KR850001040B1 - Process for preparing allophanoylpiperazine compounds - Google Patents

Abstract

Allophanoylpiperazine compds. I [R1 = lower alkyl, phenyl; R2 = H, lower alkyl; R3 = H, lower alkyl; R5 = pyridyl, pyrimidyl, thiazoyl, benzyl, cyclohexyl, (un)substd. lower alkyl, lower alkenyl are prepd. by the reaction of allophanoylpiperazine compds. II with halo- compds., X-R5 [X = halogen . The title compds. are new and useful as antiphlogistics and anodynes.

Description

[Name of invention]

Method for preparing allophanoylpiperazine Compound

Detailed description of the invention

The present invention relates to a method for producing a novel allophanoylpiperazine Compound.

It is represented by following General formula (1) of the allophanoyl piperazine compound which concerns on this invention.

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 ⁵ is a pyridyl group, pyrimidyl group, thiazoyl group. Substituted lower alkyl group which has a chlorine atom or a hydroxyl group as a benzyl group, cinnamic group, a cyclohexyl group, a lower alkyl group, and a substituent; Or a lower alkenyl group.

The compounds according to the invention are novel compounds which have never been described in the literature, have analgesic action and are useful as analgesics as well as anti-inflammatory action. Conventionally, a compound having a structure represented by the following formula, not to mention the allophanoylpiperazine Compound represented by Formula (1)

There was no record at all. The inventors of the present invention have conducted extensive studies on allophanoyl-piperazine Compounds of the above-described type for the development of compounds having analgesic effect, and have achieved the present invention by finding a compound of formula (1) suitable for the purpose. .

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

Manufacturing method

The present invention is a halogen compound represented by the general formula (3) to the allophanoyl piperazine represented by the general formula (2) (X is a halogen atom, R ⁵ is a pyridyl group, pyrimidyl group, thiazolyl group, benzyl group, thinner Wheat, cyclohexyl group, lower alkyl group substituent is a substituted lower alkyl group having a chlorine atom or a hydroxy atom).

The allophanoylpiperazine of the general formula (2) used in the present invention is a novel compound, its preparation and physical and chemical constants are shown in Example 1 below, and the halogen compound of the general formula (3) is a known compound. Condensed Chemical Dictionary, 9th ed, 1977. Page 484, Van Nostrand Reinhold Co.

The reaction between the allophanoylpiperazine (2) and the halogen compound (3) according to the above scheme is carried out in a solvent, for example in the presence of a basic compound such as trialkylamine, pyridine or alkali carbonate. Although any solvent that does not participate in the reaction can be used, the solvent generally uses halogenated hydrocarbons such as lower alcohols such as methanol, ethanol and propanol, methylene chloride, chloroform and hydrocarbons and aromatic hydrocarbons such as benzene, toluene and xylene . Although the ratio between the allophanoylpiperazine (2), the halogen compound (3) and the basic compound can be appropriately selected, it is preferable to use the reactants in an equimolar amount. The reaction temperature may also be appropriately selected, but the reaction generally proceeds advantageously at -20 ° C to the boiling point of the solvent. The allopiperazin (2) used as a reactant in the reaction is converted into the compound of the general formula (5) by the above-mentioned method A or B and the known method [Yakugaku Zasshi ( Journal of the Pharmaceutical Society of Japan, 74, 1049-1052 (1954)] is a novel compound easily prepared by the formyl removal reaction of compound (5).

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 and preferably 1 to 500 mg with respect to allophanoyl piperazine of formula (1) in 1 to 4 doses in adults. 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 dosages, injections, rectal suppositories, and external preparations.

The analgesic agents according to the present invention generally comprise a composition such as calcium carbonate, calcium phosphate, starch, sucrose, lactose, talc, magnesium stearate, gelatin, polyvinylgitololidon, gum arabic, sorbitol, microcrystalline cellulose, polyethylene It is prescribed for medicaments containing excipients used in methods such as glycols, carboxymethylcellulose, silica, polyvinyl acetal diethylamino-acetate, hydroxypropylmethylcellulose and shellac. 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 siblings in methods 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 material or the like by conventional methods.

