SU529601A1 - 4- (bis (2-chloroethyl) aminr) phenylacetic acid trioxytartin-butylamide derivatives with antitumor activity and method for their production - Google Patents

Description

medium at temperatures from -5 to -10 ° C. Mono. the ligate and triaiyl derivatives of tr. hydroxy-greg-butylamide (2-chloroethyl) amino-phenylacetic acid are obtained by acylation of a compound of the indicated offenses of the formula, where R, RI and R2 are hydrogen, with carboxylic acid chlorides (anhydrides) in an alkaline solvent, precursor of benzene, or without a solvent.

Cyclic derivatives of trioxygregutyl1M, ida (2-chloroethyl) amine of phenylacetic acid are obtained by treating compounds of the indicated general formula, where R, R2 and R2 are hydrogen or acyl, ketones, aldepides or their acetals in the presence of acid catalysts.

The synthesized compounds: acrylic and cyclic O, O-alkyl and trialkigreg-butylamide (2-chloroethyl) amino-phenylacetic acid, are hydroxycrystalline, which are soluble in tetrahydrofuran, chloroform, moderately soluble in ethylene dichloride. hexane, ether and water.

The composition and structure of the obtained compounds was proved by elemental analysis (C, H, C1, N), determination of chlorine equivalent by the Folgard method after boiling (25-30 minutes} weight of the substance in water-organic (4: 1) 1 and. caustic soda solution. 1IKir UV spectrum.m.

In the IR spectra of suspensions of substances in vaseline oil (spectrophotometer LR-10), absorption bands characteristic of the OH and NH groups (3200-3390 el / -) were found for the corresponding compounds. C-OH and C-O-C (1030-1230 C.1G-), C O complex estefirou (1750), bands of the aromatic ring (in the 1530 area), as well as bands "amide-1 (1645-1675) and “Amide-H (1560-1630 ate / -).

The UV spectra of the proposed compounds in alcohol (spectrophotometer SF-8) are characterized by the presence of two absorption spectra; 261-262 nl; (e 2.1., 4 10) and 300 nm (shoulder) (e 2-W).

At present, it is generally accepted to divide the molecule of the anticancer alkylating agent into cytotoxic groups and their carrier. At the expense of the former, chemical interaction with biopolymer1I cells is carried out, and the carrier facilitates the transport of drugs through the cell membrane. Recently, these carrier properties have become associated with hydrophobic-hydrophilic and balance, which is directly dependent on the structure of the drug molecule. While the hydrophobic sites of the latter promote binding to the lipid fragments of the cell (due to the so-called hydrophobic interactions), the polar groups give the whole molecule a greater or lesser degree of endrophilicity. Lipophilicity facilitates the drug to overcome cell membranes even in the absence of active transport. Hydrophilicity makes this process difficult, but at the same time it ensures the further advancement of drugs in the cytoplasm and inside the core to the point of application. Thus, the optimal combination of the Ob properties indicated above not only favors the transport of the drug, it can also have a decisive influence on the selectivity of its action, since worse organized cell membranes and tumor cells can be overcome more easily by molecules of an alien compound unusual for the body. The conducted studies show that the number of drugs that have beneficial hydrophobic-hydrophilic balais for realization of the antitumor effect can be attributed to the proposed amide derivatives of (2-chloroethyl) aminophenylacetic acid with an unsubstituted and substituted trioxy-gret-bupply group.

Of the proposed substances, trioxy-gret-butylamide (2-chloroethyl) amino-phenylacetic acid (R, RI, and R2-H) and its cyclic derivatives have the best balance of hydrophilic and hydrophobic properties.

R-hydrogen, Ri + (CH3) 2 and CJCHz) ,,,

where / 2 is 4 or 5. In the molecules of these compounds, along with a hydrophobic aromatic fragment (residue 4-i5wc- (2-chloroethyl) amiophenylacetic acid) are

sharply expressed. Hydrophilic sites - unsubstituted trioxy-butyl group and 1,3-dihydric cycles. The latter contain, along with non-polar C-C-p and p-: C-O-bonds, which also give the Union a certain degree of hydrophilicity.

All acetyl derivatives of the compounds of the indicated general formula and, consequently, relatively less EO, have antitumor activity.

(see tab. 1).

The test results indicate that all the synthesized compounds have a high biological activity, show the ability to completely or almost

completely suppress the development of the Ehrlich asymmetric tumor and inhibit the growth of a number of dense transplantable tumors in mice and rats (see Table 1). Lofetzal, for example, inhibits the growth of Ehrlich ascites tumor by only 60.9%.

