JPWO2006059713A1 - Agents for preventing and / or treating drug addiction - Google Patents

Abstract

For example, in the above formula (I) (wherein R1, R2 and R3 are the same or different and each represents a hydrogen atom, lower alkyl, lower alkenyl or lower alkynyl, R4 is cycloalkyl,-(CH2) n-R5 or the above formula ( II), wherein X1 and X2 are the same or different and each represents an oxygen atom or a sulfur atom) and a compound having an adenosine A2A receptor antagonistic activity such as a xanthine derivative or a pharmaceutically acceptable salt thereof as an active ingredient An agent for the prophylaxis and / or treatment of drug dependence is provided.

Description

  The present invention relates to a prophylactic and / or therapeutic agent for drug dependence.

  “Drug dependence” is a state of only “mental dependence” or “mental dependence” and “physical dependence” of the living body resulting from the interaction between the body and the drug. It is defined as a state that always has the urge to take the drug continuously or periodically in order to obtain a mental effect or to avoid discomfort resulting from a lack of the drug (World Health Organization) (WHO) 16th meeting of the Expert Committee on Drug Addiction).

“Mental dependence” is a mental state that can no longer be avoided without using a drug. By stopping or reducing the use of the drug, mental anxiety such as a strong anxiety, a strong desire for the drug, This is a state in which behavioral abnormalities such as search behaviors occur.
“Physical dependence” means discomfort (such as insomnia, anxiety, tremors, sweating, seizures, delusions, hallucinations, vomiting, diarrhea, etc.) by discontinuing or reducing the use of the drug. "Drug withdrawal symptoms": A condition that causes physical abnormalities such as withdrawal symptoms and withdrawal symptoms.

  Behavioral disorders, mental disorders, organ disorders and the like resulting from such drug dependence are collectively referred to as “drug dependence”. In the WHO International Disease Classification 10th Edition (ICD-10: International Statistical of Diseases and Related Health Probes-10), “drug dependence” is positioned as a mental and behavioral disorder due to the use of psychoactive substances. It includes various degrees of disability such as acute poisoning, harmful use (abuse etc.), dependence, addiction, psychotic disorders, amnesia, etc. due to the active substance. On the other hand, in the diagnostic classification of DSM-IV (Diagnostic and Statistical Manual of Mental Disorder-IV; published by the American Psychiatric Association) and related events, substance dependence and substance abuse are positioned as substance use disorders among substance related disorders. Others are positioned as substance-induced disorders that are diffused into psychotic and mood disorders.

In WHO, drugs that form dependence (addictive drugs) are: Alcohol, 2. Opium; 3. Cannabis; 4. 4. antitussives or sleep aids; Cocaine, 6; 6. psychostimulants including caffeine, Hallucinogens, 8. 8. tobacco and 9. 9 types of volatile solvents and 10. Classified as other psychoactive substances. Dependent drugs belonging to these all form “mental dependence”. Alcohol, 2. Opium species, 4. An antitussive or sleeping agent, 8. 8. tobacco and Five types of volatile solvents form “mental dependence” and “body dependence”. Furthermore, the use of devastating drugs originated from magic mushrooms has increased in recent years, and these are also known to form dependence (clinical psychopharmacology, 6 , 1111-1119 (2003)). .

Due to the abuse of addictive drugs, the tragedy that causes the collapse of the family and crimes has become a serious social problem. As a countermeasure, the goal is to cut off somewhere in the social environment related to drug-related disorders, including abuse, dependence and addiction. Therefore, as a means of doing so, we will make full use of all methods such as drug treatment, promotion of education, reform of social system including laws (Pharmacia, 34 , 905-909 (1998), Principles of Drugs ADDICTION TREATMENT: A Research Based Guide (published by NIH (1999), Principles of Drug Addition Treatment: A Research Based Guide). Drug treatment includes, for example, treatment that maintains the replacement of addictive drugs with safer analogs, replacement taper therapy, elimination therapy with antagonists, inhibitors, etc., and symptomatic therapy for withdrawal symptoms that appear as a result of physical dependence Yes (clinical psychopharmacology, 6 , 1121-1129 (2003)).

Alcoholism, which is one of the drug addictions, is widely recognized in each group regardless of gender, and there is a report that the prevalence rate in Japan is close to 2%. Only so-called anti-alcohol drugs (for example, disulfiram, cyanamide, etc.) are used in Japan as drugs for alcoholism, but important points in the treatment of alcoholism are withdrawal management and prevention of recurrence. In Europe and the United States, acamprosate, which is said to exert an effect by affecting the strengthening effect of alcohol and craving for drinking, is clinically used (Clinical Psychopharmacology, 6 , 1151-1160 (2003)). That is, there is a demand for a prophylactic and / or therapeutic agent for drug dependence that suppresses the formation of “mental dependence” or “physical dependence” on addictive drugs such as alcohol and does not itself form drug dependence.

On the other hand, many xanthine derivatives including a compound represented by the formula (I) described later have been known to have, for example, an anti-Parkinson disease action, a central excitatory action, a neurodegeneration inhibitory action, etc. (Patent Document 1, Patent) Reference 2, Patent Document 3, Patent Document 4, Patent Document 5, etc.). Further, it is known to have, for example, adenosine A ₂ receptor antagonistic action, antidepressant action, anti-asthma action, bone resorption inhibitory action, hypoglycemic action, platelet growth inhibitory action, etc. [International Publication No. 92/06976 pamphlet] International Publication No. 94/01114, International Publication No. 95/23165, International Publication No. 99/35147, Journal of Medicinal Chemistry, Vol. 34, p. 1431 (1991), Journal of Medicinal Chemistry (J. Med. Chem.), 36, p. 1333 (1993)].
Japanese Examined Patent Publication No. 47-26516 JP-A-6-21856 JP-A-6-239862 Japanese Patent Laid-Open No. 6-16559 WO99 / 12546 pamphlet

An object of the present invention is to provide, for example, a prophylactic and / or therapeutic agent for drug dependence containing, as an active ingredient, a compound having an adenosine A _2A receptor antagonistic action or a pharmacologically acceptable salt thereof.

The present invention relates to the following (1) to (44).
(1) A prophylactic and / or therapeutic agent for drug dependence comprising as an active ingredient a compound having an adenosine A _2A receptor antagonistic action or a pharmacologically acceptable salt thereof.
(2) The preventive and / or therapeutic agent for drug dependence according to (1) above, wherein the compound having an adenosine A _2A receptor antagonistic action is a xanthine derivative.

