SU1342421A3 - Method of producing derivatives of purine - Google Patents

Abstract

The invention relates to purine derivatives, in particular compounds of the general formula I -NHcH H, NC NC-NCHj -OCH R, -CH, jR2, where R ,, Rj is hydroxyl, or R ,, Rj is a benzoyloxy group having antiviral activity that allows you to use them in medicine. New compounds 1 were obtained to reveal the pharmacological properties of purine derivatives. They are synthesized from 2-amino-6-chloro-9 (2-benzoyloxy-1-benzosh10 Xymethyl ethoxy) methyl 3-9H-purine, which is subjected to catalytic hydrogenation if necessary, the resulting product is subjected to hydrolysis. Studies I show that they have a higher antiviral activity against herpes viruses than adiclovir, and they are classified as low-toxic compounds. Oj

Description

The invention relates to a method for producing purine derivatives, new biologically active compounds, which can be used in medicine.

The purpose of the invention is new purine derivatives having a higher antiviral activity while maintaining low toxicity.

Example 1. a) 2-Amino-9 - // 2-benzoyloxy-1-benzoyloxymethyl ethoxy (methyl) -6-chloro-9H-purine.

A mixture of 7.0 (41.2 mmol) of 2-amino-6-chloro-9H-purine, 4.55 g (34.4 mmol) of ammonium sulfate and 200 ml of hexamethyl disilazane is boiled under nitrogen atmosphere with stirring for 5 hours. The resulting product is sublimated, 8.8 g (23.6 mmol) of 2-0- (acetyl methyl) -, 3-bis- (0-benzoyl) glycerol, in about 10 ml of benzene are added. The mixture is heated for 1.5 hours in an oil bath under reduced pressure with a distillation head. Then cooled to room temperature. The reaction was diluted with methanol and left on the steam bath for another 30 minutes. The mixture is then washed with water and extracted three times with ethyl acetate, the organic layer is separated and dried with anhydrous magnesium sulfate for about 30 minutes, after which the mixture is filtered, washed with ethyl acetate, and then quickly evaporated. After passage through the chromatography column and zylation (acetone 6: 1), the compound indicated in the preform is obtained in the form of an analytically pure white crystalline substance with „„ 130-131 ° C.

b) 2-Amino-9 - // 2-benzoyloxy-1-bezoyloxymethyl-toxy (methyl) -9H-purine

A mixture of 3.393 g (7.04 mmol) of 2-amino-9- (2-benzoyloxy-1-benzoyloxymethyl-toxy) methyl-6-chloro-9H purine 100 ml of ethanol, 100 ml of tetrahydrofuran, 1.9 ml triethylamine is added to 0.600 g of Pd-C catalyst in a Parr flask. The mixture was shaken under a hydrogen atmosphere for 24 hours. Pd-C was filtered through a Celite filter and 0.650 g of fresh Pd-C was added to the reaction mixture, after which hydrogenation was carried out for 4 days. After passing the reaction product through a chromatographic column and using 100%, 4: 1,; : acetone and 100% acetone

ten

15

133 ° C, yield 2.037 g (65%).

EXAMPLE 2. 2-AMINO-9- (2-hydroxy- -1-hydroxymethyl-ethoxy) methyl-9H-purine.

A mixture of 0.844 g (1.88 mmol) of 2-amino-9- (2-benzoyloxy-benzoyloxymethyl-toxo) methyl-911-purine and 100 ml of 40% aqueous methylamine solution was stirred at room temperature for 30 minutes. The mixture was evaporated to give a yellow oily product, which was then washed with water. Then the aqueous layer is extracted twice with methylene chloride. The aqueous layer containing the product is evaporated and a yellow oil is obtained. After recrystallization of the oil from hot acetonitrile, the indicated compound is obtained in the form of an analytically pure ivory solid, Tp 148-151 ° C, yield 0.23 g (51%)

Biological tests have been carried out. Antiviral effect is determined.

40 smaller CDIs are infected with the herpes virus type I strain 1C1 300 LD. intracerebral injection of 0.025 ml.

The smaller group was divided into 4 groups of 10 each, the I group was left as a control. Experimental group 1 received a 100 mg / kg dose of the compound of Example 3, experimental group 2 received a 100 mg / kg dose of the compound of Example 1 b, and experimental group 3 received a 100 mg / kg dose of acyclovir as a positive control. Survival times are fixed for 14 days and compared as shown in the table.

20

25

thirty

roll

one

Cont

1 + 2 4 + 2 + 4 + 3 1 + 4 0.37

1 + 9-1 + 0 8 survival 0.02

1 + 4 2 + 4 + 3 + 5 1 + 71 + 81 + 9 1 injection 0.17

1 + 2 1 + 3 1 + 3 1 + 4. 2 + 5 2 + 6 1 + 13 1 survival 0.21

31342421

Conducted tests showed where R | -Rj is hydroxyl or Rj-R -eeH- that the purine derivatives obtained by the yoyloxy group,

under the conditions of the proposed method, it is not distinguished by the fact that

possess toxicity and a more active-derived purine formula than acyclovir in relation to the virus

herpes.s1,

Claims (1)

Invention Formula L jc / The method of obtaining derivatives of pur-H2 sjVj on the general formula | g4mrOCH-cHjOC-ocjHs H, NV / CHjOCOCeHs I15. The CHO-OCH-CH T5 is subjected to catalytic hydrogenation and, if necessary, the semi-Cn2Rured product is subjected to hydrolysis.