KR840001967B1 - Process for the 1,1,3,5-substituted biuret compound - Google Patents

Abstract

Title comps. [I; R2 = C1-4 alkyl; R4 = -R1NCH3- (R1 = C1-4 alkyl) or -NHR3 (R3 = cyclohexyl, Ph, or substituted Ph (halogen, CF3, Me, OMe, NMe2, NO2, OH, OAc, or SMe); R5 = -NHR3 when R4 = -NR1-CH3 having an anti-inflammatory and anti-pyretic activity were prepd. from the reaction of II and amine ≮R5-H≉. Thus, Me2NCONHMe reacted with 4-ClC6H4NCO in THF contg. NaH to give MeNMeCONMeCONHFC6H40.

Description

Method for preparing 1,1,3,5-substituted biuret compound

The present invention relates to a method for producing a novel 1,1,3,5-substituted biuret compound represented by the following general formula (1).

(Wherein R ¹ and R ² are the same or different from each other, and each represent an alkyl group having 1 to 2 carbon atoms, and R ³ is a cyclohexyl group or a phenyl group which may be unsubstituted, or chlorine, cancelled, fluorine, methyl, A phenyl group which may be substituted with at least one substituent selected from trifluoromethyl, dimethylamino, methoxy, methylthio, nitro and acetyl.)

Several kinds of 1,1,3,5-substituted biuret compounds having different definitions of R ¹ , R ² and R ³ in the general formula (1) have been known from the past. [Reference: British Patent Publication No. 1,096,006, US Patent Publication No. 3,189,431, American Chemical Publications 62, 1595 (1940) and Heterocyclic Chemical Journal 9, pages 459-460 (1972)]

However, these known 1,1,3,5-substituted burette compounds are mostly chemicals only.

The present invention has been completed based on the fact that the novel 1,1,3,5-substituted burette compounds have an effective analgesic, anti-inflammatory and / or antipyretic effect.

An object of the present invention is to provide novel 1,1,3,5-substituted burette compounds.

Another object of the present invention is to provide an analgesic, anti-inflammatory and / or antipyretic composition containing the compounds according to the present invention.

Among the novel 1,1,3,5-substituted biuret compounds represented by the general formula (1), the following compounds are preferable.

1,1,3-trimethyl-5-phenylburette

1,1,3-trimethyl-5- (2-fluorophenyl) burette

1,1,3-trimethyl-5- (4-fluorophenyl) burette

1,1,3-trimethyl-5- (2,3,5,6-tetrafluorophenyl) burette

1,1,3-trimethyl-5- (2-chlorophenyl) burette

1,1,3-trimethyl-5- (3-chlorophenyl) burette

1,1,3-trimethyl-5- (4-chlorophenyl) burette

1,1,3-trimethyl-5- (2,4-dichlorophenyl) burette

1,1,3-trimethyl-5- (2,6-dichlorophenyl) burette

1,1,3-trimethyl-5- (3,4-dichlorophenyl) burette

1,1,3-trimethyl-5- (4-bromophenyl) burette

1,1,3-trimethyl-5- (2-trifluoromethylphenyl) -buret

1,1,3-trimethyl-5- (3-trifluoromethylphenyl) -buret

1,1,3-trimethyl-5- (4-dimethylaminophenyl) burette

1,1,3-trimethyl-5- (4-nitrophenyl) burette

1,1,3-trimethyl-5- (2-methoxyphenyl) burette

1,1,3-trimethyl-5- (4-methoxyphenyl) burette

1,1,3-trimethyl-5- (3,4-dimethoxyphenyl) burette

1,1,3-trimethyl-5- (3,4,5-trimethoxyphenyl) burette

1,1,3-trimethyl-5- (2-methoxyphenyl) burette

1,1,3-trimethyl-5- (3-methoxyphenyl) burette

1,1,3-trimethyl-5- (4-methoxyphenyl) burette

1,1,3-trimethyl-5- (2,3-dimethylphenyl) burette

1,1,3-trimethyl-5- (2,6-dimethylphenyl) burette

1,1,3-trimethyl-5- (3,4-dimethylphenyl) burette

1,1,3-trimethyl-5- (2-methyl-3-chlorophenyl) -buret

1,1,3-trimethyl-5- (4-acetylphenyl) burette

1,1,3-trimethyl-5- (4-methylthiophenyl) burette

1,1,3-trimethyl-5-cyclohexyl burette

1,1-dimethyl-3-ethyl-5-phenylburet

1,1-dimethyl-3-n-propyl-5-phenylburet

1,1-dimethyl-3-n-butyl-5-phenylburette

1-ethyl-1,3-dimethyl-5-phenylburet

1-n-propyl-1,3-dimethyl-5-phenylburet

1-n-butyl-1,3-dimethyl-5-phenylburet

In the said General formula (1), the compound whose R <^1> and R <^2> is a methyl group each is preferable.

