JPS6323966B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an analgesic containing a biuret compound represented by the following general formula (1) as an active ingredient. (In the formula, R ¹ is a hydrogen atom, a lower alkyl group, a chlorine atom, a cyano group, a dimethylamino group, a hydroxyl group, a lower alkyl group having a methoxy group or a carboxyl group as a substituent, a lower alkenyl group, a hydroxyl group, a methoxy group, an acetyl group) , or a phenyl group, R ² is a hydrogen atom, a lower alkyl group, or a phenyl group, R ³ is a phenyl group, and as a substituent a halogen atom, a trifluoromethyl group,
Methyl group, methoxy group, methylenedioxy group, hydroxyl group, dimethylamino group, phenyl group having a carboxyl group or carboxymethyl group, benzyl group, pyridyl group, pyridyl group having a methyl group as a substituent, pyridylmethyl group, pyrimidinyl group , thiazolyl group, or thienyl group. In the following, like symbols mean the same thing. ) Conventionally, some of the biuret compounds represented by the general formula (1) are known as compounds, and although they are different from the biuret compounds represented by the general formula (1), Some of the other biuret compounds that share the same skeleton were also known as compounds. Among these known biuret compounds, there are some compounds that have been reported to have hypnotic, sedative, or anticonvulsant effects, particularly among the latter known compounds. However, not only the biuret compound represented by general formula (1) but also other biuret compounds that have the same skeleton as described above,
There has been no report that it has an analgesic effect, and in this sense, the present invention provides a novel analgesic agent that has never been seen before. The biuret compound represented by general formula (1) can be synthesized by any of the methods exemplified below. Method A Urea represented by general formula (2) or (4) and general formula (3) or
It is characterized by reacting the isocyanate shown in (5) and is expressed by the following reaction formula. In this reaction formula, the reaction between urea and isocyanate is usually carried out without a solvent or in a solvent. (The solvent is not particularly limited as long as it does not participate in the reaction, but generally ethers such as ether, dioxane, and tetrahydrofuran, methylene chloride,
Lower halogenoalkanes such as chloroform and carbon tetrachloride, and aromatic hydrocarbons such as benzene, toluene and xylene are used. The ratio of urea and isocyanate to be used may be selected as appropriate, but it is generally advantageous to use equimolar amounts. Although the reaction temperature may be selected appropriately, the reaction generally proceeds advantageously when carried out at room temperature to the boiling point of the solvent. The above reaction produces biuret compound (1), which can be isolated by conventional separation means. Method B is characterized by reacting an allofanoyl chloride represented by general formula (6) or (8) with an amine represented by general formula (7) or (9), and is represented by the following reaction formula. In this reaction scheme, the reaction between allofanoyl chloride and amine is usually carried out in a solvent. The solvent is not particularly limited as long as it does not participate in the reaction, but generally methylene chloride, chloroform,
Lower halogenoalkanes such as carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, xylene, etc. are used. In the reaction, if necessary, a suitable condensation auxiliary agent such as a trialkylamine and a base such as pyridine is used. The ratio of allofanoyl chloride and amine to be used may be selected as appropriate;
Generally, it is advantageous to use the amine in an amount of about 1 to 2 times the molar amount of allofanoyl chloride. The reaction temperature may be selected appropriately, but generally -20 to 50
The process progresses advantageously when carried out at a temperature of about °C. The above reaction produces biuret compound (1), which can be isolated by conventional separation means. The allofanoyl chloride used as a raw material in this reaction formula is usually a known compound, but if necessary, a method in which urea is reacted with phosgene in the reaction formula of Method A (J.Org.Chem., 29 ,
2401 (1964)). Method C is characterized by reacting 1,3-diazetidine-2,4-dione represented by general formula (10) or (11) with an amine represented by general formula (7) or (9), and is characterized by the following: It is expressed by a reaction formula. In this reaction formula, 1,3-diazetidine-
The reaction between 2,4-dione and amine is usually carried out in a solvent. The solvent is not particularly limited as long as it does not participate in the reaction, but water, acetone, acetonitrile, etc. are generally used. The ratio of 1,3-diazetidine-2,4-dione and amine to be used may be selected as appropriate, but generally the ratio of amine to 1,3-diazetidine-2,4-dione is 1 to 2.