(3) A compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (I)

[Wherein R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom, lower alkyl, lower alkenyl or lower alkynyl,
R ⁴ is cycloalkyl, — (CH ₂ ) _n —R ⁵ (wherein R ⁵ represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, and n represents an integer of 0 to 4) Or formula (II)

Wherein Y ¹ and Y ² are the same or different and each represents a hydrogen atom, halogen or lower alkyl, and Z represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group,
X ¹ and X ² are the same or different and each represents an oxygen atom or a sulfur atom], and the agent for preventing and / or treating drug dependence according to (1) above.

(4) The agent for preventing and / or treating drug dependence according to (3) above, wherein X ¹ and X ² are oxygen atoms.
(5) R ⁴ is the formula (II)

(Wherein Y ¹ , Y ² and Z are as defined above, respectively), and the agent for preventing and / or treating drug dependence according to (3) or (4) above.
(6) The agent for preventing and / or treating drug dependence according to (5) above, wherein Y ¹ and Y ² are hydrogen atoms.
(7) Z is substituted or unsubstituted aryl or formula (III)

(Wherein R ⁶ represents a hydrogen atom, hydroxy, lower alkyl, lower alkoxy, halogen, nitro or amino, and m represents an integer of 1 to 3) The drug dependence described in (5) or (6) above Preventive and / or therapeutic agent.
(8) Z is the formula (IV)

Wherein at least one of R ⁷ , R ⁸ and R ⁹ represents lower alkyl or lower alkoxy, the other represents a hydrogen atom, and R ¹⁰ represents a hydrogen atom or lower alkyl) or formula (III)

(Wherein R ⁶ and m are the same as defined above, respectively), and the agent for preventing and / or treating drug dependence according to (5) or (6).
(9) The above (3), wherein X ¹ and X ² are oxygen atoms, R ¹ and R ² are ethyl, R ³ is methyl, and R ⁴ is (E) -3,4-dimethoxystyryl. The preventive and / or therapeutic agent for the described drug dependence.

(10) A compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (V)

[Wherein R ¹¹ represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group;
R ¹² represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group;
R ¹³ represents a hydrogen atom, halogen, or —WR ¹⁴ (wherein W represents —O— or —S—, R ¹⁴ represents substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted. Represents a heterocyclic group)
Q ¹ represents a hydrogen atom or 3,4-dimethoxybenzyl] (for example, 5-amino-7- (4-benzopiperazinyl) -2- (2-furyl) [1,2, 4) The agent for preventing and / or treating drug dependence according to (1) above, which is triazolo [1,5-c] pyrimidine and the like.

(11) A compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (VI)

[Wherein R ^11A represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group;
R ^12A represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aromatic heterocyclic group;
n1 and m1 are the same or different and represent an integer of 0 to 4,
Q ^1A represents a hydrogen atom or 3,4-dimethoxybenzyl,
R ¹⁵ represents a hydrogen atom, a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, or —CR ¹⁷ R ¹⁸ R ¹⁹ (wherein R ¹⁷ , R ¹⁸ and R ¹⁹ are the same or different and represent a hydrogen atom, hydroxy Represents a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group, or R ¹⁸ and R ¹⁹ together with adjacent carbon atoms To form a substituted or unsubstituted carbocycle)
R ¹⁶ represents a hydrogen atom, halogen, hydroxy or substituted or unsubstituted lower alkyl] (for example, 5-amino-2- (2-furyl) -7- [4- (2-hydroxy- 2-methylpropyl) piperazinyl) [1,2,4] triazolo [1,5-c] pyrimidine, 5-amino-2- (2-furyl) -7- [4- (3-hydroxy-3-methylpropyl) The agent for preventing and / or treating drug addiction according to the above (1), which is (piperazinyl) [1,2,4] triazolo [1,5-c] pyrimidine and the like.

(12) R ¹⁵ represents —CR ^17A R ^18A R ^19A (wherein R ^17A represents hydroxy, hydroxy lower alkyl, substituted or unsubstituted lower alkoxy or imidazo [1,2-a] pyridyl;
R ^18A and R ^19A are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl or substituted or unsubstituted aryl, or R ^18A and R ^19A together with adjacent carbon atoms are substituted or non-substituted. The agent for preventing and / or treating drug dependence according to (11) above, which forms a substituted carbocycle).

(13) A compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (VII)

[Wherein R ²⁰ represents a hydrogen atom, a substituted or unsubstituted lower alkyl, or a substituted or unsubstituted lower alkanoyl;
R ²¹ represents a substituted or unsubstituted heterocyclic group,
R ²² represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group;
W ¹ is a single bond, —O—, —S—, —S (═O) —, —S (═O) ₂ — or —NR ²³ — (wherein R ²³ is a hydrogen atom or substituted or unsubstituted. Represents lower alkyl),
X ³ represents a nitrogen atom or CR ²⁴ (wherein R ²⁴ represents a hydrogen atom or a substituted or unsubstituted lower alkyl); / Or therapeutic agent.

(14) A compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (VIII)

Wherein B represents furyl or thienyl,
W ² represents a single bond, —O— or —S—,
Z ¹ represents a hydrogen atom, halogen or substituted or unsubstituted lower alkyl,
The agent for preventing and / or treating drug dependence according to the above (1), wherein n2 is a compound represented by the following formula:

(15) A compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (IX)

[Wherein R ²⁵ represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group;
R ²⁶ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted Represents a heterocyclic group,
X ⁴ represents an oxygen atom, a sulfur atom or NR ²⁷ (wherein R ²⁷ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl),
A is a compound represented by the above-mentioned (1), which forms a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring together with two adjacent carbon atoms. Prophylactic and / or therapeutic agent.

(16) A compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (X)

Wherein R ²⁸ represents a hydrogen atom, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted amino or substituted or unsubstituted heterocyclic group,
R ²⁹ represents a hydrogen atom, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group;
R ³⁰ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted Represents an aromatic heterocyclic group,
R ³¹ represents substituted or unsubstituted lower alkyl or substituted or unsubstituted aryl;
W ³ _-CH 2 _CH 2 is -, - CH = CH- or -C = (1) prevention and / or treatment of drug addiction, wherein the compound represented by C- a representative).

(17) The compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (XI)

Wherein R ³² represents a hydrogen atom or a substituted or unsubstituted lower alkyl,
R ³³ and R ³⁴ are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, or substituted or unsubstituted aryl;
R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group. The agent for preventing and / or treating drug dependence according to the above (1), which is a compound represented by

(18) The compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (XII)

Wherein R ⁴¹ represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group,
R ⁴² represents a substituted or unsubstituted lower alkyl or a substituted or unsubstituted heterocyclic group,
R ⁴³ represents hydroxy, halogen or substituted or unsubstituted lower alkyl,
X ⁵ represents a nitrogen atom or CH) (for example, 3- [2- (thiazol-2-ylmethyl) -3-oxo-2,3-dihydropyridazin-6-yl] -2-phenyl) The prophylactic and / or therapeutic agent for drug dependence according to (1) above, which is pyrazolo [1,5-a] pyridine and the like.

