JPH10298078A - Anxiolytics - Google Patents

Abstract

(57) [Problem] To provide a medicine having an anxiolytic effect. SOLUTION: The following general formula (I): [In the above general formula (I), R ¹ , R ² , R ³ , R ⁴ , R
⁵ represents hydrogen and the like, and Ar represents a phenyl group which may have a substituent or a 2- or 3-thienyl group.
n represents an integer of 2 or 3. [2,3]
-D] A thienopyrimidine derivative, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof is used as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an anxiolytic drug useful for the prevention and / or treatment of neurotic disorders represented by generalized anxiety disorder, stress-related disorders and physical expression disorders.

[0002]

2. Description of the Related Art A neurotic disorder is a psychiatric disorder characterized by morbid anxiety that does not fit the situation, such as symptoms such as tension and frustration, tremor, muscle tone, sweating, palpitations, and epigastric discomfort. Often accompanied by complaints. Benzodiazepines are the mainstay of treatment for this disease, but their side effects include drowsiness, lightheadedness, weakness, and malaise based on their pharmacological effects, such as muscle relaxation and sedative hypnosis. Occurs. In addition, there have been reports of cases of drug dependence. On the other hand, in recent years, a serotonin 1A receptor stimulant has been developed as a new anxiolytic drug which has improved these side effects, but it is reported that the anxiolytic effect is weak. On the other hand, the following equation:

[0003]

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[0004] wherein, R ¹ and R ² represents a hydrogen atom, a halogen atom or an alkyl group of C ₁ ~C _6, R ³
And R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group. R ⁵ is a hydrogen atom or a C ₁ -C ₆ alkyl group,

[0005]

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(M is an integer of 1 to 3, X is a halogen atom) or

[0007]

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(R ⁶ represents a C ₁ -C ₆ alkyl group). Ar represents a phenyl group which may have a substituent or a 2- or 3-thienyl group. n
Represents an integer of 2 or 3. [2,3]
-D] Thienopyrimidine derivatives are known (JP-B-3-67071, JP-B-5-48208).

These publications have the general formula shown above.
[2,3-d] thienopyrimidine derivative is reserpine
Has an antagonistic effect on the hypothermic effect by
Improvement for various depressive symptoms including manic depression
It is disclosed as being useful as a drug. Specifically
Is R¹= CH_ThreeR^Two= H; R^Three= H; R^Four= H; R
^Five= H; Ar = phenyl; n = 2 (No.
1), R¹= CH_ThreeR^Two= CH_ThreeR^Three= H; R^Four=
H; R^Five= H; Ar = phenyl; n = 2 (N
o. 4), R¹= H; R^Two= CH_ThreeR^Three= H; R^Four=
H; R^Five= H; Ar = phenyl; n = 2 (N
o. 5), R¹= Cl; R^Two= H; R^Three= H; R^Four=
H; R^Five= H; Ar = phenyl; n = 2 (N
o. 7), R¹= CH_ThreeR^Two= H; R^Three= H; R^Four=
H; R^Five= H; Ar = 2-fluorophenyl; n = 2
Compound (No. 14), R¹= CH_ThreeR^Two= H; R^Three
= H; R^Four= H; R^Five= H; Ar = 2-bromopheni
Compound with n = 2 (No. 15), R¹= CH_ThreeR
^Two= H; R^Three= H; R^Four= H; R^Five= H; Ar = 2-me
Tylphenyl; a compound with n = 2 (No. 16), R¹=
CH_ThreeR^Two= H; R^Three= H; R^Four= H; R^Five= H; A
r = 2-cyanophenyl; compound of n = 2 (No. 2)
About 0), body temperature by reserpine using mouse
50% antagonistic dose (ED₅₀) Is disclosed
Have been.

[0010] In addition, the publication discloses the above-mentioned No. Compound No. 1 Compound No. 14; 16 compounds have an activity against a model of passive avoidance response disorder (memory impairment model) due to electric shock in rats, and as an agent for improving higher brain dysfunctions such as presenile dementia and memory impairment due to sequelae of brain injury It is disclosed to be useful. However, these publications do not suggest or teach that the compounds are useful as anxiolytics.

[0011]

An object of the present invention is to provide a medicament having an anxiolytic effect. Another object of the present invention is to have the above-mentioned effects, and to make sleepiness, amnesia,
An object of the present invention is to provide a medicament in which side effects such as dependence are substantially reduced.

