Terpenoid derivatives useful as anticancer agents

 

(57) Abstract:

The invention relates to medicine, namely to terpenoid derivatives, known as sarcodictyin, for use as therapeutic agents and containing pharmaceutical compositions which are useful as therapeutic antineoplastic agents in the treatment of malignant tumors of humans and animals. The proposed connection can be used for tumors that are resistant to other drugs. 2 S. and 3 C. p. F.-ly, 3 tables.

The present invention relates to terpenoid derivatives, known as sarcodictyin (Sarcodictyins) (Helvetica Chimica Acta, volume 70, 1987, 2019-2027 and Helvetica Chimica Acta, volume 71, 1988, 964-976), which may be useful as therapeutic agents.

On the possible therapeutic use of sarcodictyin referred to in this application has not previously been reported.

In particular, according to the present invention, sarcodictyin due to their cytotoxic activity can be used as a therapeutic antineoplastic agents in the treatment of malignant tumors in humans or animals.

Accordingly, the present invention relates to a connection, vibrational)-1,10-dimethyl-4-(1-methylethyl)benzocyclobutene-11-yl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate (sarcodictyin A);

(-)-(4R, 4aR, 7R, 10S, 11S, 12aR, 1Z, 5E, 8Z)-7,10-epoxy-6-(etoxycarbonyl)-3,4,4 and 7,10,11,12,12 and octahydro-7-hydroxy-1,10-dimethyl-4-(1-methylethyl)benzocyclobutene-11-yl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate (sarcodictyin);

(-)-(3R, 4S, 4aS, 7S, 10R, 11R, 12aS, 1Z, 5E, 8Z)-7,10-epoxy-3,4,4 and 7,10,11,12,12 and octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-Metzler)benzocyclobutene-11-yl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate (sarcodictyin C);

(-)-(3R, 4S, 4aS, 7S, 10R, 11R, 12aS, 1Z, 5E, 8Z)-3-acetoxy-7,10-epoxy-3,4,4 and 7,10,11,12,12 and octahydro-7-hydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclobutene-11-yl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate (sarcodictyin D);

(+)-(3R, 4S, 4aS, 7S, 10R, 11R, 12aS, 1Z, 5E, 8Z)-7,10-epoxy-3,4,4 and 7,10,11,12,12 and octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclobutene-11-yl (Z)-3-(1-methyl-1H-imidazol-4-yl)acrylate (sarcodictyin E); and

(+)-(1R, 4R, 4aR, 7R, 10S, 11S, 12aR, 2Z, 5E, 8Z)-7,10-epoxy-1,4,4 and 7,10,11,12,12 and octahydro-1,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclobutene-11-yl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate (sarcodictyin F);

for use as a therapeutic agent.

Structural formulas of the above compounds are shown in table 1, below, with reference to the following formula:

< / BR>
< / BR>
In carried away>/BR>symbol Et means ethyl;

symbol SLA means of ASON3;

the symbols (E)u and (Z)u represent, respectively, (E) and (Z) urbanology part of a formula

< / BR>
In particular, the above sarcodictyin A-F may be useful as therapeutic agents in the treatment of malignant tumors of humans and animals due to their cytotoxic antitumor activity. A malignant tumor can be a sarcoma, carcinoma, lymphoma, neuroblastoma, melanoma, myeloma, Wilms tumor, leukemia and adenocarcinoma.

Sarcodictyin of the present invention can be obtained by selection of Mediterranean forming stolons of coral Sarcodictyon Roseum" (Rolandia rosea) (Forbes 1847), in accordance with the method described in Helvetica Chimica Acta, volume 70, 1987, page 2025.

The biological activity of sarcodictyin of the present invention was demonstrated by (a) testing in vitro evaluation of their activity in relation to the promotion of tubulin Assembly and (b) tested in vitro evaluation of their cytotoxic activity against both cells L 1210 and cells L 1210 resistant to doxorubicin (L 1210/Dx).