Of particular interest was the effect of the proposed combination of pa. CC mice .-, 7W with xigenia for this line with an NRK tumor (squamous cell carcinoma of the skin). This tumor is extremely low.

sensitivity to known anticancer drugs, therefore obtaining a highly reliable and well-reproducible effect on such a model (see Table 1) significantly increases the value of these compounds

as antitumor agents and the biological results of some of the proposed compounds

Table 1

Squamous skin cancer in mice CCsrW (syngenic tumor). all other braking indicators are reliable. One of the main features of the compounds obtained is their low toxic effect and high therapeutic index (LD50 / MTD 2.5-10 for rats and 10-21 for mice). In contrast to most of the known, the preference of some of the proposed compounds for the content of leukocytes in the peripheral

blood of mice | And rats with tumors The difference with the original is not significant. The proposed compounds can be administered to the body in two ways: parenterally (as suspensions in saline) and orally. When administered orally, the same pattern is observed as with intraperitoneal: adequate inhibition of tumor growth and the absence of a damaging effect on blood formation. For example, a compound of the indicated general formula, where R is hydro. At a dose of 80. at

Table 2, including n from chlorambucil - 4-b "c- (2-chloroethyl) aminophenyl butyric acid, these compounds do not cause leukopenia in animals (see table 2) and do not affect lymphocytic tissue. intraperitoneal and oral administration inhibits the growth of sarcoma 37.to 69%. In both cases, the drug does not reduce the number of leukocytes and does not act on the lymphatic tissue. Thus, it is extremely important that in addition to the use of these compounds in the clinic, they can also be used: on an outpatient basis. Example 1. Trioxy-treg-butylamide (2-chloroethyl) amino-phenylacetic acid. To a solution of 0.138 g mol of trioxygregutylamine in 47 ml of water and 23 ml of acetone at -10 ° C and with vigorous stirring, a solution of 0.046 g of hydrochloride (2-chloroethyl) amino-phenylacetic acid hydrochloride in 85 ml of acetone is added in 30 minutes. The mixture is stirred for 15 minutes at −10 ° C. and poured into 100 ml of ice water. The precipitated precipitate is filtered, washed with water, then with hexal with the addition of a small amount of ethanol. From the filtrate after acetone distillation in vacuum, an additional amount of matter is isolated. Both portions of the crude product are combined and dried in a vacuum desiccator over potassium hydroxide. After recrystallization from dichloroethane and ethyl acetate with coal, 8.7 g (50% of the theoretical) of pure weight are obtained, mp. 143-144 ° C. The compound is soluble in tetrahydrofuran, moderately paiCTBOpinMO in chloroform, alcohols, crumbled in water. Found,%: C 51.10; H 6.29; C1 18.73; N 7.35. Ci6H24Cl2N204. Calculated,%: C 50.62; H 6.38; C1 18.75; N 7.38. Chlorine equivalent: found 189.7; calculated 189.6. Example 2. Triacetoxy-treg-butylamide 4- (2-chloroethyl) amino-phenylacetic acid. 0.001 g mol of trioxy-treg-butylamide (2-chloroethyl) amino-phenylacetic acid is boiled in 5 ml of acetyl chloride for 2 hours. The mixture is then evaporated to dryness in vacuo. Traces of acetyl chloride are removed by distillation in vacuo, successively with 3 and 5 ml of anhydrous benzene. The residue is recrystallized from benzene to obtain 0.39 g (78% of theory) of colorless crystals, mp. 122-123 ° C. Vesh, soluble in tetrahydrofuran.ne, chloroform, less soluble in alcohols, insoluble in hexane, water. Found,%: C 52.47; H 5.68; C1 14.13; N 5.53. CsaHsoCbNaOy. Calculated,%: C, 52.28; H 5.98; C1 14.06; N 5.54. Chlorine equivalent: found 251.0; calculated 252.7. Example 3. (5-Okoimethyl-2,2-dimethyl1, 3-dioxane-5-yl) 1 amide (2-chloroethyl) a.mino-phenylacetic acid. 0.01 g mol of trioxy tert-butylamide 4. Phenylacetic acid bis- (2-chloroethyl) aiMMHo and 0.012 g mol of acetone diethyl acetal are boiled to dissolve (1 hour) in 30 ml of anhydrous benzene 1 in the presence of several p-toluenesulfonic acid crystals. Then activated charcoal is added, the mixture is heated to kiopi and filtered through a layer of 0.5 cm of alumina. 1.5 volumes of hexane are added to the filtrate. After cooling and filtration, 3.11 g (74.5% of theory) of colorless crystals are obtained, m.p. 106-107 ° C. The substance is soluble in chloroform, tetra, alidrofuran, moderately soluble in alcohols, insoluble in hexane, water. Found,%: C 54.97; H 6.54; C1 17.13; N 6.68. C, 9H28Cl2N204. Calculated,%: C 54.42; H 6.73; C1 16.91; N 6.67. Chlorine equivalent: found 213.1; found out 209.7. Example 4. 4-bis- (2-chloroethyl) amino-phenylacetic acid (5-oximethyl-2,2-dimethyl1, 3-dioxan-5-yl) amide. 0.01 g mole of triocoie-gret-butylamide (2-chloroethyl) amino-phenylacetic acid and 0.012 g mole of acetone diethyl acetal in 30 ml of anhydrous benzene are boiled to dissolve in the presence of 0.4 g of KU-2 catalyst in the H + form. The catalyst is filtered off, the reaction mass is further processed as indicated in example 3. The yield and product constants are the same as in example 3. Example 5. (5-Oxymethyl-2,2-dimethyl1, 3-dioxane-5-yl) amide (2 -chloroethyl) a.mino-phenylacetic acid. A mixture of 0.005 g. a mole of triocoie-greg-butylamide (2-chloroethyl) amino-phenylacetic acid and 100 mg of l-toluenesulfonic acid in 15 ml of anhydrous acetone is kept at 20–25 ° C until completely dissolved, then basified with an alcoholic solution of potassium hydroxide to pH 8, filtered and evaporated vacuum to dryness. The residue is recrystallized from a mixture of benzene and hexa. Obtain 0.9 g (50% of theoretical) of the substance, the conctaiHTbi of which coincide with the constants (5-hydroxy | methyl-2,2-di | methyl - 1,3 - dioxan-5-yl) amide (2-chloroethyl) amino phenylacetic acid, obtained by the methods given in examples 3 and 4. Example 6. (2-Okoimethyl-2,2-ientamethylene-1, 3-dioxan-5-yl) amide (2-chloroethyl) amino phenylacetic acid. A mixture of 0.005 g mol of trioxygreg-butyl. Amide (2-chloroethyl) amino phenylacetic acid and 0.0065 g mol of diethyl acetal cyclohexanone. A is boiled to dissolve in the presence of several p-toluenesulfonic acid crystals or KU-2 in H + - form. The catalyst was separated, the benzene was removed in vacuo, the residue was recrystallized from a mixture of anhydrous ethanol and hexava. Obtain 1.58 g of colorless cr | Ist; allov (70% of theoretical), so pl. 134-135 ° C. The product is soluble in tetrahydrophsphae, chloroform, moderately soluble in alcohols, ether, carbon tetrachloride, insoluble in water, cyclohexyl. Found,%: C 57.95; H 7.22; C1 15.70; N 6.03. C22H82C12N204. Calculated,%: C 57.50; H 7.02; C1 15.41; N 6.09. Equivalent to chlorine chlorine: found 230.0; calculated 229.7.

