SE435180B - HYDROXIDE DERIVATIVES OF 2-ISOPROPYLAMINO-PYRIMIDINE AND SETS FOR PREPARING THEREOF - Google Patents

Description

, aee1s12-o 2 110_120 ° C. The resulting mixture is evaporated to dryness, treated with acetone and diethyl ether (50/50), filtered, washed with water and recrystallized from isopropyl acetate. 17 g (84% yield) of a white crystalline product with a melting point of 140 DEG C. are thus obtained, the analysis of which shows good agreement with the formula C1H11N50. The hydrochloride of this compound is also prepared, m.p. 255 DEG-254 DEG C. (mint), which is also a white crystalline product. Data for UV spectrum: In water (for the hydrochloride) In methanol (for the base) amax = 266 nn Elfm = 210V nmax = 295 nn Eïfm = 510 1 ° 10 amax: 217 Dm Elšm = 740 ñmax: 222 nm Elšm = 730 fi max : 290 nm The base is a white crystalline product (molecular weight 155,18), insoluble in water but soluble in chloroform. Example 2: 5-hydroxy-2-isopropylaminopyrimidine The procedure of Example 1 was repeated but 5-hydroxy-2- thiomethyl-pyrimidine was used. Yield 85%. The reaction temperature was 105 ° C, melting point 161 ° C (Tottoli). U.V. ~ spectrum Å water 60 / methanol 40: Hmax = 541 nn E1fm = 205 amax; 241 nn Elfm = 1210 Example 5: 4,6-Dihydroxy-2-isopropylamino-pyrimidine The procedure of Example 1 was repeated but 4,6-dihydro--2-thiomethyl-pyrimidine was used. Yield 67%. Reaction temperature 11000. Melting point 215-220 ° C during decomposition (Tottoli) of the hydrochloride of the formula C7H11N5O3, HCl. This is a white crystalline product, insoluble in water at room temperature.

Toxicity to bone The acute toxicity (mg / kg) of the compounds of the invention was determined in mice i.p. and per os, and the values are given in the following table; sea1s12-o Association “\ ~ Ex. 1 Ex. 2 Ex. Administration: “\» - \\ way “* ~ i.p. 200 240 260 per os 205 555 285 Pharmacology The pharmacological activity of the compound according to the invention has been investigated by the following comparative experiments, which have been carried out with respect to the regeneration of the hip nerve in adult male rats (Wistar).

An injury is caused to the hip nerve of the rats by applying a thermal probe at -2000 for 20 min. on the nerve. The rats are then treated i.p. with the reference product or with the compounds of the invention for a predetermined time. At the end of the treatment, the rats are killed, the hip nerves are separated and placed in contact with a series of 70 thin parallel platinum wires (range 1 mm) and an electrical signal, applied upstream of the point of the eccentricity, is sought on the platinum wires.

The farthest wire, where the signal can be collected, gives the regenerated length.

For each composition tested and each treatment time, a group of 8 rats was used.

For the sake of comparison, the following compounds have been tested i.p .: compound of Example 1, compound of Example 2, compound of Example 5, all at the i.p. dose of 10 mg / kg and as a reference a mixture of vitamins B1 (500 mg / kg), (500 mg / kg) and B12 (5 mg / kg), which is known in the art to be the most effective composition in this area.

Controls received no treatment at all. Five groups of 8 animals were used for each time period (7, 11, 14, 17 and 21 days) both for controls and for compounds 1, 2, 5 and the reference mixture.

The results of this experiment are given in the following table together with the figures obtained for the control animals. The length of regenerated nerves is given in mm in the respective day columns as an average of the lengths measured for all: øe1s12-o 4 animals in each group. When no numbers appear (17 and 21 days), this means that the regenerated length exceeded the length of the sample taken.

Time (days) 7 11 14 17 21 trout and dose i.p.

I Controls 5.1 10.2 12.6 17.8 22.4 Example 1 1 6.6 14.1 26.5 _ _ mg / kg _ Example 2 6.8 14¿4 26.1 _ _ me / Example 5 '6.7 15.6 26.7 _ _ mg / kg B1, B6, B12' 8.8 15.4 15.5 20.4 25.7 500 må / kå, 500 mg / kg and ma / ke Pharmaceutical form and daily dose These derivatives may be in any therapeutically acceptable form, e.g. in the form of tablets or gelatin capsules containing 5 mg per dosage unit together with an excipient. For injectable form, the product may be metered into ampoules containing at least 1 mg of active ingredient in its hydrochloride, dissolved in water. The daily dose for humans is for oral administration from 20 mg to 1 g per day, while injectable form may be administered in doses between 1 mg and 50 mg per day.

An example of tablet form is given below = compound of any of the examples -5 mg - lactose 70 mg - talc 20 mg e-magnesium stearate 2 mg 100 mg

Claims (2)

A 2-isopropylamino-pyrimidine hydroxide derivative of the general formula wherein each of A, A and Aè represents a hydrogen atom or the hydroxy group, with the proviso that at least one of A4, A5 and A6 does not represent a hydrogen atom. 2. Methods of preparing 2-isopropylamino-pyrimidine hydroxide derivatives of the general formula A. 4 * N I I cH I 5 - A5 NH-cn / / \ cH. A6 N in 3 - wherein each of A4, A5 and A6 represents a hydrogen atom or hydroxy group, at least one of A4, A5 and A6 does not represent a hydrogen atom, characterized in that the corresponding 2-thiomethyl-pyrimidine is reacted with isopropylamine in a non-pert solvent at 100 DEG-120 DEG C. under pressure according to the following scheme AA 4 -NH4 * N CH A5> _s 0115 + HZN-cl1 / C5 -e A5- \ »NH-cn / 5 \ \ A \ c fl š - AN en; 5. The invention relates to 2-isopropylamino-pyrimidine-hydroxy derivatives of the general formula 'A4 4 N ca A5 __m1_cn <5 \ N /' CH 5 wherein each of A4, A5 and A6 represents a hydrogen atom hydroxy group, with the proviso that at least one of A4, A5 and A6 does not represent a hydrogen atom. The invention also relates to a process for the preparation of these derivatives by reacting the corresponding 2-thiomethyl-pyrimidine with isopropylamine in a non-polar solvent at 100-12000 under pressure according to the following scheme: A4 The compounds of the invention can be used for nerve regeneration and for treatment of muscular dystrophies. > \ ls cnš + H2N ___ cH / CH3_ A5 /> - avH - cH / CH5Ä / \ CH5 \ N \ cH¿¿. A6 /