboxylic acid ethyl ester; 2- [4- (4-formyl-1-piperazinyl) -6 -[4- (1H-tetrazol-5-yl) -benzylamino] -pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[[4-[[(4-chlorophenyl) ) Methyl] amino] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[(4-aminosulfonylphenyl) ) Methyl] amino] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-morpholino-6- (5-oxazolyl) -2 −Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[(3,4-dimethoxyphenyl) methyl] amino] -6- (5-oxazolyl) -2-pyrimidi Nyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- (1,4-dioxa-8-aza-spiro [4.5] deca-8-yl) -6- ( 5-Oxazoly) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-hydroxy-4-phenyl-piperidinyl] -6- (5-) Oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[(4-methylsulfonylphenyl) methyl] amino] -6- (5-oxazolyl)- 2-Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-hydroxy-piperidinyl] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4- Methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4-ethoxycarbonyl-piperidinyl] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl Ester; 2-[[4-piperidinyl-6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [N-methylpiperazinyl] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [N- (2-furylcarbonyl) piperazinyl-6- (5-) Oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [N-acetyl- [1,4-diazepil] -6- (5-oxazolyl) -2 -Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [N-methyl-N- (N-methyl-4-piperidinyl) -amino] -6- (5-oxazolyl) ) -2-Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [N-methyl- [1,4] -diazepill] -6- (5-oxazolyl) -2 -Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-N, N-dimethoxyethylamino-6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl -5-Thiazole Carboxylic Acid Ethyl Ester 2-[[4-[(1', 4) -bipiperidinyl] -6- (5-oxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- (4-Hydroxy-piperidin-1-yl) -6- (3,4,5-trimethoxy-phenyl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2-[(4) -(4-Hydroxy-piperidin-1-yl) -6- [4- (1H-tetrazol-5-yl) -phenyl] -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4-Hydroxy-piperidin-1-yl) -6-pyridine-3-yl-pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4-( 4-Methanesulfonyl-benzylamino) -6-pyridine-3-yl-pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4-hydroxy-piperidine-1-) Il) -6-pyrimidine-4-yl-pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4-cyano-phenyl) -6- (4-hydroxy-) Piperidine-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4-acetyl-phenyl) -6- (4-hydroxy-piperidin-1-) Il) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester;
2- [4- (4-Hydroxymethyl-phenyl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [ 4- (4-Hydroxy-phenyl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4) -Methanesulfonyl-benzylamino) -6- (3,4,5-trimethoxy-phenyl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4-methane) Sulfinylphenyl) -6- (4-hydroxypiperidine-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4- (amino) phenyl)- 6- (4-Hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4-carboxymethyl-phenyl) -6- ( 4-Hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4- (trifluoromethylcarbonylamino) phenyl) -6- (4-Hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4- (ethoxycarbonylmethyl) phenyl) -6-( 4-Hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (1,2,3,6-tetrahydropyridine-4-yl) ) -6- (4-Hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (3- (cyano) phenyl) -6 -(4-Hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4- (methoxycarbonyl) phenyl) -6-( 4-Hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (2- (methoxy) -5-pyridinyl) -6-( 4 -Hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4-tertbutyloxycarbonyl-1,2,3,6- Tetrahydropyridine-4-yl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (1,4) -Dioxaspiro [4.5] Deca-7-en-8-yl) -6- (4-Hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester 2- [4- (4-Methyl-1-piperazin-yl) -6- (3,4,5-trimethoxy-phenyl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester 2- [4- (4-morpholinyl) -6- (3,4,5-trimethoxy-phenyl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4-Morphorinyl) -6- (3-pyridinyl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (piperazin-4-yl) -6- (4) -Hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2-[[4- [4-hydroxy-piperidinyl] -6- (3,5-) Dimethyl-4-isooxazolyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazole-carboxylic acid ethyl ester; 2- [4- (4-tert-butoxycarbonylamino-phenyl) -6- (4-hydroxy) -Piperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- (4-cyano-phenyl) -6- (4-methanesulfonyl-benzylamino) ) -Pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- (4-methanesulfonylphenyl) -6- (4-hydroxypiperidine-1-yl) -pyrimidine-2 -Ilamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4-methanesulfanylphenyl) -6- (4-hydroxypiperidine-1-yl) -pyrimidine-2-ylamino] -4-Methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4-carboxy-phenyl) -6- (4-hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl -Thiazole-5-carboxylic acid ethyl ester; 2- [4- (4-carboxy-phenyl) -6- (3-oxo-piperazin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5 -Carboxylic acid ethyl ester; 2- [4- (4-carboxy-phenyl) -6- (4-methyl-piperazin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl Ester; 2- [4- (4-carboxy-phenyl) -6-morpholin-4-yl-pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4- (4- (4- (4-) Carboxy-phenyl) -6- (4-methyl- [1,4] diazepan-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4) -Carboxy-phenyl) -6- (3-R-hydroxy (hydrox) -piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester;
2- [4- (4-carboxy-phenyl) -6- (3-hydroxymethyl-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [ 4- (4-Acetyl- [1,4] diazepan-1-yl) -6- (4-carboxy-phenyl) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4- (4-Carboxy-phenyl) -6- [N-methyl-N- (1-N-methyl-piperidin-4-yl) -amino] -pyrimidine-2-ylamino] -4-methylthiazole-5 -Carboxylic acid ethyl ester; 2- [4- (4-carboxy-phenyl) -6-piperazin-1-yl-pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2- [4 -(4-carboxy-phenyl) -6- (4-sulfamoyl-benzylamino) -pyrimidine-2-ylamino] -4-methylthiazole-5-carboxylic acid ethyl ester; 2-[[4-[[5-allyl) [4- (Aminosulfonyl) phenyl] methyl] amino] -6-chloro-2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[[4- (aminoamino) Sulfonyl) phenyl] methyl] amino] -5-methyl-6- (1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester, trifluoroacetate (1: 3); 2 -[[4-[[[4- (Aminosulfonyl) phenyl] methyl] amino] -5-methyl-6- (4-morpholinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazole carboxylate ethyl Ester; 2-[[4-[[5-allyl [4- (aminosulfonyl) phenyl] methyl] amino] -6- (4-methylpiperazinyl) -2-pyrimidinyl] amino] -4-methyl-5 -Thiazolcarboxylic acid ethyl ester; 2-[[4- [[5- [2- [2-methylprop-3-ene]]-4- [4- (aminosulfonyl) phenyl] methyl] amino] -6-( 4-Methylpiperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[[(3,4,5- (trimethoxy) phenyl] methyl] Amino] -5-methyl-6- (1-piperazinyl) -2-pyrimidinyl] Ami No] -4-methyl-5-thiazolecarboxylic acid ethyl ester, trifluoroacetate; 2-[[4-[[5- [2,3-propanediol] [4- (aminosulfonyl) phenyl] methyl] amino] -6- (4-Methylpiperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[[3,4,5- (trimethoxy) phenyl ] Methyl] amino] -5-methyl-6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester, trifluoroacetate; 2-[[4] -[[5- [2- [2-methylprop-3-ene]]-4- [4- (aminosulfonyl) phenyl] methyl] amino] -6-chloro-2-pyrimidinyl] amino] -4-methyl- 5-Thiazole Carboxylic Acid Ethyl Ester; 2-[[4-[[[4- (aminosulfonyl) phenyl] methyl] amino] -5-methyl-6- (4-tertbutyloxycarbonyl-1-piperazinyl) -2 -Pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [N-[[3,4,5- (trimethoxy) phenyl] methyl] -N-methylamino] -5 −Methyl-6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4,6-bis- (4-hydroxy-piperidin-) 1-yl) -5-methylpyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4,6-bis- (3-oxo-piperazin-1-yl) -5 -[Ethoxycarbonylmethyl] pyrimidin-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2- [4,6-bis- (4-hydroxy-piperidin-1-yl) -5-methoxy Pyrimidine-2-ylamino] -4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[[4- [N-[[3,4,5- (trimethoxy) phenyl] methyl] -N-methylamino] -5-methoxy-6- (4-methyl-1-piperazinyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[3-pyridyl] methyloxy ] -5- (2-Propenyl-6- (4-morpholinyl) -2-pyrimidinyl] Amino] -4-methyl-5-thiazole carboxylic acid ethyl ester; 2-[(4-ethoxycarbonylmethyl-6-morpholin-4-yl-pyrimidine-2-yl) -amino] -4-methyl-5-thiazole Carboxylic acid ethyl ester; 2-[(4-ethoxycarbonylmethyl-6- [3-oxo-1-piperazinyl] -pyrimidine-2-yl) -amino] -4-methyl-5-thiazole carboxylic acid ethyl ester; 2 -[(4-Carboxymethyl-6-morpholin-4-yl-pyrimidine-2-yl) -amino] -4-methyl-5-thiazolecarboxylic acid; 2- [4-morpholin-4-yl-6- [ (3,4,5-trimethoxy-phenylcarbamoyl) -methyl] -pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [2-oxo-2- (3) -Oxo-piperazin-1-yl) -ethyl] -6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- (4-( 4-Sulfamoyl-benzylamino) -6-[(4-Sulfamoyl-benzylcarbamoyl) -methyl] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- [2-] (1,4-Dioxa-8-aza-spiro [4.5] dec-8-yl) -2-oxo-ethyl] -6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4 -Methyl-5-thiazolecarboxylic acid ethyl ester;
2-[[4-[[(4-Chloro-phenyl) -methyl-carbamoyl] -methyl] -6- (4-sulfamoyl-benzylamino) 2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid Ethyl ester; 2-[[4- [2- (4-hydroxy-piperidin-1-yl) -2-oxo-ethyl] -6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4 -Methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [2- (4-ethoxycarbonyl-piperidin-1-yl) -2-oxo-ethyl] -6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- (2-oxo-2-piperidin-1-yl-ethyl) -6- (4-sulfamoyl-benzyl) Amino) 2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [2- [4- (fran-2-carbonyl) -piperazin-1-yl] -2-yl] Oxo-ethyl] -6- (4-sulfamoyl-benzylamino) 2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[(cyclohexyl-methyl-carbamoyl) -methyl ] -6- (4-Sulfamoyl-benzylamino) 2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [2- (4-acetyl- [1,4]] Diazepan-1-yl) -2-oxo-ethyl] -6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-] [[Methyl- (1-methyl-piperidin-4-yl) -carbamoyl] -methyl] -6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazole carboxylate ethyl Ester; 2-[[4- [2- (4-methyl- [1,4] diazepan-1-yl) -2-oxo-ethyl] -6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] Amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[[bis- (2-methoxy-ethyl) -carbamoyl] -methyl] -6- (4-sulfamoyl-benzylamino)- 2-pyrimidinyl] amino] -4-me Tyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- (2- [1,4'] bipiperidinyl-1'-yl-2-oxo-ethyl) -6- (4-sulfamoyl-benzylamino)- 2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [2- (4-hydroxy-4-phenyl-piperidin-1-yl) -2-oxo-ethyl]] -6- (4-Sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-ethoxycarbonyl-6- (4-sulfamoyl-benzylamino)) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-carboxy-6- (4-sulfamoyl-benzylamino) -2-pyrimidinyl] amino] -4-methyl- 5-Thiazole Carboxylic Acid Ethyl ester; 2-[[4- (Carboxymethyl-Carbamoyl) -6- (4-Sulfamoyl-benzylamino) -2-pyrimidinyl] Amino] -4-Methyl-5-Thiazole Carboxylic Acid Ethyl ester 2- [4- (4-Hydroxy-piperidin-1-yl) -6- (4-methylsulfanyl-benzyl) -pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- (4-Hydroxy-piperidin-1-yl) -6- (4-methanesulfinyl-benzyl) -pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4 -(4-Hydroxy-piperidin-1-yl) -6- (4-methanesulfonyl-benzyl) -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4- [4- [ 4-Methyl-1-piperazinyl] -6- [N-methyl-N-[(3,4,5-trimethoxyphenyl) methyl] amino] -2-pyrimidinyl] amino] -4-trifluoromethyl-5- Thiazolcarboxylic acid ethyl ester; 2-[[4- [4-methylpiperazin-1-yl] -6- (N-methyl-N-[[(3,4,5-trimethoxyphenyl) methyl] amino]-]- 2-pyrimidinyl] amino] -4-methyl-5-cyanothiazole; 2-[[4- [4-methylpiperazin-1-yl] -6-methyl-6-[[(3,4,5-trimethoxy) Phenyl) methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid, 2-methoxyethyl ester; 2-[[4- [4-hydroxy-piperidine-1-yl] -6- [N-methyl [[ N-[(3,4,5-trimethoxyphenyl) methyl] [-N-methyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid butyl ester; 2-[[4- [1-morpholinyl] -6-[[2- [1-morpholinyl] ethyl] amino] -2-pyrimidinyl] amino] -4-methyl-5-thiazolecarboxylic acid butyl ester; 2-[[4- [4- [4- [4- [4-] 4-] Methyl-1-piperazinyl] -6-[[N-[(3,4,5-trimethoxyphenyl) methyl]]-N- (methyl) amino] -2-pyrimidinyl] amino] -4-isopropyl-5- Thiazolcarboxylic acid ethyl ester; 2-[[4- [4-methyl-1-piperazinyl] -6-[[N-[(3,4,5-trimethoxyphenyl) methyl]]-N- (methyl) amino ] -2-Pyrimidinyl] Amino] -4-Methyl-5-thiazole Carboxylic Acid Methylamide; 2- [4- [4- (2-diisopropylamino-ethylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidin-) 1-yl) -pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- [4- (3-dimethylamino-propylcarbamoyl) -phenyl] -6- (4-) Hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester;
2- [4- [4- (Cyclohexylmethylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidine-1-yl) -pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- [4- (pyridine-4-ylmethylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid Acid ethyl ester; 2- [4- [4- (isobutylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid Ethyl ester; 2- [4- [4- (N-cyclohexyl-N-methylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl- 5-Thiazole Carboxylic Acid Ethyl Ester; 2- [4- [4- (N-cyclopropylmethyl-N-propylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidine-2- Ilamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- [4- (4-ethoxycarbonylpiperidin-1-carbamoyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) ) -Pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- [4- (3-hydroxymethyl-piperidin-1-carbonyl) -phenyl] -6- (4-) Hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- [4- (N-2-hydroxyethyl-N-ethylcarbamoyl)- Phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- [4- (thiomorpholin-1-yl) Carbonyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl-5-thiazolecarboxylic acid ethyl ester; 2- [4- [4- (morpholin-) 1-carbonyl) -phenyl] -6- (4-hydroxy-piperidin-1-yl) -pyrimidine-2-ylamino] -4-methyl-5-thiazole carboxylate ethyl este Ester; and 2- [4- [4- (4-chloro-phenylcarbamoyl) -phenyl] -6- (4-hydroxy-piperidine-1-yl) -pyrimidine-2-ylamino] -4-methyl-5- Thiazole carboxylic acid ethyl esters; or their stereoisomers, pharmaceutically acceptable salts or hydrates.