[0012]

The present inventors have made intensive efforts to solve the above-mentioned problems, and as a result, a specific [2,3-d] thienopyrimidine derivative known to have an antidepressant action has been obtained. It has an excellent anti-conflict effect and has been found to be useful for the prevention and treatment of neurotic disorders, stress-related disorders and somatoform disorders. The present invention has been completed based on the above findings. That is, the present invention provides the following formula (I):

[0013]

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[In the above general formula (I), R ¹ and R ²
Represents a hydrogen atom, a halogen atom or a C ₁ -C ₆ alkyl group, and R ³ and R ⁴ represent a hydrogen atom or a C ₁ -C 6
Represents an alkyl group of ₆ . R ⁵ is a hydrogen atom or C
Alkyl group of ₁ -C _6,

[0015]

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(M is an integer of 1 to 3, X is a halogen atom) or

[0017]

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(R ⁶ represents a C ₁ -C ₆ alkyl group). Ar represents a phenyl group which may have a substituent or a 2- or 3-thienyl group. n
Represents an integer of 2 or 3. [2,3-
d] An anxiolytic comprising a thienopyrimidine derivative, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as an active ingredient. In a preferred embodiment, Ar may be substituted with a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a hydroxyl group, a nitro group, an amino group, a cyano group, or an alkyl-substituted amino group. The above anxiolytic is provided which is a phenyl group or a 2- or 3-thienyl group. In a preferred embodiment, the active ingredient [2,3-d] thienopyrimidine derivative is represented by the following formula (II):

[0019]

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The present invention provides an anxiolytic which is a compound represented by the formula (I), a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof. Further, as a preferred embodiment, the above-mentioned anxiolytic drug used for prevention and / or treatment of a neurotic disorder, a stress-related disorder, and a body expression disorder is provided.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a [2,3-d] thienopyrimidine derivative represented by the above formula (I) as an active ingredient and a pharmaceutical additive. Anxiolytics: [2,3-d] thienopyrimidine derivatives represented by the above formula (I), pharmaceutically acceptable salts thereof, or hydrates or solvates thereof for the production of the above-mentioned anxiolytics And use of the above-mentioned medicines in mammals to prevent diseases associated with morbid anxiety, such as general anxiety disorder, mixed anxiety depressive disorder, and other physical disorders caused by anxiety. A method for treating is provided.

[0022]

BEST MODE FOR CARRYING OUT THE INVENTION The prophylactic / therapeutic agent of the present invention is a [2,3-d] thienopyrimidine derivative represented by the above formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof or It is characterized in that those solvates are used as an active ingredient. During the definitions, C ₁ -C ₆ alkyl group is preferably a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, n- pentyl group, and a n- hexyl , C ₁ -C _6, for example a methoxy group as an alkoxy group, an ethoxy group, n- propoxy group, isopropoxy group, n- butoxy group, n- pentyloxy group, and an n- hexyloxy and the like. As the halogen atom, any of a fluorine atom, a chlorine atom, a bromine atom or an iodine atom may be used, and as the alkyl-substituted amino group, for example, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, etc. Can be.

The use of an acid addition salt or the like as a pharmaceutically acceptable salt of the [2,3-d] thienopyrimidine derivative represented by the general formula (I) is also included in the scope of the present invention. Examples of the acid addition salts include salts with inorganic acids such as hydrochloric acid, phosphoric acid, and sulfuric acid, and organic acids such as acetic acid, formic acid, citric acid, and paratoluenesulfonic acid. In addition to salts and compounds in free form,
Any of these hydrates or solvates may be used as an active ingredient of the medicament of the present invention.

