CS264454B1 - 2'-Deoxy-5,6-dihydro-5-azacytidine; - Google Patents

Abstract

The solution relates to a new 2'-deoxy-5,,6- -dihydro-5-azacytidine and a method for its production. The substance can be used in the pharmaceutical industry.

Description

The invention relates

2'-deoxy-5,6-dihydro-5-azacytidine of formula

and its addition salts with non-toxic inorganic or organic acids. The present invention also provides a process for the preparation of 2'-deoxy-5,6-dihydro-5-azacytidine of formula I which is a novel analog of 2'-deoxycytidine and its addition salts with said acids.

The 2'-deoxy-5,6-dihydro-5-azacytidine of formula I is a novel analog of 2'-deoxyoytidine from which it can be formally derived by substituting the CH group at the 5-position of the pyrimidine nucleus with an nitrogen atom and subsequently adding hydrogen to the double bond in the position 5,6 of the triazine ring. The 2-deoxy-5,6-dihydro-5-azacytidine of the formula I belongs to the group of 5,6-dihydroderivatives of 2'-deoxy-5-azapyrimidine nucleosides. The most prominent of this group is the nucleoside antibiotic 5,6-dihydro-5-azathymidine (DHAdT), which was isolated from culture filtrates of S. platensis var. clarensis ^ DeBoer, Bannister: U.S. Pat. No. 3,907,643 (1975)) and shows activity against DNA viruses and gram-negative bacteria. The effect of DHAdT is reversed by thymidine, 2'-deoxyuridine and 2'-deoxycytidine. For this reason, 2'-deoxy-5,6-dihydro-5-azaoytidine (I) can also be expected to have antiviral or antibacterial activity. pH range and is also substantially better soluble in water.

The process for the preparation of 2'-deoxy-5,6-dihydro-5-azacytidine of formula I is characterized in that the free or blocked 2'-deoxy-5-azacytidine of formula II

(II),

ROCH,

Where R is hydrogen or acyl, it is reduced by zinc powder in anhydrous carboxylic acid having 1 to 4 carbon atoms, and when a compound of formula II wherein R is acyl is used, 2'-deoxy-3 ', 5'-di-O is formed -acyl-5,6-dihydro-5-azacytidine of formula III

Where R is acyl, or an organic or inorganic acid addition salt thereof, is subjected to an alcoholic reaction and the resulting 2'-deoxy-5,6-dihydro-5-azacytidine of formula I is converted, if necessary, to a non-toxic inorganic or organic acid.

The reduction proceeds very well already at room temperature using five to ten times the theoretical amount of zinc powder. Commercially available acetic acid has proved to be a carboxylic acid. The reduction of the less stable blocked 2'-deoxy-5-azacytidine is desirably carried out in a mixture of carboxylic acid and 2,2-dimethoxypropane, which guarantees the anhydrous nature of the reaction medium. The isolation of the free dihydroderivative of formula (I) is preferably carried out by an ion exchange technique. The blocked nucleoside of formula III is preferably isolated by shaking it into chloroform and converting it into an organic or inorganic acid addition salt. The alcoholysis of the 2'-deoxy-3,5'-tri-O-acyl-5,6-dihydro-5-azacytidine of formula III, or its addition salt with an inorganic or organic acid, is carried out with a solution of an alkali metal alkoxide in an 4 carbon atoms, preferably sodium methoxide in methanol.

The invention is further illustrated by the following non-limiting examples.

Example 1

Preparation of 2'-deoxy-5,6-dihydro-3 ', 5'-di-O-p-toluoyl-5-azacytidine acetate

A mixture of acetic acid (5 mL) and 2,2-dimethoxypropane (2 mL) was allowed to stand at room temperature in a sealed flask for 24 hours. Then zinc powder (0.65 g) and 2'-deoxy-3 ', 5'-di-O-p-toluoyl-5-azacytidine (0.465 g; 1 mmol) were added sequentially. The mixture was vigorously magnetically stirred at room temperature for 2.5 hours and the insoluble material was filtered off with suction through a frit. The frit material was washed sequentially with acetic acid, methanol and richly chloroform-methanol (9: 1). The combined filtrates were shaken with water and 5% sodium bicarbonate solution. After drying (MgSO4) and addition of acetic acid (0.1 mL), the organic layer was evaporated in vacuo. Crystallization of the residue from methanol-petroleum ether yielded a total of 0.401 g (76%) of 2'-deoxy-5,6-dihydro-3 ', 5'-di-O-p-toluoyl-5-azacytidine acetate m.p. M.p. 142-146 ° C (dec.).

