2-/3-(2-chloroethyl)-3-nitrosourea/-1,3-propandiol with antitumor activity


(57) Abstract:

Usage: in medicine, as the product exhibits antitumor activity. The inventive 2-(3-2-chloroethyl)-3-nitroso-ureido formula: lCH2CH2(N=O) N (O) CNHCH (CH2OH)2. Reagent 1: 2-charaterization. Reagent 2: 2-amino-1,3-propandiol. The condition of the reaction: reagent 1 is treated with reagent 2 to obtain 2-(3-(2-chloroethyl)ureido)-1,3-propane diol, which nitrosonium in 50% acetic acid. 7 table.

The invention relates to the field of biological active compounds, namely 2-[3-(2-chloroethyl)-3-nitrosourea]-1,3-propane diol, having antitumor activity against tumors in mice and rats.

This connection can be used as anticancer drugs. The claimed compound was synthesized in the Institute of Oncology and registered in the research Institute for BIHS number 10181391 19. 02. 91.

The prototype of the proposed connection is a drug CHNM - 1-cyclohexyl-3-(2-chloroethyl)-3-nitrosoanatabine used in medical practice and synthesized by American researchers (N. M. Emanuel, D. B. Corman and other Nitrosoaniline a new class of anticancer preparepage funds. The goal has been achieved by the synthesis of the compounds of formula:

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with high antitumor effect.

The synthesis of this compound is carried out according to the following scheme:

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The interaction of 2-chlorotriazine with 2-amino-1,3-propane diol in acetonitrile get 2-[3-(2-chloroethyl)ureido]-1,3-propandiol, which nitrosonium in 50% acetic acid with sodium nitrite, receiving 2-[3-(2-chloroethyl)-3-nitrosourea]-1,3-propandiol.

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

Obtain the claimed compound and its biological properties are illustrated by the following examples.

The original 2-amino-1,3-propandiol 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-dioxanes and 2-[2,4-bis(1-aziridinyl)-1,3,5-triazine-6= yl] amino-1,3=propandiol. Zhur.org.chem.. 1985, T. 21, vol. 2. S. 419 427.

Example 1. Synthesis of 2-[3-(2-chloroethyl)ureido]-1,3-propane diol.

To mix the races of the Mino-1,3-propane diol in 5 ml of acetonitrile. Stirring is continued at 5oC until the disappearance of the amine in the reaction mixture (control with indicator yellow diamond). Then the acetonitrile is distilled off in vacuum (at 20oC, 30-40 mm RT. Art. ). Precipitated colorless residue is distilled presidenial mixture of acetone five times by volume the amount of hexane. The output of 3.56 g (92%). So pl. 107 108oC. TLC on plates of Silufol UV-254 Rf=0,06.

Found, Cl 17,95. Calculated Cl 18,03.

PMR spectrum (in DMSO-D6), M. D. 3,31 t (2N, lCH2); 3,36 kV (4H, 1,3-CH2O); 3,52 kV (2H, CH2N); 5,98 d (1H, NH); 6,39 t (1H, NH).

NMR13C (in DMSO-D6): 41,57 (ClCH2); 44,84 (CH2N); 52,96(C2); 60,55 (C1C3); 157,92 (C=O).

The IR spectrum of the suspension in vaseline oil, cm-1: 3250-3350 (NH, OH), 1634 (C=O), 1587 (NH), 727 (C-Cl).

Example 2. Synthesis of 2-[3-(2-chloroethyl)-3-nitrosourea]-1,3-propane diol.

To a stirred solution of 1 g of 2-[3-(2-chloroethyl)ureido)-1,3-propane diol in 10 ml of 50% aqueous acetic acid at -5oC portions over 1 h was added 0.75 g of sodium nitrite. After the addition of all NaNO2the reaction mixture was stirred for another 2 h at 0-(-5)oC. Then the solvent was distilled in vacuum (1-2 mm RT. Art. residual pressure). To the residue pribadi CH3COOH in the filtrate was neutralized by addition of Na2CO3deposited precipitate was filtered, washed with 5 ml of ethyl acetate. The filtrate was dried over magnesium sulfate. The solvent was distilled in a water jet vacuum pump (30-40 mm RT. Art. residual pressure). Got yellow precipitate. Yield 1.10 g (85%). TLC (eluent acetone-hexane 1 2) Rf=0,10.

Found, Cl: 15,68. Calculated CL: 15,71.

Range PMR (l3d M. D. 3,50 t (2N, lCH2); 3,52 c (2H, OH); 3.70 m (1H, CH); 3,89 kV (4H, CH2O); 4,18 t (2H, CH2N); a 7.62 (1H, NH).

An NMR spectrum13C (l3d M. D. 39,44 (ClCH2), 40,22 (CH2N), 54,73 (C2), 61,11 (C1C3), 153,0 (C=O).

IR spectrum (suspension in vaseline oil), cm-1: 3200-3400 (NH, OH), 1700 (C=O), 1553 (NH), 1506 (N=O), 741 (C-Cl).