Solvents that can form solvates with the above compounds include, for example, methanol, ethanol, isopropanol, acetone, ethyl acetate and the like.
It is preferable to use a physiologically acceptable solvate, such as ethanol solvate, for the medicament of the present invention. The compound included in the general formula (I) is itself a compound of Japanese Patent Publication No.
The compound is a known compound disclosed in Japanese Patent No. 7071, or can be easily synthesized by the method described in the same publication, and can be easily obtained by those skilled in the art. Among the compounds included in the above general formula, compounds wherein R ¹ is a hydrogen atom, a halogen atom or a C ₁ -C ₆ alkyl group, compounds wherein R ² is a hydrogen atom or a C ₁ -C ₆ alkyl group, A compound wherein R ³ and R ⁴ are a hydrogen atom or a C ₁ -C ₆ alkyl group, R ⁵ is a hydrogen atom,

[0025]

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Wherein Ar is a halogen atom, C ₁
Compounds which are a phenyl group or a 2-thienyl group which may be substituted with a C ₆ to C ₆ alkyl group, a C _{1 to} C ₆ alkoxy group, a hydroxyl group, a nitro group, an amino group or a cyano group are preferred compounds. Preferred compounds as the active ingredient of the medicament of the present invention are shown below, but the active ingredients of the medicament of the present invention are not limited to the following compounds.

[0027]

[Table 1]

[0028]

[Table 2]

[0029]

[Table 3]

For example, among the compounds exemplified in Table 1 above, particularly preferred compounds are 14 compounds can be exemplified.
Japanese Patent Application Laid-Open No. 7071 and Japanese Patent Publication No. 5-48208 specifically show this. In addition, JP-B-3-67071 and JP-B5-48208 disclose that the compound, which is an active ingredient of the present invention, has an antagonistic effect on the body temperature lowering effect of reserpine, and that the compound is passively induced by electric shock in rats. Due to its activity in avoidance response disorder models, these compounds are used as ameliorating agents for various depressive symptoms such as psychosomatic disorder, manic-depressive disorder, Although it has been shown to be useful as an agent for improving higher brain dysfunction such as memory impairment, it has not been specifically explained that these compounds have an anti-conflict effect.

The medicament of the present invention has an anti-conflict effect and an anti-anxiety effect. Therefore, the medicament of the present invention can be used as an anxiolytic drug for treating and / or preventing a neurotic disorder characterized by pathological anxiety, for example, general anxiety disorder. Conventionally, anxiolytics have been used for the treatment of diseases involving anxiety, such as stress-related disorders and physical expression disorders, and the medicament of the present invention is applicable to these.

The above compound, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof which is an active ingredient of the medicament of the present invention may be administered to a patient as a medicament itself. In general, it is preferable to prepare and administer a pharmaceutical composition containing one or more of these active ingredients to a patient. Such pharmaceutical compositions include tablets, capsules, fine granules, powders, pills, troches, sublinguals, or liquid preparations for oral administration, or injections, suppositories, ointments, patches and the like. Preparations for parenteral administration can be exemplified.

Tablets or capsules for oral administration are usually presented as unit doses, containing binders, fillers, diluents, tablets, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents. It can be produced by adding such ordinary carriers for pharmaceuticals. Tablets may be coated according to methods well known in the art, for example, with an enteric coating, for example, a filler such as cellulose, mannitol, or lactose; starch, polyvinylpolypyrrolidone, a starch derivative, or Disintegrants such as sodium starch glycolate; lubricants such as magnesium stearate;
It may be manufactured using a wetting agent such as sodium lauryl sulfate.

Solutions for oral administration are provided, for example, as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or as dry preparations which can be redissolved with water or a suitable vehicle before use. . Such solutions include conventional additives such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, precipitation inhibitors such as aluminum stearate gel or hydrogenated edible fat, lecithin, sorbitan monooleate, and arabic. Emulsifiers such as gums, almond oil, rectified coconut oil, non-aqueous media (including edible oils) such as oily esters (e.g. esters of glycerin), propylene glycol, ethyl alcohol, methyl p-hydroxybenzoate Preservatives such as esters, ethyl esters, or propyl esters, or sorbic acid, and if desired, conventional flavoring or coloring agents can be included.

Preparations for oral administration can be produced by methods known in the art, such as mixing, filling, or tableting. Further, the active ingredient may be distributed in a preparation using a large amount of a filler or the like by using a repetitive blending operation. Formulations for parenteral administration are generally provided as liquid unit dosage formulations containing the compound, the active ingredient, and a sterile vehicle. Solutions for parenteral administration are usually prepared by dissolving the compound in a vehicle, sterile-filtering and then filling suitable vials or ampoules and sealing. To enhance stability, the composition may be filled into vials after freezing and the water removed under vacuum. Parenteral suspensions are prepared substantially in the same manner as for parenteral solutions, but can be suitably prepared by suspending the active ingredient in a vehicle and sterilizing the suspension with ethylene oxide or the like. Further, a surfactant, a wetting agent, and the like may be added as necessary so that the active ingredient has a uniform distribution.

