5-oxymethyl-5-[3-(2-chloroethyl)-3-nitrosourea]-2 - cyclohexyl-1,3-dioxane with antitumor activity

 

(57) Abstract:

The invention relates to medicine, namely to biologically active compounds with antitumor activity against tumors in rats and mice. Describes a new connection 5-oxymethyl-5-[3-(2-chloroethyl)-3-nitrosourea] -2-cyclohexyl-1,3-dioxane of the formula I with antitumor activity. Compound I is highly active cytotoxic agent with a pronounced therapeutic effect on all 3 strains investigated transplantable tumors. Comparison of antitumor activity of the claimed compounds and TELEMETRY in mice with leukemia P-388 showed an advantage of the claimed compounds. 3 table.

The invention relates to medicine, namely to the field of biologically active compounds with antitumor activity against tumors in rats and mice.

Object of the invention is the creation of new, more effective anti-cancer agents. The task is achieved by the synthesis of the compounds of formula

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This connection can be used as anticancer drugs. The proposed compound synthesized is - -cyclohexyl-3-(2-chloroethyl)-3-nitrosoanatabine used in medical practice and synthesized in the United States. The disadvantage of the prototype is its low solubility in water, which prevents the establishment of an injectable dosage form. (Perevozchikova N. I. Chemotherapy of neoplastic diseases. M , 2000, 384 S. ).

The synthesis of this compound is carried out as follows.

The interaction of 2-cyclohexyl-5-amino-1,3-dioxane with pentachlorphenol ether N-nitroso-N-(2-chloroethyl)carbamino acid in anhydrous dimethylformamide obtained 5-[3-(2-chloroethyl)-3-nitrosourea] -2-cyclohexyl-1,3-dioxane.

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The proposed connection is a low-melting substance is light yellow in color. This connection proved elemental analysis, individuality TLC, the structure of the IR and NMR spectra.

Receipt of the proposed compound and its biological properties are illustrated by the following examples.

The original 2-cyclohexyl-5-amino-oxymethyl-1,3-dioxane obtained by the method described in the work: Kris B. O. , Schoenberg N. N. , Ivin A. B. VI. Compounds with electrophilic reactivity. Synthesis and properties of new 2,2-dimethyl-5-[2,4-bis(1-aziridinyl)-1,3,5-triazine-6-yl] amino-1,3-dioxaborinane ether N-nitroso-N-(2-chloro-ethyl) - carbamino acid synthesized by the method, described in: J. Martinez, J. Oiry, Imbach J., F. Winternitz. Activated N-Nitrosocarbamates for Regioselective Synthesis of N-Nitrosoureas. - J. Med. Chem. 1982, v. 25, p. 178-182.

Example 1. Synthesis of 5-oxymethyl-5-[3-(2-chloroethyl)-3-nitrosourea] -2-cyclohexyl-1,3-dioxane.

A solution of 0.01 mole of 2-cyclohexyl-5-amino-5-oxymethyl-1,3-dioxane and 0.01 mole pentachlorphenol ether N-nitroso-N-(2-chloroethyl)carbamino acid in 10 ml of anhydrous DMF was stirred 4 h at 0-5oC. Then the reaction mass was poured into 50 ml ice water, the precipitated yellow precipitate was filtered, washed with water (310 ml), the residue was purified by presidenial from acetone five times by volume the amount of hexane. The output of 2.23 g (75%). So pl. 66-70oC (with decomp. ), TLC on plates of Silufol UV-254, Rf= 062 (eluent acetone: hexane 1: 2).

Found, %: CL 11.87 Per. Calculated, %: CL 11,70.

PMR spectrum (in CDCl3), M. D.: 1.3 to 1.85 m (10H, 2-C6H10), 3,98 D. (2H, 4,6-CH2-Equatorial), 4,10 D. (2H, 4,6-CH2-axial), 3,45 t (2N, l2), 4,11 t (2H, CH2N), 4,84 (2H, CH2IT), with a 7.62 (1H, NH).

NMR13(In CDCl3), M. D.: 38,5 (l2), AND 39.7 (CH2N), 152,8 (C= O), 62,4 (4WITH6), 55,1 (5), 79,8, 62,9 (CH2IT), 98,8 (5), 22,2, 25,2, 29,4, 34,6 (2-WITH6H10).

The IR spectrum suspect proposed connection.

Acute toxicity of the compounds was studied in mice SHR. A portion of the substance was dissolved in alcohol, the resulting alcoholic solution is diluted with isotonic sodium chloride solution and was injected into mice intraperitoneally. LD50in mice with a single intraperitoneal injection was 49 mg/kg Maximum tolerated dose for a single intraperitoneal injection was 20 mg/kg

Example 3. The impact of the proposed connection to the leukemia P-388.

Leukemia P-388 transplanted intraperitoneally to mice TWO2the introduction of the 106tumor cells. After a single intraperitoneal administration proposed connection at a dose of 20 mg/kg on day 3 after inoculation the lifespan of mice increased by 451% compared to control, while under the influence of CCNU entered in the maximum tolerated dose of 40 mg/kg, the lifespan of mice increased by 298% (table. 1).

Example 4. The impact of the proposed connection on the growth of squamous cell carcinoma, Lewis lung.

The Lewis lung carcinoma was inoculated subcutaneously to mice WITH57L the introduction of 0.2 ml of 10% suspension of tumor cells in physiological solution. The proposed connection was introduced intraperitoneally in a dose of 20 mg/kg / day 3

Example 5. The impact of the proposed connection on the growth of carcinosarcoma Walker in rats.

Carcinosarcoma Walker was inoculated rats subcutaneously introduction to 0.4 ml of 10% suspension of minced tumor tissue in physiological solution. The proposed connection was introduced once on day 6 after inoculation, at a dose of 20 mg/kg intraperitoneally. The inhibition of tumor growth in different periods after the introduction of the proposed connection was 92-98% (table. 3).

Thus, the proposed connection is highly active cytotoxic agent with a pronounced therapeutic effect on all 3 strains investigated transplantable tumors. Comparison of antitumor activity of the proposed connection and CCNU in mice with leukemia P-388 showed the advantage of the proposed connection.

5-Oxymethyl-5-[3-(2-chloroethyl-3-nitrosourea] -2-cyclohexyl-1,3-dioxane of the formula I

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with antitumor activity.

 

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