LU82333A1 - PREPARATION OF HYDROXYL DERIVATIVES OF ISOPROPYL-AMINO-PYRIMIDINE - Google Patents

Description

-1- ”

The present invention relates to a process for the preparation of hydroxylated derivatives of isopropylamino-pyrimidine, useful in the therapeutic field, and more particularly for the treatment of various neuropathies and muscular dystrophies.

The general formula of these derivatives is as follows: A5 — 1 - "H“ CH <^ N CH3 A6 in which A ^, A ^ and Ag each represent: - a hydrogen atom, - a hydroxy radical, with the restriction that at least one of the substituents A ^, A, -and Ag is not a hydrogen atom.

These compounds can be prepared, for example, by reacting the corresponding isopropylamino-2-halo pyrimidine on an inorganic basis, in water at 10 ° -150 ° C., in the presence of copper, according to the following scheme: A4 A4> = R CH 3 Cu V = rN CH3 A '_ / \ -NH — Ch / + MOH-> A, - / VnH-CH (5Λ // V 5Λ tvy — N 3> -— N 3 A6 A6 wherein A'4 / A '^ and A'g each represent a hydrogen atom or a halogen atom, with the same restriction as above, and where MOH represents a mineral base.

The present invention will be better understood from the following examples:

Example 1: 2-isopropylamino-5-hydroxypyrimidine.

80 ml of water, 3 g of sodium hydroxide, copper powder and 4.3 g (0.02 mole) of 2-isopropylamino-5 bromo-pyrimidine are poured into a one-liter reactor; the reaction mixture -2-

K

* is maintained at 130 ° C-135 ° C for one hour, with stirring and then at 130 ° C-140 ° C for about 12 hours, also with stirring.

After filtration of the copper, the reaction mixture is extracted twice with chloroform. The combined extracts are acidified with acetic acid to pH 6.5-7.0. The solution is then saturated with sodium chloride, causing the precipitation of the product which is recovered and washed with water and then with pentane. The product is then taken up in diethyl ether and treated with carbon black. The solution is concentrated, again causing precipitation of the product which is recovered and recrystallized from water or isopropyl acetate.

The crystals are dried to give 2.45 g (80% yield) of 2-isopropylamino-5 hydroxy-pyrimidine. Elementary analysis shows a good correspondence with the formula C7E11N30 ·

The starting material isopropylamino-2 bromo-5 pyrimidine had been easily obtained by reacting, in stoichiometric portions, isopropylamino-2 pyrimidine and * N-bromo succinimide in the presence of acetic acid (rendering 84 %).

Example 2: isopropylamino-2 hydroxy-4 pyrimidine.

The method of Example 1 is repeated, but using 2-isopropylamino-4-chloro pyrimidine instead of isopropylamino-2-bromo-5 pyrimidine. The yield is 77% of a white crystalline product melting at 140 ° C. (Tottoli), the analysis of which shows a perfect correspondence with the formula C ^ H ^ N ^ O. Structural analysis (UV spectrum) confirms the position of the hydroxy radical.

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

The method of Example 1 is repeated, but using 2-isopropylamino-4,6-dichloro pyrimidine instead of 2-isopropylamino-5 bromo-pyrimidine. The yield is 35 73% of a white crystalline product melting at 221-225 ° C.

-3- ”. (Tottoli), with decomposition / whose analysis shows a perfect correspondence with the formula HCl.

Structural analysis (UV spectrum) confirms the position of the hydroxy radical.

5 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: t - ^^ compound track "" "Ex * 1 Ex * 2 Ex · 3 i.p. 200 240 260 per os 205 355 285

PHARMACOLOGY

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 rats are then treated i.p. with the product in reference 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 thin platinum wires (interval 1 mm) and an electrical signal, applied upstream of the point of injury, is sought on platinum wires: the most distant wire, where the signal can be picked up, gives the regenerated length.

-4- *

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.

—------ Duration (days)

Compound and dose ~~ T7p7 ----- 7 il 14 17 21 j; References 5.1 10.2 12.8 17.8 22.4 'fHgAg1__6.6 14.1 26.3 - l ^ mg / kg2__6'8 14'4 - I0emg ^ g3__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 Ί * * ί ♦ -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 i i i: i i! i i

Claims (1)

-6- i · Ψ ♦ CLAIM Process for the preparation of hydroxylated derivatives of isopropylamino-pyrimidine corresponding to the formula: A4 / \ ch3 H XN 3 A6 in which A ^, Ag and Ag each represent: - an atom d hydrogen, 5. a hydroxy radical, with the restriction that at least one of the substituents A4, A, -and Ag is not a hydrogen atom, consisting in reacting the isopropylamino-2-halo pyrimidine on a mineral basis, in water at 100-150 ° C, in the presence of 10 copper, according to the following diagram: A'4 a4 VV / ° 13 cu Z “3 'A5 \\ // - NH CH \ + M0H-►A5_ / \ _NH — CH / y ~ / c "3 y_ / ch3 A'6 <in which A'4, A'g and A'g each represent a hydrogen atom or a halogen atom, with the same restriction as above, and where MOH represents a mineral base.