JPS63246329A - Composition for medicinal purposes - Google Patents

Abstract

PURPOSE:To obtain a psychotropic agent which has antidepressant and antipsychotic activity and is used in improvement and treatment for human psychoneuroses without side-effects, by using a specific 2-piperazinopyrimidine derivative as an active ingredient. CONSTITUTION:The subject composition contains, as an active ingredient, a compound of formula I [R<1> is H, 1-5C alkyl, 2-hydroxyethyl; R<2> is formula II (A, B bond to the 4- and 5-positions in the pyrimidine ring; R<3> is methylene which may be substituted with lower alkyl or hydroxyl; R<4> is imino which may be substituted with lower alkyl, O; R<5> is methylene which may be substituted with lower alkyl or hydroxyl; l is 0, 1, 2; m, n, t are 0, 1; s is 0, 1, 2)] or its salt such as hydrochloride or hydrobromide. The composition containing the compound of formula I is prepared together with pharmaceutically permissible carriers such as lactose or glucose, into tablets, dust or the like and can be given orally, subcutaneously, intramuscularly and through other routes.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a psychotropic drug containing a specific 2-piperazinopyrimidine derivative or a salt thereof as an active ingredient.

[Conventional technology]

Some of the compounds used in the present invention are described in Japanese Patent Application Publications No. 61-65873 and No. 61-140568, and are said to have herbicidal activity and to be effective as intermediates for therapeutic agents for hypertension and heart failure. It has been revealed that.

On the other hand, it has hypoglycemic effect and platelet aggregation inhibiting effect5,6
-Alkylpyrimidine derivatives are disclosed in JP-A-57-13177
It is disclosed in Publication No. 1. In addition, the inventor of this patent publication reports the synthesis of 2-(1-piperazinyl)-5,6-polymethylenebilimicin derivatives and its hypoglycemic effect (Chew).

Pharm, Bull, 31(7) 2254-22
61.1983). Some of the compounds of general formula (1) described below are known compounds disclosed in these four patent publications and papers. Other compounds are described in the international application PCT/JP87/120.

[Problem that the invention seeks to solve]

It has been known that various compounds have psychoactive effects, but the present inventors have been searching for various compounds that have psychoactive effects, particularly antidepressant, anxiolytic, and antipsychotic activities. It was unexpectedly discovered that a specific 2-piperazinopyrimidine derivative represented by general formula (1) below has such a psychoactive effect, and a new use for the above-mentioned known compound as a medicine was developed.

[Means for solving problems]

The present invention is directed to general formula (1) [wherein R' is hydrogen, an alkyl group having 1 to 5 carbon atoms (
(hereinafter referred to as a lower alkyl group), a 2-hydroxyethyl group, a phenyl group, a benzyl group or a formyl group which may be substituted with a methylene dioxyl group, and R2 represents the general formula (n) (wherein A and B are Indicates bonding to the 0-position and 0-position of the pyrimidine ring, respectively, R3 is a lower alkyl group,
Represents a methylene group optionally substituted with a group selected from the group of hydroxyl group, lower alkoxyl group, lower alkanoyl group, and lower alkanoyloxyl group, and R4 is an imino group optionally substituted with a lower alkyl group, or is an oxygen atom, and R5 represents a methylene group which may be substituted with a group selected from the group consisting of a lower alkyl group, a hydroxyl group, a lower alkoxyl group, a lower alkanoyl group, and a lower alkanoyloxyl group, and two methylene groups are bonded together. (if those carbons form a double bond),
The ingredients indicate 0, 1 or 2.1. indicates 0 or 1, or 0
or 1. indicates 0.1 or 2 and 1. is O or 1
shows. ) represents a group. ] 2-
The present invention relates to a psychotropic drug containing a piperazinopyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[Compound used in the present invention]

The compound used in the present invention is a compound represented by the general formula (1), and RI in the formula has 1 to 5 carbon atoms.
Examples of alkyl groups (lower alkyl groups) include both straight-chain and branched ones (methyl group, ethyl group, propyl group, butyl group, and amyl salts). Among RI, hydrogen or benzyl groups are particularly preferred. Preferred.Also, as the substituents for R3, R4 and RS, and the lower alkyl group, R
The same thing as shown in I can be exemplified. R3 and R
The substituent of the optionally substituted methylene group of S is more preferably a hydroxyl group or a lower alkyl group.