This invention is described in detail below about the synthesis example of the allophanoyl piperazine compound represented by General formula (1), the test result about the analgesic action of the compound thus obtained, and the Example of the agent 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. 9 in Table 1)

To 20 ml of ethanol, 5.0 g of 1- (2,4,4-trimethylallopanoyl) piperazine hydrochloride and 3.7 g of sodium carbonate are added. 2.5 g of isopropyl bromide is added dropwise to the resulting mixture with stirring. The mixture is reacted under reflux for 8 hours and the precipitate is filtered off. The excess is concentrated and the residue is removed with a silica gel column to give an oil. This oil is converted to hydrochloride by conventional methods and recrystallized from ethanol to yield 3.8 g (yield: 65%) of 1- (isopropyl) -4- (2,4,4-trimethyl with a melting point of 213 ° to 215 °. Allophanoyl) piperazine hydrochloride is obtained.

1- (2,4,4-trimethylallopanoyl) -pyrazine hydrochloride used in the above examples is synthesized as follows.

Dissolve 41 g of 1-formylpiperazine and 54.5 g of triethylamine in 600 ml of tetrahydrofuran. 56 g of 2,4,4-trimethylallophanoylchloride is added dropwise to the solution with stirring and ice cooling. The mixture is allowed to react for 6 hours at room temperature and the precipitate is filtered off. The fruit solution is concentrated and the residue is recrystallized from tetrahydrofuran to obtain 41 g of 1-formyl-4- (2,4,4-trimethylallopanoyl) piperazine.

The compound is mixed with 800 ml of 6N hydrochloric acid and the mixture is heated with stirring at 60 ° C. for 1 hour. The reaction mixture is concentrated and the residue is recrystallized from ethanol to give 35.2 g of 1- (2,4,4-trimethylallopanoyl) -piperazine hydrochloride with a melting point of 215 ° C.

Elemental Analysis: (C ₉ H ₁₈ N ₄ O ₂ HCl)

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:

Acetic acid-induced stretching method:

Koster et al. [Fed. Pro., 18, 412 (1959)], ddy male mice (20-25 g each) 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 was administered intraperitoneally to each mouse, the elastic symptoms were observed, and the inhibition rate (in%) was calculated. In Table 2, the number marked with an asterisk (*) is the mean effective dose ED ₅₀ (mg / kg) and NT means not tested.

2. Haffner Method:

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

Thirty minutes after oral administration of 100 mg / kg of test drug, administration is performed by avoiding threshold dose (2.5 mg / kg) of morphine hydrochloride. Inhibition ratio (in%) was determined by observing the analgesic response of the mice by clamping for 1 hour. In Table 2, the number marked with an asterisk (*) is the average effective dose [ED ₅₀ (mg / kg)] and NT means “not tested”.

Acute Toxicity:

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

는 표 2에서 볼 수 있고, 별표(*)가 표시된 숫자는 치사복용량 [ED₅₀(mg/kg)]이다.Dose (mg / kg) and correspondence costs

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

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

Consequently, some examples of medicaments containing the allophanylpiperazine Compounds according to the invention are given below.

Preparation 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.

Preparation 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.

Preparation Example 6

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

Claims (1)

A method for producing the allophanoylpiperazine Compound represented by the general formula (1) characterized by reacting the allophanoylpiperazine Compound of the following General Formula (2) and the halogenated compound of the following General Formula (3).

In the above formula, R ¹ is a lower alkyl group; R ² is a hydrogen atom or a lower alkyl group; R ³ is a hydrogen atom or a lower alkyl group; R ⁵ is cinnamil group, lower alkyl group, or lower alkenyl group; X is a halogen atom.