In another related embodiment, PDE7 inhibitors useful for the methods of the invention include the following compounds:

Or their stereoisomers, pharmaceutically acceptable salts or hydrates.

Preparation of such compounds is described in US Pat. No. 7,087,614, U.S. Pat. S. It is described in 20130162802 and WO2002 / 102313.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are generally or specifically disclosed in US2007 / 0129388 and WO2007 / 063391, each of which is expressly incorporated herein by reference in its entirety. It is selected from the compounds selected. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

m is 0, 1 or 2; X is O, S or N-CN; R is F, Cl or CN; A is optionally substituted with _{C 1-4 alkyl groups.} The C _3-6 cycloalkylene group obtained; and B is a single bond or C _1-2 alkylene group; or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.

With respect to the above compounds, the term "alkylene" means a divalent saturated hydrocarbon chain having one or two carbon atoms. Examples of the alkylene group include methylene, ethylene and methylmethylene, of which methylene is preferred.

The term "cycloalkylene" means a divalent saturated carbocyclic ring having 3 to 6 carbon atoms. Examples of cycloalkylene groups include cyclopropylene (eg 1,1-cyclopropylene and cis- and trans-1,2-cyclopropylene), cyclobutylene (eg 1,1-cyclobutylene, cis and trans-1). , 2-Cyclobutylene and cis and trans-1,3-cyclobutylene), cyclopentylene (eg 1,1-cyclopentylene, cis and trans-1,2-cyclopentylene and cis- and trans-1 , 3-Cyclopentylene) and cyclohexylene (eg, 1,1-cyclohexylene, cis- and trans-1,2-cyclohexylene, cis- and trans-1,3-cyclohexylene) and cis- and trans- 1,4-Cyclohexylene). Preferred examples include cyclobutylene and cyclohexylene, more preferably cyclobutylene, even more preferably 1,3-cyclobutylene, and most preferably trans-1,3-cyclobutylene.

The term "alkyl" means a monovalent, straight or branched saturated hydrocarbon chain containing 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Preferred examples include methyl and ethyl, especially methyl.

The cycloalkylene group is optionally substituted with a _{C 1-4 alkyl group.} Preferably, the alkyl substituent, if present, is a methyl or ethyl group, more preferably a methyl group. The alkyl substituent, if present, may be present at any position on the ring, but is preferably at the 1-position (ie, the same position as the carboxylic acid group).

Preferably m is 1 or 2, more preferably 1.

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

Preferably R is F or Cl, more preferably Cl.

Preferably, A is a cyclobutylene or cyclohexylene group optionally substituted with a methyl group. More preferably, A is a cyclobutylene group. Even more preferably, A is a 1,3-cyclobutylene group, particularly a trans-1,3-cyclobutylene group.

Preferably, B is a single bond or a methylene group. More preferably, B is a single bond.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are selected from the following compounds:
Sis-3-[(8'-chloro-2'-oxo-2', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazoline] -5'-yl) oxy] cyclobutane carboxylic acid Trans-3-[(8'-chloro-2'-oxo-2', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazoline] -5'-yl) oxy] cyclobutanecarboxylic acid Acid; 3-[(8'-fluoro-2'-oxo-2', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazoline] -5'-yl) oxymethyl] cyclobutanecarboxylic acid Acid; Trans-3-[(8'-cyano-2'-oxo-2', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazoline] -5'-yl) oxy] cyclobutane Carboxylic acid; 1-[(8'-fluoro-2'-oxo-2', 3'-dihydro-1'H-spiro [cyclohexane-1,4'-quinazoline] -5'-yl) oxymethyl] cyclobutane Carboxylic acid; trans-3-[(8'-chloro-2'-oxo-2', 3'-dihydro-1'H-spiro [cycloheptyl-1,4'-quinazoline] -5'-yl) oxy ] Cyclobutane carboxylic acid; and trans-3-[(8'-chloro-2'-oxo-2', 3'-dihydro-1'H-spiro [cyclopentyl-1,4'-quinazoline] -5'-yl ) Oxy] cyclobutane carboxylic acids; or pharmaceutically acceptable salts, solvates, polyforms or prodrugs thereof.

Preparations of the above compounds are described in US2007 / 0129388 and WO2007 / 063391.

In another embodiment, PDE7 inhibitors useful in the methods of the invention include Kadoshima-Yamaoka, K. et al. Et al., "ASB16165, a novel inhibitor for phosphodiesterase 7A (PDE7A), suprecesses IL-12-induced IFN-g product by lymphocytes: The compound ASB16165 (1-cyclohexyl-N- [6- (4-hydroxy-1-piperidinyl) -3-pyrazinyl] -3-methyl-1H-thieno [2,3-c] described in the book). Pyrazole-5-carboxamide monohydrate). In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Methods for preparing the above compounds are described in WO 2006/004040.

In another embodiment, PDE7 inhibitors useful in the methods of the invention include Yamamoto, S. et al. Et al., "The effects of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on T-cell-related cytokine compound The compound YM-393059 ((±) -N- (4,6-dimethylpyrimidin-2-yl) -4- [2- (4-methoxy), which is expressly incorporated herein in its entirety). -3-Methylphenyl) -5- (4-methylpiperazin-1-yl) -4,5,6,7-tetrahydro-1H-indol-1-yl] benzenesulfonamide difumarate). In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

In another embodiment, a PDE7 inhibitor useful for the methods of the invention is Martinez et al., "Benzyl benzene of 2,1,3-benzo-and benzodino 3,2-azidiazine 2,2-dioxides: phodiesterase". , J. Med. Chem. 43: 683-689, 2000 (which is expressly incorporated herein by reference in its entirety) is selected from the compounds commonly or specifically disclosed. In one embodiment, PDE7 inhibitors useful for the methods of the invention include the following compounds:
1-[(4-Methoxyphenyl) carbonylmethyl] benzothieno- [3,2-a] -1,2,6-thiadiadin-493H) -one 2,2-dioxide; and 1-[(3,4-dichlorophenyl) ) -Methyl] -2,1,3-benzothiadiadin-4 (3H) -one 2,2 dioxide.

The preparation of the above compounds was carried out by J. Mol. Med. Chem. 43: 683-689, 2000.

In another embodiment, PDE7 inhibitors useful in the methods of the invention are described in Castro, A. et al. Et al., "CODES, a novel for ligand-based virtual screening: PDE7 inhibitor as an application sample", J. Mol. Med. Chem. 43: 1349-1359, 2008 (which is expressly incorporated herein by reference in its entirety) is selected from the compounds commonly or specifically disclosed. In one embodiment, PDE7 inhibitors useful for the methods of the invention include the following compounds:

In another embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

X = O or S,
R = H, Ph, 4-OMePh, 2,6-diFPh, 2,3,4-tri FPh, 2-BrPh, Bn, naphthyl or Me.