It is advantageous to use about twice the molar amount. Although the reaction temperature may be selected appropriately, it generally proceeds advantageously when carried out at room temperature to about 100°C. The above reaction produces biuret compound (1), which can be isolated by conventional separation means. 1,3 used as a raw material in this reaction formula
-Diazetidine-2,4-dione is usually a known compound, but if necessary, it may be used by a known method of reacting allofanoyl chloride with boron trichloride in the reaction formula of Method B (Angew.Chem.internat.
Edit., 9 , 372 (1970)). Method D This method can also be applied to the compound where R ¹ =R ² or R ² =R ³ in the biuret compound (1). That is, the general formula
It is characterized by reacting 1,3,5-oxadiazine-2,4,6-trione represented by (12) or (13) with an amine represented by general formula (7) or (9), and the following It is expressed by a reaction formula. In this reaction formula, the reaction between 1,3,5-oxadiazine-2,4,6-trione and the amine is usually carried out in a solvent. The solvent is not particularly limited as long as it does not participate in the reaction, but acetonitrile, tetrahydrofuran, etc. are generally preferably used. 1,3,5-oxadiazine-2,
The ratio of 4,6-trione and amine to be used may be selected as appropriate, but generally the ratio of amine to 1,3,5-oxadiazine-2,4,6-trione is 1 to 1.
It is advantageous to use about twice the molar amount. The reaction temperature can be selected appropriately, but generally it is between room temperature and 100°C.
It progresses advantageously if done to a certain extent. The above reaction produces biuret compound (1), which can be isolated by conventional separation means. 1, which is used as a raw material in this reaction formula,
3,5-Oxadiazine-2,4,6-trione is usually a known compound, but if necessary, it may be used in accordance with the known method of reacting isocyanate with carbon dioxide in Method A (Bull.Soc.Chim.Fr., 1974 , 1497)
It can be easily manufactured according to the following. The dosage of the analgesic according to the present invention is usually 10 to 2000 mg, preferably 50 to 1000 mg, per adult per day of the active ingredient, the biuret compound of general formula (1), which is administered in 2 to 3 divided doses. . The dosage is adjusted depending on the individual case, taking into account the patient's condition, age, etc. Administration is carried out in various forms such as oral preparations, injections, suppositories for rectal administration, and external preparations. The analgesic according to the present invention is prepared as a composition containing any conventional pharmaceutical carrier or excipient by a commonly used method, and then used. Tablets, capsules, granules, powders, etc. for oral administration may contain excipients commonly used in the art, such as calcium carbonate, calcium phosphate,
Contains starch, sucrose, lactose, talc, magnesium stearate, gelatin, polyvinylpyrrolidone, gum arabic, sorbitol, microcrystalline cellulose, polyethylene glycol, carboxymethylcellulose, silica, polyvinyl acetal diethylaminoacetate, hydroxypropyl methylcellulose, silica, etc. Good too.
The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be aqueous or oily suspensions, solutions, syrups, elixirs, and the like, and are prepared by commonly used methods. Injectables may be aqueous or oily suspensions, solutions, powder fillers to be dissolved at the time of use, freeze-dried agents, etc., and are prepared by commonly used methods. For rectal administration, the composition may be provided as a suppository and may contain pharmaceutical carriers well known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglycerides, and the like. External preparations are preferably administered in the form of ointments or creams, and are prepared by adding commonly used bases and the like by conventional methods. Hereinafter, the present invention will be explained in more detail with reference to synthesis examples of the biuret compound represented by general formula (1), analgesic effect tests of the biuret compounds synthesized thereby, and formulation examples. A of the biuret compound represented by general formula (1),
Synthesis examples using methods B, C, and D are as shown below, and the physical properties of the compounds obtained by these synthesis examples and the compounds obtained according to these synthesis examples are as shown in Table 1. It was hot. Synthesis Example 1 by Method A (Synthesis of compound No. 23 in Table 1) 3.5 g of ethyl urea (0.04 g) in 50 ml of anhydrous dioxane
4.8 g (0.04 mol) of phenyl isocyanate was added while stirring. After reacting at room temperature for 15 hours, the solvent was distilled off under reduced pressure and the residue was recrystallized from ethanol-water to give 1.
-Ethyl-5-phenyl biuret 4.6g (yield
55%). 2 (Synthesis of compound No. 3 in Table 1) 1,3-dimethylurea in 50 ml of anhydrous dioxane
3.5 g (0.04 mol) is dissolved and 4.8 g (0.04 mol) of phenyl isocyanate is added while stirring. After reacting at room temperature for 15 hours, the same treatment as in Synthesis Example 1 was performed and recrystallization from ethanol-petroleum ether yielded 5.0 g of 1,3-dimethyl-5-phenyl biuret with a melting point of 93-95°C (yield 60%). ) is obtained. Synthesis example by method B (synthesis of compound No. 31 in Table 1) Add ethylamine to 50 ml of anhydrous tetrahydrofuran.