Moreover, in the said General formula (1), the compound whose R <^3> is unsubstituted or substituted phenyl group is preferable, In said General formula (1), R <^1> and R <^2> are respectively methyl groups, and R <^3> is unsubstituted or substituted Further preferred are compounds that are phenyl groups.

The 1,1,3,5-substituted burette compound represented by the said General formula (1) can be manufactured by the method mentioned later.

Reaction Method B

A method for obtaining the 1,1,3,5-substituted biuret compound of the following general formula (1) by reacting the allophanoyl chloride of the following general formula (4) with the amine of the following general formula (3) by the following reaction formula. .

In this reaction method B, reaction of the allophanoyl chloride of General formula (4) and the amine of General formula (5) may be used in a solvent.

Although the solvent used for this reaction is not specifically limited, The well-known inert solvent which does not adversely affect this reaction can be used. Among these solvents, ethers such as ether, dioxane and tetrahydrofuran, halogenated lower alkanes such as methylene chloride, chloroform and carbon tetrachloride and aromatic hydrocarbons such as benzene, toluene and xylene can be exemplified.

If necessary, basic compounds such as triethylamine and pyridine may be used as suitable condensing agents.

In this reaction, the amount of allophanoyl chloride (4) and amine (5) to be used can be appropriately selected within a wide range, but is usually equimolar to amine (5) per 1 mole of allophanoyl chloride (4). Preference is given to using in an amount of from 2 to 2 times. It does not specifically limit about reaction temperature, either, Usually, it carries out in -20-50 degreeC.

In this reaction, the 1,1,3,5-substituted biuret compound of the general formula (1) thus produced can be easily separated by a normal separation operation.

The 1,1,3,5-substituted biuret compound of the general formula (1) can also be prepared by reacting the allophanoyl chloride of the general formula (6) with the amine of the general formula (7) by the following reaction formula. have.

The present reaction of allophanoyl chloride (6) with amine (7) was carried out in the above-described allophanoyl chloride (4).

The 1,1,3,5-substituted biuret compound of the general formula (1) according to the present invention can be administered at 10 to 2000 mg per day, preferably 50 to 1000 mg per day for adults as a therapeutic agent for analgesics, anti-inflammatory or antipyretic agents. There is a number.

The method of administration of the compound is usually divided into two or three divided doses of the above-mentioned daily dose, and the daily dose of the compound can be adjusted in consideration of clinical conditions and the age of the patient, and oral administration or topical treatment or injection. It can be conveniently administered as a suppository.

An analgesic, anti-inflammatory or antipyretic agent composed of the biuret compound of the general formula (1) according to the present invention is formulated and administered by combining a conventional carrier or excipient with a pharmaceutically acceptable excipient to the biuret compound.

Oral preparations such as tablets, capsules, granules, powders and the like can be blended with excipients which have been used in the art. These excipients include calcium carbonate, calcium phosphate, starch, sucrose, lactose, talc magnesium stearate, gelatin, polyvinyl. Pyrrolidone, gum arabic, sorbitol, microcrystalline cellulose, polyethylene glycol, carboxymethyl cellulose, silica, polyvinyl acetal diethyl, amino acetate, hydroxypropyl methyl cellulose, shellac and the like can be exemplified. Tablets can also be suitably coated by conventional methods known in the art. Oral liquid preparations can be prepared by conventional methods in the form of aqueous or oily suspensions, syrups, and elixirs. Injectables can be prepared by conventional methods in the form of aqueous or oily suspensions, soluble powders or lyophilized formulations in use.

The substituted biuret compounds may also be administered as rectal suppository compositions.

For external preparations, the substituted biuret compounds according to the present invention can be administered by the preparation of ointments or creams. These external preparations are formulated by combining the appropriate ointment and other additives with the biuret compounds according to the present invention by conventional methods.

Examples for the synthesis of substituted biuret compounds shown in Table 1 below, and examples for pharmacological tests such as analgesic test, anti-inflammatory action and antipyretic test described in Formulation Example 2 in Table 2 below The present invention will be described in more detail.

Example 1

Synthesis of 1,1,3-trimethyl-5-phenylbutet (Compound in Table 1)

7.4 g (0.08 mol) of aniline was further dissolved in 50 ml of anhydrous tetrahydrofuran, and the mixture was cooled to 0 DEG C or lower while stirring.

Next, a solution obtained by dissolving 6.4 g (0.04 mol) of 2,4,4-trimethylallophanoyl chloride in 10 ml of anhydrous tetrahydrofuran was added dropwise while stirring in the above-described cooling mixture. After the reaction was continued for 1 hour at room temperature, water was added to the residue obtained by distilling off the solvent under reduced pressure, the insoluble substance was filtered off, and then recrystallized in ethanol to have a melting point of 8,9,9,5 ° C. 13.0 g (yield 73%) of trimethyl-5-phenyl burettes were obtained.

Table 1 below describes the physicochemical characteristics of the novel 1,1,3,5-substituted burette compounds, including the compound prepared in Example 1.

TABLE 1

In the 1,1,3,5-substituted burette compound according to the present invention represented by the general formula (1)

The test methods are described as follows.