(19) A compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (XIII)

Wherein R ⁴⁴ and R ⁴⁵ are the same or different and each represents a hydrogen atom, hydroxy, cyano, nitro, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, or substituted or unsubstituted aryl, or R ⁴⁴ and R ⁴⁵ together form an oxo, hydroxyimino, imino or hydrazono;
R ⁴⁶ represents substituted or unsubstituted lower alkyl or substituted or unsubstituted aryl;
R ⁴⁷ , R ⁴⁸ and R ⁴⁹ are the same or different and each represents hydroxy, halogen, cyano, nitro, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, or substituted or unsubstituted aryl;
The agent for preventing and / or treating drug dependence according to (1) above, wherein X ⁶ represents an oxygen atom or a sulfur atom.

(20) The compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (XIV)

Wherein R ⁵⁰ represents a hydrogen atom, hydroxy, halogen, substituted or unsubstituted lower alkyl or substituted or unsubstituted amino;
R ⁵¹ represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkoxy, or substituted or unsubstituted amino;
R ⁵² represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group;
R ⁵³ represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group;
X ⁷ and X ⁸ are the same or different and each represents a nitrogen atom or CH) (for example, 5- [6-amino-8- (3-fluorophenyl) -9H-9-purinyl] -1-methyl (1), (2-dihydro-2-pyrimidine, etc.).

(21) The compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (XV)

Wherein R ⁵⁴ represents a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group,
R ⁵⁵ represents a substituted or unsubstituted lower alkyl,
The agent for preventing and / or treating drug dependence according to the above (1), wherein W ⁴ is a compound represented by a single bond or —C (═O) —.

(22) A compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (XV-A)

Wherein R ⁵⁴ is as defined above,
n3 represents an integer of 1 to 4,
R ⁸⁰ represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group) (for example, 5-amino-2- (2-furyl) -7- (2- {4- [4 -(2-methoxyethoxy) phenyl] piperazinyl} ethyl) pyrazolo [4,3-e] -1,2,4-triazolo [1,5-c] pyrimidine, etc.) Preventive and / or therapeutic agent.

(23) The compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (XVI)

[Wherein, R ⁵⁶ represents a hydrogen atom, halogen, cyano, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, or substituted or unsubstituted cycloalkyl,
R ⁵⁷ represents a hydrogen atom, halogen, cyano, nitro, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, or substituted or unsubstituted aryl,
R ⁵⁸ represents a substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group;
R ⁵⁹ and R ⁶⁰ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group;
W ⁵ is a single bond, —S—, —N (R ⁶¹ ) — (wherein R ⁶¹ represents a hydrogen atom or a substituted or unsubstituted lower alkyl), —CH ₂ CH ₂ —, —CH═CH— , -C = C- or -O-
X ⁹ and X ¹⁰ are the same or different and each represents a nitrogen atom or CH]. The agent for preventing and / or treating drug dependence according to (1) above.

(24) The compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (XVII)

Wherein R ⁶² represents a substituted or unsubstituted lower alkoxy, a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group;
R ⁶³ and R ⁶⁵ are the same or different and each represents a hydrogen atom, cyano or phenylsulfonyl,
R ⁶⁴ represents a hydrogen atom, halogen, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted amino;
R ⁶⁶ represents substituted or unsubstituted amino) (for example, 2- (4,5-dihydrofuran-2-yl) -7-m-tolyl- [1,2,4] triazolo [1 , 5-a] pyrimidin-5-ylamine, etc.) for preventing and / or treating drug dependence according to (1) above.

(25) The compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (XVIII)

Wherein R ⁶⁷ represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group;
R ⁶⁸ represents a substituted or unsubstituted aromatic heterocyclic group;
The agent for preventing and / or treating drug dependence according to the above (1), wherein R ⁶⁹ and R ⁷⁰ are the same or different and each represents a hydrogen atom or a substituted or unsubstituted amino group.

(26) The compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (XIX)

Wherein R ⁷¹ represents cyano, carboxy or substituted or unsubstituted carbamoyl,
R ⁷² represents a hydrogen atom, hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group;
R ⁷³ and R ⁷⁴ are the same or different and each represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group), and prevention and / or treatment of drug dependence according to (1) above Agent.

(27) The compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (XX)

Wherein R ⁷⁵ represents a hydrogen atom, hydroxy, halogen, benzyloxy, trifluoromethyloxy, substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkoxy,
R ⁷⁶ and R ⁷⁷ are the same or different and each represents hydroxy, halogen, substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkoxy;
R ⁷⁸ represents a hydrogen atom, halogen, carboxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aryl, or Represents a substituted or unsubstituted heterocyclic group,
R ⁷⁹ represents substituted or unsubstituted phenyl,
-C (= X ¹¹ )-represents -C (= O)-, -C (= S)-or -CH _2- ]] Prevention of drug dependence according to (1) above And / or therapeutic agent.

(28) The compound having an adenosine A _2A receptor antagonistic action is (−)-(11S, 2′R) -α-2-piperidinyl-2,8-bis (trifluoromethyl) -4-quinolinemethanol. The preventive and / or therapeutic agent for drug dependence according to (1) above.
(29) A compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (XXI)

Wherein R ⁸¹ represents a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkenyl or a substituted or unsubstituted heterocyclic group,
W ⁶ represents a single bond or —C (═O) —,
R ⁸² represents substituted or unsubstituted lower alkyl), and the agent for preventing and / or treating drug dependence according to (1) above.

(30) A compound having an adenosine A _2A receptor antagonistic activity is represented by the formula (XXI-A)

(Wherein R ⁸¹ has the same meaning as above,
n4 represents an integer of 1 to 4,
R ⁸³ represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group) (for example, 5-amino-2- (2-furyl) -7- (2- {4- [4 -(2-methoxyethoxy) phenyl] piperazinyl} ethyl) imidazo [4,3-e] -1,2,4-triazolo [1,5-c] pyrimidine, etc.) Preventive and / or therapeutic agent.

(31) The agent for preventing and / or treating drug dependence according to any one of (1) to (30), wherein the drug dependence is mental dependence.
(32) The preventive and / or therapeutic agent for drug dependence according to any one of (1) to (30), wherein the drug dependence is physical dependence.
(33) The prophylactic and / or therapeutic agent for drug dependence according to any one of (1) to (30) above, wherein the drug dependence is alcohol dependence.

