Antitumor remedy taken per os and method for producing the remedy

FIELD: medicine.

SUBSTANCE: preparation belongs to gestagen class as 17α-acetoxy-3β-butanoyloxy-6-methyl-pregna-4,6-dien-20-on allowing peroral application. The compound shows no toxic activity and has no androgenic side effect. It is found to be better than Depo-Provera gestagen used in clinical practice and possesses chemosensitizing activity. The preparation is obtained by megestrol acetate reduction with sodium borohydride with following product etherification with butyric acid anhydride. The reaction mixture is treated with ammonia solution after etherification with butyric acid excess being removed to increase output and target product separation.

EFFECT: enhanced effectiveness of treatment.

3 cl, 3dwg, 1 tbl

 

Antitumor agent for oral administration and how to obtain it.

The invention relates to medicine, in particular to the chemistry of steroids, and related specifically to the gestagen with antitumor activity.

Know the use of gestagens in Oncology for the treatment of hormone-dependent tumors such as cancer of the uterus, breast cancer, endometrial cancer. As preparations on the basis of progestogen use such as Megas, depo-provera, depostit [Mashkovsky PPM "Drugs", Moscow, "Medicine", part 2, 1993, str-548]. The most widely used drug depo-provera, which as progestogen use of medroxyprogesterone acetate for the treatment of breast cancer, endometrial cancer ["Federal guidance on the use of medicines for doctors". Issue I, 2000, str].

Specified in these preparations contain progestogen Δ4-3-ketogluterate, is characteristic not only of progesterone, and testosterone. The latter may be the reason for the availability of these gestagen adverse androgenic properties, causing virilization women.

In the present application as antitumor agents offered gestagen formulas 1-3β-butanoyloxy-6-methyl-17α-acetoxy-pregna-4,6-Dien-20-he (compound 1) and its production method.

The claimed compound has a high antitumor activity, does not detect adverse androgenic properties (test of Hershberger), and its structure does not contain Δ4-3-ketogluterate.

Figure 1 - the effect of compound 1 in combination with vincristine on the growth of transplantable acute lymphocytic leukemia mouse R resistant vincristine;

figure 2 - cytotoxic activity of gestagens in respect of MCF-7 cells;

figure 3 - cytotoxic gestagen activity against HeLa cells.

Antitumor activity of the claimed means shown in experiments on mice CBA with human cervical cancer cervical cancer-5. As the comparison drug used depo-provera (MPA, medroxyprogesterone acetate).

Example 1.

The study of antitumor activity of the compounds was carried out on human cervical cancer cervical cancer-5 sensitive progestinas when the orthotopic perebivke. The tumor initially induced by methylcholanthrene in dermal autograft cervical mouse - IAS in 1970 Tumor transplanted at laparotomy fragment size of 1 mm3in one of the horns of the uterus by means of a trocar mice CBA under geksenalovy anesthesia. When perebivke used female mice of line CBA, weighing 18-20 grams. Treatment was started on day 3 after inoculation SDA is Oli. The course of treatment was 14 days, with daily introduction the study of gestagens. The killing of the mice was carried out on the 17th day after the start of the experiment. The antitumor effect was evaluated by inhibition of tumor growth (change in tumor mass), calculating the ratio TRO (inhibition of tumor growth). In the experimental groups used the 8 mice in the control and 13 mice.

The scheme is the introduction:

Compound 1 was administered in doses of 0.5, 1 and 2 mg/mouse orally through a feeding tube daily for 14 days. The solvent is 1% starch paste. Depo-provera was administered at doses of 1 and 2 mg/mouse orally through a feeding tube daily for 14 days. The solvent is distilled water.

The effect of compound 1 on tumor growth of cervical cancer-5 are presented in table 1.

Table 1.