1. Rapid toxicity test

ddy male mice (weight: 20-25 g) were used as test animals. Mice were fasted overnight and the test compound was orally administered.

General symptoms for the mice were observed for 7 days after administration, and the lethal dose (mg / kg, body weight) of the test compound was measured in relation to the number of deaths of mice / test of mice.

In Table 2, the values marked Δ are 50% lethal dose LD ₅₀ (mg / kg body weight).

2. antipyretic effect

Wistar male rats were used as test animals according to the method of Tanabe Folia pharmacologia Japonica, Vol, 73, pp. 803 (1977).

These mice were fasted overnight and injected 1 ml / 100 g (body weight) of 10% dry yeast suspension subcutaneously into the rat's back.

Five hours after the injection, the test compound was orally administered and the body temperature of the mice was continuously measured every hour.

The antipyretic effect of the test compound was measured as a FI (fabril index) by integrating the exothermic curve up to 4 hours after the test compound was administered, as described in the following formula.

3. Pain Relief

(1) Acetic acid induced expansion test

Mr. Koster's Fed. According to the procedure of proc, Vol 18, pp. 412 (1959), ddy male mice (weight: 20 to 25 g) were used as test animals. Mice were fasted overnight, the test compound was orally administered in an amount of 100 mg / kg, and 1 hour after the administration, 0.2 ml of 0.7% acetic acid solution was intraperitoneally injected. Acetic acid-induced expansion and contraction symptoms were observed in rats, and analgesic activity of the test compound was calculated as inhibition rate (%).

In Table 2, the values in parentheses are test data obtained using other values without using the amount of 100 mg / kg of body weight, and the values indicated by Δ are 50% effective amount and ED ₅₀ (mg / kg body weight).

(2) Haffner method

Ddy male mice (weight: 20 to 25 g) were used as test animals by the method reported by Fujimura's (University of Chemical Research Institute of Tokyo, Vol. 25, No. 36, page 36 (1951)).

)(1.5 내지 2.5mg/kg 체중)을 피하주사하였다. 클램프에 의한 1시간 통증 반응의 관찰을 행하고, 시험화합물의 진통작용을 억제비율(%)로 산정하였다. 표 2에 있어서 괄호 내의 값은 체중 100mg/kg의₅₀ Mice were fasted overnight, the test compound was orally administered in an amount of 100 mg / kg, and after 45 minutes, the threshold amount of morphine hydrochloride was added.

) (1.5-2.5 mg / kg body weight) was injected subcutaneously. The pain response was observed for 1 hour by clamping, and the analgesic action of the test compound was calculated as the inhibition rate (%). In Table 2, the values in parentheses are _{50 at} 100 mg / kg of body weight.

4. Anti-inflammatory action

Acute Carrageenan Induced Inflammation Test Folia pharmacologia Japonica, Vol. 56, pp. 575 (1960) according to the method Wistar male mice (weight: 150 to 180g) was used as a test animal. These mice were fasted overnight, the test compound was orally administered in an amount of 100 mg / kg, and 1 hour after administration, 0.1 ml of a 1% carrageenin solution was injected subcutaneously into the rat's hind paw as an inflammatory agent, and the volume of the hind paw was changed every hour. Measured. The anti-inflammatory action of the test compound was calculated as the percentage of inhibition of inflammation 3 hours after the administration of the proinflammatory agent.

TABLE 2

Below, the preparation example of the analgesic agent, antipyretic agent, and anti-inflammatory composition which mix | blended the 1,1,3,5, -substituted biuret compound as an active ingredient is described.

[Production Example 1]

The granules were prepared by the conventional method by combining the aforementioned components.

[Production Example 2]

The capsules were prepared by the conventional method by combining the aforementioned components.

[Manufacture example 3]

The capsules were prepared by the conventional method by combining the aforementioned components.

[Production Example 4]

The suppository was prepared by the conventional method by combining the above-mentioned ingredients.

Production Example 5

Injectables (ampoules) were formulated by combining the aforementioned ingredients.

[Manufacture example 6]

The above ingredients were combined to prepare an ointment by the conventional method.

Claims (1)

A method for producing a biuret compound of the general formula (1) characterized by reacting an allophanoyl chloride represented by the following general formula (2) with an amine derivative of the general formula (3).

In the above general formula, R ² is an alkyl group having 1 to 4 carbon atoms, R ⁴ is a general formula

(R ¹ is an alkyl group having 1 to 4 carbon atoms) or a group of formula -NHR ³ (R ³ is a cyclohexyl group; or chlorine, clear, fluorine, methyl, trifluoromethyl, dimethylamino, methoxy, methyl Unsubstituted or substituted with one or more substituents selected from thio, nitro and acetyl), and R ⁵ represents R ⁴

When R ¹ represents a group, R ³ represents a group of the formula -NHR ³ (R ³ represents the above), and R ⁴ represents a group -NHR ³ (R ³ represents the above).

(R ¹ is as described above).