Mixed anhydride of dichloroacetic and aminoacetic acid and production method thereof

FIELD: chemistry.

SUBSTANCE: anhydride is a physiologically active substance and can be used, for example, in chemotherapy as a low-toxic agent for inhibiting growth of carcinoma 755 (breast cancer). The object of the present invention is synthesis of a novel mixed anhydride based on dichloroacetic and aminoacetic acid which, for instance, enables to inhibit growth of carcinoma 755 (breast cancer) in monotherapy. The given task is solved through synthesis of a novel mixed anhydride based on dichloroacetic acid and aminoacetic acid of formula 1, which can be used in medical practice as an anti-tumour agent which enables, for example, to inhibit growth of carcinoma 755. The other objective of the invention is designing a method of producing the mixed anhydride based on dichloroacetic acid and aminoacetic acid. This task is solved using a method which involves successive reaction of aminoacetic acid with an alkali metal hydroxide in an aqueous medium followed by treatment of the reaction mass with dichloroacetyl chloride in a chloroalkane solution, acidation of the reaction medium with aqueous hydrochloric acid solution and extraction of the end product using existing techniques. The disclosed compound can be used in medical practice as an anti-tumour compound.

EFFECT: use of said compound in oncological practice inhibits growth of carcinoma.

2 cl, 1 ex

 

The invention relates to anhydrides of carboxylic acids and to a method of obtaining them. Specifically, the invention relates to a mixed anhydride dichloracetic and aminouksusnoy acids of the formula:

and how to obtain it. This connection can be used in medicine as a promising antitumor agent, for example, to inhibit the growth of carcinoma 755 (breast cancer).

Currently in oncological practice during chemotherapy cancer patients are widely used cisplatin and carboplatin. However, cisplatin, and carboplatin have high toxicity (LD50for cisplatin and carboplatin respectively 12.5 and 36 mg/kg). In addition, the Lewis lung carcinoma and carcinoma 755 resistant to these drugs. Also known complexes based on substituted amides of nicotinic and isonicotinic acids that can inhibit the process of metastasis in experimental Lewis lung carcinoma and melanoma b-16 in 96-98% [Bshadow, Mahadev, Geason, Npomogaeva, Lampolla. Pat the Russian Federation No. 2241713 and 2245328. Bestidores, Mahadev, Geason, Sgiliau, Smolderin, Npomogaeva, Teachingua, Spohn. Chemical therapy journal, 2009, Vol.13, No. 3, 6-12]. Unfortunately, these complexes do not affect primary tumor, and near the point mainly on the calcium-magnesium-dependent ATP-ABC sarcoplasmatic reticulum and inhibit the transport of calcium ions across biological membranes. This breaks the normal ratio of calcium ions on the outside and the intracellular surface of the membrane, with subsequent disruption of platelet aggregation and binding of metastatic cells, which contributes to preventing the adhesion of the latter to the walls of blood vessels. In other words, complex compounds on the basis of tetravalent platinum and substituted amides of nicotinic and isonicotinic acids do not act on the enzymes that are responsible for the growth of the primary tumor [Luvtheheaven, Npomogaeva, Genmodel, Avetaranots and Bshadow. Biomedical chemistry, 2006, T, Issue 1, 52-59].

The present invention is the development of a previously unknown mixed anhydride based aminouksusnoy acid (glycine) and dichloracetic acid, which has satisfactory toxicity. This anhydride allows you to inhibit the growth of carcinoma 755.

Another object of the invention is to develop a method of producing a mixed anhydride dichloracetic and aminouksusnoy acids.

This object is achieved by the method lies in the fact that aminouksusnoy acid is subjected successively to the influence of the alkali metal hydroxide in the aqueous medium, followed by treatment with acid chloride dichloracetic acid in solution chloroalkane, acidification of the reaction medium in the s ' solution of hydrochloric acid and isolation of the target product by known methods.

The invention is characterized by the following example.

Example. To a suspension of 7.5 g of glycine in 10 ml of water with stirring and the temperature of 10-15°C was added a solution of 4 g of sodium hydroxide in 4 ml of water. The resulting solution was cooled to 2-5°C and at this temperature was added a solution of 10.1 g of acid chloride of dichloracetic acid in 15 ml of dichloroethane or methylene chloride. After mixing of the reagents were stirred for another 10 min, and then added a few drops of concentrated hydrochloric acid. Cooled the reaction mixture to 0°C and filtered colorless precipitate. The substance is pressed on a vacuum filter and dried in air. Obtained 10.2 g (54.8%) of the mixed anhydride and dichloracetic aminouksusnoy acids TPL 130-131°C. Found (%): 25.6, H, 2.57; N, 7.42; Cl 38.06; C4H5N1O3Cl2. Calculated (%): at 25.81, H 2.69, N 7.53, Cl 38.17. IR spectrum (ν, cm-1): 740, 864, 880, 916, 1088, 1224, 1232, 1032, 1276, 1308, 1384, 1540, 1620, 2080, 2748, 2840, 3116, 3280, 650, 700, 750, 1470, 1484, 2510 (C-Cl); 668, 690, 708, 1276, 3264 (N-H2); 1624 (C=O); 1380 (CH, CH2).

Thus, the proposed method allows to achieve the project objectives and to provide a mixed anhydride dichloracetic and aminouksusnoy acids of formula 1.

Tests on General toxicity and antitumor activity was conducted in the laboratory of experimental cancer chemotherapy IPCP RAS in mice BDF1. It is shown that the claimed connected the e has the General toxicity of 380 mg/kg These data allow us to classify the claimed substance classified as toxic compounds. The use of this compound as monotherapy experimental carcinoma 755 allows you to slow the growth of the primary tumor by 51%.

1. Mixed anhydride dichloracetic and aminouksusnoy acids of formula 1

2. A method of obtaining a mixed anhydride dichloracetic and aminouksusnoy acids by affecting aminouksusnoy acid successively with alkali metal hydroxide in the aqueous medium, followed by treatment of the reaction mixture with acid chloride dichloracetic acid in solution chloroalkane, acidification of the reaction medium with an aqueous solution of hydrochloric acid and isolation of the target product known techniques.



 

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3 cl, 2 ex

FIELD: chemistry.

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FIELD: chemistry.

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25 cl, 3 tbl, 12 ex

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5 cl, 17 ex, 6 dwg

FIELD: chemistry.

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1 cl, 5 ex

FIELD: organic chemistry, chemical technology, amino acids.

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5 ex

FIELD: organic chemistry, medicine, oncology.

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27 cl, 13 dwg, 5 ex

FIELD: analytical methods.

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2 tbl, 9 ex

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8 ex

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1 tbl, 11 ex

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26 cl, 17 ex, 1 tbl

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25 cl, 3 tbl, 12 ex

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22
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