In another embodiment, PDE7 inhibitors useful for the methods of the invention include the following compounds:
5.2.4.3- (2,3,4-trifluorophenyl) -2-thioxo- (1H) -quinazoline-4-one;
5.3.2.3-Phenyl-2-thioxo- (1H) -thieno [3,2-d] pyrimidine-4-one;
5.3.3.3- (2,6-difluorophenyl) -2-thioxo- (1H) -thieno [3,2-d] pyrimidine-4-one; and 5.4.2.3- (2) , 6-Difluorophenyl-2-thioxo- (1H) -benzo [4,5] -thieno [3,2-d] -pyrimidine-4-one.

The preparation of the above compounds was carried out by J. Mol. Med. Chem. 43: 1349-1359, 2008.

In another embodiment, PDE7 inhibitors useful in the methods of the invention include Yang, G. et al. Et al., "Phosphodiesterase 7A-deficient meeting have functional T cells", J. Mol. Immunol 171: 6414-6420, 2003 (which is expressly incorporated herein by reference in its entirety), BMS-586353.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are described in Pitts, W. et al. J. Et al., "Identification of purine inhibitors of phosphodiesterase 7 (PDE7)", Bioorg. Med. Chem. Lett. 14: 2955-2958, 2004 and Kempson, J. Mol. Et al., "Fused pyrimidine based inhibitor of phosphodiesterase 7 (PDE7): synthesis and initial structure-activity restriction systems", Bioorg. Med. Chem. Lett. It is selected from the compounds generally or specifically disclosed in 15: 1829-1833, 2005, each of which is expressly incorporated herein by reference in its entirety. In one embodiment, PDE7 inhibitors useful in the methods of the invention are:

Have.

Substituents for the above compounds are defined as follows.

R1 is

Is.

R2 is

(In the formula, the ethyl group can be attached at the 7 or 9 position)
Is.

In a related embodiment, PDE7 inhibitors useful for the methods of the invention are:

Have.

In another related embodiment, PDE7 inhibitors useful in the methods of the invention are:

(In the equation, X = CH2, CH2CH2 or OCH2;
Ar is

Is;
And NRR'

Is)
Have.

In another embodiment, PDE7 inhibitors useful for the methods of the invention are described in Kang, N. et al. S. Et al., "Docking and 3-D QSAR studios of dual PDE4-PDE7 inhibitors", Molecular Simulation 33: 1109-1117, 2007 (which is expressly incorporated herein by reference in its entirety), general or specific. It is selected from the compounds disclosed in. In one embodiment, PDE7 inhibitors useful for the methods of the invention include the following compounds:

Methods for preparing the above compounds are described in Molecular Simulation 33: 1109-1117, 2007.

Polypeptides or Peptide Inhibitors In some embodiments, PDE7 inhibitors include isolated PDE7 polypeptides or peptide inhibitors, including isolated native and synthetic peptide inhibitors that inhibit PDE7 activity. .. As used herein, the term "isolated PDE7 polypeptide or peptide inhibitor" is by binding to PDE7, competing for binding of PDE7 to a substrate, and / or interacting directly with PDE7. Polypeptides or peptides that inhibit PDE7-dependent cleavage of cAMP by inhibiting PDE7-dependent cleavage of cAMP, which are substantially pure and may be found together in their natural state. , Which is essentially not included to the extent practical and appropriate for its intended use.

Peptide inhibitors have been successfully used in vivo because they interfere with protein-protein interactions and catalytic sites. For example, peptide inhibitors for adhesion molecules structurally associated with LFA-1 have recently been approved for clinical use in coagulopathy (Ohman, EM et al., European Heart J. 16: 50-55, 1995). ). Short-chain linear peptides (less than 30 amino acids) that suppress or interfere with integrin-dependent adhesion have been reported (Murayama, O. et al., J. Biochem. 120: 445-51, 1996). Long chain peptides ranging in length from 25 to 200 amino acid residues have also been successfully used to block integrin-dependent adhesions (Zhang, L. et al., J. Biol. Chem. 271 (47): 29953). -57, 1996). In general, long-chain peptide inhibitors have higher affinity and / or lower off-rates than short-chain peptides and can therefore be more effective inhibitors. Cyclic peptide inhibitors have also been shown to be effective inhibitors of integrin in vivo for the treatment of human inflammatory diseases (Jackson, DY et al., J. Med. Chem. 40: 3359). -68, 1997). An example of a method for making a cyclic peptide involves the synthesis of a peptide in which the terminal amino acid of the peptide is cysteine, whereby the peptide can be present in cyclic form by disulfide bonds between the terminal amino acids. Peptides have been shown to improve affinity and in vivo half-life in the treatment of hematopoietic neoplasms (eg, US Pat. No. 6,649,592 for Larson).

Synthetic PDE7 Peptide Inhibitors PDE7 inhibitory peptides useful in the methods of the invention are exemplified by amino acid sequences that mimic target regions important for PDE7 enzyme activity, such as the catalytic domain of PDE7. PDE7A and PDE7B have 70% identity in the catalytic domain (Hetman, JM et al., PNAS 97 (1): 472-476, 2000). The catalytic domain of PDE7A1 is amino acid residues 185-456 of SEQ ID NO: 2. The catalytic domain of PDE7A2 is the amino acid residues 211-424 of SEQ ID NO: 4. The catalytic domain of PDEB is the amino acid residues 172-420 of SEQ ID NO: 6. Inhibitor peptides useful in practicing the methods of the invention range in size from about 5 amino acids to about 250 amino acids. In addition, molecular model design and rational molecular design can be used to generate and screen peptides that mimic the molecular structure of the PDE7 catalytic region and inhibit the enzymatic activity of PDE7. Molecular structures used in model design include the CDR regions of anti-PDE7 monoclonal antibodies. Methods for identifying peptides that bind to a particular target are well known in the art. For example, molecular imprinting can be used to denovate macromolecular structures (such as peptides that bind to a particular molecule). For example, Shea, KJ. , "Molecular Imprinting of Synthetic Networks: The De Novo Synthesis of Polymer Binding and Catalytic Series", 1994, TRIP2 (5).

As an example, an example of a method for preparing a PDE7-binding peptide mimetic is as follows. The functional monomer (template) of the binding region of the anti-PDE7 antibody showing PDE7 inhibition is polymerized. After removing the template, the second type of monomer is polymerized in the voids created by the template to obtain a new molecule exhibiting one or more desired properties similar to the template. In addition to the preparation of peptides in this manner, other PDE7 binding molecules that are PDE7 inhibitors, such as polysaccharides, nucleosides, drugs, nucleoproteins, lipoproteins, carbohydrates, glycoproteins, steroids, lipids, and others. Bioactive substances and the like can also be prepared. This method typically yields compounds with non-biodegradable backbones by preparation by free radical polymerization of functional monomers, thus providing a wider variety of biological mimetics that are more stable than their natural counterparts. It is useful for designing.

PDE7-inhibiting peptides include well-known techniques in the art, such as solid-phase synthesis techniques (first reported by Merrifield in J. Amer. Chem. Soc. 85: 2149-2154, 1963). Can be prepared using. Autosynthesis can be accomplished using, for example, Applied Biosystems 431A Peptide Synthesizer (Foster City, California) according to the instructions provided by the manufacturer. Other methods include, for example, Bondanzaky, M. et al. Et al., Peptide Synthesis, 2nd Edition, John Wiley & Sons, 1976, and other reference research materials known to those of skill in the art. The peptide can also be prepared using standard genetic engineering techniques known to those of skill in the art.

Candidate PDE7 inhibitory peptides can be tested for their ability to function as PDE7 inhibitors in one of several assays, such as the PDE7 phosphodiesterase assay.

Expression of PDE7 Inhibitor In some embodiments of the methods of the invention, the PDE7 inhibitor is a PDE7 expression inhibitor capable of inhibiting PDE7-dependent cAMP cleavage (PDE7A, PDE7B, or both). In the embodiment of this embodiment of the present invention, typical PDE7 expression inhibitors include PDE7 antisense nucleic acid molecules (such as antisense mRNA, antisense DNA, or antisense oligonucleotide), PDE7 ribozymes, and PDE7RNAi molecules. ..

Antisense RNA and DNA molecules hybridize to PDE7 mRNA and act to directly block translation of PDE7 mRNA by interfering with translation of PDE7 protein. The antisense nucleic acid molecule can be constructed in many different ways, but it is assumed that the molecule has the ability to interfere with the expression of PDE7. For example, an antisense nucleic acid molecule has a coding region (or part thereof) of the PDE7A1 cDNA (SEQ ID NO: 1), PDE7A2 cDNA (SEQ ID NO: 3) or PDE7B cDNA (SEQ ID NO: 5) in its normal transcription orientation. It can be constructed by reversing the above and allowing transcription of its complementary strand. Methods for the design and administration of antisense oligonucleotides are well known in the art, eg, Matino et al., Hum Gene Ther 13: 1027-37, 2002; and Pachori et al., Hypertension 39: 969-75, Reported in 2002, each of which is incorporated herein by reference.

The antisense nucleic acid molecule is usually substantially identical to at least a portion of the target gene (s). However, the nucleic acids do not have to be exactly the same in order to inhibit expression. In general, the shorter the antisense nucleic acid molecule used, the higher the homology can be used to compensate. The minimum percentage of identity is typically greater than about 65%, but higher percentages of identity can also result in more effective suppression of the expression of endogenous sequences. A fairly large percentage of identity greater than about 80% is typically preferred, and full identity from about 95% is typically most preferred.

The antisense nucleic acid molecule does not have to have the same intron or exon pattern as the target gene, and the non-coding segment of the target gene can be equally effective as the coding segment in achieving antisense suppression of target gene expression. A DNA sequence of at least about 8 nucleotides can be used as the antisense nucleic acid molecule, but longer sequences are also preferred. A representative example of a useful PDE7 inhibitor in the present invention is an antisense PDE7 nucleic acid molecule that is at least 90 percent identical to the complementary strand of a portion of the PDE7A1 cDNA consisting of the nucleic acid sequence set forth in SEQ ID NO: 1. Another representative example of a useful PDE7 inhibitor is an antisense PDE7 nucleic acid molecule that is at least 90 percent identical to the complementary strand of a portion of the PDE7A2 cDNA consisting of the nucleic acid sequence set forth in SEQ ID NO: 3. Another representative example of a useful PDE7 inhibitor is an antisense PDE7 nucleic acid molecule that is at least 90 percent identical to the complementary strand of a portion of the PDE7B cDNA consisting of the nucleic acid sequence set forth in SEQ ID NO: 5.

Targeting antisense oligonucleotides that bind to PDE7 mRNA is another mechanism that can be used to reduce the level of PDE7 protein synthesis. For example, the synthesis of polygalacturonase and muscarinic type 2 acetylcholine receptors is inhibited by antisense oligonucleotides to their respective mRNA sequences (US Pat. Nos. 5,739,119 to Cheng and US Pat. No. 5,739,119 to Shewmaker). 5,759,829). In addition, examples of antisense inhibition include nuclear protein cyclin, multidrug resistance gene (MDG1), ICAM-1, E-selectin, STK-1, striatum GABA _A receptor and human EGF (eg, US patent for Baracchini). No. 5,801,154; US Pat. No. 5,789,573 to Baker; US Pat. No. 5,718,709 to Considine; and US Pat. No. 5,610,288 to Receptin). There is.