Pharmaceutically acceptable salts of the compound [1] include hydrochloric acids, hydrobromide, sulfate, bisulfate, phosphate, acidic phosphoric acid, acetate, maleate, fumarate, succinate, lactate, tartrate, benzoate, citrate,
Salts formed from acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions such as gluconate, saccharide, methanesulfonate, p-toluenesulfonate, naphthalenesulfonate, etc. These include hydrates thereof and quaternary ammonium (or amine) salts or hydrates thereof.

Formula used in the present invention [! ] Specific examples of preferable compounds include the following. Note that the numbers are compound numbers.

C.I.

H3 The manufacturing method and physical properties of these compounds are described in this specification or the above-mentioned known documents.

[Psychotropic drugs]

The compound of formula ([] is usually used in the form of a pharmaceutical composition,
It is administered by a variety of routes including oral, subcutaneous, intramuscular, intravenous, intranasal, percutaneous and rectal routes.

The present invention comprises a pharmaceutically acceptable carrier and a compound of general formula (1) or an acid addition salt thereof or a quaternary salt thereof as an active ingredient.
ammonium (or amine) salts. When manufacturing the compositions of the present invention, tablets, capsules, powders, ffJI pellets, troches, cachets, elixirs, emulsions, solutions, syrups, suspensions, aerosols, ointments, sterile syringes, molded poultices, tapes, It can be in the form of soft and hard gelatin capsules, herbal medicines and sterile packaged powders, etc. Examples of pharmaceutically acceptable carriers are lactose, glucose, sucrose, sorbitol, mannitol, corn starch, crystalline cellulose, gum arabic, calcium phosphate, alginate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, gum tragacanth, Gelatin, syrup, methylcellulose, carboxymethylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, inert polymers, water or mineral oil. Either solid or liquid compositions may contain fillers, binders, lubricants, wetting agents, disintegrants, emulsifying and suspending agents, preservatives, sweetening or flavoring agents, and the like, such as those mentioned above.

The composition also provides for rapid release of the active ingredient after administration to the patient.
They can be formulated to be sustained or delayed release.

For oral administration, the compounds of formula (I) are mixed with carriers and diluents and placed in the form of tablets, capsules, and the like. For parenteral administration, the active ingredient is dissolved in 10% aqueous dextrose, isotonic saline, sterile water, or similar liquid and placed in vials or ampoules for administration by intravenous infusion or injection, or by intramuscular injection. It will be sealed.

Advantageously, solubilizing agents, local anesthetics, preservatives and buffers may also be included in the vehicle. To increase stability, the composition can also be lyophilized after being poured into vials or ampoules. Other examples of parenteral administration include preparations administered transdermally in the form of ointments and poultices. In this case, molded poultices or tapes are advantageous.

The composition may contain from 0.1 to 2000 per unit dosage form.
(1), more preferably 0.5 to 1000 (2) active ingredients.

Compounds of formula [I] are effective over a wide dosage range. For example, the dosage per day is usually 0.003+
*In the range of g/kg to 100■/kg.

The actual amount of compound administered will be determined by the physician depending on the compound being administered and on the age, weight, response, severity of the patient's symptoms, route of administration, etc. of the individual patient. Therefore, the above dosage ranges are not intended to limit the scope of the invention. The appropriate number of doses on day - is 1 to 6 times, usually 1 to 4 times.

[For production]

The compounds of formula (I) are effective antidepressants, anxiolytics, antipsychotics, anorexics in their own right, but if necessary in combination with one or more other equivalent agents. can also be administered.

