SU1373323A3 - Versions of method of producing 2-amino-9-(2-oxyethoxymethyl)-9h-purine - Google Patents

Abstract

The invention relates to heterocyclic substances, in particular the preparation of 2-amino-9- (2-hydroxyethoxymethyl) -9H-purine (AP), a biologically active substance that can be used in veterinary medicine and medicine. The goal is to create more active and low-toxic substances. Synthesis of APs is carried out: a) from 2-amino-6-chloro-9- - 2-benzoyloxyethoxy- ethylene purine, which is hydrogenated in absolute ethanol in the presence of 5% Pd / C with subsequent removal of the benzoyl group by acetylamine treatment; b) from 2-acetamido-9- (2-acetoxy-ethoxymethyl) -6-mercapto-9H-purine, which is hydrogenated on Rene nickel at boiling. AP has so pl. 186-187.5 ° C. AP tests show its antiviral effect and low toxicity — LDjo 3100 mg / kg. 2 sec. f-ly, 3 tab. WITH

Description

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The invention relates to a process for the preparation of 2-amino-9- (2-hydroxyethoxymethyl) -9H-purine, a new biologically active compound that can be used in medicine and veterinary medicine.

The purpose of the invention is to search for new derivatives in the range of purine, low-toxic and possessing higher antiviral activity.

Example 1. 2-Amino-9- (2-hydroxyethoxymeth1) -9H-purine.

A mixture of 2.48 g (7.13 mm) of 2-amino-6-chloro-9- (2-benzoyloxyethoxymethyl) purine, 250 ml of absolute ethanol, 1.9 ml of triethylamine and 0.6 g of 5% palladium on activated carbon shake in hydrogen at an initial pressure of 3.52 kg / cm at room temperature for 20 hours, filter, add 0.265 g of fresh palladium catalyst and 1.9 ml of triethylamine to the filtrate and shake the mixture in hydrogen for 16 hours

The ethanol solution after filtration through a filter of celite is evaporated under vacuum and the resulting white residue is extracted with boiling benzene several times. The combined benzene extracts containing 2-amino-9- (2-benzoyloxyethoxymethyl) -9H-purine are concentrated, 20 ml of 40% aqueous methylamine and 20 ml of methanol are added and evaporated in an open flask on a steam bath to dryness. The resulting mixture was triturated with diethyl ether to remove N-methylbenzamide, and then recrystallized from 100% ethanol to give 2-amino-9- (2-hydroxyethoxymethyl) -9H-purine as analytically pure granules, t pl. 186-187,5 ° C.

Example 2. 2-Acetamido-9-α-acetyl-6-mercapto-9H-purine.

A mixture of thioguanidine (54.0 g), acetic anhydride (250 ml) and p-tolu ylenesulfonic acid (2.0 g) was boiled overnight. The reaction mixture is cooled, the resulting solid is filtered, washed thoroughly with acetone, 2-acetamido-9-acetyl-6-mercapto-9H-purine (62.3 g) is obtained as a brown solid, the NMR spectrum corresponds to the structure described.

2-Acetamido-9- (2-acetoxyethoxymethyl) -6-mercapto-9H-purine.

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To a mixture of 2-acetamido-9-acetyl-6-β-mercapto-9H-purine (30.0 g) and p-toluylene sulfonic acid (2.0 g) in toluene (150 ml) is added dropwise over 4 hours at 90-95 C, 2-ox-1,4-butanediol diacetate (40.0 g). After 10 h, the reaction mixture is cooled and the solid formed is filtered and washed with acetone. Recrystallize from dimethylformamide / acetonitrile (1/1) with discoloration using activated carbon. Get 2- -acetamido-9- (2-acetoxyethoxymethyl) -6-mercapto-9H-purine (25.6 g) as a yellow substance, so pl. 205-206 ° C.

2-AMINO-9- (2-hydroxyethoxymethyl) -9H-purine.

2-Acetamido-9- (2-acetoxyethoxy-simethyl) -6-mercapto-9H-purine (0.50 g, 1.53 mmol), freshly prepared Rene Nickel W-2 (2 g) and 58% ammonium hydroxide (25 ml) is boiled for 2 hours. The catalyst is filtered off and the filtrate is evaporated to 5 ml, acetone (20 ml) is added and the precipitated precipitate is filtered off and dried. Obtain 0.21 g (65%) of a white crystalline substance, according to TLC and NMR data corresponding to an authentic sample, so pl. 188-189 ° C.