Example 3. The study of the toxicity of the claimed compounds.

Acute toxicity of the compounds was studied in mice SHR. A portion of the drug was dissolved in alcohol and the resulting solution was diluted with physiological saline and were injected into mice intraperitoneally. LD50was 34 mg/kg Maximum tolerated dose for a single intraperitoneal injection was 20 mg/kg

Example 4. The effect of the claimed compounds for leukemia P-388.

what do intraperitoneally a single dose of 15 mg/kg on day 3 after inoculation. All 4 mice received the claimed compound lived longer than 60 days. Control mice were killed via 9,50,2 days after inoculation. The claimed connection according to the leukemia P-388 surpassed CGNM. Intraperitoneal injection CGNM in the maximum tolerated dose of 50 mg/kg over 60 days lived only 1 mouse 4. The average life expectancy of the remaining mice was 49,29,2 day.

Example 5. The effect of the inventive compounds on the growth of sarcoma 180 in mice SHR.

Sarcoma 180 was perepevalas mice subcutaneously. The drug was administered once intraperitoneally at the maximum tolerated dose of 20 mg/kg 3 days after inoculation. 12 days after inoculation (i.e., 10 days after injection of the drug) inhibition of tumor growth compared with control was 95% the same level of inhibition of tumor growth was observed at day 17 (table. 1).

Example 6. The effect of the inventive compounds on the growth of carcinoma of the lung Lewis.

The Lewis lung carcinoma was inoculated intramuscularly to mice C57Bl. The next day after inoculation the mice were intraperitoneally introduced the claimed preparation in the dose of 20 mg/kg. Another group of mice was introduced CGNM dose of mg/kg On day 10 after inoculation in mice, which was introduced Zaya is respectively 100% and 78% on day 14, respectively, 96% and 51% and 17 days respectively 92% and 19% (table. 2).

In the second series of experiments the claimed connection and CGNM was injected into mice C57Bl with carcinoma Lewis on day 5 after inoculation in doses of 20 mg/kg and 50 mg/kg, respectively. On day 10 after inoculation the inhibition of tumor growth relative to control mice, which was introduced by the claimed compound was 92% and in mice that received TGNM, 44% on day 12 the inhibition of tumor growth was equal respectively 98% and 25% on day 14, respectively, 91% and 35% and on day 18, respectively, 92% and 44% (table. 3).

Thus, in mice with carcinoma Lewis antitumor activity of the claimed compounds is much superior activity CGNM.

Example 7. The impact of the proposed drug and CGNM on the growth of melanoma b-16 in mice WITH57Bl.

Melanoma b-16 was inoculated intramuscularly 50 mice (males) lines WITH57Bl. The claimed preparation and CGNM were injected intraperitoneally simultaneously on the fifth day after inoculation. On the 10th day after inoculation in mice that received the drug at a dose of 15 mg/kg, tumor growth was inhibited by 97% and in mice that received CGNM dose of 50 mg/kg 85% to 14 days at 95% and 66% to 16 days at 92% and 76%, respectively (table 4).

Example 8. The effect of the claimed compounds and CGNM implemented the connection was introduced at a dose of 20 mg/kg, and CGNM dose of 50 mg/kg once intraperitoneally 24 hours after transplantation of the tumor. On the 8th day after inoculation, none of the mice that received the claimed connection, ascitic fluid in the abdominal cavity have been identified. In the control average volume of ascites was 5,30,6 ml, and in the group of mice that received CGNM 0,230,14 ml (table. 5).

Example 9.

There is a correlation between the decrease in concentration OVER in tumor cells and therapeutic effect of cytostatic agents that damage DNA. The rate of recovery of the structure of DNA is also limited by the concentration of the ABOVE. In this regard, we have studied the influence of the proposed drug in comparison with CGNM on the intensity of use of precursors (nicotinic acid and nicotinamide) for the biosynthesis of NAD in tumor cells. The claimed preparation and CHNM at a dose of 20 mg/kg and 50 mg/kg, respectively, were injected intraperitoneally in 5 min after administration of nicotinic acid (pre-neutralized to a pH of 7.3) or nicotinamide at a dose of 100 mg/kg Animals were deceptional through 0, 1, 2, 3, 4, 5, 6, 7, 24 hours after drug injection. It is established that the claimed compound inhibits the use of neoplastic cells as nicoti is their nicotinamide and does not affect the use of nicotinic acid for the biosynthesis of NAD (PL. 6).

On this basis, we can assume that claimed the drug causes significant DNA damage in tumor tissue and, therefore, the antitumor effect of the claimed compounds would be more irreversible than with CHNM.

Thus, the claimed drug is highly effective cytotoxic agent with a broad spectrum of antitumor activity. In comparative experiments established that the claimed drug significantly outperforms its antitumor activity CGNM in mice with leukemia P-388, melanoma b-16, Lewis lung carcinoma and tumor Ehrlich. (Summary table). TTT

2-[3-(2-Chloroethyl-3-nitrosourea]-1,3-propandiol formula

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with antitumor activity.


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