(34) A drug-dependent formation inhibitor comprising, as an active ingredient, the compound having an adenosine A _2A receptor antagonistic activity according to any one of (1) to (30) or a pharmaceutically acceptable salt thereof.
(35) A mentally dependent formation inhibitor comprising, as an active ingredient, a compound having an adenosine A _2A receptor antagonistic activity according to any one of (1) to (30) or a pharmacologically acceptable salt thereof.
(36) A body-dependent formation inhibitor comprising, as an active ingredient, a compound having an adenosine A _2A receptor antagonistic activity according to any one of (1) to (30) or a pharmacologically acceptable salt thereof.

(37) A method for preventing and / or treating drug dependence, comprising administering an effective amount of a compound having an adenosine A _2A receptor antagonistic action or a pharmacologically acceptable salt thereof.
(38) A method for inhibiting formation of a drug dependency, comprising administering an effective amount of a compound having an adenosine A _2A receptor antagonistic action or a pharmacologically acceptable salt thereof.
(39) A method for inhibiting formation of mental dependence, comprising administering an effective amount of a compound having an adenosine A _2A receptor antagonistic action or a pharmacologically acceptable salt thereof.

(40) A method for inhibiting formation of body dependence, which comprises administering an effective amount of a compound having an adenosine A _2A receptor antagonistic action or a pharmacologically acceptable salt thereof.
(41) Use of a compound having an adenosine A _2A receptor antagonistic activity or a pharmacologically acceptable salt thereof for the manufacture of a prophylactic and / or therapeutic agent for drug dependence.
(42) Use of a compound having an adenosine A _2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof for the manufacture of a drug-dependent formation inhibitor.

(43) Use of a compound having an adenosine A _2A receptor antagonistic activity or a pharmacologically acceptable salt thereof for the production of a psychodependent formation inhibitor.
(44) Use of a compound having an adenosine A _2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof for the production of a body-dependent formation inhibitor.

According to the present invention, for example, a prophylactic and / or therapeutic agent for drug dependence containing a compound having an adenosine A _2A receptor antagonistic action such as a xanthine derivative or a pharmacologically acceptable salt thereof as an active ingredient is provided.

  The drug dependence to be prevented and / or treated in the present invention includes “psychiatric dependence” alone or behavioral disorder resulting from “drug dependence” on “addictive drugs” forming “psychological dependence” and “physical dependence”. , Mental disorders, organ disorders, and the like, specifically, mental and behavioral disorders described in ICD-10 due to the use of addictive drugs, and substance-related disorders described in DSM-IV.

The “mental dependence” is a mental state that can not be avoided without using a drug. By stopping or reducing the use of the drug, mental anomalies such as strong anxiety, a strong desire for the drug, This is a state in which abnormal behavior such as drug search behavior occurs.
The “physical dependence” is an unpleasant symptom caused by lack of drugs such as insomnia, anxiety, tremor, sweating, seizures, delusions, hallucinations, vomiting, diarrhea, etc. by stopping or reducing the use of the drug It is a condition that causes physical abnormalities such as “withdrawal symptoms” (also called withdrawal symptoms, withdrawal symptoms).

The “drug dependence” is a state in which only the “mental dependence” of the living body with respect to the drug, or “mental dependence” and “physical dependence” are generated as a result of the interaction between the living body and the drug.
Examples of the “addictive drug” include alcohols (for example, ethanol, foods and drinks containing ethanol), opiates (for example, opioids such as opium, heroin, opium, morphine, codeine, methadone, and analgesics containing them). Cannabis (for example, cannabis, marijuana, hashish, cannabinoids), antitussives (antitussives containing methylephedrine hydrochloride, codeine phosphate, dihydrocodeine phosphate, etc.), sleeping agents (for example, barbiturates, benzodiazepines, Other tranquilizers, etc., cocaine, caffeine-containing psychostimulants (eg, amphetamine, methamphetamine and other stimulants, caffeine, caffeine-containing beverages, etc.), hallucinogens (eg, LSD (lysergic acid diethylamide), Silobicine, MDMA ( , 4-methylene-4-methylamphetamine), 2,5-dimethoxy-4-methylamphetamine, peyote, etc., tobacco (eg, nicotine, nicotine-containing products), volatile solvents (eg, toluene, acetone, ethyl acetate, ether) , Chloroform, carbon tetrachloride, etc.), psychoactive substances (eg, designer drugs, magic mushrooms, etc.).

The adenosine A _2A receptor antagonistic activity, for example, be combined with the adenosine A _2A receptor, or by interfering or prophylactically inhibiting the binding of the adenosine A _2A receptor, the physiological effects of adenosine is involved Examples thereof include an action of inhibiting, suppressing or stopping at least one.
Examples of the compound having adenosine _{A 2A} receptor antagonistic activity is not particularly limited as long as it is a compound having adenosine _{A 2A} receptor antagonistic activity, for example US 5,484,920, US 5,703,085, WO 92/06976 , WO 94/01114, US 5,565,460, WO 98/42711, WO 00/17201, WO 99/43678, WO 99/26627, WO 01/92264, WO 99/35147, WO 00/13682, WO 00 / 13681, WO 00/69464, WO 01/40230, WO 01/02409, WO 01/02400, EP 1054012, WO 01/62233, WO 01/17999, WO 01/80893, WO 02/14282, WO 01/97786 , WO 0 / 032996, compounds described in WO 03/048163, WO 03/049164, WO 03/049165, and the like. Specifically, for example, compounds represented by the above formula (I), formulas (V) to (XXI), formula (XV-A) and formula (XXI-A) (hereinafter referred to as compound (I) and compound, respectively) (V) to (XXI), compound (XV-A) and compound (XXI-A)), (−)-(11S, 2′R) -α-2-piperidinyl-2,8-bis (trifluoro) Methyl) -4-quinoline methanol and the like. Among them, xanthine derivatives such as compound (I) or (X), [1,2,4] triazolo [1,5-c] pyrimidines such as compound (V), (VI), (IX) or (XV) Derivatives, [1,2,4] triazolo [1,5-a] pyrimidine derivatives such as compound (VII) or (VIII) are preferable, and the following compounds are particularly preferable.

In the definition of each group of formulas (I) to (XXI), formula (XV-A) and formula (XXI-A):
The lower alkyl part of lower alkyl, hydroxy lower alkyl, lower alkoxy, lower alkoxycarbonyl and lower alkanoyl includes, for example, linear or branched alkyl having 1 to 8 carbon atoms, specifically, methyl, ethyl, propyl Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl and the like.