A system has been reported that allows one of ordinary skill in the art to determine which oligonucleotide is useful in the present invention, which uses Rnase H cleavage as an indicator of the reachability of sequences in the transcript. It involves probe binding to a suitable site within the target mRNA. Scherr, M. et al. Et al., Nucleic Acids Res. 26: 5079-5085, 1998; Lloyd et al., Nucleic Acids Res. 29: 3665-3673, 2001. To create sites sensitive to RNase H, a mixture of antisense oligonucleotides complementary to specific regions of the PDE7 transcript is added to the PDE7 expressing cell extract and hybridized. This method is a computer that can predict optimal sequence selection of antisense compositions based on their relative ability to form other secondary structures in which specific binding to target mRNAs in dimers, hairpins or host cells can be reduced or prohibited. Auxiliary sequence selection may be combined. Consideration of such secondary structure analysis and target site selection includes OLIGO primer analysis software (Rychlik, I., 1997) and BLASTN 2.0.5 algorithm software (Altschul, SF et al., Nucl. Acids Res). .25: 3389-3402, 1997). The antisense compound against the target sequence preferably comprises from about 8 to about 50 nucleotides in length. Antisense oligonucleotides containing about 9 to about 35 nucleotides are particularly preferred. We envision any oligonucleotide composition and range from 9 to 35 nucleotides (ie, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or those with a base length of about 35) are used to carry out the method based on the antisense oligonucleotide of the present invention. Very preferred. Highly preferred target regions for PDE7 mRNA are those at or near the AUG translation initiation codon and the 5'region of the mRNA, eg, the PDE7 gene nucleotide sequence (SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5). It is a sequence that is substantially complementary to the region between 0 and +10.

The term "oligonucleotide" as used herein refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or a mimic thereof. The term also includes oligonucleic acid bases composed of naturally occurring nucleotides, sugars and covalent nucleoside (backbone) bonds and oligonucleotides with non-naturally occurring modifications. Such modifications can introduce certain desired properties not available with naturally occurring oligonucleotides, such as reduced toxicity, increased stability to nuclease degradation, and improved intracellular uptake. It becomes. In an embodiment of the example, the antisense compounds of the invention are naturally occurring by modifying the phosphodiester backbone (backbone) to extend the life of the antisense oligonucleotide (phosphate substituents are replaced by phosphorothioates). Different from (native) DNA. Similarly, one or both ends of an oligonucleotide may be replaced with one or more acridine derivatives, which intercalate between adjacent base pairs within a nucleic acid chain.

Another alternative to antisense is the use of "RNA interference" (RNAi). Double-stranded RNA (dsRNA) can induce gene silencing in mammals in vivo. The natural function of RNAi and co-suppression appears to be the protection of the genome against invasion by mobile genetic elements (such as retrotransposons and viruses) that, when activated, produce abnormal RNA or dsRNA in the host cell. (See, for example, Jensen, J. et al., Nat. Genet. 21: 209-12, 1999). Double-stranded RNA molecules are made by synthesizing two RNA strands, each having a length of about 19-25 (eg, 19-23 nucleotides) and capable of forming a double-stranded RNA molecule. obtain. For example, a dsRNA molecule useful for the methods of the invention may include RNA corresponding to at least one portion of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 and a complementary strand thereof. Preferably at least one RNA strand has a 1-5 nucleotide overhang at 3'. Synthetic RNA strands are combined under conditions where double-stranded molecules are formed. The RNA sequence can include a portion of at least 8 nucleotides of SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5 and have a total length of 25 nucleotides or less. The design of siRNA sequences for a given target is within the normal skill of one of ordinary skill in the art. Commercial supplies are available that design siRNA sequences and guarantee at least 70% expression knockdown (Qiagen, Valencia, CA). Exemplary PDE7 shRNAs and siRNAs are commercially available from the Sigma-Aldrich Company (Product No. SHDNA_-NM_002603; SASI_Hs01_00183420 to SASI_Hs01_00010490).

The dsRNA can be administered as a pharmaceutical composition, which can be done by known methods, where the nucleic acid is introduced into the desired target cell. Commonly used gene transfer methods include calcium phosphate, DEAE-dextran, electroporation, microinjection and viral methods. Such methods are described by Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, Inc. , 1993. Therapeutic nucleic acid molecules can be modified to cross the blood-brain barrier. For example, a phosphorothiolate antisense oligonucleotide for the central region of Abeta of amyloid precursor protein (APP) can be found in i. c. v. Administration has been shown to reduce learning and memory deficiencies in Alzheimer's mouse models. Banks W. A. Et al., Journal of Pharm. and Exp. Therapeutics, 297 (3): 1113-121, 2001.

Ribozyme:
In some embodiments, the PDE7 inhibitor is a ribozyme that specifically cleaves the mRNA of the target PDE7 (eg, PDE7A, PDE7B, or both). Ribozymes that target PDE7 can be utilized as PDE7 inhibitors to reduce the amount and / or biological activity of PDE7. A ribozyme is a catalytic RNA molecule capable of cleaving a nucleic acid molecule having a sequence completely or partially homologous to the sequence of the ribozyme. It is possible to design a ribozyme transgene that encodes an RNA ribozyme that specifically pairs with a target RNA and cleaves the phosphodiester backbone at a specific location, thereby functionally inactivating the target RNA. .. In performing this cleavage, the ribozyme does not change itself and is therefore capable of reuse and cleavage of other molecules. Inclusion of ribozyme sequences within the antisense RNA confer RNA cleavage activity on them, thereby increasing the activity of the antisense construct.

Ribozymes useful in the practice of the present invention typically include a hybrid region of at least about 9 nucleotides, which is complementary to at least a portion of the target PDE7 mRNA in the nucleotide sequence, and a catalytic region, which is: Includes (fitted to cleave target PDE7 mRNA) (Summary is European Patent No. 0321201; WO 88/04300; Haselov, J. et al., Nature 334: 585-591, 1988; Fedor, M.J. Et al., Proc. Natl. Acad. Sci. USA 87: 1668-1672, 1990; see Cech, TR et al., Ann. Rev. Biochem. 55: 599-629, 1986).

The ribozyme can either be directly targeted to the cell in the form of an RNA oligonucleotide incorporating the ribozyme sequence, or introduced into the cell as an expression vector encoding the desired ribozyme RNA. Ribozymes can be used and applied in much the same manner as described for antisense polynucleotides.

Antisense RNA and DNA, ribozyme and RNAi molecules useful in the methods of the invention can be prepared by any DNA and RNA molecule synthesis method known in the art. Examples of such a method include a method for chemically synthesizing oligodeoxyribonucleotides and oligoribonucleotides, which are well known in the art, such as solid-phase phosphoramidite chemical synthesis. Alternatively, the RNA molecule can be made by in vitro and in vivo transcription of the DNA sequence encoding the antisense RNA molecule. Such DNA sequences can be integrated into a wide variety of vectors into which a suitable RNA polymerase promoter (such as the T7 or SP6 polymerase promoter) has been incorporated. Alternatively, an antisense cDNA construct that constructively or inductively synthesizes antisense RNA depending on the promoter used can be stably introduced into the cell line.

Various well-known DNA molecular modifications can be introduced as a means of increasing stability and half-life. Useful modifications include, but are not limited to, the addition of flanking sequences of ribonucleotides or deoxyribonucleotides to the 5'and / or 3'ends of the molecule, or phosphorothioate or 2'O rather than phosphodiesterase binding in the oligodeoxyribonucleotide backbone. -Use of methyl can be mentioned.

IV. Screening Methods for PDE7 Inhibitors Useful for Treating Addiction In another embodiment, methods for identifying agents that inhibit PDE7 activity useful for treating addiction in mammalian subjects in need of the treatment. I will provide a. The method of this aspect of the present invention is to measure the _{IC 50} for inhibition of PDE7 activity for each of (a) a plurality of agents; (b) from the plurality of agents, _{IC 50} of less than about 1μM for inhibition of PDE7 activity selecting an agent having; (c) PDE7 measuring the _{IC 50} for PDE4 inhibition activity of the drug with an _{IC 50} of less than about 1μM for inhibition of activity; (d) 10 times the _{IC 50} for inhibition of PDE7 by selecting compounds with an IC ₅₀ for inhibition of greater PDE4 activity and identifying an agent useful in the treatment of addiction; and (e) a activity of the identified compounds, it is evaluated in addiction model system _{(Here, it has an IC 50 of} less than about 1 μM for PDE7 inhibition _{and an IC 50} for inhibition of PDE4 activity greater than 10-fold greater than the _{IC 50} for inhibition of PDE7, and is effective in treating habits in animal models. The determined agents include (indicating that they are PDE7 inhibitors useful for treating habits in mammalian subjects).

Representative agents that can be used in the practice of this aspect of the invention include molecules that bind to PDE7 and inhibit the enzymatic activity of PDE7 (eg, small molecule inhibitors that bind to PDE7 and reduce enzymatic activity). Block peptides), as well as molecules that reduce the expression of PDE7 at transcriptional and / or translational levels (eg, PDE7 antisense nucleic acid molecule, PDE7 specific RNAi molecule and PDE7 ribozyme, etc.), thereby causing PDE7 to cAMP. Prevents disconnection.

V. Description and definition of general compositions.
In one aspect, the invention provides a method of treating addiction, comprising administering to a patient in need of treatment an amount of a PDE7 inhibitor effective in inhibiting the enzymatic activity of PDE7. Thus, inhibition of PDE7 enzyme activity is the primary therapeutic mode of PDE7 inhibitor in the treatment of addiction. Addictions include addictive drugs or addiction to addictive sexual activity. Addiction agents include, but are not limited to, psychostimulants, alcohol, opioids, and nicotine. The preferred psychostimulant for the treatment of addiction with PDE7 inhibitors is cocaine or metaamphetamine. The preferred addictive behavior for treatments using PDE7 inhibitors is binge eating.

For each PDE7 inhibitory chemical compound useful in the methods of the invention, any possible stereoisomer and geometric isomer is included. The compound includes not only racemic compounds but also optically active isomers. If the PDE7 inhibitor is desired as a type of enantiomer, it may be the partitioning of the final product or the use of an isomerically pure starting material or chiral auxiliary (eg, Ma, Z. et al., Tetrahedron: Asymmetry 8). (6): 883-888, see 1997), which can be obtained by any of the stereospecific synthesis. Division of the final product, intermediate or starting material can be made by any suitable method known in the art. Moreover, in situations where tautomers of a compound are possible, the invention is intended to include all tautomeric forms of the compound.