Dissolve 9.0g (0.2mol) and cool to below 0℃,
While stirring, a solution of 21.3 g (0.1 mol) of 2-methyl-4-phenylallophanoyl chloride dissolved in 50 ml of anhydrous tetrahydrofuran is added dropwise. After reacting at room temperature for 1 hour, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitate was filtered and dried. Ether - melting point 80.5 ~ when recrystallized from petroleum ether
17.7 g (yield: 80%) of 1-ethyl-3-methyl-5-phenyl biuret at 81.5° C. is obtained. Synthesis example using method C (synthesis of compound No. 22 in Table 1) Add 1,3-diphenyl to 30 ml of acetonitrile.
1,3-diazetidine-2,4-dione 6.0g
(0.025 mol) and dropwise added 3.9 ml (0.05 mol) of methylamine aqueous solution (40%) while stirring.
After reacting at 50°C for 0.5 hours, the solvent was distilled off under reduced pressure.
When the residue is recrystallized from ethanol, the melting point is 145-147.
1-Methyl-3,5-diphenyl biuret at °C
5.1 g (yield 76%) is obtained. Synthesis example using method D (synthesis of compound No. 14 in Table 1) 3,5-dimethyl-2,
Add 5.0 g (0.0316 mol) of 4,6-trioxohydro-1,3,5-oxadiazine and 3.0 g (0.0319 mol) of 2-aminopyridine, and stir and reflux for 7 hours to react. After cooling, water was added and filtered, the liquid was extracted with chloroform, the extract was dried over anhydrous sodium sulfate, the chloroform was distilled off, and the residue was recrystallized from benzene to give 1,3-dimethyl- with a melting point of 112-115°C. 3.0 g (yield 46%) of 5-(2-pyridyl)biuret is obtained.

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[Table] In Table 1, the * mark means a known compound. For each coded part a and b in Table 1, the following measurement results were obtained by nuclear magnetic resonance and mass spectrometry instead of elemental analysis. aNMR (CDCl ₃ ) δ: 0.88 (3H, m, N ₁ -
CH ₂ CH ₂ CH ₂ - CH ₃ ), 1.00 - 1.68 (4H, m, N ₁
―CH ₂ ―CH ₂ C H ₂ ―CH ₃ ), 3.18 (2H, m, N ₁ ―
CH ₂ - CH ₂ CH ₂ CH ₃ ), 3.18 (3H, s, N ₃ -
CH ₃ ), 6.00 (1H, broad, N ₁ -H), 6.88 - 7.49
(5H, m, Ar-H), 10.62 (1H, broad S, N ₅
-H). MS m/e: 249 (M ⁺ ). bNMR ( _CDCl3 )
δ: 0.88 (3H, broad t, J=6Hz, N ₁ - CH ₂
CH ₂ CH ₂ CH ₂ - CH ₃ ), 1.07 - 1.92 (6H, m, N ₁
--CH ₂ --CH ₂ C H ₂ C H ₂ --CH ₃ ), 2.99-3.27 (2H,
m, N ₁ - CH ₂ - CH ₂ CH ₂ CH ₂ CH ₃ ), 3.12 (3H,
S, N ₃ - CH ₃ ), 5.89 (1H, broad t, N ₁ -
H), 6.80-7.43 (5H, m, Ar-H), 10.44 (1H,
broad S, N ₅ - H). MS m/e: 263 (M ⁺ ). The test methods for analgesic effect, hypothermic effect, and acute toxicity were as follows, and the results were as shown in Table 2. Analgesic effect 1 Acetic acid stretching method Koster et al.'s method [Fed.Pro., 18 , 412 (1959)]
Accordingly, ddy male mice (body weight 20-25 g) were fasted overnight, and 1 hour after oral administration of 100 mg/Kg of the drug, 0.7% acetic acid was administered per animal.
A 0.2 ml dose was administered intraperitoneally, and stretching symptoms were observed to determine the inhibition rate (%). Dose 100mg/
Dosages other than kg are shown in parentheses. Also, the values marked with △ in Table 2 are the 50% effective dose ED50
(mg/Kg). 2 Hafner method Modified method by Fujimura et al. [Kyoto University Chemical Research Institute Report No. 25]
36 (1951)], DDY male mice (body weight 20-25 g) were fasted overnight, and then 100 doses of drug were administered.