Examples of the lower alkenyl include linear or branched alkenyl having 2 to 8 carbon atoms, specifically vinyl, allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl. , 5-hexenyl, 2-heptenyl, 2-octenyl and the like.
Examples of the lower alkynyl include linear or branched alkynyl having 2 to 8 carbon atoms, and specifically include ethynyl, propargyl, 2-butynyl, 3-butynyl, 2-pentynyl, 4-pentynyl, 2-hexynyl. 5-hexynyl, 4-methyl-2-pentynyl, 2-heptynyl, 2-octynyl and the like.

Examples of cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
Examples of cycloalkenyl include cycloalkenyl having 4 to 8 carbon atoms, and specific examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like.

Halogen means each atom of fluorine, chlorine, bromine and iodine.
Examples of aryl include aryl having 6 to 14 carbon atoms, and specific examples include phenyl, naphthyl, anthryl and the like.
As the aromatic heterocyclic group, for example, a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring are condensed. A bicyclic or tricyclic fused ring aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, specifically, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl , Oxopyridazinyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, pyrrolyl, pyrazolyl, imidazolyl, triazinyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxazolyl, azozolyl Ryl, indolyl, isoindolyl, indazolyl, 2-oxobenzoimidazolyl, benzofuryl, benzothienyl, benzoimidazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, purinyl, dibenzofuranyl, imidazo [1,2-a] pyridyl It is done.

  Examples of the heterocyclic group include alicyclic heterocyclic groups in addition to the groups mentioned in the definition of the aromatic heterocyclic group. Examples of the alicyclic heterocyclic group include a 5-membered or 6-membered monocyclic alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring. A condensed or alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the like, specifically, pyranyl, thiopyranyl, Pyrrolidinyl, piperidino, piperazinyl, piperidinyl, imidazolidinyl, thiazolidinyl, morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, homopiperidino, homopiperazinyl, tetrahydropyridinyl, dihydroisoquinolyl, tetrahydroquinolyl oxalidinoxal Zolidinyl, oxadiazolini Oxolanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrobenzofuranyl, oxopiperazinyl, 2-oxopyrrolidinyl, dioxolanyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, 3,4 -Dihydro-2H-1,5-benzodioxepinyl, benzopyranyl, benzodihydropyranyl, perhydrodiazepinyl, perhydrodiazosinyl, perhydrodiazoninyl and the like.

  The heterocyclic ring formed by combining two adjacent carbon atoms with A includes, for example, a 5-membered or 6-membered monocyclic ring containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. A heterocyclic ring, a bicyclic or tricyclic condensed 3- to 8-membered ring, for example, a condensed heterocyclic ring containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, Specific examples include pyrrole, pyran, thiopyran, pyridine, thiazole, imidazole, pyrimidine, triazine, indole, quinoline, benzothiazole, pyrroline, tetrahydropyridine, tetrahydropyrazine, tetrahydroquinoline, tetrahydroisoquinoline and the like.

Examples of the carbocycle formed by combining two carbon atoms adjacent to A include cycloalkene having 4 to 8 carbon atoms, and specifically include cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene. Etc.
Examples of the carbocyclic ring formed together with adjacent carbon atoms include cycloalkanes having 4 to 8 carbon atoms, cycloalkenes, and the like. Specifically, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. , Cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and the like.

  Substituents (A) in substituted lower alkyl, substituted lower alkoxy, substituted lower alkanoyl, substituted lower alkoxycarbonyl, substituted lower alkenyl and substituted lower alkynyl are the same or different and include, for example, substituents having 1 to 3 substituents, Specifically, hydroxy, cyano, nitro, carboxy, carbamoyl, amino, benzyloxy, phenoxy, halogen, substituted or unsubstituted lower alkoxy, cycloalkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkylamino, di-lower alkylamino, Examples thereof include substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group.

  The halogen, cycloalkyl, aryl and heterocyclic groups mentioned as examples of the substituent (A) have the same meanings as described above, and the lower alkyl part of lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, lower alkylamino and di-lower alkylamino. Is synonymous with the lower alkyl, and the two lower alkyl moieties of the di-lower alkylamino may be the same or different.

Examples of the substituents in the substituted aryl and substituted heterocyclic groups exemplified in the substituent (A) include the same or different substituents having 1 to 3 substituents, specifically, the substituents (C ), And the like.
Examples of the substituent (a) in the substituted lower alkoxy exemplified in the substituent (A) include the same or different substituents having 1 to 3 substituents, specifically, halogen, hydroxy, amino, carboxy. , Azide, lower alkoxy, lower alkoxycarbonyl and the like. The halogens exemplified in the substituent (a) are as defined above, and lower alkoxy and the lower alkyl part of lower alkoxycarbonyl are as defined above.

Examples of the substituent (B) in the substituted amino and the substituted carbamoyl include the same or different substituents having 1 or 2 substituents, such as substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, etc. Can be given.
The lower alkyl and lower alkoxy exemplified in the examples of the substituent (B) have the same meanings as described above, and the substituents in the substituted lower alkyl and substituted lower alkoxy exemplified in the examples of the substituent (B) are the same or different. For example, a substituent having 1 to 3 substituents is exemplified, and specific examples thereof include the substituents exemplified in the substituent (a).

  Substituted cycloalkyl, substituted cycloalkenyl, substituted carbocycle formed with adjacent carbon atoms, substituted carbocycle formed with two adjacent carbon atoms together, substituted aryl, substituted phenyl , A substituted heterocyclic group, a substituted aromatic heterocyclic group, and a substituted heterocyclic ring formed by combining two adjacent carbon atoms with each other (C) are the same or different, for example, 1 -3, specifically hydroxy, nitro, amino, carboxy, sulfo, trifluoromethyl, halogen, lower alkyl, lower alkenyl, lower alkynyl, substituted or unsubstituted lower alkoxy, lower alkylamino, di-lower alkylamino, Substituted or unsubstituted aryl, aryloxy, aralkyl, aralkyloxy, lower alkanoyl, lower alkyl Noiruokishi, aroyl, aroyloxy, aryl alkanoyloxy, lower alkoxycarbonyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, lower alkoxysulfonyl, lower alkylsulfamoyl, di-lower alkylsulfamoyl and the like.