Claims (3)

1. Derivatives of trnoxi-g / Eg-butclamide - (2 - chloroet 1l) a: mino-phenylacetic acid of the general formula tea OH 1 CH2SOYN - (;, - CH20Rg (С1СНгСН2 К SNROB where R, RI and Rj are the same or different and mean hydrogen or acetyl or two radicals R and Rj mean coarse Sn-Sn.5 2 / y7w e CH) j, (W  X / ("4 or 5) and Cg is hydrogen or acetyl, possessing antitumor activity. 2. A method of producing compounds according to claim 1, This is due to the fact that (2-chloroethyl) amino-phenylacetic acid hydrochloride hydrochloride is condensed with trioxy-greg-butylamine in an aqueous acetone medium at (-5) - (-10) ° С and the target the product is isolated in free form or in the form of ai-methyl derivatives, or in the form of cyclic acetals. Sources of information taken into account in the examination: 1. Ross W. “Biological alkylating substances, M., 1964, p. 150-152. 2. Rubtsov M.V. and Baychikov A.G., “Synthetic chemical and pharmaceutical preparations, L., 1971, p. 64. 3. S. Kablas., Proceedings of the VIth Scientific Session, 06.03.65., Oncological Research Institute of the Lithuanian SSR, Vilnius, 1965, p. 84-86 (prototype).