The antitumor activity of compound 1 when administered orally for 14 days to mice with cervical cancer cervical cancer is 5.
GroupDose (mg/mouse)The tumor weight, M±m (mg)TRO(inhibition of tumor growth), %
Control-417±93,5-
0,5265,4±126,8536
Connection 11113,6±27,762285,3±128,9932
MPA1205±71,7655*
2187,1±73,755*
Note: * - significant difference from control p≤0,01; ** - significant difference from the TRO for MPA (p≤0,05).

The experimental results indicate that compound 1 at a dose of 1 mg/mouse inhibits tumor growth of cervical cancer-5 73%, whereas MPA at the same dose for 55%. Thus, the claimed remedy for oral application has antitumor activity against HPV-5, and therapeutic effect superior to drug comparison MPA.

Example 2.

The claimed compound has a strong chemosensitizers action, enhancing the antitumor effect of vincristine against transplantable acute lymphocytic leukemia mouse R resistant vincristine.

To assess chemosensitizing activity of a compound 1 compared the antitumor activity of vincristine as a separate compounds with anti-tumor activity of vincristine in combination with compound 1.

The DBA2 mice inoculated lymphoblastic R resistant vincristine, 2 million cells/mouse, the next day the group "In Kristen" (7 mice, the middle column in figure 1) introduced vincristine 1 mg/g intraperitoneally (20 μg/mouse), the group Vincristine + connection 1" (7 mice, right from the center column in figure 1) vincristine 1 mg/g intraperitoneally (20 μg/mouse) and after 2 hours the connection 1 1 mg/mouse (50 mg/kg) orally in oil.

The control group (7 mice, the first column in figure 1) has received oil orally. On day 7 after vaccination has estimated the growth of the tumor by the number of cells in the ascitic fluid. Figure 1 presents the results of the experiment to assess the effect of compound 1 in combination with vincristine on the growth of transplantable acute lymphocytic leukemia mouse R resistant vincristine.

On the y - axis tumor growth (percentage growth, %), * - significant difference in the number of cells in the group "Vincristine + connection 1" from group "Vincristine".

In the control group, the tumor has grown for 7 days at 185%, in the group "Vincristine" - 80%, in the group "Vincristine + connection 1" - 35%. Thus, compound 1 at a dose of 1 mg/mouse (50 mg/kg) shows chemosensitizers action, enhancing the antitumor effect of vincristine on 16% and the inhibition in combination with vincristine tumor growth by 53%. Vincristine as an independent compound inhibits tumor growth by 37%.

Compound 1 significantly (P<0,001) enhances the antitumor effect of vincristine against harmonizovani the CSOs resistant acute lymphoblastic mouse R, therefore, it is against this tumor chemosensitization.

Example 3.

The inventive tool has cytotoxic activity against breast cancer cells human (line MCF-7) and cervical cancer man (line HeLa).

Cytotoxic activity was defined as suppression of cell viability (%) in the presence of the compounds under study. The effect of progestogen on the viability of tumor cells was estimated using MTT (3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide) [Mealey K.L., Barhoumi R, Burghardt R.C. et al. Doxycycline dosage expression of P glycoprotein in MCF-7 breast carcinoma cells // Antimicrob. Agents Chemother. - 2002 - V.46. N 3. - P.755-761]. As compounds comparisons used MPA and progesterone.

Data on the cytotoxic activity of gestagens in respect of MCF-7 cells are presented in figure 2. Cytotoxic activity of gestagens in respect of HeLa cells are presented in figure 3.

The figures on the y - axis the percentage of live cells %; in each of this on the concentration figures 1 through 4 column respectively: progesterone, connection 1, MPA, control; * - significant difference from control at P<0,001, ◆ - significant difference from control at P<0,05.

Regarding breast cancer cells human MCF-7 connection 1 has a more pronounced cytotoxic effect than progesterone and similar cytostatic effect with the PA (P< 0,05). Connection 1 has a more pronounced cytotoxic effect than MPA and progesterone in the culture of HeLa cells (P<0,05).

Example 4.

The inventive compound is not toxic. This is shown in studies on acute toxicity in rats at a dose of connections exceeding therapeutic 50-100 times (taking into account a wide range of recommended doses).