  Lower alkyl, lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl, lower alkanoyloxy, lower alkoxycarbonyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, lower alkoxysulfonyl, lower listed as examples of the substituent (C) The lower alkyl part of alkylsulfamoyl and di-lower alkylsulfamoyl has the same meaning as the lower alkyl, and halogen, lower alkenyl and lower alkynyl have the same meanings as described above. The two lower alkyl moieties of di-lower alkylamino, di-lower alkylcarbamoyl and di-lower alkylsulfamoyl may be the same or different. The aryl part of aryl and aryloxy has the same meaning as the above aryl, and examples of the aralkyl part of aralkyl and aralkyloxy include benzyl and phenethyl. Examples of the aroyl moiety of aroyl and aroyloxy include benzoyl and naphthoyl. Examples of the arylalkyl moiety of arylalkanoyloxy include benzyl and phenethyl.

The substituent (c) in the substituted lower alkoxy and substituted aryl exemplified in the substituent (C) is the same or different and has, for example, 1 to 3 substituents, specifically, the substituent (a). And the like.
Examples of the pharmacologically acceptable salt of the compound having an adenosine A _2A receptor antagonistic action include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. can give.

Examples of the pharmacologically acceptable acid addition salt of a compound having an adenosine A _2A receptor antagonistic action include inorganic acid salts such as hydrochloride, sulfate, and phosphate, acetate, maleate, and fumarate. Organic acid salts such as tartrate, citrate and methanesulfonate, and pharmacologically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt, magnesium salt and calcium salt Alkaline earth metal salts such as aluminum salts, zinc salts and the like, and pharmacologically acceptable ammonium salts include, for example, salts such as ammonium and tetramethylammonium, which are pharmacologically acceptable. Organic amine addition salts include addition salts such as morpholine and piperidine, and pharmacologically acceptable amino acid addition salts include lysine, glycine and phenyl. Examples include addition salts such as alanine.

  Compound (I), compounds (V) to (XXI), compound (XV-A) and compound (XXI-A) are disclosed in, for example, Japanese Patent Publication No. 47-26516, Journal of Medicinal Chemistry (J. Med). Chem.), 34, p. 1431 (1991), Journal of Medicinal Chemistry (J. Med. Chem.), 36, p. 1333 (1993), WO 92/06976, JP-A-6-21856, JP-A-6-239862, WO 95/23165, JP-A-6-16559, WO 94/01114, WO 99/12546, WO 99/35147, US 5,484,920, US 5,703,085, WO 92/06976, WO 94/01114, US 5,665,460, WO 98/42711, WO 00/17201, WO 99/43678 , WO 99/26627, WO 01/92264, WO 99/35147, WO 00/13682, WO 00/13681, WO 00/69464, WO 01/40230, WO 01/02400, WO 01/02400, EP 1054012, WO 01/6 233, WO 01/17999, WO 01/80893, WO 02/14282, WO 01/97786, WO 03/032996, WO 03/048163, WO 03/049164, WO 03/049165, or the like. It can be manufactured according to. The target compound in each production method can be isolated and purified by subjecting it to purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography.

When it is desired to obtain respective salts of compounds having an adenosine A _2A receptor antagonistic action such as compound (I), compounds (V) to (XXI), compound (XV-A) and compound (XXI-A), compound (I ), Compounds (V) to (XXI), compound (XV-A) and compound (XXI-A), etc., each having adenosine A _2A receptor antagonistic activity can be purified as it is. And when it is obtained in a free form, adenosine A _2A receptors such as compound (I), compounds (V) to (XXI), compound (XV-A) and compound (XXI-A) A compound having an antagonistic action may be dissolved or suspended in an appropriate solvent, and an acid or base may be added to form a salt.

In addition, compounds having an adenosine A _2A receptor antagonistic activity, such as compound (I), compounds (V) to (XXI), compound (XV-A) and compound (XXI-A), and pharmacologically acceptable thereof The salt may exist in the form of an adduct with water or various solvents, and these adducts can also be used for the prophylactic and / or therapeutic agent for drug dependence of the present invention.
Among compounds having adenosine A _2A receptor antagonistic activity such as compound (I), compounds (V) to (XXI), compound (XV-A) and compound (XXI-A), stereoisomers such as optical isomers All possible stereoisomers and mixtures thereof can also be used for the prophylactic and / or therapeutic agents of the drug dependence of the present invention, although some may exist in the body.

  Specific examples of compound (I) are shown in Table 1.

The effects of the present invention will be specifically described below with test examples.
Test Example 1: Influence on alcohol preference <Evaluation method of alcohol preference>
C57BL / 6J mice (Charles River, male, 7 weeks old) were purchased, and after a habituation period of 1 week, they were housed in individual cages (hereinafter, the C57BL / 6J mice are referred to as mice). Two drinking bottles of the same type were installed in each cage, with one drinking bottle containing only water and the other drinking bottle containing water containing 10% ethanol. The left and right positions of the bottle containing ethanol were changed each time the contents of the bottle were changed. The weight of each drinking bottle was measured before and after installation in the cage, and the difference was taken as the intake. The alcohol preference was calculated by the following formula.

Hereinafter, the effect on alcohol preference by administration of the test compound was evaluated by each treatment.
<Treatment 1>
The mice were divided into two groups so that the average alcohol preference before administration of the test compound was equal. One was a test compound administration group and the other was a solvent administration group. The test compound was suspended in distilled water for injection containing 0.5% methylcellulose (manufactured by Otsuka Pharmaceutical; 0.5% MC solution) and used for the test. Test compound (3 mg / kg) was administered to the test compound administration group, and 0.5% MC solution was orally administered to the solvent administration group in a volume of 10 mL / kg twice a day for 4 days. The alcohol preference was evaluated in two portions for two days. For the analysis of the test results, only mice with an alcohol preference of 0.4 or more before test compound administration were used. The influence on the alcohol preference by the administration of the test compound or the solvent was evaluated as the degree of alcohol preference when the alcohol preference before administration was 100% based on the value calculated by the following formula. The results are shown in Table 2.

As a result of treatment 1, the following was found. By administering Compound 2 during the alcohol intake period, alcohol preference decreased.
<Treatment 2>
Mice with an average alcohol preference of 0.6 days or more for 8 days before the start of the test were divided into two groups so that the average values of the preference before administration of the test compound were equal (at this time) Based on alcohol preference values). One was a test compound administration group and the other was a solvent administration group. These mice were further evaluated for palatability for a total of 10 days, and it was confirmed that the palatability after being divided into two groups was stable (the alcohol preference value at this time was taken as the pre-dose value). ). The test compound was suspended in distilled water for injection containing 0.5% methylcellulose (manufactured by Otsuka Pharmaceutical; 0.5% MC solution) and used for the test. The test compound (3 mg / kg) was orally administered to the test compound administration group and the 0.5% MC solution was orally administered to the solvent administration group at a volume of 10 mL / kg twice a day for 4 days. For 4 days during the administration period, both groups of mice received water only from both bottles. Thereafter, alcohol preference was evaluated for 3 days from the day after the final administration. The results are shown in Table 3.