As an example, the activity sarcodictyin And (internal code FCE 29123) and Sarko is pytanie on the Assembly of tubulin

Tubulin from brain of a calf prepared by two cycles of Assembly-destructuring (Shelanski, M. L. , Gaskin F. and Cantor, C. R. , Proc. Natl. Acad. Sci. USA 70, 765-768, 1973) and kept in liquid nitrogen in the MAV (0.1 M MES, 2.5% mm EGTA, 0.5 mm MgSO4, 0.1 mm EDTA, 0.1 mm DTT, pH 6.4).

All experiments were performed on the protein, which was kept less than 4 weeks.

Before each experiment tubulin was kept for 30 minutes at 4oC. the Assembly was evaluated by the method Gaskin et al. (Gaskin F. , Cantor C. R. and Shelanski, M. L. , J. Molec. Biol. 89, 737-758, 1974).

Cuvettes (optical path length 1 cm) containing tubulin (1 mg/ml) and 1 mm GTP, was heated to 37oWith and produced a continuous measurement of turbidity at 340 nm on a two-beam two-wavelength spectrophotometer Perkin-Elmer 557, equipped with an automatic recorder and thermostatically controlled sample chamber.

After 30 minutes, was added 4 mm CaCl2and measured depolymerization for 10 minutes to reduce turbidity.

With regular intervals of 15 minutes was added large doses of the tested compounds was evaluated by turbidity change.

Data were expressed as the percentage of repolymerization caused by the test compounds. The results obtained are presented in table 2.

2that usually inhibits tubulin Assembly.

It is well known that microtubules are one of the most strategically important subcellular targets of anticancer chemotherapy (Rowinsky et al. Review , volume 82, 15, 1 August 1990).

In contrast to the classical agents acting against microtubules, such as colchicine and Vinca alkaloids, which cause the depolymerization of microtubules, sarcodictyin seem to have a mechanism of action similar to that of Taxol, one of the most interesting anti-cancer agents, resulting from the screening of natural products, which consists in inducing tubulin polymerization and the formation of extremely stable, not capable of functioning of microtubules.

Thus, sarcodictyin can be used as therapeutic antineoplastic agents in the treatment of malignant tumors of humans and animals due to their ability to catalyze the rapid formation and stabilization of microtubules, which leads to the suspension of dividing tumor cells.

(b) cell culture and sensitivity analysis medicine

Cell lines murine leukemia L1210 and L1210/Dx (abutment is NY) supplemented with 10% serum fetal cow Flow, Irvine, UK), 2 mm L-glutamine (Gibco Europe, Glasgow, UK), 10 mm mercaptoethanol, 100 U/ml penicillin and 100 μg/ml streptomycin.

Exponentially growing cells were sown (1105cells/ml) in 12-well plates (Costar, Cambridge, MA) and immediately after sowing was added compound in various concentrations.

The plates were incubated for 48 h at 37oC in humidified atmosphere containing 5% CO2.

Inhibition of cell growth was assessed by counting surviving cells on the counter ZBI Coulter (Hialeah, FL). 50% inhibitory concentration (IC50) considered by the obtained curve, the concentration-response. For each concentration of the test compounds used duplicate culture.

The results are presented in table 3.

As can be seen from the table, sarcodictyin showed good cytotoxic activity in vitro against L1210 cells, as well as against L1210 cells resistant to doxorubicin (L1210/DX).

Because of their effectiveness against L1210 cells/DX sarcodictyin can be useful in the treatment of tumors resistant to chemotherapeutic agents, such as, for example, anthracycline g introduction he pharmaceutically effective amount of the compounds selected from sarcodictyin And sarcodictyin, sarcodictyin With, sarcodictyin D, sarcodictyin E and sarcodictyin F. By this state of a person or animal can improve.

Sarcodictyin of the invention can be assigned to receive in the form of multiple dosage forms, e.g. orally, in the form of tablets, capsules, pills, coated with sugar or film of liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous injection or infusion.

The dose depends on age, weight, condition of the patient and the method of administration; for example, the dose intended for oral administration adults, for example, for typical compounds of the present invention, FCE 29213 (sarcodictyin a) may vary from about 0.01 g to 1 g per day.