Formulation examples and biological activity of compound (1) used in the present invention will be explained in more detail in Examples and Test Examples below, but the present invention is not limited thereto.

The composition examples given below use as active ingredient one of the compounds described in the text or one of the other pharmaceutical compounds included in general formula (I).

[Examples, etc.]

The method for producing the compound represented by the general formula (1) used in the present invention is described in the above-mentioned known literature.

Compounds not described in this document can also be produced in the same manner.

Next, formulation examples will be shown in Examples.

Example 1 Tablets containing 10 ml of active ingredient are manufactured as follows.

Active ingredients per tablet: 10 ■ Corn starch 55 ■ Crystalline cellulose
35■ Polyvinylpyrrolidone
5■ (as a 10% aqueous solution) Carboxymethyl cellulose/calcium 10■ Magnesium stearate 41■ Pass through a sieve and mix thoroughly. The obtained powder is mixed with a polyvinylpyrrolidone solution and granulated, and then passed through an 18-mesh sieve. 50 to 60 granules produced in this way
Dry at ℃ and sieve again using an 18-mesh sieve. Calcium carboxymethyl cellulose and magnesium stearate and talc, previously sieved through an 80 mesh sieve, are added to the granules and, after mixing, tablets each weighing 120 mg are produced in a tablet machine.

Example 2 Tablets containing 25 ml of active ingredient are manufactured as follows.

Active ingredients per tablet: 25 ■ Corn starch 75 mg crystalline cellulose
42N light silicic anhydride
7 ■ Total 150 mg Pass the above ingredients through an 80 mesh sieve and mix thoroughly. The resulting powder is compression molded to produce tablets weighing 150 square meters.

Example 3 Capsules containing 25 cm of active ingredient are prepared as follows.

Active ingredients per capsule: 25 ■ Corn starch 45 ■ Lactose 5
■Total 80■ Mix the above ingredients and pass through an 80 mesh sieve to mix thoroughly. The obtained powder is filled into capsules in an amount of 80 mg.

Example 4 A ready-to-dissolve injection in a vial containing 10 mg of active ingredient is produced as follows.

□Active ingredient per vial: 10■Mannitol 50■When using, 1 portion of distilled water for injection
- Dissolve and use.

Example 5 An ampoule injection containing 25 mg of active ingredient is produced as follows.

Active ingredients per amp 25 parts w Sodium chloride 18 ■ Distilled water for injection
Dosage Example 6 An adhesive patch containing 20 mg of active ingredient is produced as follows.

10 parts of ammonium polyacrylate are dissolved in 60 parts of water. Meanwhile, add 2 parts of glycerin diglycidyl ether to 10 parts of water.
Dissolve while heating. Furthermore, on the other hand, 10 parts of polyethylene glycol (grade 400), 10 parts of water,
Dissolve 1 part of the active ingredient with stirring. Next, while stirring the aqueous solution of ammonium polyacrylate, an aqueous solution of glycerin diglycidyl ether and an aqueous solution containing the active ingredient of polyethylene glycol were added and mixed to form a drug-containing hydrogel solution, and the solution for the drug-containing hydrogel was spread onto a flexible plastic film so that the active ingredient was sized to a square centameter. The mixture was coated at a coating weight of 0.5 square centimeters per coat, and the surface was covered with release paper and cut into 35 square centimeters to prepare a preparation.

Example 7 An adhesive patch containing 10 mg of active ingredient is manufactured as follows.

100 parts of sodium polyacrylate, 100 parts of glycerin
A mixed aqueous sol solution containing 150 parts of water, 0.2 parts of triepoxypropyl isocyanurate, 100 parts of ethanol, 25 parts of isopropyl myristate, 25 parts of propylene glycol, and 15 parts of the active ingredient was prepared. Next, this sol solution was applied to a thickness of 100 μm on the nonwoven surface of a composite film consisting of a rayon nonwoven fabric and a polyethylene film to form a drug-containing adhesive layer. The content of release aids (isopropyl myristate and propylene glycol) contained in this layer was approximately 20% by weight. Then at 25℃
After crosslinking for 4 hours, a release film was attached to the adhesive interface, and this was further cut into 35 square centimeters to prepare a preparation.