As a result of treatment 2, the following was found. By administering Compound 2 during the period of interruption of alcohol intake, the alcohol preference at the time of re-drinking was significantly lower than that of the solvent group.
Test Example 2: Evaluation of alcohol withdrawal (withdrawal) symptoms <Method of evaluating alcohol withdrawal symptoms>
SD rats (Charles River, male, 6 weeks old) were purchased, and after a 6-day acclimatization period, they were housed in plastic cages (hereinafter referred to as rats). During the 16-day breeding period, dextrin was given to the non-alcohol treatment group, and a liquid food containing 7.4% ethanol was given to the alcohol treatment group. The liquid food was changed once a day. On the 17th day of breeding, ethanol (3 g / 10 mL / kg) was orally administered to the alcohol-treated group, and distilled water for injection (Otsuka Pharmaceutical, 10 mL / kg) was orally administered to the non-alcohol group, and 6 hours later. A 5-minute elevated plus maze test was conducted. In other words, there is a runway at a height of 50 cm above the floor, and the runway with a wall (closed arm) of the same length (50 cm) and a runway without a wall (open arm: open arm) are crossed. The mouse was placed in the center of an elevated cross maze constructed in the shape of the mouse, and the time for the mouse to stay in the open arm during the 5-minute test was measured.

The withdrawal symptoms of alcohol were evaluated based on the stay time in the open arm, which is an index of anxiety behavior (anxiety state) that occurs due to withdrawal of ethanol. Note that a decrease in stay time in the open arm (extension of stay time in the closed arm) indicates that anxiety behavior has been induced, and an increase in stay time in the open arm (decrease in stay time in the closed arm). Indicates that anxiety behavior is suppressed.
<Treatment 1>
One hour before the start of the test, 0.5% MC solution was orally administered to the alcohol-treated group and the alcohol-untreated group at a dose of 5 mL / kg, respectively. As the alcohol treatment group, only rats whose ethanol intake during the breeding period was 8 g / kg / day or more on average were used.

  The results are shown in Table 4.

As a result of treatment 1, the following was found. In the alcohol-treated group, the time spent in the open arm was significantly reduced, confirming that anxiety behavior was induced by withdrawal of ethanol. It has been reported in, for example, “Alcohol”, 32 , 101-111 (2000) that anxiety behaviors and the like induced under these conditions are symptoms of withdrawal symptoms due to withdrawal of ethanol.
<Treatment 2>
Of the alcohol-treated groups, only rats whose ethanol intake during the breeding period averaged 8 g / kg / day or more were used, and were randomly divided into a total of 3 groups: a solvent administration group and a test compound administration group. . The test compound was suspended in distilled water for injection containing 0.5% methylcellulose (manufactured by Otsuka Pharmaceutical; 0.5% MC solution) and used for the test. One hour before the start of the test, the test compound administration group was orally administered with the test compound and the solvent administration group with 0.5% MC solution in a volume of 5 mL / kg.

  The results are shown in Table 5.

As a result of treatment 2, the following was found. By administering Compound 2, anxiety behavior due to ethanol withdrawal was significantly suppressed, and the withdrawal symptoms of alcohol were alleviated.
From the results of Test Example 1 above, the compound having an adenosine A _2A receptor antagonistic action such as compound (I) or a pharmacologically acceptable salt thereof suppresses the desire for ingestion of dependent drugs such as alcohol. That is, it became clear that it had the effect of suppressing “mental dependence” on addictive drugs. In addition, from the results of Test Example 2, a compound having an adenosine A _2A receptor antagonistic action such as compound (I) or a pharmacologically acceptable salt thereof is caused by stopping the intake of dependent drugs such as alcohol. It became clear that it had the effect of suppressing “expression of withdrawal symptoms (withdrawal symptoms)”, ie, “body dependence”.

In addition, regarding the effect of suppressing the formation of “mental dependence” or “mental dependence” and “body dependence” for other addictive drugs, tests similar to the above-described test examples, tests using palatability as an index (for example, CPP method, etc .: see Life Science “Life Science”, 57 , 1277-1284 (1995), Psychopharmacology “Psychopharmacology”, 102 , 438-442 (1990), etc.), indicators of anxiety behavior due to withdrawal of addictive drugs (For example, an elevated plus maze test), a test described in Molecular Medicine "Molecular Medicine", 32 , 140 (1995), and the like.

In other words, a compound having an adenosine A _2A receptor antagonistic action such as compound (I) or a pharmacologically acceptable salt thereof, for example, suppresses the formation of drug dependence (psychiatric dependence on a dependence drug, or mental dependence and physical dependence). It was suggested that it is useful as an agent, a preventive and / or therapeutic agent for drug dependence, and the like.
A compound having an adenosine A _2A receptor antagonistic action such as compound (I) or a pharmacologically acceptable salt thereof can be used as it is or in various pharmaceutical forms. The pharmaceutical composition of the present invention comprises, as an active ingredient, an effective amount of a compound having an adenosine A _2A receptor antagonistic activity such as compound (I) or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier. Can be mixed and manufactured uniformly. These pharmaceutical compositions are preferably in unit dosage forms suitable for administration such as rectal administration, oral or parenteral (including subcutaneous, intravenous and intramuscular).

  Any useful pharmacologically acceptable carrier can be used in preparing the compositions in oral dosage form. For example, oral liquid preparations such as suspensions and syrups include sugars such as water, sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil, p -It can be produced using preservatives such as hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint. Powders, pills, capsules and tablets are excipients such as lactose, glucose, sucrose and mannitol, starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol, hydroxypropyl It can be produced using a binder such as cellulose and gelatin, a surfactant such as fatty acid ester, and a plasticizer such as glycerin. Tablets and capsules are the most useful unit oral dosages because they are easy to administer. When producing tablets and capsules, solid pharmaceutical carriers are used.

An injection can be prepared using a carrier comprising distilled water, a salt solution, a glucose solution, a mixture of salt water and a glucose solution, or the like. At this time, it is prepared as a solution, suspension or dispersion using an appropriate auxiliary agent according to a conventional method.
A compound having an adenosine A _2A receptor antagonistic action such as compound (I) or a pharmacologically acceptable salt thereof can be administered orally or parenterally as an injection in the above pharmaceutical form, The effective dose and the frequency of administration vary depending on the administration form, patient age, weight, symptoms, etc., but 1-100 mg / 60 kg / day, preferably 1-20 mg / 60 kg / day, divided into once or several times a day. It is appropriate to administer.

  In the following, embodiments of the present invention will be described by way of examples.

