RU2522449C1 - Agent possessing antiproloferative and antimetastatic action for treating malignant diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to a new agent representing rhodanine derivatives of formula

(I), wherein X=N or CH for treating malignant diseases of varying sites.

EFFECT: agent is antiproloferative and antimetastatic action for treating malignant diseases.

3 tbl, 1 ex

Description

The invention relates to a new tool, which is a derivative of rhodanine, which has antiproliferative and antimetastatic action. The specified tool can find application in medicine and pharmacology for the treatment of tumor diseases of various localization.

Achieving greater efficacy of chemotherapy in the treatment of cancer is hindered by the high toxicity inherent in traditional chemotherapeutic drugs. To improve the results of treatment of malignant neoplasms, new highly effective drugs with low toxicity are needed. Such preparations can be obtained artificially as a result of chemical synthesis or found among natural substances of plant or animal origin. Among the objects of plant origin that are promising for the search for substances with the ability to suppress tumor growth are edible plants, since in this case there is a certain guarantee that the substances obtained from these plants will not cause serious side effects. Among the promising for the search for compounds with antitumor activity and suitable for the creation of appropriate drugs include cruciferous vegetables. In places where residents consume large quantities of cruciferous vegetables, the incidence of certain types of cancer is much lower. It is known that cruciferous vegetables contain a large number of glucosinolates, of which a number of isothiocyanates are formed enzymatically in violation of the integrity of the plants. It has been established that natural isothiocyanates (ITCs) in varying degrees in in vitro systems inhibit cell proliferation, suppressing the origin of cells by the cell type, and, in addition, induce apoptosis of tumor cells.

For the treatment of cancer, purified ITCs should be used, which are easy to dose and the intake of which does not depend on the intake of certain types of vegetables, which greatly simplifies prevention. However, an obstacle to the use of ITC is the fact that ITCs are pungent, oily liquids with strong irritating effects on the mucous membrane.

In plants, ITCs are part of thioglycoside conjugates called glucosinolates, which have a faint odor and do not irritate the mucous membrane. Currently, more than 120 plant-derived glucosinolates are known.

Known plant-derived chemoprotective chemoprotective agents, for example glucosinolates, which are metabolic precursors of isothiocyanates, are described, for example, in US Pat. No. 5,968,505 or US Pat. No. 5,968,567. Such agents reduce carcinogens in animals.

However, the use of natural isothiocyanates is limited by their low concentration in plant materials, as well as the fact that they are not subject to long-term storage.

C. Ernst Redemann; Roland N. Icke; Gordon A. Alles (1955), ″ Rhodanine ″, Org. Synth .; Coll. Vol.3: 763, describes a method for producing unsubstituted rhodanine by reacting ammonium dithiocarbamate with sodium chloroacetate, followed by cyclization of the resulting acetic acid dithiocarbamate salt. The purpose of the indicated compound is not indicated. In Johannes S. Buck and Clifford S. Leonard ″ Rhodanines I. derivates of β-phenylethylamines ″, J. Am. Chem. Soc., V. 53, issue 7, pp.2688-2692, 1931, describes the preparation of a compound of formula 1 at X = CH.

RU 2405782C2 describes 5-quinazolin-6-ylmethylene-2-thioxothiazolidin-4-one as an intermediate for the preparation of 5- [1-quinazolin-6-ylmeth- (Z) -ilidene] -2-substituted amino] thiazole- 4-one, intended for the treatment of cancer, especially solid tumors, most preferably lung cancer, breast cancer, colon cancer and prostate cancer.

From the application US 2003/0195238 A1, 2003, the previously known substance 3- (2-phenylethyl) -2-thioxo-4-thiazolidinone) showed an antiproliferative effect on the N2A neuroblastoma cell culture.

The objective of the present invention is to find new tools for the treatment of tumor diseases of various localization, which simultaneously have the following characteristics:

- show antiproliferative and antimetastatic action,

- have improved organoleptic properties,

- retain high antitumor and antimetastatic activity,

- maintain stability during storage and, therefore, have improved technological properties in the manufacture of the dosage form.

The invention relates to a new tool with antiproliferative and antimetastatic action for the treatment of tumor diseases, which is a derivative of rhodanine of the following structural formula (I):

where X = CH (Preparation 1) or N (Preparation 2).

The use of compounds of the present invention exhibiting antiproliferative and antimetastatic effects for the treatment of tumor diseases was not previously known.

Compounds of formula (I) are prepared by cyclizing acetic acid 2-phenylethyldithiocarbamate or (2-pyridin-4-yl-ethylthiocarbamoylsulfanyl) -acetic acid, respectively, according to the procedure described in C. Ernst Redemann; Roland N. Icke; Gordon A. Alles (1955), ″ Rhodanine ″, Org. Synth .; Coll. Vol. 3: 763.