Biological tests of 2-amino-9- (2-hydroxyethoxymethyl) -9H-purine (6-deoxyacyclovir) have been carried out.

The following experiments were performed to determine levels of acyclovir in urine and plasma. (known compound) after oral dosed administration to rats and 6-deoxyacyclovir (the proposed compound).

Experimental procedure.

To rats (male long rats of Evans) the preparation is metered with the help of an intra-intestinal needle and placed in metabolic cells, where the separation of urine and feces occurs. Samples of collected urine and plasma are analyzed for acyclovir content by radioimmunoassay. It has been shown that 6-deoxyacyclovir does not interact with the antiserum used during this test.

In tab. 1 given the content of acyclovir in the urine after oral dose

administration of acyclovir, aminoacyclovir and 6-deoxyacyclovir to rats.

In tab. Table 2 gives a comparative plasma content of acyclovir after oral, dosed administration to rats of 6-deoxyacyclovir and aminoacyclovir.

Toxicity study. Four Beagle dogs (two females and two males) were given 6-deoxyacyclovir per. OS. (once a day for five days) at 40 mg / kg per day. Negative effects on one male and one female were not detected after they were killed at the end of the drug administration period, and one male and one female after they were killed two weeks after the end of the drug administration. Ld 6-deoxyacyclovir 3100 mg / kg.

Antiviral effect. 70 mice of type 1 diabetes are infected with the herpes virus type I of strain ICI 300 LD, intracerebral injection of 0.025 ml. Mice were divided into groups of ten each, one group was left as a control, not infected with the virus, and the remaining groups were administered acyclovir, respectively, at a dosage of 100 mg / kg (I) subcutaneously (sc), (II) orally, ( III) intraperitoneally (ip) and the compound of Example 1 (6-deoxyacyc Lovir) at a dosage of 100 mg / kg (I) subcutaneously (sc), (II) orally, (III) intraperitoneally (ip). Experienced groups receive doses of the drug 2-3 hours after infection and twice a day for four days. The evaluation is made after 14 days and the survival time is recorded.

The results are presented in Table. 3

Thus, the obtained results show that the 6-deoxy-acyclovir obtained by the proposed method and its variant, while maintaining low toxicity, has a higher antiviral activity than the known compound (acyclovir) when administered orally.

Claims (2)

Invention Formula one . The method of obtaining 2-amino-9- - (2-hydroxyethoxymethyl) -9H-purine formula gh) one N I SN OSHAS OH characterized in that the purine derivatives of the general formula X Ty L SL N t CHiOCH2.CHiOR where M is Cl; G - NH; R is benzoyl subjected to catalytic hydrogenation in absolute ethanol in the presence of 5% Pd on activated carbon, followed by removal of the benzoyl group by interaction with acetylamine. 2. The method of obtaining 2-amino-9- - (2-hydroxyethoxymethyl) -9H-purine formula B1 SNGOC SN HE characterized in that the purine derivative of the formula A6  N b1 CHiOCH CH OR where G is the CHjCONH group; M - SH; R - COCHj, subjected to hydrogenation over Ni-Pe-. Table 1 Note. In brackets are numbers of animals. 3733236 table 2 Plasma acyclovir concentration 6 DeoxiacycloBir Rat 1 rat 3 Control 4 + 2 1 + 2 + 5 + 30.407 Experienced in managing: acyclovir (s.c.) 3 + 3 4 + 4 2 + 4 1 + 6 0.261 6-deoxyacyclovir (s.c.) 1 + 2 3 + 3 1 + 4 2 + 4 2 + 50.289 acyclovir (oral) 2 + 2 3 + 3 5 + 40,325 6-deoxyacyclovir (oral) 1 + 2 + 1 + 4 2 + 5 3 + 6 1 + 8 0.186 (I survival) acyclovir (i.p.) 2 + 2 2 + 4 2 + 5 2 + 7 0.242 (1 survival) 6-deoxyacyclovir (i.p.) 1 + 2 + 2 + 3 1 + 4 4 + 6 1 + 80.233