Tablets Tablets having the following composition are prepared by a conventional method.
40 g of Compound 1, 286.8 g of lactose and 60 g of potato starch are mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this was added 1.2 g of magnesium stearate and mixed, and tableted with a tableting machine (RT-15 type, manufactured by Kikusui Co., Ltd.) having a 8 mm diameter punch to contain tablets (containing 20 mg of active ingredient per tablet). To get).

Formulation Compound 1 20mg
Lactose 143.4mg
Potato starch 30mg
Hydroxypropylcellulose 6mg
Magnesium stearate 0.6mg
200mg

Capsule A capsule having the following composition is prepared by a conventional method.
200 g of compound 2, 995 g of Avicel and 5 g of magnesium stearate are mixed by a conventional method. This mixture is filled into hard capsule No. 4 (120 mg capacity per capsule) by a capsule filling machine (manufactured by Zanasi, LZ-64 type) to obtain a capsule (containing 20 mg of active ingredient per capsule).

Formulation Compound 2 20mg
Avicel 99.5mg
Magnesium stearate 0.5mg
120mg

Injectable Injectable with the following composition is prepared by a conventional method.
1 g of compound 3 is dissolved in 100 g of purified soybean oil, and 12 g of purified egg yolk lecithin and 25 g of glycerin for injection are added. This mixture is kneaded and emulsified to 1000 mL with distilled water for injection by a conventional method. The obtained dispersion is aseptically filtered using a 0.2 μm disposable membrane filter and then aseptically filled into glass vials in an amount of 2 mL to give an injection (containing 2 mg of active ingredient per vial).

Formulation Compound 3 2mg
Refined soybean oil 200mg
Purified egg yolk lecithin 24mg
50mg glycerin for injection
Distilled water for injection 1.72mL
2.00 mL

According to the present invention, for example, a prophylactic and / or therapeutic agent for drug dependence containing a compound having an adenosine A _2A receptor antagonistic activity or a pharmacologically acceptable salt thereof as an active ingredient is provided.

Claims (24)

Formula (I)

[Wherein R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom, lower alkyl, lower alkenyl or lower alkynyl,
R ⁴ is cycloalkyl, — (CH ₂ ) _n —R ⁵ (wherein R ⁵ represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, and n represents an integer of 0 to 4) Or formula (II)

Wherein Y ¹ and Y ² are the same or different and each represents a hydrogen atom, halogen or lower alkyl, and Z represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group,
X ¹ and X ² are the same or different and each represents an oxygen atom or a sulfur atom]. A prophylactic and / or therapeutic agent for drug dependence comprising a xanthine derivative represented by the formula: or a pharmaceutically acceptable salt thereof as an active ingredient. The prophylactic and / or therapeutic agent for drug dependence according to claim [1], wherein X ¹ and X ² are oxygen atoms. R ⁴ is the formula (II)

(Wherein Y ¹ , Y ² and Z have the same meanings as defined above), the agent for preventing and / or treating drug dependence according to claim [1] or [2]. The preventive and / or therapeutic agent for drug dependence according to claim [3], wherein Y ¹ and Y ² are hydrogen atoms. Z is substituted or unsubstituted aryl or formula (III)

(Wherein R ⁶ represents a hydrogen atom, hydroxy, lower alkyl, lower alkoxy, halogen, nitro or amino, and m represents an integer of 1 to 3). A preventive and / or therapeutic agent for drug dependence. Z is the formula (IV)

Wherein at least one of R ⁷ , R ⁸ and R ⁹ represents lower alkyl or lower alkoxy, the other represents a hydrogen atom, and R ¹⁰ represents a hydrogen atom or lower alkyl) or formula (III)

The agent for preventing and / or treating drug dependence according to claim [3] or [4], wherein R ⁶ and m are as defined above. The range [1], wherein X ¹ and X ² are oxygen atoms, R ¹ and R ² are ethyl, R ³ is methyl, and R ⁴ is (E) -3,4-dimethoxystyryl. Agents for the prevention and / or treatment of drug addiction.   The prophylactic and / or therapeutic agent for drug dependence according to any one of claims 1 to 7, wherein the drug dependence is mental dependence.   The prophylactic and / or therapeutic agent for drug dependence according to any one of claims 1 to 7, wherein the drug dependence is physical dependence.   The agent for preventing and / or treating drug dependence according to any one of claims [1] to [7], wherein the drug dependence is alcohol dependence.   A drug-dependent formation inhibitor containing the xanthine derivative according to any one of claims 1 to 7 or a pharmacologically acceptable salt thereof as an active ingredient.   A mentally dependent formation inhibitor containing the xanthine derivative or a pharmacologically acceptable salt thereof according to any one of claims [1] to [7] as an active ingredient.   A body-dependent formation inhibitor comprising, as an active ingredient, the xanthine derivative according to any one of claims 1 to 7, or a pharmacologically acceptable salt thereof. A drug-dependent formation inhibitor comprising, as an active ingredient, a compound having an adenosine A _2A receptor antagonistic action or a pharmacologically acceptable salt thereof. A _{psychodependent} formation inhibitor comprising, as an active ingredient, a compound having an adenosine A _2A receptor antagonistic action or a pharmacologically acceptable salt thereof. A body-dependent formation inhibitor comprising, as an active ingredient, a compound having an adenosine A _2A receptor antagonistic action or a pharmacologically acceptable salt thereof. A method for preventing and / or treating drug dependence, comprising administering an effective amount of a compound having an adenosine A _2A receptor antagonistic action or a pharmacologically acceptable salt thereof. A method for inhibiting formation of a drug dependence, comprising administering an effective amount of a compound having an adenosine A _2A receptor antagonistic action or a pharmacologically acceptable salt thereof. A method for inhibiting formation of mental dependence, comprising administering an effective amount of a compound having an adenosine A _2A receptor antagonistic action or a pharmacologically acceptable salt thereof. A method for inhibiting formation of body dependence, comprising administering an effective amount of a compound having an adenosine A _2A receptor antagonistic action or a pharmacologically acceptable salt thereof. Use of a compound having an adenosine A _2A receptor antagonistic activity or a pharmacologically acceptable salt thereof for the manufacture of an agent for preventing and / or treating drug dependence. Use of a compound having an adenosine A _2A receptor antagonistic activity or a pharmacologically acceptable salt thereof for the manufacture of a drug-dependent formation inhibitor. Use of a compound having an adenosine A _2A receptor antagonistic activity or a pharmacologically acceptable salt thereof for the manufacture of a psychodependent formation inhibitor. Use of a compound having an adenosine A _2A receptor antagonistic activity or a pharmacologically acceptable salt thereof for the manufacture of a body-dependent formation inhibitor.