KR850001039B1 - Process for preparing allophanoylpiperazine compounds - Google Patents

Abstract

Allophanoylpiperazine compds. I [R1 = lower alkyl, phenyl; R2,R3 = H, lower alkyl; R4 = (un)substd. phenyl, thiazoyl, cyclohexyl, (un) substd. lower alkyl were prepd. for use as an antiphlogistic and as an anodyne. Thus, 2,4-dimethylallophanoyl chloride was added to 1- phenylpiperazine soln.. Removing the solvent via recrystallization, produced 1-(2,4-dimethylallophanoyl)-4-phenylpiperazines that was melted at 79-80≰C.

Description

Process for preparing allophanoyl piperazine compound

The present invention relates to a method for producing a novel allophanoylpyrazine compound.

The allophanoyl piperazine compound according to the present invention is represented by the following general formula (1).

In the above formula,

R ¹ is a lower alkyl group or a phenyl group;

R ² and R ³ are each a hydrogen atom or a lower alkyl group;

R ⁴ is a phenyl group or a substituted phenyl group having a halogen atom or a methyl, trifluoromethyl, hydroxyl, methoxy, methylenedioxy, nitro or carboxyl group as a phenyl group or a substituent; Pyridyl group, pyrimidyl group, thiazoyl group, benzyl group, cinnamic group, cyclohexyl group, lower alkyl group; Substituted lower alkyl group which has a chlorine atom or a hydroxyl group as a substituent: Or lower alkenyl group.

The compounds according to the invention are novel compounds which have not been described in the literature, which have analgesic action and are useful as analgesics as well as anti-inflammatory action. Conventionally, there has been no record of a compound having a structure represented by the following formula, not to mention the allophanoylpiperazine compound represented by the general formula (1).

MEANS TO SOLVE THE PROBLEM As a result of extensive research on the allophanoyl- piperazine compound of the type mentioned above for the development of the compound which has analgesic action, this inventor completed this invention by finding the compound of the said General formula (1) suitable for the objective. It was.

The allophanoylpiperazine according to the present invention is prepared by the following illustrated method.

Manufacturing method

The present invention is characterized in that the allophanoyl chloride of the following general formula (2) is reacted with the piperazine of the following general formula (3) according to the following reaction scheme.

The allophanoyl chloride of the general formula (2) used in the present invention is a known compound, the preparation method of which is described in detail in US Pat. Also, it is described in Japanese Patent Laid-Open No. 47-34710 as a known compound.

The reaction of the allophanoyl chloride (2) and piperazine (3) according to the above scheme can generally be used with any solvent that does not participate in the reaction carried out in the solvent, but generally with ethyl ether, dioxane and tetrahydrofuran Same ethers; Halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; And aromatic hydrocarbons such as benzene, toluene and xylene are preferred.

If necessary for the reaction, basic compounds such as trialkylamines and pyridine can be used with appropriately concentrated promoters.

In special cases, other ratios may be chosen, but the preferred molar ratio of allophanoyl chloride (2) and piperazine (3) is 1: 2.

The reaction temperature may be appropriately selected, but the reaction generally proceeds preferably in the temperature range of -20 ° C to 50 ° C.

The allophanoylpiperazine Compound (1) formed by the above method can be easily isolated by a conventional separation method.

The daily dose of this analgesic is 0.5 to 1,000 mg with respect to allophanoylpiperazine of Formula (1) in an amount of 1 to 4 doses for adults, preferably 1 to 500 mg.

In special cases, the dosage is appropriately adjusted according to the clinical characteristics and age of the patient.

It is administered in various forms such as oral administration, injections, rectal suppositories and external preparations.

Painkillers according to the present invention are generally used as compositions such as calcium carbonate, calcium phosphate, starch, sucrose, lactose, talc, magnesium, stearate, gelatin, polyvinylpyrrolidone, gum arabic, sorbitol, microcrystalline cellulose, Used in methods such as polyethylene glycol, carboxymethyl cellulose, silica, polyvinyl acetal diethylamino-acetate, hydroxypropylmethylcellulose and shellac are prescribed for medicaments containing excipients. Purification is coated by a known method. Liquid preparations for oral administration are generally suspensions, solutions, syrups, elixirs in water or oil prepared by known methods.

Injectables are suspensions or solutions in water or oil, or micropowders or lyophilized powders which can be dissolved before use. Injections are made by the method of practice.

For rectal use, the analgesic is provided as a suppository composition containing known pharmaceutical excipients such as polyethylene glycol, lanolin, cacao butter and fatty acid triglycerides.

The external preparation is preferably used as an ointment or cream prepared by mixing the active ingredient according to the present invention with an ointment base or the like in a conventional manner.

