FI66357B - REFERENCE TO A FRAMEWORK FOR PHARMACOLOGICAL PROPERTIES OF HYDROXIDERS OF AV 2-ISOPROPYLAMINOPYRIMIDE - Google Patents

Description

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Patent- och register sty reiwn '* AmMcan irtfcfd och wcLskrMaa peMkand 29.06. 84 (32) (33) (31) Pyy4 «qrewoHcn Bfird pctartft 10.03.79 30.0¾.79 English-England (GB) 7908494 7914987 (71) SociStS d'Etudes de Produits Chimiques, 4, rue Thdodule Ribot, 75017 Paris, France-France (FR) (72) AndrS Esanu, Paris, France-France (FR) (74) Leitzinger Oy (54) Method for the preparation of pharmacologically valuable hydroxy derivatives of 2-isopropylaminopyrimidine - For the preparation of pharmacologically active hydroxylated compounds 2-iso-propy1 am i nopy rimidine

The process for the preparation of pharmacologically valuable hydroxy derivatives of 2-isopropylaminopyrimidine of the general formula I is A <\> = N CH3

Ac - (.Λ- NH-CH 2 5 ^ H 3 (T) Ä 6 / in which each of A4, A5 and Ag is a hydrogen atom or a hydroxy group, provided that at least one of A4, Ag and Ag is not a hydrogen atom.

Of particular interest are their effect on nerve regeneration and their use in the treatment of muscular dystrophy.

The method according to the invention is characterized in that

A hydroxy derivative of 2-thiomethylpyrimidine of formula II

2 66357

A \ N

α5 - (/) - s CK3 (II) is reacted with isopropylamine in a non-polar solvent at 100-120 ° C under pressure.

The following examples illustrate the invention:

Example 1: 4-Hydroxy 2-isopropylaminopyrimidine The starting methylthiouracil is prepared by reacting methyl iodide with thiouracil in the presence of sodium methanolate. 20 g (0.14 mol) of methylthiouracil are obtained. Methylthiouracil, 200 ml of dry toluene and 200 ml of isopropylamine are placed in a 1 liter pressure reactor. The reaction is carried out under pressure at 110 to 120 ° C for 24 hours. 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 are thus obtained, m.p. 140 ° C. Based on the analysis, the product corresponds well to the formula c7HnN3 ° · This compound is also used to prepare the hydrochloride (m.p. 233-234 ° C (Tottoli)), which is also a white crystalline substance with a UV spectrum of:

In water (for hydrochloride) In methanol (for base) X__v: 266 nm 1% Xmax: 293 nm max E s 210 max E - 510 lcm lcm

Xm3V: 217 nm 1% Xmax: 222 nm 1% max E _ 740 max E _ 730 lcm lcm

Λmax: 290 nm 3 66357

The 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 procedure of Example 1 was repeated but 5-hydroxy-2-thiomethylpyrimidine was used. Yield 83%. The reaction temperature was 105 ° C. Melting point 161 ° C (Tottoli). UV spectrum, water 60 / methanol 40: Nax: 341 nm = 205 lcm \ nax: 241 nm Emax = 1210 lcm

Example 3: 4,6-Dihydroxy 2-isopropylaminopyrimidine

The procedure of Example 1 was repeated but 4,6-dihydro was used O ΐ1 2-thiomethylpyrimidine. Yield 67%. Reaction temperature 110 C. j

The hydrochloride of formula HCl has a melting point of 215-220 ° C, decomposes (Tottoli). This is a white crystalline product which is insoluble in water at room temperature. 1

toxicity

The acute toxicity (mg / kg) of the compounds of the invention was determined in mice i.p. and per os. The results are shown in the following table: ^ '^^^ Compound ~ ^ _ Example 1 Example 2 Example 3

Tie _ —______ i.p. 240 200 260 j per os 355 205 285

Pharmacology

The pharmacological activity of the compound of the invention has been studied in the following comparative experiment in which complete regeneration of the sciatic nerve of a growing male rat (Wistar) was examined.

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The sciatic nerve of rats is damaged by applying heat to the nerve for 20 minutes at -20 ° C. The rats are then treated i.p. for a period of time. reference product or compounds of the invention. At the end of the treatment, the rats are sacrificed, the sciatic nerves are separated and combined with 70 thin parallel platinum wires (1 mm apart). The electrical signal conducted above the damaged point is monitored by platinum wires: The farthest wire at which the signal can be detected indicates the regenerated length.

For each compound tested and each treatment time, 8 groups of rats are used.

Four compounds have been tested i.p .: Example 1 compound, Example 2 compound, Example 3 compound, all i.p. at a dose of 10 mg / kg, and as a reference a mixture of vitamins B1 (500 mg / kg), B6 (500 mg / kg) and B12 (5 mg / kg), which is known to those skilled in the art to be the most effective mixture in this field. Control animals were not treated at all. For each time point (7, 11, 14, 17, and 21 days), five groups of eight animals were used for both comparison, compounds 1, 2, 3, and control mixture.

The results of this experiment are summarized in the following table together with the results obtained with the control animals. The lengths of the regenerated nerves are presented in mm in the corresponding time vertical rows as the average of the lengths measured in all animals in each group. When no figure is shown (17 and 21 days), the regenerated length is greater than the length of the sample taken.

5 66357 -------- ^ Duration (days) 7 11 14 21

Compound and dose iTp ^

Comparisons 5.1 10.2 12.8 17.8 22.4

Example 1 a Q. . . .

10 mg / kg 6-8 14'4 26.1

Example 2, c _ 10 mg / kg 6'6 14'χ 26'3

Example 3,. c, _ 10 mg / kg 6'7 15'6 26'7

B1, B6, B12 500 mg / kg, 500 mg / kg and 5 mg / kg 8.8 13.4 15.8 20.4 23.7

Form of Administration - Dosage These derivatives may be administered in any therapeutically acceptable form, for example, as tablets or gelatin capsules containing 5 mg per dosage unit, together with an excipient.

In injectable form, the product may be presented in vials containing 1 mg of active ingredient dissolved in water as hydrochloride. Again, for administration to humans, the oral route of administration requires 20 mg to 1 g per diem, while the injectable form may be administered in doses ranging from 1 mg to 50 mg per diem.

The following is an example of a tablet form: - Compound according to one example 5 mg - Lactose 70 mg - Talc 20 mg - Magnesium stearate 5 mg 100 mg

Claims (1)

A process for the preparation of pharmacologically valuable hydroxy derivatives of 2-isopropylaminopyrimidine of the general formula I is a4 A6 in which each of A4, A5 and Ag is a hydrogen atom or a hydroxy group, provided that at least one of A4, A5 and Ag is not a hydrogen atom, characterized in that a hydroxy derivative of 2-thiomethylpyrimidine of formula II A, 4s> r = r N A5— / ^ - s CH3 (II) N A6 in which A4, Ag and Ag have the same meaning as above is reacted with isopropylamine in a non-polar solvent 100- At 120 ° C under pressure.