LU82185A1 - NOVEL HYDROXYLATED PYRIMIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE - Google Patents

Description

-1-

The present invention relates to the hydroxylated derivatives of 2-isopropylamino pyrimidine of general formula: v / \ / CH3 K r—

> - N

in which A ^, A ^ and Ag each represent: - a hydrogen atom, 5 - a hydroxy radical, with the restriction that at least one of the substituents A ^, A ,. and Ag is not a hydrogen atom.

These compounds are particularly interesting for their action in the field of nerve regeneration and for the treatment of muscular dystrophies.

These compounds can be prepared, for example, by reacting the corresponding 2-thiomethyl pyrimidine on isopropylamine in a non-polar solvent at the temperature of 100-120 ° C., under pressure, according to the following scheme:

A4 V

) = "Ν \ / CH3 \ ^ ch3

V \ cH \ CH

A / - N 3 A6 / - "CH3 15 The present invention will be better understood from the following examples;

Example 1: 4-hydroxy-2-isopropylamino pyrimidine

The starting methyl thiouracil is obtained by reacting methyl iodide on the thiouracil in the presence of sodium methanolate. The 20 g (0.14 mol) thus obtained are placed in a pressurized reactor of one liter with -2-200 ml of dry toluene and 200 ml of isopropylamine. The reaction is carried out in 24 hours, under pressure, at 110-120 ° C. The resulting mixture is evaporated to dryness, treated with acetone and ethyl ether (50/50), filtered, washed with water and recrystallized from iso- acetate. propyl. 17 g (84% yield) of white crystals, melting at 140 ° C., are obtained, the analysis of which shows a good correspondence with the formula C ^ H ^ N ^ O. Its hydrochloride (melting point 233-234 ° C - Tottoli) is also a white Cris-10 tallized product; the UV spectrum characteristics of the base and of the hydrochloride are as follows:

In water (for the hydrochloride) „λ ï 266 nm e} * = 210 15 max 1cm λ: 217 nm ΕΓ * = 740 max 1cm λ: 290 nm 20 max

In methanol (for the base) λ; 293 nm E?% = 510 max 1 cm; 25: 222 nm E ** = * 730 max 1cm. The base (molecular weight 153.18) is insoluble in water, but soluble in chloroform.

Example 2: 5-hydroxy-2-isopropylamino pyrimidine

The method of Example 1 is repeated, but using 5-hydroxy-2-isopropylamino pyrimidine. Yield 83%. The reaction temperature was 105 ° C. Melting point 161 ° C (Tottoli). UV spectrum in water 60 / methanol 40; • ^ 5 1%: 341 nm E, * = 205 max lem 40 λ: 241 nm eJ% = 1210 mx 1cm -3-

Example 3: 4,6-dihydroxy-isopropylamino-2 pyrimidine

The method of Example 1 is repeated, but using 4,6-dihydro-2-thiomethyl pyrimidine. Yield 67%. Reaction temperature 110 ° C. Melting point 215-220 ° C, 5 with decomposition (Tottoli) for the hydrochloride corresponding to the formula C ^ H ^^ N ^ 02HC £, which is a white crystalline product insoluble in water at room temperature.

TOXICITY

The acute toxicity (mg / kg) of the compounds of the invention was determined in i.p. mice. and per os and the values are given in the following table: compound track ^^^^ - "-_ Ex. 1 Ex. 2 Ex. 3 i.p. 200 240 260 per os 205 355 285 PHARMACOLOGY t

The pharmacological activity of the compounds according to the invention was investigated by carrying out a comparative experiment on the regeneration of the sciatic nerve of the adult male rat "(Wistar).

A lesion of the sciatic nerve of rats is created by applying a thermoprobe to the nerve for 20 minutes. The 20 rats are then treated i.p. with the reference product or the compounds of the present invention for a predetermined period. At the end of the treatment, the rats are killed, the. sciatic nerves are separated and brought into contact with a% series of 70 parallel platinum wires (interval 1 mm) very fine and an electrical signal, applied upstream of the point of injury, is sought on the platinum wires: the wire the more distant, where the signal can be received, gives the regenerated length.

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For each compound tested and each treatment duration, a batch of 8 rats is used.

Four compounds were tested i.p. : the compound of Example 1, the compound of Example 2, the compound - of Example 3, all at a dose of 10 mg / kg and, as reference, a mixture of vitamins B1 (500 mg / kg), B6 (500 mg / kg) and B12 (5 mg / kg), which is known to be the most effective composition in this area. Control animals received no treatment.

Five batches of 8 animals were used for each period (7, 11, 14, 17 and 21 days) either for controls, or for compounds 1, 2, 3 or for the reference mixture.

The results of this experiment are summarized in the following table, with the figures obtained for the control animals; the lengths of the regenerated nerves are indicated in the respective columns of the days as the average value of the lengths measured for all the animals in each batch. When no figure appears (17 and 21 days), this means that the regenerated length exceeded the length of the sample taken. "---_ I) urea (days)

Compound and dose ~ TTp7 --------- 7 n 14 17 21 References 5.1 10.2 12.8 17.8 22.4 10¾1_ ^ 14 ^ __ 1¾2 ____ iHg / kg3__6.7 15.6 26 .7 - 500 mg / kg, 500 mg / kg and 5 mg Ag 8.8 13.4 15.8 20.4 23.7 -5-

PRESENTATION - DOSAGE

These derivatives can be presented in any therapeutically acceptable form, and, for example, in tablets or capsules containing 5 mg per dosage unit with an excipient; as regards the injectable form, the product can be presented in ampoules containing at least 1 mg of active product in the form of its hydrochloride dissolved in water. As for the dosage in human therapy, the doses range from 20 mg to 1 g per day by the oral route and from 1 mg to 50 mg per day by the injectable route.

An example of the tablet form is given below: - Composed of one of the examples 5 mg - Lactose 70 mg - Talc 20 mg - Magnesium stearate 5 mg „100 mg (“ a.

not

Claims (3)

1. Hydroxylated derivatives of 2-isopropylamino pyrimidine of general formula: A4 A _ / \ / C “3 a6> - 3 in which A ^, A ^ and Ag each represent: - a hydrogen atom, 5. a hydroxy radical, with the restriction that at least one of the substituents A ^, A5 and Ag is not a hydrogen atom. 2. Process for the preparation of the derivatives according to claim 1, consisting in reacting the corresponding 2-thiomethyl-pyrimidine on isopropylamine in a non-polar solvent at the temperature of 100-120 ° C, under pressure, according to the following scheme: A4 A4) = \ / Ch3) = ^ A5— ^ // S CH3 + H2N “C'nv ^ - ^ A5” \ ^ -NH— CH 3 a} - "a / N '/ XcH3 3. Therapeutic composition comprising, as active principle, one of the compounds according to claim 1.>