PDE7 inhibitors containing acidic moieties can form pharmaceutically acceptable salts with suitable cations. Suitable pharmaceutically acceptable cations include alkali metal (eg, sodium or potassium) and alkaline earth metal (eg, calcium or magnesium) cations. A pharmaceutically acceptable salt of a PDE7 inhibitor containing a basic center is an acid addition salt formed with a pharmaceutically acceptable acid. Examples include hydrochloride, hydrobromide, sulfate or bicarbonate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate. , Citrate, tartrate, gluconate, methaneflugonate, benzenesulfonate, and p-toluenesulfonate. In view of the above, all references to compounds useful in the methods of the invention presented herein are intended to include PDE7 inhibitors, as well as pharmaceutically acceptable salts and solvates thereof.

The compound of the present invention may be administered therapeutically with the chemical substance as it is, but it is preferable to administer the PDE7 inhibitor as a pharmaceutical composition or a preparation. Accordingly, the present invention further comprises a PDE7 inhibitor or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable carriers, and optionally other therapeutic and / or prophylactic components. Provided is a pharmaceutical composition or preparation containing both. Suitable carriers are those that are compatible with the other components of the formulation and are not harmful to their recipients. In addition, the compounds of the present invention are delivery systems that provide sustained release or uptake or increased activity of the compound, such as liposome-based or hydrogel-based injections, microparticles, nanoparticles, or micelles for oral or parenteral delivery. It may be carried on a system or a stepwise capsule system for oral delivery.

Blood-brain barrier:
In some embodiments, the PDE7 inhibitor is administered to either cross or bypass the blood-brain barrier. Preferably, the inhibitor, compound or composition administered in the treatment method is capable of crossing the blood-brain barrier in sufficient quantity and at a sufficient rate to allow treatment of the movement disorder. Methods for allowing a drug to cross the blood-brain barrier are known in the art, minimizing drug size, providing hydrophobic factors that facilitate passage, and considerable crossing of the blood-brain barrier. Conjugation with a permeable carrier molecule can be mentioned.

In some embodiments, the effective amount of PDE7 inhibitor is an amount that IC ₅₀ concentrations above are achieved with respect to the activity of a given PDE7 inhibitors in brain tissue. In some embodiments, PDE7 inhibitor is about 1,1.5,2,2.5,5,10,20 fold or more peaks larger _{IC 50} of concentration for the inhibition of PDE7A or PDE7B It is administered in the form and dosage at which the concentration is obtained.

Example 1: PDE7 inhibition alleviates cocaine addiction a. Reduction of Cocaine Self-Administration The ability of PDE7 inhibition to reduce cocaine use by reducing the recurrence of cocaine addiction and chronic cocaine self-administration was shown in a rat model of cocaine addiction. Cocaine hydrochloride (obtained from the National Institute on Drug Abuse, Bethesda, MD) was dissolved in sterile physiological saline at a concentration of 0.25 mg / 0.1 mL. The drug or vehicle solution was injected in a volume of 0.1 mL over 4 seconds. Two PDE7 inhibitors according to formula 1A (OMS182506) and formula 1B (OMS181869) above in the present specification, and one PDE7 inhibitor (OMS182401) according to the above formula 6 in the present specification for the effect on cocaine self-administration. Tested. OMS182506 and OMS181869 were given in an intraperitoneal (ip) procedure 12 hours and 1 hour prior to the start of cocaine self-administration. OMS182401 was given intraperitoneally.

Male Wistar rats (weighing 180-200 g upon arrival in the laboratory) were used. The above rats were placed in a group of 3 animals in a breeding facility where humidity (45-55%) and temperature (22 ° C.) were controlled, for 12 hours: 12 hours, backlit / dark cycle (17:00 lighting; 05:00). It was housed with lights off), and food and water were given at will. Experiments were performed during the dark period of the light / dark cycle described above. One week after arrival, the rats were surgically operated and a silastic catheter was implanted in the right jugular vein. The experimental station consisted of an operant conditioning chamber (Med Associate Inc.) surrounded by a soundproof and ventilated environment chamber. Cocaine was delivered by a plastic tube attached to a catheter prior to the start of the session. While the injection pump was actuated by the response to the active lever, the response to the inactive lever was recorded but did not produce any programmed results. The operation of the pump resulted in the delivery of 0.1 mL of fluid. An IBM compatible machine controlled fluid delivery and recording of behavioral data.

For studies assessing the PDE7 inhibitors OMS182056 and OMS181869, rats were subjected to cocaine in a 2-hour daily session with a constant rate of 5 enrichment schedule that resulted in delivery of 0.25 mg / 0.1 ml of fluid cocaine solution in each response. Trained to self-administer. Cocaine self-administration training was continued until the response reached a stable baseline (less than 10% variability for 3 consecutive days calculated for each rat). At this point the drug test was started.

Rats were treated with PDE7 inhibitors (0.0, 0.3, 1.0 and 3.0 mg / kg) 12 and 1 hours prior to the start of the self-administration session i. p. Treated with administration. The number of responses to active and inactive levers was recorded. The drug test period was 3 days. During this period, cocaine self-administration was continued and the baseline lever response was reestablished.

The results are shown in FIGS. 1 and 2. Treatment with either OMS182506 or OMS181869 did not significantly reduce cocaine self-administration, but tended to decrease at higher doses.

For studies assessing OMS182401, rats were delivered with 0.25 mg of cocaine by pressing each active lever, but no cocaine was delivered by pressing the inactive lever, 2 hours a day (short access). Or trained to self-administer cocaine in a 6-hour (long-term access) training session per day; after 1 week, 5 lever presses were required to receive equal doses of cocaine. , The above rate was increased. Cocaine self-administration training was continued until the response reached a stable baseline (less than 10% variability for 3 consecutive days calculated for each rat). At this point the drug test was started. The animals were injected with vehicle or drug 15 minutes prior to the test session. The number of responses to active and inactive levers was recorded.

The results are shown in FIG. Treatment with OMS182401 significantly reduced cocaine self-administration over long-term access, but not in the short-term access model.

PDE7 inhibitors increase intracellular levels of cAMP by reducing the degradation of cAMP by phosphodiesterase-7 activity. Intracellular cAMP levels are also increased by activation of Gs-selective G protein-coupled receptors (eg, the dopamine D1 receptor (DRD1)). To test the effect of DRD1 activation on increasing cAMP levels on cocaine self-administration, the above DRD1 agonist SKF82958 was applied to rats trained to self-administer cocaine i. p. It was administered. (±) -SKF-82958 Hydrobromid [(±) -6-Chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzoazepine hydrobromid 6-Chloro-N-allyl-SKF-383393 hydrobromide], or "SKF82958" is available from Sigma Aldrich. SKF82958 was administered at 1.0 mg / kg. The results are shown in FIG. Treatment with SKF82958 significantly reduced cocaine self-administration in the short-term access model. The long-term access model described above was not evaluated in this case. In the first hour after treatment, a significant reduction in self-administration was observed at both doses. Two hours after treatment, the tendency to reduce self-administration was no longer significant (data not shown). However, animals also showed significantly abnormal behavior and became extremely aggressive, suggesting that administration of SK82958 with cocaine impaired their ability to push the lever. The behavior shown was similar to that shown after cocaine overdose (data not shown).

To determine if such agents were addictive, the PDE7 inhibitor OMS182056 and the dopamine D1 agonist SKF82958 were administered without cocaine during the elimination period. The results are shown in FIGS. 5 and 6. Neither drug caused increased lever pressing by rats when administered alone. OMS182506 showed a slight decreasing tendency of lever pressing, although not statistically significant. Therefore, neither drug was addictive.

Both PDE7 inhibitors and dopamine D1 agonists can increase intracellular levels of cAMP, but these two cumulative drugs have very different effects when administered with cocaine.

OMS182401 was also tested for long-term effects on cocaine self-administration. Rats were surgically implanted with a jugular vein catheter and recovered for 1 week. The animals were then subjected to a 6 hour daily (long access) training session in which delivery of 0.25 mg cocaine was induced each time the lever was actively pressed. After one week, the rate was increased so that five lever presses were required to receive the same amount of cocaine. Animal training lasted about 6 weeks. Once a stable active lever push rate has been obtained for 6 consecutive days, the animal should be given a vehicle or drug (4.5 mg / kg) twice daily i. p. I injected it. Reinforced response was evaluated over 2 hours.

The results are shown in FIG. Chronic OMS182401 treatment reduced cocaine self-administration in long-term access rat models. The effect of OMS182401 remained stable after treatment for at least 6 days. Cocaine self-administration returned to baseline levels when treatment with OMS182401 was stopped. OMS182401 did not modify the inactive lever push (no data displayed). This experiment confirms the efficacy of the PDE7 inhibitor observed in an acute model of cocaine addiction treatment and indicates that OMS182401 may be suitable for chronic administration.

b. Reduction of Cocaine Demand After Erasure OMS182506 was tested for its effect on cocaine demand behavior immediately after erasure. Rats were trained to self-administer cocaine as described above and then exposed to elimination conditions. On the first day, cocaine was replaced with saline, OMS182506 (1.0 mg / kg and 3.0 mg / kg), and i. p. It was administered and lever presses were counted. The results are shown in FIG. At 3 mg / kg OMS182056, the amount of cocaine demanding activity at the start of the elimination process was significantly reduced. This indicates that OMS182506 accelerates cocaine erasure.

c. Reducing post-recurrence cocaine demand OMS182506 and OMS182401 were also tested for their effect on post-recurrence cocaine demand behavior of stress-induced addiction. Rats were trained to self-administer cocaine as described above and then exposed to elimination conditions. During the resurrection period the day after the final erasure session, rats were injected with yohimbine (1.25 mg / kg) and 30 minutes later placed in an operant chamber and lever press was monitored for 30 minutes. It is known that administration of yohimbine, an α-2 adrenergic receptor antagonist, increases cell firing and release of noradrenaline in the brain, acts as a pharmacological stress factor, and promotes recurrence of alcohol demand (Le et al.). , Psychopharmacology 179: 366-73 (2005)). The results are shown in FIGS. 9 and 10. At doses of 1.0 mg / kg and 3.0 mg / kg (FIG. 9), OMS182506 showed a significant effect in preventing the recurrence of stress-induced cocaine addiction. Similarly, at doses of 0.3 mg / kg, 1.0 mg / kg and 3.0 mg / kg (FIG. 10), OMS182401 showed a significant effect in preventing the recurrence of stress-induced cocaine addiction.

OMS182506 was tested for its effect on cocaine demanding behavior after recurrence of cue-induced addiction. Rats were trained to self-administer cocaine with visual or sensory cueing and then exposed to cocaine-free scavenging conditions. During the resurrection period the day after the last erasure session, the rats were re-exposed to the previously learned queue. The lever press is monitored and the results are shown in FIG. Although the results were not statistically significant, increasing doses of OMS182056 (1.0 or 3.0 mg / kg) provided a tendency for dose-related reduction in cue-induced recurrence in animals. OMS182401 was also tested for its effect on cocaine demanding behavior after recurrence of cue-induced addiction. The results are shown in FIG. Three concentrations of OMS182401 were tested: 0.3 mg / kg, 1.0 mg / kg, and 3.0 mg / kg, and the results were statistically significant at all three concentrations. Administration of escalating doses of OMS182401 resulted in a statistically significant dose-related reduction in cue-induced recurrence in animals in a dose-related manner.