The psychoactive effects, ie, antidepressant, anxiolytic, and antipsychotic effects of the compound of formula CI) were tested in mice. Compound (I) is apomorphine (high dose), reserpine,
It showed an antagonistic effect against tetrabenazine that was equal to or greater than that of the control, imipramine.

Furthermore, in the despair model (despair test), compounds [! ] has been shown to have antidepressant activity as it shortens immobility time. In addition, we investigated the presence or absence of central anticholinergic effects, which is the main side effect of existing antidepressants, using the drug's effect on tremor induced by tremoline or physostigmine as an indicator.
It has been confirmed that isopropyl has a strong anticholinergic effect, whereas the compound used in the present invention has little or no anticholinergic effect, and is considered to be a useful central nervous system drug in this respect. The anti-instabilizing effect of the compound used in the present invention was investigated based on the hypomorphic effect, and the antipsychotic effect was also investigated using the antagonism of low-dose apomorphine-induced hypothermia as an indicator, and it was shown that each compound has activity.

The compounds of the present invention are also expected to have anorectic activity.

Experimental Example 1 Antagonism of high-dose apomorphine-induced hypothermia The hypothermia induced by high-dose apomorphine is specifically antagonized by many antidepressants A.
J, Peuch et al.'s method (Peycho-Phar
Macology, 75.84-91.1981)
The experiment was conducted according to the following. A group of 10 5-week-old ddY male mice were used. 30 minutes after intrathecal administration of drug or saline, or 60 minutes after oral administration, 16 mg of apomorphine
/kg was administered subcutaneously to the back. Apomorphine administration 50
Min IQ thermistor was used to determine the body temperature of mice in the drug administration group (
Measure the rectal temperature) and compare the suppression rate (%) with that of the control group.
) was calculated and considered as medicinal efficacy. The results are shown in Table 1.

Table 1 Inhibition of hypothermia induced by high-dose apomorphine (16 mg/kg subcutaneous administration) As shown in Table 1, it is clear that the compounds used in the present invention have antidepressant activity equivalent to or higher than that of imipramine, both orally and parenterally. It was done.

Experimental Example 2 Antagonism of reserpine-induced hypothermia Most antidepressants antagonize the hypothermia induced by reserpine, but the method of H. Wengl et al.
Forschung, 2B (If), Heft 1
0b, 1874-1879.1978). After 60 minutes of oral administration of drug or saline to each of 10 mice, 10 mg/kg of reserpine was administered intraperitoneally. The body temperature of the mouse was measured using a thermistor before drug administration, immediately before and 2.4.6 hours after reserpine administration, and the effect of the drug on the normal body temperature of the mouse and the effect of the drug on the reserpine-induced decrease in mouse body temperature was investigated. The results are shown in Table 2.

Experimental Example 3 Despair Model Porsolt et al.'s Despair Model
st) Archive of International Pharmacodynamics (Arch, Int, Pharm
-acodyn, .

229.327 to 336.1977)) was used as an index for the experiment. ddY strain male mice kept cold for 5 weeks,
The control group used 20 mice per group, and the drug administration group used 10 mice per group.

60 minutes after oral administration of the drug or saline, the mice were dropped into the water in the measurement cage, observed for 6 minutes, and the immobility time was recorded. The values for the latter 4 minutes of the recorded 6 minutes of immobility were accumulated and used as data. The results are shown in Table 3.

Experimental Example 4 Presence or absence of central anticholinergic effect In order to investigate the presence or absence of central anticholinergic effect, which is a major undesirable side effect of antidepressants, we used the method of F. Leuschner et al.
.

