IE49547B1

IE49547B1 - Pyrimidine derivatives

Info

Publication number: IE49547B1
Application number: IE477/80A
Authority: IE
Original assignee: Soc D Etudes Prod Chimique
Priority date: 1979-03-10
Filing date: 1980-03-07
Publication date: 1985-10-30
Also published as: FI66357B; GB2045756A; FR2451191A1; NL184833B; JPS55122768A; DE3016752A1; MX6218E; DE3050999C2; NO154054B; FR2451370A1; CH644368A5; SG22683G; EG14282A; AU5624880A; DE3009071A1; FR2451370B1; IN153791B; PT70882A; NO154054C; NL184833C

Abstract

There are provided compounds of the general formula A4=H or OH A5=H or OH A6=H or OH A4=A5=A6=H excluded These compounds are prepared by reacting compounds of the general formula A4=H or OH A5=H or OH A6=H or OH A4=A5=A6=H excluded with isopropylamino under pressure in a non-polar solvent at from 100 DEG C to 120 DEG C. There are of interest in the field of nervous regeneration and in the treatment of muscular distrophy. Therapeutic compositions containing them are disclosed.

Description

The invention relates to pyrimidine derivatives, to a method for their preparation, and to compositions containing them.

The invention provides a method for the preparation of a hydroxy derivative of 2-isopropylamino-pyrimidine of the general formula I — CH CH, CH, wherein each of A^, Ag and Ag independently represents a hydrogen atom or a hydroxy group, with the proviso that at least one of A4, Ag and Ag represents a hydroxy group, the method canpris ing reacting hydroxy derivatives of 2-methylthio-pyrimidine of the general formula II wherein A^, Ag and Ag are as above defined (including the proviso) with isopropyl amine under pressure in a non-polar solvent at from 100°C to 120°C.

The compounds I as above defined are of special interest for their action in the field of nervous regeneration and for the treatment of muscular dystrophy. They are novel, with the exception of 4-hydroxy-2-isopropylamino-pyrimidine and hence the invention further provides a hydroxy derivative of 2-isopropylamino-pyrimidine of the general formula I wherein each of A^, Ag and Ag independently represents a hydrogen atom or a hydroxy group, with the provisos that at least one of A^, Ag and Αθ represents a hydroxy group and that if only one of A4, Αθ and Αθ represents a hydroxy group that one is Αθ, and their acid addition salts.

The invention also provides 4-hydroxy-2-isopropylamino15 pyrimidine or an acid addition salt thereof for use in nervous regeneration or the treatment of muscular dystrophy.

Moreover, the invention also provides a therapeutical composition comprising a therapeutically effective amount of a hydroxy derivative of 2-isopropylamino-pyrimidine of the general formula I wherein each of A4, Αθ and Αθ independently represents a hydrogen atom or a hydroxy group, with the proviso that at least one of A4, Αθ and Αθ represents a hydroxy group or a therapeutically acceptable salt thereof in admixture with a therapeutically acceptable diluent or carrier.

The invention is illustrated by the following Examples.

EXAMPLE 1: 4-hydroxy-2-isopropylamino-pyrimidine 4-Hydroxy-2-methylthio-pyrimidine was obtained by reacting methyl iodide with 4-hydroxy-2-mercapto-pyrimidine (thiouracil) in the presence of sodium methanolate. The S-methyl-thiouracil thus obtained (20 g, 0.14 mol) was placed in a one litre pressurized reactor with 200 ml of dry tolueue and 200 ml of isopropylamine. The reaction was carried on for 24 hours under pressure at 110°C and 120°C.

The resulting mixture was evaporated to dryness, treated with acetone and diethyl ether (50/50), filtered, washed with water and recrystallized frcm isopropyl acetate. There were thus obtained 17 g (yield 84%) of a white crystalline product, insoluble in water but soluble in chloroform, melting at 140°C, elemental analysis of which showed a good correspondence with the formula CyH^NjO 'molecular. weight 153.18). The hydrochloride of this compound was also prepared; it was also a white crystalline product and had a melting point of 233°C to 234°C (Tottoli).

U.V. Spectral data for the base and hydrochloride were: In water (for hydrochloride) In Methanol (for base) W266 ™ekm = 210 \iax ‘293 ™Eicm = 510 λ : :217nmE,% 740 λ : 222 nmEn = 730 max icm max 1cmAmax' ;290 nm of reaction was 105 C. in water:methanol (60 · 341 nmE^m max 1 cm Xmlv: 241 max 1 cm EXAMPLE 3: EXAMPLE Ζ: -hydroxy-2-i sopropy1 ami no-pyrimidi ne The method described in Example 1 was repeated but 5-hydroxy-2-methylthio-pyrimidine was used instead of 5 4-hydroxy-2-me thy 1th io-pyrimidine. Yield 83%. The temperature Melting point 161°C (Tottoli). U.V. Spectrun 40): = 205 = 1210 4,6-dihydroxy-2-isopropylamino pyrimidine The method described in Example 1 was repeated but 4,6-dihydroxy-2-methylthio-pyrimidine was used instead of 4-hydroxy-2-methylthio-pyrimidine. Yield 67%. Temperature of reaction 110°C. Melting point 215°C to 220°C with decomposition (Tottoli), for the hydrochloride of formula CyH-jHCl. This was a white crystalline product insoluble in water at room temperature.

