SU1553013A3 - Method of producing 9-(1,3-diadamanthylcarboxy-2-propoxymethyl)guanine - Google Patents

Abstract

EP--85424 A (A) 9-(2-acyloxy-1-hydroxymethyl ethoxymethyl) purine derivs. of formula (I) and their acid-addn. salts are new, (R1 is H or R7CO; R7 is H, 1-19C alkyl, 1-8C hydroxyalkyl, 2-9C alkoxyalkyl, 2-19C alkenyl, Ph, 1-adamantyl, 2-carboxyethyl, or carboxymethyl or their alkali metal salts; R2 is R7CO; R3 is H, halogen, SH, 1-6C alkylthio, N3, NR9R19 or NH-COR8; R8 is H, 1-19C alkyl or 1-adamantyl; R9 and R10 are H or 1-6C alkyl; and either (a) R4+R5 form a single bond and R6 is H, halogen, 1-6C alkoxy, N3, SH, 1-6C alkylthio, NR9R10 or NH-COR8; or (b) R4 is H and R5+R6 form a keto group). (B) Intermediates of formula (I) are new when (1) R1 and R2 are H; R3 is other than NY-COR8; R4 and R5 form a bond and R6 is other than NH-COR8; and (2) R1, R2 and R4 are H; R3 is NH-COR8; and R5+R6 form a keto gp. - Cpds. (I) are antivirals esp. effective against Herpes simplex virus I and II, cytomegalovirus, Epstein-Barr virus and varicella zoster virus and viral hepatitis B. Intermediates defined in paragraph (B) are also antivirals. Dose is 0.1-300 mg/kg. orally or parenterally. (0/0) USAB- US4612314 A Substd. 9-(1 or 3-monoacyloxy or 1,3-diacyloxy-2-propoxymethyl) purines of formula (I) are new. In (I), R1 and R2 are both -C(O)R7 in which R7 is 1-adamantyl; R3 is NH2 a R6 is H or NH2 and R4 with R5 is a bond or b R5 with R6 is keto and R4 is H. Esp. cpd. is 9-(1,3-di(1-adamantyl carboxy)-2-propoxy methyl)guanine. (I) may be prepd. e.g. by esterifying cpds. (X) and (IV).

Description

This invention relates to a process for the preparation of new 9- (1,3-di-; hydroxy-2-propoxymethyl) guanine derivatives having antiviral properties and which can be used as pharmaceuticals.

The purpose of the invention is a method of obtaining new derivatives, 3 Dioxy-2- -propoxymethyl) i of uanine, which have a higher antiviral activity.

The following examples illustrate the synthesis of the compounds of the invention and their antiviral activity.

Getting 1,3-di-0-benzylglycerol.

100 g of sodium hydride (50% dispersion in mineral oil, 2.08 mol) are washed twice with 1 l of hexane, followed by drying under nitrogen atmosphere. Then, 1.5 l of dry dimethylformamide (DMF) is added and 400 ml of benzyl alcohol are added over 2 hours at such a rate that the temperature is kept below 50 ° C. Then 92.5 g (1 mol) is added dropwise in half an hour epichlorohydrin with ice cooling to keep the temperature below. The resulting solution is first stirred for 16 hours at 21 ° C, and then for 2.5 hours at 50 ° C. Then, DMF is removed by evaporation under reduced pressure. The resulting oily residue is dissolved in 2.5 liters of diethyl ether. The organic solution is washed with 2 L of water, 2 L of 2% hydrochloric acid, 2 L of 1% sodium bicarbonate and 1 L of saturated sodium chloride, dried with sodium sulfate and then concentrated; get brown oil. In the distillation get 147,8 g 1,3-di-0л

SP

00

cm

s155301

benzylglycerol (BP. 1 0-180 C / 1 mm Hg).

Preparation of 1.3 bi-0-benzyl-2-0-chloroethylglycerol.

Dry hydrogen chloride is bubbled in for 1.5 hours into a solution of 1.3 Di-0-benzylglycerol prepared earlier (15 g, 55 mmol) and paraformaldehyde (3.3 g, 110 mmol) in 175 ml of 1,2-di - JQ loretana at 0 ° C. The solution is then removed in a closed stopper flask for 21 € h at ° C. Then the solution is dried with magnesium sulphate with heating to 21 ° C, after which it is filtered and concentrated; 17.5 g of 1.3 Di-0-benzyl-2-0-chloromethyl-glycerol are obtained.

Preparation of 2-0-acetoxymethyl-1,3-di - 0 -be kzyl glycerol on .20

To a solution of 17.5 g (55 mmol) of 1.3 DI-0-benzyl-2-0-chloromethylglycerol in tOO ml of DMF, protected from moisture, at 0 ° C, add 6 g of sodium acetate. The solution is then heated to 25–21 ° C and stirred using a magnetic stirrer for 15 h. The solvent is evaporated under reduced pressure, and the oily residue is dissolved in diethyl ether (k $ k g). The ether solution is washed once with 750 ml of water, twice with 250 ml of water and once with 250 ml of a saturated solution of sodium chloride, dried with sodium sulfate and concentrated; 19 g of -35 2-0-acetoxymethyl-1,3-di-0-benzylglycerol are obtained in the form of an oil.

Getting N, 9-diacetylguanine.