28 (n), HefL 10b, 1883-1893
．． (1978), the effects of the drug were investigated using tremorine-induced tremor as an index. 60 minutes after oral administration of the drug or saline to 10 mice, 20 mg/kg of tremoline was intraperitoneally administered to examine the appearance of tremor. Efficacy was calculated as the inhibition rate (%) by dividing the number of mice in which tremor appeared by the total number of mice.

Table 4 Central anticholinergic activity As shown in Table 4, although the control imipramine at 30 mg/kg p,o suppressed tremors,
It has been shown that the compounds used in the present invention do not inhibit and do not have central cholinergic effects.

Experimental Example 5 Anxiolytic effect Aron et al.
ogy, 10°459-469.197L) was used to examine the anxiolytic activity.

In other words, a mouse is placed on a copper plate divided into four parts, and when the mouse tries to move from one to the other, an electric current is applied to the copper plate and an electric shock is given to the legs, so that the mouse will not move even if it wants to move. It becomes a state of conflict where you can't move. Anti-anxiety drugs such as diazepam are effective against this condition (eliminating the conflict state (action, anti-conflict action)).

After 30 minutes of intraperitoneal administration of the drug or saline, 5-week-old ddY male mice (10 in each group) were placed in the device, position movement and electric shocks were started, and the number of shocks received per minute was recorded as data. . The efficacy of the drug was evaluated by comparing the number of shocks received with that of a control group administered at the same time.

Experimental Example 6 Antagonism of low-dose apomorphine-induced hypothermia According to the method of Experimental Example 1, the dose of apomorphine was 1
mg/kg, drug administration group (intraperitoneal,
10 mg/kg) was measured and compared with that of the control group to calculate the inhibition rate. The results are shown in Table 6.

Table 6 Low dose apomorphine (1 mg/kg subcutaneous administration)
Suppression of induced hypothermia The compounds used in the present invention also have some antipsychotic activity.

Experimental Example 7 Acute Toxicity A group of 10 ddY male mice aged 5 weeks were used. The drug was dissolved in physiological saline and used. The dose of the drug was 0.1 mg/10 g body weight to the mice, and the drug was orally forcibly administered using an oral sonde. The progress of the mice was then observed 24 hours after drug administration. Table 7 shows the results.
Shown below.

Table 7 Acute Toxicity [Effects of the Invention] As mentioned above, the compound of general formula CI) used in the present invention is a novel compound having antidepressant activity, anxiolytic activity, antipsychotic activity, etc., and is a psychotropic drug for humans etc. It can be applied to the improvement and treatment of various neuropsychiatric disorders.

Claims (1)

[Claims] (1) General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc. are available▼ [I] [In the formula, R^1 is hydrogen, an alkyl group having 1 to 5 carbon atoms (hereinafter referred to as a lower alkyl group), 2-hydroxy Indicates a benzyl group or formyl group which may be substituted with an ethyl group, phenyl group, or methylene dioxyl group, and R^2 is the general formula [II]▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, A and B indicates bonding to the [4] and [5] positions of the pyrimidine ring, respectively, and R^3 is a group selected from the group of lower alkyl group, hydroxyl group, lower alkoxyl group, lower alkanoyl group, and lower alkanoyloxyl group. Indicates a methylene group that may be substituted with R^
4 is an imino group which may be substituted with a lower alkyl group or an oxygen atom, R^5 is a lower alkyl group,
Indicates a methylene group that may be substituted with a group selected from the group of hydroxyl group, lower alkoxyl group, lower alkanoyl group, and lower alkanoyloxyl group (if two methylene groups are bonded, their carbon-carbon bond is a double bond). ), _l represents 0, 1 or 2, _m represents 0 or 1, _n represents 0 or 1, _s represents 0, 1 or 2, _t represents 0 or 1. show. ) represents a group. ] A psychotropic drug containing a 2-piperazinopyrimidine derivative represented by the following or a pharmaceutically acceptable salt thereof as an active ingredient.