The present invention is described in detail below with respect to the synthesis examples of the allophanoylpiperazine Compound represented by the general formula (1), the test results for the analgesic action of the compounds thus obtained, and the examples of the medicaments containing the same. Synthesis Examples of the allophanoylpiperazine Compounds of Formula (1) by the method are as described below.

The properties of the compounds obtained by other experiments of this example and of methods similar to this example can be seen in Table 1.

Synthesis Example by the Method

Example 1

(Synthesis of Compound No. 6 in Table 1)

Dissolve 6.5 g of 1-phenylpiperazine in 40 ml of dichloromethane. To the solution is added 3.0 g of 2,4-dimethylallopanoylchloride while stirring and ice-cooling. After reacting at room temperature for 0.5 hour, the reaction mixture is washed with water and dehydrated with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized from a mixture of ethanol and petroleum ether to obtain 4.0 g (yield: 72%) of 1- (2,4-dimethylalopanoyl) -4-phenylpipe with a melting point of 79 to 80 ° C. Get Razine

Example 2

(Synthesis of Compound No. 19 in Table 1)

Dissolve 10.8 g of 1- (p-fluorophenyl) -piperazine and 6.1 g of triethylamine in 80 ml of dichloromethane.

10.0 g of 2,4,4-trimethylallophanoylchloride is added dropwise to the solution while stirring and ice-cooling. After 1 hour of reaction at room temperature, the reaction mixture is washed with water and dehydrated with anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized from a mixture of ethanol and ether to give 13.7 g (yield 74%) of 1- (p-fluorophenyl) -4- (2,4,4-trimethyl having a melting point of 83-84 ° C. Allophanoyl) piperazine is obtained.

Compounds prepared by the method of the present invention are shown in Table 1 below.

TABLE 1

Pharmacological examination

The methods for testing analgesic action and acute toxicity are described below and the test results can be seen in Table 2.

TABLE 2

Analgesic:

1. Acetic acid-induced new construction

Koster et al. [Fed. Pro., 18,412 (1959)], ddy line male mice (20-25 g each weight) are used for testing. After 1 hour of oral administration of 100 mg / kg of test drug, 0.3 ml of 0.6% acetic acid solution is administered intraperitoneally to each mouse, the elastic symptoms are observed, and the inhibition ratio (in%) is calculated.

The number marked with asterisk (*) in Table 2 is the mean effective dose ED ₅₀ (mg / kg) and NT means not tested.

2. Haffner Method

Using ddy line male mice (20-25 g each weight) are tested by an improved method such as Fujimura et al. [Bulletin of the Institute for Chemical Research, Kyoto University 25, 36 (1951)].

Thirty minutes after oral administration of a test drug of 100 mg / kg, a threshold dose (2.5 mg / kg) of morphine hydrochloride is administered avoided.

Inhibition rate (in%) was determined by observing the analgesic response of the mice by clamping for 1 hour. The numbers marked with an asterisk (*) in Table 2 are the average effective dose [ED ₅₀ (mg / kg)] and NT means “not tested”.

Acute Toxicity:

Acute toxicity studies are performed using ddy male mice (20-25 g each). One week after the test drug oral administration, the general symptoms of each rat are observed.

는 표 2에서 볼 수 있고, 별표(*)가 표시된 숫자는 평균 치사복용량[ LD₅₀(mg/kg)]이다.Dose (mg / kg) and correspondence costs

Are shown in Table 2, and the number marked with an asterisk (*) is the average lethal dose [LD ₅₀ (mg / kg)].

In this test, the drug is used as a solution or suspension in 0.1-0.25% carboxymethyl-cellulose.

Finally some examples of medicinal herbs containing other allophanyl pyreazine compounds in the present invention are given below.

Production Example 1

Granules are prepared by the method of practice according to the formula below.

Production Example 2

Tablets are prepared by the method of practice according to the formula below.

Production Example 3

Capsules are prepared by the method of practice according to the formula below.

Production Example 4

Suppositories are prepared by the method of practice according to the formula below.

Production Example 5

Injections are prepared by the method of practice according to the formula below.

Production Example 6

Ointments are prepared by the method of practice according to the formula below.

Claims (1)

A method for preparing allophanoylpiperazine of the following general formula (1), wherein the allophanoyl chloride of the following general formula (2) is reacted with the piperazine compound of the following general formula (3):

Where R ¹ is a lower alkyl group or a phenyl group; R ² and R ³ are each a hydrogen atom or a lower alkyl group; R ⁴ is a phenyl group, a substituted phenyl group having a halogen atom, methyl group, trifluoromethyl group, hydroxy group, methoxy group, methylenedioxy group, nitro group or carboxyl group as a substituent; Pyridyl group, pyrimidinyl group, thiazolyl group, benzyl group, cyclohexyl group; Lower alkyl group; Or a substituted lower alkyl group having a chlorine atom or a hydroxy group.