45 minutes after oral administration of morphine (mg/Kg), a threshold dose of morphine hydrochloride (1.5 to 2.5 mg/Kg) was injected subcutaneously, and the pain response due to cramping was observed for the next 1 hour to determine the inhibition rate (%). . For doses other than 100 mg/Kg, the doses are shown in parentheses. Further, the value marked with △ in Table 2 indicates the 50% effective dose ED50 (mg/Kg). Hypothermic action Tanabe's method [Japanese Pharmacological Journal, 73 , 803
(1977)] in male Wistar rats (body weight
After an overnight fast, 1 ml/100 g of 10% baker's yeast was injected subcutaneously into the back of the rats. Five hours later, the drug was orally administered, and the body temperature was measured over time. The hypothermic effect is determined by integrating the fever curve over time for up to 4 hours after drug administration to obtain the fever index (FI), and then calculate the suppression rate (%) using the following formula:
It was expressed as (1 - FI of drug administration group / FI of control group) x 100 (%) Acute toxicity Acute toxicity test was conducted in male DDY mice (body weight 20~
After an overnight fast, the drug was orally administered. General symptoms after administration were observed for 7 days and expressed as the number of deaths/number of animals per group relative to the dose (mg/Kg). Further, the value marked with △ in Table 2 indicates the 50% lethal dose LD50 (mg/Kg). In the above tests, all drugs were suspended in 0.25% carboxymethylcellulose solution.

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[Table] In addition, the same tests as above were conducted for aminopyrine and phenylbutazone, which were adopted as control drugs, and the results are shown in Table 2 as follows.

[Table] Finally, some examples of formulations of the present invention are listed. Formulation Example 1 Compound 3 200mg Lactose 500mg Corn starch 280mg Hydroxypropylcellulose 20mg 1000mg per package Granules are prepared using the above blending ratio in a conventional manner. Formulation Example 2 Compound 8 100 mg Lactose 85 mg Crystalline cellulose 50 mg Hydroxypropyl starch 30 mg Talc 4 mg Magnesium stearate 1 mg 270 mg per tablet Tablets are prepared using the above blending ratio in a conventional manner. Formulation Example 3 Compound 15 100mg Lactose 50mg Potato starch 50mg Crystalline cellulose 109mg Magnesium stearate 1mg 310mg per capsule Capsules are prepared using the above blending ratio in a conventional manner. Formulation Example 4 Compound 31 200mg Lactose 100mg Crystalline cellulose 98mg Magnesium stearate 2mg 400mg per capsule Capsules are prepared using the above blending ratio in a conventional manner. Formulation Example 5 Compound 37 250mg Witepzol W-35 750mg (trade name manufactured by Dynamite Nobel) 1000mg per unit Suppositories are prepared according to the usual method using the above compounding ratio. Formulation Example 6 Compound 57 100mg Sodium chloride 16mg Distilled water for injection Appropriate amount 2ml per tube Prepare an injection using the above mixing ratio according to the usual method. Formulation example 7 Compound 31 2.0g White petrolatum 23.0g Stearyl alcohol 22.0g Propylene glycol 12.0g Sodium lauryl sulfate 1.5g Ethyl paraoxybenzoate 0.025g Propyl paraoxybenzoate 0.015g Purified water Appropriate amount 100g Ointment according to the usual method with the above mixing ratio Prepare the agent.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a hydrogen atom, a lower alkyl group, a chlorine atom, a cyano group, a dimethylamino group, a hydroxyl group, a lower alkyl group having a methoxy group or a carboxyl group as a substituent, a lower alkenyl group, a hydroxyl group, a methoxy group, an acetyl group) , or a phenyl group, R ² is a hydrogen atom, a lower alkyl group, or a phenyl group, R ³ is a phenyl group, and as a substituent a halogen atom, a trifluoromethyl group,
Methyl group, methoxy group, methylenedioxy group, hydroxyl group, dimethylamino group, phenyl group having a carboxyl group or carboxymethyl group, benzyl group, pyridyl group, pyridyl group having a methyl group as a substituent, pyridylmethyl group, pyrimidinyl group , thiazolyl group, or thienyl group. ) is an analgesic containing the biuret compound as an active ingredient.