The dose of the compound as an active ingredient may be appropriately determined in consideration of the purpose of treatment or prevention, the type of disease to be treated or prevented, the condition, weight, age, sex, etc. of the patient. In the usual case, about 0.01 mg to 1,000 mg can be administered orally per adult per day, preferably 1 to 100 mg. It is desirable to administer such a dosage in one to several portions per day.

[0037]

Examples The active ingredients of the medicament of the present invention are shown in Table 1 above.
No. illustrated in FIG. 14 compounds (R ¹ ＣＨCH ₃ ; R ² ＝
^{R 3 = R 4 = R 5} = H; Ar = 2- fluorophenyl;
n = 2: hereinafter, abbreviated as “the compound of the present invention” in Examples), and the following test was conducted.

Example 1 As anxiety model, Vogel type conflict method (Vo
gel, J.M. R. Other, Psychopharmacol
ogia, 21: 1-7, 1971). In this method, rats with limited water intake and drought were put into an experimental device (Muromachi Kikai MCV-005), and when drinking water from the mouthpiece, an electric shock was given from the floor grid to cause an experimental conflict. Is set, and the number of times of shock is measured as an index. It has been reported that the number of times of drinking decreases with the load of electric shock (conflict behavior), but the number of times of drinking increases with the administration of benzodiazepine-based anxiolytics. For the experiment, 40-hour water-absorptive load was applied to the male Wisat rats that had been used to the experimental apparatus in advance.
Only animals that drank 100 times or more when the animals were placed in the experimental device for 10 minutes under the condition that no shock was applied were used. After a further 28 hours of water withdrawal as a pretest, the rats were put back into the experimental apparatus, and after the rats drank 20 times of water, shock shock (240 VAC, internal resistance 230 kΩ,
2 seconds). Shock was applied every time the rat drank water 20 times or continuously for 2 seconds, and only animals whose number of shocks was less than 20 in a 3-minute pretest were used in this experiment. The test compound was orally administered 30 minutes after the pretest, and one hour later, the present experiment was performed under the same conditions as the pretest, and the number of shocks was measured. The activity of the compound of the present invention is as shown in FIG.

[0039]

EFFECT OF THE INVENTION The medicament of the present invention has an anti-conflict effect, and has general anxiety disorder, panic disorder, obsessive-compulsive disorder, acute stress reaction, post-traumatic stress disorder, adaptation disorder, body expressive autonomic dysfunction. Neurotic disorders, such as
It is useful for the prevention and / or treatment of stress-related disorders and physical expression disorders.

[Brief description of the drawings]

FIG. 1 is a diagram showing the results of measuring the number of times of shock when a compound of the present invention was administered to rats.

Claims (6)

[Claims] 1. The following general formula (I): [In the above general formula (I), R ¹ and R ² represent a hydrogen atom,
Represents a halogen atom or a C ₁ -C ₆ alkyl group,
R ³ and R ⁴ represent a hydrogen atom or a C ₁ -C ₆ alkyl group. R ⁵ is a hydrogen atom or a C ₁ -C ₆ alkyl group; (M represents an integer of 1 to 3, and X represents a halogen atom.) Or (R ⁶ represents a C ₁ -C ₆ alkyl group). Ar represents a phenyl group which may have a substituent or a 2- or 3-thienyl group. n is 2 or 3
Represents an integer. [2,3-d] thienopyrimidine derivative, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as an active ingredient. 2. Ar may be substituted with a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a hydroxyl group, a nitro group, an amino group, a cyano group, or an alkyl-substituted amino group. A phenyl group, or 2- or 3-
The anti-anxiety agent comprising the [2,3-d] thienopyrimidine derivative according to claim 1, which is a thienyl group, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, as an active ingredient. 3. The [2,3-d] thienopyrimidine derivative has the following formula (II): The anxiolytic agent according to claim 1, which is a compound represented by the formula: or a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof. 4. The anti-anxiety agent according to claim 1, which is used for prevention and / or treatment of a neurotic disorder. 5. The anti-anxiety agent according to claim 1, which is used for prevention and / or treatment of a stress-related disorder. 6. The anti-anxiety agent according to claim 1, which is used for prevention and / or treatment of a somatoform disorder.