Example 2

Preparation of 2'-deoxy-5,6-dihydro-5-azacytidine

A mixture of 2'-deoxy-5,6-3-dihydro-3 ', 5'-di-O-p-toluoyl-5-azacytidine acetate (0.527 g; 1 mmol), methanol (6 mL) and methanolic 1 M-NaOCH ₃ (2 mL) was stirred magnetically at room temperature for 24 hours. The mixture was acidified with acetic acid (0.2 mL) and evaporated in vacuo. The residue was washed with petroleum ether and dissolved in water. The crude product solution was applied to a strongly acidic cation exchange column in NH4 ⁺ form (20 mL) and the column was washed with water (300 mL). The product was eluted from the column with 1 H-NH 4 OH (150 mL) and the eluate was evaporated in vacuo. Crystallization of the residue from methanol gave a total of 0.193 g (84 2'-deody-5,6-dihydro-5-azacytidine, mp 195-196 ° C (dec.)) After mother liquor treatment.

Example 3

A mixture of 2'-deoxy-5-azacytidine (0.338 g; 1 mmol), acetic acid (5 mL) and zinc powder (0.65 g) was magnetically stirred at room temperature for 24 hours. The insoluble material is filtered off with suction and washed successively with acetic acid and rich methanol. The combined filtrates were evaporated in vacuo, the residue was dissolved in water, and the solution was applied to a strongly acidic cation exchange column in NH ₄ ⁺ form (20 mL) and the column was washed with water (300 mL). The product was washed with 1 N-NH 4 OH (150 mL) and the eluate evaporated in vacuo. Crystallization of the residue from methanol gave a total of 0.189 g (82%) of 2'-deoxy-5,6-dihydro-5-azacytidine, m.p. 195-196 ° C (decomposition) after mother liquor treatment.

Example 4

Preparation of 2'-deoxyl-5,6-dihydro-5-azacytidine acetate

A solution of 2'-deoxy-5,6-dihydro-5-azacytidine (0.230 g; 1 mmol) in methanol was neutralized with acetic acid (0.06 g, 1 mmol). The mixture was evaporated in vacuo and the residue crystallized from methanol. After treatment of the mother liquors, a total of 0.261 g (90%) of 2'-deoxy-5,6-dihydro-5-azacytidine acetate was obtained; m.p. Mp 152-158 ° C (dec.).

Claims (5)

OBJECT OF THE INVENTION A 2'-deoxy-5,6-dihydro-5-azacytidine of formula X NHq (I) BOY, HO and its addition salts with non-toxic inorganic or organic acids. 2. A process for the preparation of 2'-deoxy-5,6-dihydro-5-azacytidine according to claim 1 of formula I, and its addition salts with non-toxic inorganic or organic acids, characterized in that the free or blocked 2'-deoxy-5- azacytidine of formula II wherein R is hydrogen or aoyl, is reduced by zinc powder in an anhydrous carboxylic acid having 1 to 4 carbon atoms, and when a compound of formula II wherein R is acyl is used, 2'-deoxy-5,6- dihydro-3 ', 5'-di-o-acyl-5-azacytidine of the general formula III wherein R is acyl, or an inorganic or organic acid addition salt thereof, is subjected to alcoholysis and the obtained 2'-deoxy-5,6-dihydro- If desired, the 5-azacytidine of formula I is converted into a non-toxic inorganic or organic acid addition salt. 3. A process according to claim 2 wherein the reduction of the compound of formula (II) is carried out at about five to ten times the theoretical amount of zinc powder in anhydrous acetic acid at room temperature. 4. The process of claim 2 wherein the reduction of a compound of formula II wherein R is acyl is carried out in the presence of an excess of 2,2-dimethoxypropane. 5. Process according to claim 2, characterized in that the alcoholysis of the compound of the formula (III) or its addition salt with an inorganic or organic acid is carried out with a solution of an alkali metal alkoxide in C1 -C4 alkanol, preferably sodium methoxide in methanol.