20 g (0.132 mol) of guanine is mixed with 300 ml of acetic anhydride. The mixture was heated under reflux for 16 hours and then cooled. Excess anhydride is removed by evaporation under reduced pressure. The residue is recrystallized from dimethylsulfoxy-dz da; 25.6 g kg, 9-diacetylguanine are obtained.

Preparation of N-acetyl-9 (1,3 dibenzyloxy-2-propoxymethyl) -guanine.

L4,9-Diacetylguanine (15.61 g, 50

66 mmol), 2gO-acetoxymethyl-1,3-di-0- -benzylglycerol (19 g, 55 mmol) and bis (p-nitrophenyl) phosphate (0.5 g) are stirred in 150 ml of diethyl ether. The solvent is then removed by evaporation and the resulting residue is heated on an oil bath at 175 ° C for 1.5 hours under a nitrogen atmosphere. As a result of column chromatography

34

using as eluent a mixture of methanol and methylene chloride (1: 9), followed by recrystallization from ethyl acetate, 7b g of the above product was obtained, mp. .

Preparation of N-acetyl-9 (1, 3 Dioxy-2-propoxymethyl) guanine.

To a solution of K2-acetyl-9 (1,3-dibenzyloxy-2-propoxymethyl) -guanine (g, g, 9.67 mmol) in 150 ml of methanol and 0 ml of water are added 20% padladium hydroxide on carbon in the form of a suspension in 10 ml of water. Then, the resulting mixture was hydrogenated in a steam hydrogenator under hydrogen pressure of 4, 2186 kg / cm for 38 hours, and then filtered through Celite (AlCaFeOg) and concentrated to a white solid. Recrystallization from methanol and ethyl acetate gives 1, kg of the above-named product with m.p. 205-2U8 ° C.

The mother liquor is subjected to further reduction with 10% palladium on carbon (1 g) in 150 ml of methanol and 50 ml of water at a pressure of k, 2186 kg / cm2 for 7 hours. The total yield of the above product is 2.11 g.

Preparation of 3 Dioxy-2-propoximethyl) guanine.

N-Acetyl-9- (1,3 Dioxy-2-propoximethyl) guanine (721.9 mg, 2, k mmol) is stirred with 50 ml of a methanolic ammonia solution (methanol, saturated with ammonia at UeC) for 17 h at 21 ° C. The resulting solution is concentrated to a white solid and the residue is recrystallized from water or methanol; 582.3 mg 9 (1, 3 Dioxy-2-propoxymethyl) guanine with m.p. .

PRI me R. To a solution of 0.26 g of N-acetyl-9 (1, 3 Dioxy-2-propoxymethyl) -guanine and 10 mg of α-dimethylamino-pyridine in 7 ml of pyridine was added 0.76 g of adamantanecarboxylic acid chloride as a solution in 3 ml of methylene chloride. The solution is stirred with a magnetic stirrer for 18 hours at 21 ° C, after which 1 ml of water is added. After stirring for another 1 h, the solution is concentrated (in case of release of Mg-acetyl-9.1, 3-di- (1-adamantylcarboxy) -2-propoxy-syng, 1nl guanine with mp 223 226 ° C) and the residue is treated for 16 h 110 ml of methanol containing 1 ml of con5 15530

centered ammonium hydroxide. The resulting solution is concentrated and the residue is triturated with methanol to give 0.277 g (65%), 3-di- (1-ad-5 mantilcarboxy) -2-propoxymethyl guanine, m.p. 283-285 ° C.

Similarly, 9 (1.3 dibenyl-eoyloxy-2-propoxymethyl) -guanine are obtained, m.p. .ten

The antiviral effect of orally administered compounds in mice infected with HSV-2 virus (strain G), weighing 25 g, on the 21st day after infection by intraperitoneal administration, 15 is illustrated in Table. one.

table 2

Table 1

The administration is carried out daily for k days (the first time 2k hours after infection). The increase in survival compared to control mice treated with SSV alone was statistically significant in all cases (SSV is a suspending agent). Conducted acute toxicity test in mice.

The compounds of Table 5 were subcutaneously injected subcutaneously into groups of 5 Swiss-Webster (Simonsen) male mice weighing l / 25 g. 2. The test substance is administered only on the first day of the experiment, then mortality is observed for 21 days

The tests performed showed

that the compounds of the invention are low toxic and have a higher antiviral activity than the known.

invention formula

The method of obtaining 9 (1,3 diadamantylcarboxy-2-propoxymethyl) guanine of formula

ABOUT

H2N

jJLxhL

Oq

HN

w

CH2OCHCH2OR CH2OF

where K is adamantylcarbonyl, characterized in that the compound of the general formula

ABOUT

Ls

-vs

CH2OCHCH20R

HN

CH2OR

where R has the indicated value;

Y is acetyl,

is reacted with an alcoholic base solution.

Claims (1)

Claim The method of obtaining 9 ^_ (1,3 ^_ diadamantylcarboxy-2-propoxymethyl) guanine of the formula h ₂ n N-CH ₂ OCHCH ₂ OR ch ₂ or where is the unity of the general formula K is adamantylcarbonyl, characterized in that co0 'Ά ^ν > yhn ^/ ^ N ^ ^x ^ <- ch20CHCH ₂ 0R ch ₂ or where R has the indicated meaning; Y - acetyl group, is subjected to interaction with an alcoholic solution of the base.