Unlike previously known compounds, the compounds of the present invention do not have an unpleasant odor, but are a powder with a faint cruciferous odor that can be easily tabletted. The obtained compounds were stable during storage and were tested for antitumor (antiproliferative) and antimetastatic efficacy.

The drug 1 X - SP.

The drug 2 X is nitrogen.

The efficacy of the antitumor (antiproliferative) and antimetastatic properties of preparations 1 and 2 was demonstrated in an experiment on male F ₁ mice (CBA × C57B1 / 6) with Lewis carcinoma implanted in the paw with intragastric administration in two doses: 5 mg / kg and 25 mg / kg within 3 weeks only after implantation and within 1 week before tumor inoculation.

The invention is illustrated by an example of a specific implementation.

Example. Test system. To study the antitumor (antiproliferative) and antimetastatic properties of drugs 1 and 2, 120 male mice of the first generation CBA × C57B1 / 6 hybrids were used: 10-12 each group. ~ 10 ⁶ cells (~ 0.2 cm ³ ) were implanted into the hind paw of animals. Doses and dosage regimens of drugs 1 and 2. The method of drug administration - per os implied the addition of drugs 1 and 2 to drinking water given to animals. The introduction of drugs 1 and 2 into drinking water was carried out in two schemes: for 3 weeks only after implantation and for 4 weeks with the start of administration prior to implantation. The experimental groups, doses and timing of administration are shown in table 1.

Table 1 Experimental groups # Groups Scheme of drug administration Number of animals one The control - 10 Drug 1 2 5 mg / kg Before and after tumor implantation (Scheme 1) 10-12 3 Only after tumor implantation (Scheme 2) 10-12 four 25 mg / kg Before and after tumor implantation (Scheme 1) 10-12 5 Only after tumor implantation (Scheme 2) 10-12 Drug 2 6 5 mg / kg Before and after tumor implantation (Scheme 1) 10-12 7 Only after tumor implantation (Scheme 2) 10-12 8 25 mg / kg Before and after tumor implantation (Scheme 1) 10-12 9 Only after tumor implantation (Scheme 2) 10-12

Antitumor (antiproliferative) and antimetastatic activity of drugs 1 and 2 were evaluated by the change in tumor volume and the number of metastases in the lungs. The number of metastases was estimated on the 21st day after tumor implantation (28th day after the start of the administration of drugs 1 and 2 according to the 1st scheme). For this, the lungs were removed from decapitated animals under anesthesia and the latter were transferred to Buena fluid. Counting metastases was performed visually. The volume of the neoplasm was estimated using the ellipsoid formula (1). Duration of measurement: 7, 14 and 21 days after implantation.

where d ₁ , d ₂ , d ₃ are mutually perpendicular sizes of the tumor.

The data obtained indicate that the administration of preparations 1 and 2 to animals significantly reduces their tumor volume compared to the control group (Table 2) after 7 days. Significant differences from the control were obtained for all experimental groups, including the scheme providing for the minimum consumption of drugs 1 and 2 by animals: the start of administration after implantation, the dose is 5 mg / kg.

There was also a tendency for the antitumor activity of drugs 1 and 2 to depend on the regimen and dose of its administration. So, an increase in the dose of drugs 1 and 2 led to a decrease in tumor volume by 23-24% in the case of administration both before and after implantation of the tumor and 19-21% in case of administration only after implantation of the tumor. Extension of the course of administration of drugs 1 and 2 through drinking water up to four weeks, with the beginning one before the implantation of the tumor, led to a decrease in tumor volume by 13-14% at a dose of 5 mg / kg and 15-16% at a dose of 25 mg / kg.

Analysis of the number of metastases in the lungs showed a significant difference from the control only for groups 5 and 9 - the beginning of administration at a dose of 25 mg / kg immediately after implantation (Table 3).

As a result of the study, it was found that drugs 1 and 2 have the ability to inhibit the growth of Lewis carcinoma in mice. Inhibition is dose dependent. With the introduction of drugs 1 and 2 at a dose of 25 mg / kg of animal weight, the inhibition of tumor growth is more pronounced than with the dose of 5 mg / kg. But with the introduction of both doses, the size of the tumors is statistically significantly different from the size of the control group of animals. Preliminary administration of drugs 1 and 2 within 1 week before tumor inoculation enhances the effectiveness of the drugs. A study of the effects of drugs 1 and 2 on metastasis made it possible to establish that drugs at a dose of 25 mg / kg of animal weight significantly reduced the number of metastases in the lungs after administration after tumor implantation. A tendency towards a decrease in the number of metastases in the lungs was also observed with the administration of drugs 1 and 2 at a dose of 5 mg / kg of body weight.

Claims (1)

1. The antiproliferative and antimetastatic action for the treatment of tumor diseases and representing derivatives of rhodanine of the following structural formula:

where X = N or CH.