JPS6126996B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel hydroxypyrimidine derivatives, their preparation and their therapeutic use as nerve regenerating agents. That is, the present invention is based on the following formula: (In the formula, A ₄ , A ₅ and A ₆ each represent a hydrogen atom or a hydroxyl group, but at least one of A ₄ , A ₅ and A ₆ represents a hydroxyl group)
A hydroxy derivative of 2-isopropylaminopyrimidine is provided. The compounds of the invention are particularly useful in the field of nerve regeneration and in the treatment of muscular dystrophies. Therefore, the present invention further provides 2 having the above formula.
- A nerve regenerating agent containing a hydroxy derivative of isopropylaminopyrimidine as an active ingredient is provided. As is clear from the pharmacological activity test data described below, the nerve regenerating agent of the present invention is recognized to exhibit desired effects at extremely low doses. The compounds of the invention can be prepared, for example, by combining 2-methylthio pyrimidine and isopropylamine in a non-polar solvent at elevated temperatures, preferably according to the reaction scheme below.
It can be produced by reaction under pressure at a temperature of 100 to 120°C. Next, the present invention will be further explained by examples. Example 1 4-Hydroxy-2-isopropylaminopyrimidine Methyl thiouracil as a raw material was obtained by reacting methyl iodide, thiouracil, and sodium methanolate in the presence of sodium methanolate. 20 g (0.14 mol) of this methyl thiouracil was added to a solution containing 200 ml of dry toluene and 200 ml of isopropylamine.
The reaction was carried out at 110-120° C. under pressure for 24 hours. The resulting reaction mixture was evaporated to dryness and diluted with acetone/diethyl ether (50/
50), filtered, washed with water and recrystallized from isopropyl acetate. Thus the melting point
17 g (84% yield) of white crystalline product at 140° C. was obtained. Elemental analysis of this compound was in good agreement with the formula C ₇ H ₁₁ N ₃ O. From the title compound, its hydrochloride salt was determined by a conventional method at its melting point.
Obtained as a white crystalline product at 233-234°C. ultraviolet absorption spectrum

Table: The free base is a white crystalline product (molecular weight 153.18) that is insoluble in water but soluble in chloroform. Example 2 5-Hydroxy-2-isopropylaminopyrimidine The method described in Example 1 was repeated except that 5-hydroxy-2-methylthiopyrimidine was used.
The reaction temperature was 105°C. The title compound with a melting point of 161° C. was thus obtained in 83% yield. Ultraviolet absorption spectrum in water/methanol (60/40) λ _nax : 341 nm E ¹ % ₁ cm = 205 λ _nax : 241 nm E ¹ % ₁ cm = 1210 Example 3 4,6-dihydroxy-2-isopropylaminopyrimidine 4 - The method described in Example 1 was repeated except that 6-dihydro-2-methylthiopyrimidine was used. The reaction temperature was 110°C. Yield 67%. formula
Melting point _215-220 ℃ for _{hydrochloride} of _C7H11N3HCl
(with decomposition). It is a white crystalline product that is insoluble in water at room temperature. The toxicity and pharmacological activity of the compounds according to the invention are shown below. Toxicity The acute toxicity (mg/Kg) of the compound of the present invention was investigated by intraperitoneal administration and oral administration to mice, and the values are shown in the table below.

Table: Pharmacological Activity The pharmacological activity of the compounds according to the invention was investigated in the following comparative test carried out on the regeneration of the sciatic nerve in adult Wistar rats (female). Thermosound was applied to the rat sciatic nerve at -20°C.
By applying it for 20 minutes, it causes lesions on the nerve,
The rats are then administered a control drug or a compound of the invention intraperitoneally for a predetermined duration. After the administration, the rat is sacrificed, the sciatic nerve is removed and placed in contact with 70 thin parallel platinum wires (1 mm apart), and the electrical signals applied in the upstream direction to the lesion site are examined on each platinum wire. The furthest platinum wire from which signals can be collected gives the regenerated nerve length. Group 8 for each test drug and each administration duration
Two rats were used. The compounds of Examples 1, 2 and 3 were administered intraperitoneally at a rate of 10 mg/Kg, and the control drug was vitamin B ₁ , which is the most effective composition known in the art.
(500=mg/Kg), vitamin B ₆ (500 mg/Kg) and vitamin B ₁₂ (5 mg/Kg) were administered intraperitoneally. The test results are shown in the table below, along with the results of the untreated group in which no drug was administered. The length of the regenerated nerve is shown in mm in each duration column as the average length measured for all rats in each treatment group. In the table, a dash (-) indicates that the regenerated nerve length exceeded the length of the collected sample.

[Table] The dose (10 mg/Kg) of the compound of the present invention that gives an effective result in the above pharmacological activity test is a known compound that does not have a hydroxyl substituent on the pyrimidine ring, 2-isopropylaminopyrimidine and its dichloroacetate. The fact that the dose is significantly lower than the dose (87 mg/Kg in terms of free base) that gives effective results in a similar test using phosphate is disclosed in the applicant's own Japanese Patent Application Laid-Open No. 100477/1983. This can be clearly seen by referring to the lower left column on page 2 to the upper right column on page 3 (Columns 7 and 8 of Japanese Patent Publication No. 59-28548). Methods of Administration and Effective Amounts The compounds of the invention may be administered in any known pharmaceutically acceptable form, such as tablets or gelatin capsules containing 5 mg of active compound per unit dose with excipients. In the case of injections, they can be administered as injections containing at least 1 mg of the active compound in the form of the hydrochloride salt dissolved in water. For human use, a daily dose of 20 mg to 1 g is required for oral administration.
In the case of injection administration, it can be administered in an amount of 1 mg to 50 mg per day. As an example, the composition of a tablet is shown below. Compound of the invention 5mg Lactose 70mg Talc 20mg Magnesium stearate 5mg 100mg

Claims (1)

[Claims] Primary formula: (In the formula, A ₄ , A ₅ and A ₆ each represent a hydrogen atom or a hydroxyl group, but at least one of A ₄ , A ₅ and A ₆ represents a hydroxyl group)
A hydroxy derivative of 2-isopropylaminopyrimidine having 2 formula: (wherein A ₄ , A ₅ and A ₆ have the meanings given below) and 2-methylthiopyrimidine of the formula: isopropylamine in a non-polar solvent at elevated temperature and under pressure.
The following formula: (In the formula, A ₄ , A ₅ and A ₆ each represent a hydrogen atom or a hydroxyl group, but at least one of A ₄ , A ₅ and A ₆ represents a hydroxyl group)
A method for producing a hydroxy derivative of 2-isopropylaminopyrimidine having the following. 3 The following formula as the active ingredient: (In the formula, A ₄ , A ₅ and A ₆ each represent a hydrogen atom or a hydroxyl group, but at least one of A ₄ , A ₅ and A ₆ represents a hydroxyl group)
A nerve regenerating agent comprising an effective amount of a hydroxy derivative of 2-isopropylaminopyrimidine having the following.