PDE7 inhibitors and DRD1 agonists were then tested for their effect on cocaine initial stimulation-induced recurrence. Rats were trained to self-administer cocaine as described above and then exposed to elimination conditions. Cocaine was replaced with aqueous physiological saline. The revival procedure was initiated after the lever press was significantly reduced. Rats were treated with vehicle or drug and after 10 minutes cocaine was administered. Lever pushes were counted within 1 hour after cocaine administration. The results of the PDE7 inhibitor OMS182056 are shown in FIG. Administration of OMS182056 had no significant effect on the cocaine-induced initial stimulation response. The results of the above DRD1 agonist SKF82958 are shown in FIG. Treatment with SKF82958 significantly reduced lever push induced by initial cocaine stimulation. However, as mentioned above, animals treated with SKF82958 showed significantly abnormal behavior. Again, administration of PDE7 inhibitors and dopamine D1 agonists had very different results in cocaine-addicted animals.

Example 2: PDE7 inhibition alleviates nicotine addiction a. Reduction of self-administration of nicotine The ability of PDE7 inhibition to reduce nicotine use was demonstrated in a rat model of nicotine addiction. Male Wistar rats (weighing 180-200 g upon arrival in the laboratory) were used. A group of 3 rats were housed in a humidity and temperature controlled (22 ° C.) zoo with a 12 hour: 12 hour reverse light / dark cycle (17:00 on; 05:00 off) and fed. Water was given at will.

Rats were surgically implanted with a jugular vein catheter and recovered for 1 week. Animals were given a 2-hour (short-term access) or 6-hour (long-term access) training session per day inducing delivery of 0.03 mg of nicotine with each active lever press three times. Once a stable active lever push rate is obtained, the animal is given a vehicle or drug (either OMS182401 or OMS182399 (another PDE7 inhibitor according to formula 6 above)) for 15 minutes i. p. After the injection, a test session was conducted. The measured reading is the number of enhancement responses in 2 hours. The half-life of OMS182401 in rats is 1.7-4.9 hours. The results are shown in FIGS. 15 (OMS182401, short-term access), 16 (OMS182401, long-term access) and 17 (OMS182399, short-term access). Inhibition of PDE7 by OMS182401 resulted in a dose-dependent reduction in nicotine self-administration in both short-term and long-term access rat models. PDE7 inhibition by OMS182399 reduced nicotine self-administration at 3.0 mg / kg to 9.0 mg / kg in short-term access rat models. In this compound, the inactive lever push was not modified in any case.

b. Effect of PDE7 Inhibition on Food Self-Administration The effects of PDE7 inhibitors OMS182399 and OMS1823401 on food self-administration were evaluated to determine whether the effect of PDE7 inhibition was specific to the substance of abuse. Eight male Wistar rats were tested for each compound. Each drug was tested at concentrations 0.0 mg / kg, 3.0 mg / kg and 9.0 mg / kg formulated in 0.03 M tartaric acid. The solution was administered intraperitoneally (ip).

The self-administration station consisted of an operant conditioning chamber (Med Associate Inc.) surrounded by a bright, soundproof and ventilated small room. The front door and rear wall of the chamber were made of clear plastic. The other walls were opaque metal. Each chamber was equipped with two retractable levers installed on the front panel of the chamber. A minimum downward pressure (about 25 g) on the lever was sufficient to provide a programmed response. A recessed feed bin was placed between the two levers where feed pellets (45 mg each; Bio-Servin Inc., Frenchtown, NJ) could be dispensed from the pellet dispenser. An IBM compatible machine controlled fluid delivery and behavioral data recording.

For data evaluation, analysis of variance (ANOVA) was used, followed by a post hoc comparison (Newman-Keuls) test, if appropriate. The data were analyzed for the effect of the treatment. Statistical significance was set to p <0.05.

18A and 18B show the results obtained with OMS182399 and OMS182401, respectively. None of the compounds showed a statistically significant effect on food self-administration compared to vehicles. This indicates that the effect of PDE7 inhibition is specific to the substance of abuse. The above studies provide evidence that previously observed inhibition of nicotine and cocaine-related operant responses by these PDE7 inhibitors is selective and independent of general inhibition or motivation of motor activity.

c. Reduction of Nicotine Self-Administration in Progressive Ratio Studies Male Wistar rats were first self-administered with nicotine as described above in Example 2 under a feature release 1 (fair release 1; FR1) enhancement schedule. Trained. After establishing a stable baseline of response with nicotine, animals are subjected to progressive ratio conditions with increasing response requirements (ie, the number of lever responses required to receive a dose of 0.03 mg of nicotine). Tested.

Each nicotine-enhanced response resulted in a 20-second turn-on of indoor lighting. If more than 60 minutes have passed since the last enhancement response, the session was terminated. The data collected were the stop points (number of lever pushes in the last session), the total number of lever pushes (active levers) throughout the above study, and the total number of rewards. Fifteen animals were tested using the Latin square method (ie, each animal received each dose). The effects of the PDE7 inhibitor OMS182401 at various doses were compared with the vehicle alone.

The results for the total number of rewards, the stop points and the total active lever push are shown in FIGS. 19A-19C, respectively. These data illustrate that the PDE7 inhibitor reduces the motivation of addicted animals to acquire nicotine, i.e., the motivation for nicotine in a dose-dependent manner.

Example 3: Reduction of self-administration of nicotine scavenging The ability of PDE7 inhibition to accelerate nicotine scavenging was demonstrated in a rat model of nicotine addiction. Rats were trained to self-administer nicotine at stable levels. The active lever was not associated with any enhancement rewards. Animals were injected with vehicle or OMS182401 prior to the first erasure session. The total response during the active lever for the first hour of the first erasure session was measured. The results are shown in FIG. OMS182401 facilitated nicotine elimination in a statistically significant manner.

Another study evaluated the effect of OMS182401 on the non-enhanced response on the first disappearance date in rats trained on feed pellets and confirmed the specificity of the effect of OMS182401 on the substance of abuse. Sixteen male Wistar rats were trained for self-administration of feed pellets for 8 days and then divided into two groups with either OMS182401 (9.0 mg / kg in 0.03 M tartaric acid) or vehicle for the first time. Injection was performed 15 minutes before the erasure session. The results showed that OMS 182401 did not reduce the non-enhancing response in feed pellet-trained rats (data not shown) and provided further support for the specificity of the effect of OMS 182401 on drugs of abuse.

Example 4: Reduction of nicotine use after resurrection The ability of PDE7 inhibition to reduce nicotine use after queue-induced resurrection was demonstrated in a rat model of nicotine addiction. Rats were trained to self-administer nicotine at a stable rate and to distinguish between nicotine availability and saline availability. During the nicotine session, sound (7 kHz, 70 dB) was present for the entire period and the cue light (upper part of the active lever) was turned on after the response. During the saline session, the test chamber was constantly illuminated by a household light and white noise was emitted after each response. The erasure period continued after the discriminant phase. This continued until the lever press was less than 20% of the stable rate. To test the compounds, vehicles or OMS182401 were injected and the animals were exposed to nicotine stimulating conditions. The total response during the first hour of active lever under nicotine stimulation conditions was measured. The results are shown in FIG. Inhibition of PDE7 by OMS182401 statistically significantly reduced cue-induced nicotine recurrence in subject animals. Response during inactive lever was not affected by OMS182401 administration.

The ability of PDE7 inhibition to reduce nicotine use after stress-induced resurrection was demonstrated in a rat model using the α2-adrenergic antagonist yohimbine as a stress factor. Yohimbine acts as a pharmacological stress factor and promotes the recurrence of nicotine demand. OMS182401 was tested for its effect on nicotine demanding behavior. Rats were trained to self-administer nicotine at a stable rate. The active lever was not associated with any enhancement reward (erasure), and the "active" lever push rate decreased in some sessions. When the lever press rate dropped to less than 20% of the stable rate, animals were injected intraperitoneally (ip) with either the vehicle or the test compound at 1.25 mg / kg yohimbine. The total response during the first hour of active lever after yohimbine administration was measured. The results are shown in FIG. PDE7 inhibition by OMS182401 statistically significantly reduced stress-induced recurrence of nicotine demand by subject animals. The inactive lever response was unaffected by administration of either yohimbine or OMS182401.

Example 5: PDE7 inhibition reduces binge eating in response to stress Overeating is induced by stressful exposure to a yo-yo diet and a very tasty diet (HPF) to mimic binge eating disorders in laboratory animals. Developed a binge eating model. In this model, female rats were exposed to a repetitive cycle of restricted and stressful procedures characterized by exposing animals to HPF without the possibility of accessing the HPF. This procedure induces a selective increase in very tasty feed intake, which is over-consumed in a very short period of time. PDE7 inhibitors against binge eating (one of the most significant forms of food addiction) using this model, as described below, with significant predictive and superficial validity. The effect of was investigated.

Resurrection of binge eating was obtained in laboratory animals through a combination of repeated dietary restrictions and stress [Cifani et al, Psychopharmacology 204: 113-125 (2009)]. For the present invention, stress-induced binge eating was tested as in Cifani. The effects of two different PDE7 inhibitors, OMS182401 and OMS182506, were evaluated and compared to vehicle and topiramate, an antiepileptic drug shown in clinical trials to inhibit overeating episodes.

Rats were housed in individual cages and were given optional feed and water for 2 weeks prior to the experiment. Two food sources in rats during the experiment: standard rat feed pellets (feed), or a mixture of 52% Nutella TM chocolate cream, 33% rat feed pellets, and 15% water (5.33 kcal / g; carbohydrates, lipids) And protein was given one of a very tasty feed (HPF) consisting of 56%, 31%, and 7%, respectively.

The rats were divided into 4 groups. Individual groups were served three consecutive times in the following 8-day cycle. Rats were dosed with PDE7 inhibitor or vehicle on day 25.

(1) Control group-no limitation, no stress (NR + NS). Rats were optionally fed for 4 days. On days 5 and 6, they were fed voluntarily and HPF for 4 hours. Rats were optionally fed on days 7 and 8. On day 25, the animals were not exposed to stress.

(2) Limited, no stress (R + NS). Rats were restricted to 66% of normal intake for 4 days. On days 5 and 6, they were fed voluntarily and HPF for 2 hours. On days 7 and 8, rats were fed 66% of their normal dietary intake. On day 25, the animals were not exposed to stress.

(3) No restrictions, stressed (NR + S). Rats were optionally fed for 4 days. On days 5 and 6, they were fed voluntarily and HPF for 2 hours. Rats were optionally fed on days 7 and 8. On day 25, the animals were exposed to stress.

(4) Limited and stressful (R + S). Rats were restricted to 66% of normal intake for 4 days. On days 5 and 6, they were fed voluntarily and HPF for 2 hours. On days 7 and 8, rats were fed 66% of their normal dietary intake. On day 25, the animals were exposed to stress.

