GB2055801A - Preparation of hydroxy derivatives of 2-isopropylamino-pyrimidine - Google Patents

Abstract

Compounds of the general formula <IMAGE> A4=H or OH A5=H or OH A6=H or OH A4=A5=A6=H excluded are prepared by reducing compounds of the general formula <IMAGE> A'4=H, alkoxy or aralkyloxy A'5=H, alkoxy or aralkyloxy A'6=H, alkoxy or aralkyloxy A'4=A'5=A'6=H excluded with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium. The compounds I are of therapeutical interest.

Description

250 1 GB 2 055 801 A 1

SPECIFICATION

Pyrimidine derivatives The invention relates to a method for the preparation of hydroxy derivatives of 2-isopropylamino-pyrimidine 5 of general formula 1 A 4 -N AS,,- CH 3 -M-CH 1 \- ? \ CH 3 A 6 where each of A4, A5 and A6 independently represents a hydrogen atom or a hydroxy group with the proviso that at least one of A4, AB and A6 does not represent a hydrogen atom. These compounds are claimed per se 15 in our copending Application No. and are of th,erapeutical interest.

The invention provides a method for the preparation of hydroxy derivatives of 2-isopropylaminopyrimidine of the general formula 1 as above defined, the method comprising reducing aralkyloxy or alkoxy derivatives of 2-isopropylamino-pyrimidine of the general formula 11 Ae 4 4 N /CH 3 A ' 5 NH-CH "tH 3 A' 6 II wherein each of K4, K5 and K6 independently represents a hydrogen atom or an aralkyloxy or alkoxy group with the proviso that at least one of K4, K5 and A'6 does not represent a hydrogen atom with hydrogen in the presence of a hydrogenation catalyst, such as palladium.

The invention is illustrated by the following Examples.

EXAMPLE 1: 2-isopropylamino-5-hydroxypyrimidine In a pressurized reactor of 2 litre capacity, preferably cleared by a nitrogen flow, were placed 0.8 g of 2-isopropylamino-5-benzyloxy- pyrimidine, 40 ml of methanol and 80 mg of palladium catalyst; hydrogenation was performed for 2 hours at normal pressure. After filtration off of the catalyst and evaporation off of the methanol, the product was taken up in diethyl ether and the solution was filtered to eliminate insoluble matter. The diethyl ether was evaporated off and the product was recrystallised first from water and then from ethyl acetate. After drying, there was obtained 0.4 g (yield 80%) of 2-isopropylamino-5-hydroxypyrimidine. Elemental analysis showed the expected empirical formula C71-111 Nf3O. Melting point 16loC (Tottoli). U. V. Spectroscopy confirmed the structure.

EXAMPLE 2 45 2-isopropylamino-4-hydroxypyrimidine The method described in Example 1 was applied to 2-isopropylamino-4- ethoxy-pyrimidine instead of 2-isopropyl-amino-5-benzyloxy-pyrimidine. The yield was 83% of a white crystalline product melting at 1400C (Tottoli), elemental analysis of which confirmed a good correspondence with the formula C71-111N30U.V. Spectroscopy confirmed the structure.

EXAMPLE 3

2-isopropylamino-4,6-dihydroxypyrimidine The method described in Example 1 was applied to 2-isopropylamino-4,6- dibenzyioxy-pyrimidine instead of 2-isopropylamino-5-benzy[oxy-pyrimidine. The yield was 78% of a white crystalline product (hydrochlor ide) melting at 218-221'C (Tottoli), with decomposition, elemental analysis of which confirmed a good 55 correspondence with the formula C71-111N302, HCL U.V. Spectroscopy confirmed the structure.

2 GB 2 055.801 A 2 Toxicity The acute toxicity (mglkg) of the compounds of the invention was determined on mice i.p. and per os and the values are reported in Table 1:

TABLE 1 5

Route compound Ex. 1 Ex. 2 Ex. 3 -1 Lp. 200 240 260 10 1 1 per os 205 355 285 4 Pharmacology 15 The pharmacological activity of the compounds of the invention was studied by the following comparative 15 experimentation undertaken on the regeneration of the sciatic nerve of the male adult rate (Wistar) -. A lesion was made on the sciatic nerve of the rats by application of a thermosound at -20'C for 20 minutes on the nerve. The rats were 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 were sacrificed, the sciatic nerves were 20 separated aand placed in contact with a sery of 70 thin parallel platinum wires (interval 1 mm) and an electric 20 signal applied upstream the lesion point was researched on the platinum wires: the more distant wire where the signal can be collected gave the regenerated length. Four compositions have been tested i.p.: the compounds of each of Examples 1, 2 and 3, each at the i.p. 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 mixture is known in the art to be the most effective composition in this field. Controls received no treatment at all. Five batches of 8 aminals 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 the following Table 2 together with the figures obtained for control animals. The lengths of regenerated nerves are indicated in mm. at the 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 35 Compound and dose i.p.

Controls 5.1 10.2 12.8 17.8 22.4 Example 1 6.6 14.1 26.3 mglkg Example 2 10 mglkg Example 3 10 mg/kg 14.4 26.1 15.6 26.7 B1, B6, B12 8.8 13.4 15.8 20.4 23.7 500 mg/kg, 500 mg/kg and 5 mg/kg 50 Presentation - Posology These derivatives may be presented in any therapeutically acceptable form including, for instance, in tablets or in gelatine capsules containing 5 mg per dosage unit together with an excipient; for an injectable form, the product may be dosed in phials containing at least 1 mg of active ingredient in the form of its 55 hydrochloride dissolved in water. As to the posology for human use, oral administration requires from mg to llg per diem whereas the injectable form may be administered at doses between 1 mg to 50 mg per diem.

V 2 An example of a suitable tablet formulation is:

Compounds of any of the Examples 5mg GB 2 055 801 A 3 Lactose 70 mg 5 Talc 20 mg Magnesium stearate 5M9 10 mg.

Claims (3)

1. A method for the preparation of a hydroxy derivative of 2isopropylamino-pyrimidine of the general formula 1 as herein defined, the method comprising reducing an aralkyloxy or alkoxy derivative of 2isopropylamino-pyrimidine of the general formula 11 as herein defined with hydrogen in the presence of a hydrogenation catalyst.

2. A method according to claim 1 in which the hydrogenation catalyst is palladium.

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

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon. Surrey, 1981. Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may he obtained.