Toxicity The acute toxicity (mg/kg) of the compound of the invention was determined on mice i.p. and per os and the values are reported in Table 1.: TABLE 1 Compound Ex. 1 Ex. 2 Ex. Route i.p. 200 240 260 5 per os 205 355 285 Pharmacology The pharmacological activities of the conpounds of the invention have been researched by the following canparative experimentation undertaken on the regeneration of the sciatic nerve of the male adult rat (Wistar).

A lesion is made on the sciatic nerve of the rats by application of a thermosound at -20°C for 20 minutes on the nerve. The rats are then treated i.p. by the reference product or by the compounds of the invention for a predetermined duration. At the end of the treatment the rats are killed, the sciatic nerves are separated and placed in contact with a sery of 70 thin parallel platinum wires (interval 1 mm) and an electric signal applied upstream the lesion point is researched on the platinum wires: the more distant wire where the signal can be collected gives the regenerated length.

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

Four compositions have been tested i.p.: Example 1 compound, Example 2 compound, Example 3 compound, all at the i.p. dose of 10 mg/kg and, as a reference, a mixture of vitamins BI (500 mq/kg), B6 (500 mg/kg) and B12 (5 mg/kg) which is known in the art to be the most effective composition in this field. Controle received no treatment: at all. Five batches of 8 animals were used for each duration (7, 11, 14, 17 and 21 days) either for controls or for compounds 1, 2, 3 or reference mixture.

The results of this experimentation are summarized in Table 2 together with the figures obtained for control animals. The lengths of regenerated nerves are indicated in mm at respective day columns as an average value of the lengths measured for all the animals of each batch. When no figure appears (17 and 21 days) this means that the regenerated length exceeded the length of the taken sample.

TABLE 2 Duration (days) 7 11 14 17 21 Compounds and dose i.p. Controls 5.1 10.2 12.8 17.8 22.4 Example 1 10 mg/kg 6.6 14.1 26.3 - - Example 2 10 mg/kg 6.8 14.4 26.1 - - Example 3 10 mg/kg 6.7 15.6 26.7 - - BI, B6, B12 500 mg/kg, 500 mg/kg 500 mg/kg 8.S 13.4 15.8 20.4 23.7 Presentation - Posology These derivatives may be presented in any therapeutically acceptable form, for instance, in tablets or in gelatine capsules containing 5 mg per dosage unit together with an excipient or in injectable form in phials containing at least 1 mg of active ingredient in the form of its hydrochloride dissolved in water. As to the posology for hunan use, oral administration requires from 20 mg to lg diem whereas the injectable form may be administered at doses between 1 mg and 50 mg per diem.

An example of a suitable tablet formulation is given hereunder.

Compound of any of the Examples 5 mg Lactose Talc Magnesium stearate mg 20 mg 5 mg 100 mg

Claims

1. A method for the preparation of a hydroxy derivative of 2. -isopropylamino-pyrimidine of the general formula I NH—CH .CH, CH, wherein each of A 4 , Αθ and Αθ independently represents a hydrogen atom or a hydroxy group, with the proviso that at least one of A 4 , Αθ and Αθ represents a hydroxy group, the method conprising reacting hydroxy derivatives of 2-methylthio-pyrimidine of the general fonnula II wherein A^, Αθ and Αθ are as above defined (including the proviso) with isopropylamine under pressure in a non-polar solvent at from 100°C to 120°C.

2. A hydroxy derivative of 2-isopropylamino-pyrimidine of the 15 general formula I wherein each of A^, Αθ and Αθ independently represents a hydrogen atom or a hydroxy group, with the provisos that at least one of A 4 , Αθ and Αθ represents a hydroxy group and that if only one of A^, Αθ and Αθ represents a hydroxy group that one is Αθ, and their acid addition salts.

3. 5-Hydroxy-2-isopropylamino-pyrimidine or its hydrochloride.

4. 4,6-Dihydroxy-2-isopropylamino-pyrimidine or its hydrochloride

5. 4-Hydroxy-2-isopropylami no-pyrimidine or an acid addition salt thereof for use in nervous regeneration or the treatment of muscular dystrophy.

6. A method for the preparation of a hydroxy derivative of 2-isopropylamino-pyrimidine as defined in claim 1, the method being substantially as described herein with reference to any one of the Examples.

7. 10 7. A therapeutical composition comprising a therapeutically effective amount of a hydroxy derivative of 2-isopropylaminopyrimidine as defined in claim 1 or a therapeutically acceptable salt thereof in admixture with a therapeutically acceptable diluent or carrier.

8. 15 8. A hydroxy derivative of 2-isopropylamino-pyrimidine of general formula I whenever prepared by a process as claimed in either claim 1 or claim 6.