Stress was induced by placing the HPF in an inaccessible container within reach of the animal's visible odor for 15 minutes prior to feeding the animal.

On day 25, after the suitable animals were stressed, the animals were given the PDE7 inhibitor OMS182401 (1.0 mg / kg or 3.0 mg / kg ip), the PDE7 inhibitor OMS182506 (1.0 mg / kg / p.). Either kg or 3.0 mg / kg ip), topiramate (60 mg / kg ip) or control vehicle was administered. After 1 hour, the animals were fed HPF and fed voluntarily. HPF intake was measured after 2 hours.

The results are shown in FIGS. 23A-23D for OMS182401, 24A-24D for OMS182506, and 25A-25D for topiramate.

In all groups, animals ate increased amounts of HPF over a period of 2 hours. In the NR + NS, NR + S and R + NS groups, administration of OMS182401 did not significantly affect the amount of HPF eaten by the animals. In the R + S group, both the initial HPF consumption rate and the total amount consumed in 2 hours were higher in the other 3 groups. Therefore, the above R + S conditions serve as a model for human binge eating. Furthermore, in the R + S group, the animals to which 3.0 mg / kg OMS182401 was administered consumed less HPF than the other animals. By the end of the 2 hour period, the difference in HPF consumption between the control animals and the animals fed 3.0 mg / kg OMS182401 was significant. Therefore, administration of the PDE7 inhibitor OMS182401 reduced stress-induced binge eating in the rat model under the above conditions.

Statistically significant OMS182056 effect, 4 groups of rats: R + S group [F (2,22) = 10.79, p <0.001], NR + NS group [F (2,24) = 0.31, p > 0.05]; R + NS group [F (2,24) = 0.84, p> 0.05]; NR + S group [F (2,24) = 1.41, p> 0.05] Only one group (R + S) was observed. Post-hoc comparison showed a statistically significant difference in HPF intake in response to both doses of OMS182056 in the R + S group. The effect of the higher dose (3 mg / kg ip) was observed at all observation points, while 1 mg / kg i. p. Dose was effective only at 15 and 120 minutes (* p <0.05).

Topiramate (60 mg / kg ip) also reduced HPF intake only in the R + S group: [F (1,15) = 9.03, p <0.01], but the other group: NR + NS group. [F (1,16) = 0.84, p> 0.05]; R + NS group [F (1,16) = 1.59, p> 0.05]; NR + S group [F (1,16) = 0.49, p> 0.05] did not decrease. Post-hoc comparison showed that the above effects were clear at all observation points (* p <0.05).

Statistical analysis showed that stress exposure in animals with a history of food restriction induces significant binge eating. These animals (R + S group) feed on significantly higher HPF compared to control rats (NR + NS) that have not been subjected to food restriction experience and stress. The efficacy of OMS182401 and the efficacy of OMS182506 in reducing HPF in the R + S group (but not in other groups, animals in this group do not show binge eating) further demonstrates the effectiveness of the model. These drugs appear to reduce binge eating without affecting general food consumption. Interestingly, at the highest dose, OMS182506 appeared to reduce obsessive-compulsive feeding more strongly than the reference drug topiramate above.

Example 6: PDE7 Inhibition Reduces Stress-Induced Recurrence to Food Demand To assess the ability of PDE7 Inhibitor to prevent recurrence to excessive food intake in food addiction, the PDE7 inhibitor OMS182399 was added to food demand. Was evaluated in a model of yohimbine-induced recurrence. Sixteen male Long Evans rats were first tamed and then fed 60% of their normal daily food intake during the two-month training period. During the training period, the rats were trained to self-administer a very tasty diet at a stable rate. Rats are obtained from 45 mg pellets of a very tasty feed (HPF) containing high levels of fat (35% w / w) and moderate levels of carbohydrates (45% w / w) (available from Biosave, Frenchtown NJ). Was trained to push an active lever in the test chamber for delivery. Rats were trained every other day for 3 hours / day with a fixed rate of 1 reinforcement schedule. Each lever push is enhanced with a pellet of HPF and a 20 second timeout between pushes. Depressing the inactive lever did not result in food fortification.

This self-administration phase was then followed by an elimination phase, during which the depression of the active lever did not result in any HPF or other reward. The elimination period continued daily during the 14 sessions. During the last four sessions, the rats were acclimated to injection.

After the elimination phase, the study phase was initiated, where rats were injected with yohimbine, which acts as a pharmacological stress factor and promotes the recurrence of excessive food demand. Rats were subjected to either OMS182399 (0.3 mg / kg, 1.0 mg / kg or 3.0 mg / kg) or saline i. p. Injections were made, and 10 minutes later, yohimbine or distilled water was injected. The test session was initiated 30 minutes after the yohimbine or distilled water injection above, where the rats were re-entered into a test chamber with active and inactive levers to deliver the HPF. Resurrection behavior (pushing down the active lever) was measured at 14 minutes, 30 minutes, 45 minutes, 60 minutes and 180 minutes. Comparing the total number of active liver responses over the first hour with yohimbine-treated rats, OMS182399 showed stress-induced food demand recurrence in a statistically significant and dose-dependent manner, as shown in FIG. Was shown to be reduced. Inactive lever response was unaffected by either yohimbine or OMS182399 (data not shown). In a further experiment, in contrast to the effect of OMS182399 in yohimbine-treated rats, OMS182399 injection did not reduce lever press in vehicle-treated rats (data not shown).

Example 7: Effect on basal and nicotine-induced dopamine release in the nucleus accumbens To elucidate the mechanism of action of the PDE7 inhibitor on addictive behavior, we discuss dopamine (DA) in the nucleus accumbens (NAc). ) Their effect on levels was investigated. Substances of abuse are known to increase DA levels in NAc shells (effects directly related to their addictive properties) (Laviolette, SR, Van der Koy, D., 2004. The neuroscience of nicotine addition). : Bridging the gap from moles to behavior. Nat. Rev. Neuroscience. 5,55-65). Studies were conducted by in vivo microdialysis studies to assess the effect of OMS182399 on basal and nicotine-induced DA release in NAc in Wistar rats. Male Wistar rats (Harlan, Italy) weighing 275-300 g were placed in a central animal chamber at constant temperature (23 ° C.), humidity (60%) and 12-hour light / dark cycle (8 am to 8 p.). They were housed in groups of 6 per cage under (lit up to m. M.) and were optionally fed with standard samples (Morini, Italy) and water for at least 5 days.

A concentric dialysis probe having a dialysis section of 1.5 mm was prepared by De Luca et al. Prepared with AN69 (acrylonitrile sodium methylyl sulphonate copolymer) dialysis fiber (310 μm od. 220 μm id. Hospital, Dasco, Italy) according to the method of (2007). Rats were anesthetized with chloral hydrate (400 mg / kg ip) and placed in a brain stereotaxic apparatus. An incision was made in the scalp and the skull was leveled between the Lambdoid suture and the previous section. Two small holes were drilled to expose the dura and the two probes were inserted vertically at the height of the NAc shell and core above according to the illustration by Paxinos and Watson (1998) (shell). Coordinates: A: 2.2, L: 1.0 from the previous term, V: -7.8 from the dura mater; Core coordinates: A, 1.4; L, 1.6 from the previous term; V From the dura mater-7. 6). The probe was fixed to the skull with glass ionomer cement (CX-Plus, Shofu Inc., Japan). Experiments were performed by freely moving the rats 24 hours after implanting the probe. Ringer's solution (147 mM NaCl, 4 mM KCl, 2.2 mM CaCl ₂ ) was pumped through the dialysis probe at a constant rate of 1 μl / min. Samples from each of the NAc shells and cores were taken every 10 or 20 minutes (depending on the experiment) and analyzed.

A dialysis sample (10 μl or 20 μl) is injected into an HPLC equipped with a reverse phase column (C8 3.5um, Waters, Milford, MA, USA) and a coulometric detector (ESA, Coulochem II, Bedford, MA) and DA Was quantified. The first electrode was set to +125 mV and the second electrode was set to -175 mV. The following solutions were used as mobile phases: 50 mM NaH ₂ PO ₄ , 0.1 mM Na _2- EDTA, 0.5 mM sodium n-octyl sulfate, 15% (v / v) methanol, pH 5.5. The mobile phase was pumped by a Jasco pump with a flow rate of 0.6 ml / min. The sensitivity of the assay for DA was 5 fmol per sample. At the end of the experiment, animals were sacrificed by transcardiac perfusion with 100 ml saline (0.9% NaCl) and 100 ml formaldehyde (10%). The probe was removed, and the brain was cut into continuous coronal slices with a vibratome to locate the microdialysis probe. Repeated measures analysis of variance (ANOVA) was applied to the raw data obtained from the DA continuous assay after each treatment. Treatment results showing significant overall changes were submitted to the ex post Tukey test. p <0.05 was considered statistically significant. The average of 3 consecutive samples that differed by 10% or less was regarded as the base value.

To determine the effect of OMS182399 on basal and nicotine-induced DA release in NAc shells and cores, rats were implanted with dual microdialysis probes and 24 hours later, vehicle or OMS182399 (9 mg / kg, ip). .) Was administered. NAc shell and core dialysate DA were monitored for at least 3 hours. If no effect was observed on extracellular DA levels, i.e., for any effect, at least 2 hours after returning to basal DA levels, the same animal was injected with vehicle or OMS182399 with nicotine (0.4 mg / mg /). It was injected 10 minutes before kg subcutaneous (sc). The dialysate DA was monitored for at least 3 hours after nicotine treatment.

FIG. 27 shows the effect of OMS 182399 (9 mg / kg ip) obtained on extracellular DA levels of NAc shell / core. Results are presented as mean ± standard error (SEM) of changes in DA extracellular levels, expressed as a percentage of basal values. OMS182399 had no effect on basal DA levels in any region of NAc.

FIG. 28 shows the extracellular DA level of nicotine (0.4 mg / kg sc) obtained for the extracellular DA level of the NAc shell of rats pretreated with OMS 182399 (9 mg / kg ip; 10 minutes before nicotine). Show the effect. Results are shown as mean ± standard error of changes in DA extracellular levels, expressed as a percentage of basal values. Administration of nicotine increases DA release in the NAc shell, and this effect is substantially reduced by OMS182399.