Example 5.

The subject of the invention is also a method of obtaining compound 1 borhydride recovery megestrol acetate with subsequent esterification product recovery anhydride butyric acid.

The esterification of steroids containing a hydroxyl group are usually in pyridine using an excess of the anhydride [T.W.Greene. Protective groups in organic synthesis. New York, Wiley-Interscience, 1981, page 110]. This General method is applied in the described method of obtaining the claimed compounds (U.S. Pat. Ross. 2099347). However, formed by the decomposition of the excess anhydride and butyric acid makes difficult the separation of the desired product in pure form. When playback is described in similar ways to obtain to highlight the product you want to further purification by recrystallization or chromatography on aluminium oxide, which reduces the yield of the product.

In the present invention for the release of excess butyric acid, the reaction mixture after etherify is then treated with ammonia solution.

The proposed method allows to obtain the target product without additional purification with a yield up to 90% (calculated on megestrol acetate).

Receive 3β-butanoyloxy-6-methyl-17α-acetoxy-pregna-4,6-Dien-20-he in the following way.

To a chilled suspension of 100 g of megestrol acetate in 600 ml of methanol is added portions of 9.8 g of sodium borohydride. The mixture is stirred for 30 minutes, after which when cooled add 250 ml of water and neutralize the solution by adding dilute HCl to a pH of 7.0. The precipitation With3-carbinol is filtered, washed with water and dried. Get 97.5 g of carbinol, which is dissolved in 195 ml of pyridine, poured 85 ml of butyric acid anhydride, stirred at 30°C for 1 h, and then continue stirring at room temperature for 5 hours To decompose the excess butyric acid solution is stirred with 40 ml of water for 1 h, then slowly poured to aqueous ammonia solution (44 ml of 25%aqueous ammonia in 1.1 l of water). The mixture is stirred for 1 h, the precipitate filtered and washed with water, then with methanol. Get 102,8 g of the product (86,6% (based on megestrol acetate), TPL 118-120°, [α]D- 78° (1,0; CHCl3), is identical with a deliberate sample [TPL 117-118 .5°, [α]D- 77° (U.S. Pat. Ross. 2099347)].

The claimed invention is not obvious to professionals working in the field of chemo therapy of tumors.

Despite the abundance at the present time the most diverse in structure and action of drugs antineoplastic activity, the search for new drugs in the fight against malignant neoplasms up to the present time is a challenging task both in terms of increasing the effectiveness of anticancer agents and reduce their toxicity, and the possibility of use in various combinations.

In connection with the great socio-economic importance of the problem of treatment of malignant growth, the creation of new connections is a pressing issue, both experimental and clinical medicine.

Creating a connection requires a long research, a large team of chemists, pharmacologists, biologists and other specialists who are sometimes a significant amount not only creative, but also quite time-consuming and original technical work.

Completely unobvious to date is the ability to create tools for oral administration, containing the progestogen - the inventive tool is the first domestic gestagen suitable for oral administration.

Thus, the claimed connection, gestagen 3β-butanoyloxy-6-methyl-17α-acetoxyphenyl-4,6-Dien-20-he, jumping Topolino known gestagens, included in the widely used anticancer foreign drugs, and certain indicators superior to them, which of course is very valuable and in clinical, social, and economic relations.

1. Antitumor agent for oral administration, characterized by the fact that it is a 3β-butanoyloxy-6-methyl-17α-acetoxy-pregna-4,6-Dien-20-it formula 1

2. The method of obtaining the compounds of formula 1 according to claim 1 recovery megestrol acetate by sodium borohydride followed by esterification product recovery butyric acid anhydride, wherein the reaction mixture after the esterification process with 1%aqueous solution of ammonia for binding formed by the decomposition of the excess anhydride and butyric acid, followed by separation of the resulting precipitate.

3. The method according to claim 2, characterized in that the ammonia solution used in the ratio 3:1 by volume of the reaction mass.



 

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