Example 8: Effect of PDE7 Inhibition on Spontaneous Activity of Dopaminergic Ventral Tegmental Neurons on Nicotine The following electrophysiological studies show that selective PDE7 inhibitors are effective in models of nicotine addiction and dopamine signals mediated by DRD1. It is shown to act by enhancing transmission. The enhancing effect of nicotine is thought to result from activation of dopaminergic neurons in the ventral tegmental area (VTA) (Pidoplicko VI et al., Nature 390: 401-404 (1997); Liu L, et al. , Nicotine persistently activates ventral tegmental area dopaminergic neurons via nicotine acetylcholine receiving respondors contouring α4 and α6 sub We present a PDE7 inhibitor by studying the ability to modify basal and abuse drug-induced changes in VTA dopamine activity by performing whole-cell current-fixed recordings from rat VTA horizontal slices in exobibo. I tried to evaluate the anti-addictive ability of. For this purpose, nicotine was used as an example of a substance of abuse. In addition, the PDE7 isoform is widely expressed in all major regions of the brain and is frequently co-expressed with DRD1 in the same neurons [Reyes-Irisari, E. et al. , Et al. , "Neuronal expression of cAMP-specific phosphodisterase 7B mRNA in the rat brain," Neuroscience 132: 1173-85 (2005); Miro, X. et al. , Et al. , "Differential distribution of cAMP-specific physiology 7A mRNA in rat brain and peripheral organs," Synapse 40: 201-214 (2001)], and "Synapse 40: 201-214 (2001)", and "Synapse 40: 201-214 (2001)" Considering that Example 10), the effects of these agents were also compared in electrophysiological studies.

Dopaminergic neurons were identified by the presence of large hyperpolarizing currents. Johnson, S.A. W. , Et al. , "Opioids excite dopamine neurons by hyperpolarization of local interneurons," J Neurosci 12: 483-488 (1992). Application of the PDE7 inhibitor OMS182401 significantly reduced the spontaneous combustion frequency of the dopaminergic VTA neurons at 0.3 μM and 1.0 μM (FIG. 29A). Notably, a similar effect was observed by application of the DR D1 agonist SKF82958 at concentrations of 3.0 μM and 10.0 μM, as also shown in FIG. 29A.

Moreover, when invalid concentrations of both SKF82958 and OMS182399 (ie, concentrations too low) were applied together, this combination also resulted in a substantial reduction in activity (FIG. 29B). This indicates that PDE7 inhibition enhances the action of DRD1 activation, and that the PDE7 inhibitor and the DRD1 agonist acted synergistically in this regard.

Since DRD1 stimulation increased the amplitude of GABAB-mediated inhibitory postsynaptic potentials (IPSPs) and cAMP-PKA increased GABAA-mediated inhibitory postsynaptic currents (IPSCs) [Bonci, A. et al. , Et al. , "Increased probability of GABA release daring with driving from morphine," J Neurosci 17: 796-803 (1997)], we found that either after this observation (ie, PDE7 inhibition or DRD1 activation). It was hypothesized that reduced spontaneous activity of neurons) could be attributed to an increased probability of GABA release from presynaptic terminals. This assumption was partially confirmed by analysis of microinhibitory postsynaptic potentials (mIPSPs), which show an increase in frequency rather than amplitude of mIPSP after PDE7 inhibition (FIG. 30). Furthermore, when the PDE7 inhibitor was applied in the presence of the GABA-A receptor antagonist picrotoxin (100 μM, data not shown), the inhibition was still present. This suggests the involvement of GABA-B receptors in the PDE7 inhibitor effect. In fact, in the presence of the GABA-B antagonist CGP35348 (100 μM), the inhibitory effect of OMS182401 on spontaneous combustion of VTA DA neurons was no longer observed (data not shown).

In further studies, OMS182401 was found to reverse the activation of VTA dopaminergic neurons by nicotine (Fig. 31). Furthermore, while only 30 nM OMS182401 or 1 μM SKF82958 was ineffective, the combination of 30 nM OMS182401 and 1 μM SKF82958 reversed nicotine-induced activation (p <0.05). This indicates that PDE7 inhibition enhances DRD1 signaling, and that the combination of the PDE7 inhibitor and the DRD1 agonist acted more in this regard than additively.

To demonstrate in vivo that VTA is the site of action of the PDE7 inhibitory effect, OMS182401 was delivered directly to rat VTA and its effect on nicotine self-administration was evaluated. Rats were surgically implanted with a jugular vein catheter and recovered for 1 week. They were then subjected to intracranial surgery to implant guide cannulas bilaterally within the VTA. After recovery, they were given daily training sessions for 2 hours (short term), which caused 0.03 mg of nicotine to be delivered with each active lever press. After achieving a stable probability of active lever press, the vehicle or drug was injected into the VTA just prior to the test session. Enhancing responses were recorded in Latin square experiments (ie, each animal accepting each dose). The position of the jugular vein catheter was histologically confirmed at the end of the experiment. As shown in FIG. 32, direct administration of the PDE7 inhibitor to rat VTA reduced nicotine self-administration. This confirms that VTA is the site of action for the effects of PDE7 inhibition in animals.

Example 9: Effect of PDE7 Inhibition on Ventral Tegmental Dopamine Neuronal Activity on Cocaine, Morphine and Alcohol Further electrophysiological studies assess the effect of the PDE7 inhibitor OMS182399 on VTA DA neuronal activity in the context of cocaine, morphine or alcohol. Completed to do. Preparation of VTA slices was as described in Example 8 above.

Drug-induced changes in firing frequency were calculated by averaging the effects after drug administration (5 minutes) and normalizing to pre-drug baseline. All numerical data are shown as mean ± standard error (sem). Data were compared and analyzed by using a two-way ANOVA for repeated measurements (treatment x number of times) or, where appropriate, Student's t-test for repeated measurements. Statistical analysis was performed by the GraphPad Prism program. The significance level was established with P <0.05.

The acute effects of OMS182399 were investigated on dopamine neurons of VTA in rat horizontal brain slice preparations containing the midbrain. Whole-cell current-fixed recordings were performed from VTA dopamine neurons. Acute bath application of OMS182399 (0.05 μM, 0.5 μM and 2.5 μM, 5 minutes) significantly increased the spontaneous activity of VTA dopamine neurons in a dose-dependent manner, as shown in FIG. Reduced. One-way ANOVA for repeated measurements revealed that the means differed significantly: F _3,42 = 5.67, P = 0.002 (n = 15). The data are expressed as mean ± standard error. ** P <0.005.

As also shown in FIG. 33, acute application of the PDE7 inhibitor OMS182399 (5 minutes prior to morphine application) was in a dose-dependent manner, 50 nM (P <0.0001, n = 7); 0.5 μM (P =). 0.0001, n = 8); with statistical significance (one-sided t-test) at a dose of 2.5 μM (P = 0.0002, n = 7), morphine-induced excitement of VTA DA cells (morphine 1 μM, 3) Minutes: 224.4 ± 19.5% of basal firing frequency, n = 7) could be blocked; this essentially did not affect the basal spontaneous activity of DA neurons. The dashed line in FIG. 33 represents the normalized basal spontaneous activity of VTA DA cells. The data are expressed as mean ± standard error. *** P <0.0001. Notably, statistical analysis (two-sided t-test) revealed no difference in the firing activity of VTA DA cells between the effects of OMS182399 in the presence or absence of morphine, ie. The addition of morphine could not exceed the effect of OMS182399 (P> 0.05 at all concentrations tested).

As shown in FIG. 34, the acute application of the PDE7 inhibitor OMS182399 (5 minutes prior to the application of the ethanol bath) was in a dose-dependent manner, 500 nM (P = 0.007, n = 8); 0.05 μM (P = 0.007, n = 8). P> 0.05, n = 7); ethanol-induced excitement of VTA DA cells was blocked with statistical significance (unilateral t-test) at a dose of 2.5 μM (P = 0.02, n = 7). (Ethanol 100 mM, 5 minutes: 158.3 ± 26.7% of basal firing frequency, n = 6); this essentially reduced the basal spontaneous activity of DA neurons. The dashed line in FIG. 34 represents the normalized basal spontaneous activity of VTA DA cells. The data are expressed as mean ± standard error. ** P <0.001, * P <0.05. Notably, from statistical analysis (two-sided t-test), there are differences in the firing activity of VTA DA cells between the effects of OMS182399 in the presence and absence of ethanol at a dose of OMS182399 at 500 nM. There were (P = 0.01, n = 8), whereas no statistical differences were revealed for the other two test doses (P at both concentrations tested). = 0.6).

As shown in FIG. 35, acute application of the PDE7 inhibitor OMS182399 (5 minutes prior to cocaine bath application) was 50 nM (P = 0.036, n = 7) and 0.5 μM (P = 0.049, n). At the dose of = 7), cocaine-induced inhibition of VTA DA cells could be blocked (cocaine 1 μM, 5 minutes: 36.4 ± 9.1% of basal firing frequency, n = 7). The dashed line in FIG. 35 represents the normalized basal spontaneous activity of VTA DA cells. The data are expressed as mean ± standard error. * P <0.05. Notably, at the highest dose tested (2.5 μM), which essentially produces a quantitatively similar effect on cocaine (ie, reduces the firing frequency of dopamine neurons), OMS182399 was found in dopamine neurons. It did not prevent cocaine-induced inhibition of spontaneous activity (unilateral t-test vs. cocaine P = 0.5; bilateral t-test vs. OMS182399 P = 0.8). Notably, in the presence of the lowest dose tested (ie, 50 nM), the effect of cocaine on dopamine neuronal activity is the opposite of control (ie, excitement as opposed to inhibition).

As shown in the electrophysiological studies described above, PDE7 inhibition blocks the effects of commonly used drugs of abuse, regardless of the chemical structure and mechanism of action of the drugs of abuse. Notably, as shown above, OMS182401 can block nicotine-induced excitement of dopamine cell firing frequency that may be attributed to activation of α4β2 nAChRs located in dopamine cell bodies [Picciotto MR]. , Et al. , Nature, 391: 173-177 (1998)]. Similarly, the structurally related compound OMS182399 can block both morphine-induced and ethanol-induced excitement of dopamine neurons. Both are due to the disinhibition mechanism for dopamine cells [Theile JW, et al. Neuroscience, 172: 94-103; Jalabert M, et al. , Proc Natl Acad Sci USA, 108: 16446-16450 (2011)]. Interestingly, OMS182399 can also reverse the cocaine effect. The effect on cocaine is more complex. This is because cocaine induces both a rapid increase in dopamine in the striatal region and a reduction in midbrain dopamine cell firing (via activation of D2 receptors located in the cell body).

Example 10: Effect of PDE7 Inhibition on Dopamine D1 Subtype Receptor-mediated Stimulation of Open Field Activity To assess the ability of PDE7 inhibitors to enhance DRD1 signaling in vivo, the effects of PDE7 inhibitor OMS182401 and DRD1 agonist SKF82958 , Alone and in combination, evaluated in an open field activity model using wild-type C57BL / 6 mice. As shown in FIG. 36, the DRD1 agonist stimulated open field activity at 1 mg / kg. OMS182401 was ineffective as a single agent (data not shown, even at doses higher than 1 mg / kg), but significantly enhanced the stimulatory effect of the DRD1 agonist SKF82958.

Although examples of embodiments have been exemplified and described, it is recognized that various modifications can be made in these without departing from the spirit and scope of the invention.

Embodiments of the invention claiming exclusive ownership or privilege are defined as follows:

Claims (1)

Methods, pharmaceutical compositions, kits, etc. described in the specification.

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