The present invention also includes pharmaceutical compositions containing sarcodictyin of the present invention as an active ingredient in combination with pharmaceutically acceptable excipient (which can be a carrier or a diluent).

Pharmaceutical compositions containing the compounds of the present invention, generally prepare standards for oral administration can contain, in addition to the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn or potato starch; lubricating agents, for example silica, talc, stearic acid, magnesium stearate or calcium and/or polyethylene glycols; binding agents, e.g. starches, Arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disaggregated agents, for example starch, alginic acid, alginates or glycolate, sodium starch; effervescent mixtures; dyestuffs; sweeteners; moisturizing agents, such as lecithin, Polysorbate, laurilsulfate and conventional non-toxic and pharmacologically inactive substances, used in pharmaceutical formulations.

These pharmaceutical preparations can be produced by known methods, for example by mixing, granulating, tabletting, coating film or coating of sugar.

Liquid dispersions for oral administration can consist, for example, syrups, emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

Suspension and EMU is olosu, the carboxymethyl cellulose or polyvinyl alcohol.

The suspension or solution for intramuscular injections may contain, for example, together with the active compound in pharmaceutically acceptable carrier, e.g. sterile water, olive oil, etiloleat, glycols, such as propylene glycol, and, if desired, a suitable amount hydrochloride lidocaine.

The solutions for intravenous injection or infusion may contain as carrier, for example, sterile water or preferably may be in the form of a sterile aqueous isotonic salt solutions.

Suppositories may contain together with the active compound in pharmaceutically acceptable media, such as cocoa butter, polyethylene glycol, ester of polyoxyethylenesorbitan as a surfactant or lecithin.

1. The use of compounds selected from the group consisting of

(-) - (4R, 4R, 7R, 10S, 11S, 12R, 1Z, 5E, 8Z)-7,10-epoxy-3,4,4 and 7,10,11,12,12 and octahydro-7-hydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclobutene-11-yl(E)-3-(1-methyl-1H-imidazol-4-yl)acrylate (sarcodictyin A);

(-) - (4R, 4R, 7R, 10S, 11S, 12R, 1Z, 5E, 8Z)-7,10-epoxy-6-(etoxycarbonyl)-3,4,4 and 7,10,11,12,12 and octahydro-7-hydroxy-14S, 4S, 7S, 10R, 11R, 12S, 1Z, 5E, 8Z)-7,10-epoxy-3,4,4 and 7,10,11,12,12 and octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclobutene-11-yl(E)-3-(1-methyl-1H-imidazol-4-yl)acrylate (sarcodictyin C);

(-) - (3R, 4S, 4S, 7S, 10R, 11R, 12S, 1Z, 5E, 8Z)-3-acetoxy-7,10-epoxy-3,4,4 and 7,10,11,12,12 and octahydro-7-hydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclobutene-11-yl(E)-3-(1-methyl-1H-imidazol-4-yl)acrylate (sarcodictyin D);

(+) - (3R, 4S, 4S, 7S, 10R, 11R, 12S, 1Z, 5E, 8Z)-7,10-epoxy-3,4,4 and 7,10,11,12,12 and octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclobutene-11-yl(Z)-3-(1-methyl-1H-imidazol-4-yl)acrylate (sarcodictyin E);

(+) - (1R, 4R, 4R, 7R, 10S, 11S, 12R, 2Z, 5E, 8Z)-7,10-epoxy-1,4,4 and 7,10,11,12,12 and octahydro-1,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclobutene-11-yl(E)-3-(1-methyl-1H-imidazol-4-yl)acrylate (sarcodictyin F)

as a therapeutic antineoplastic agent for the treatment of malignant tumors in humans or animals.

2. Pharmaceutical cytotoxic and antineoplastic composition, which comprises as active ingredient a compound selected from the compounds listed in paragraph 1, and a pharmaceutically acceptable carrier and/or diluent.

3. Pharmaceutical to puhalovich cells.

4. The pharmaceutical composition according to p. 2 for use as antitumor agents.

5. The pharmaceutical composition according to p. 2 for use as a therapeutic antineoplastics tools in the treatment of malignant tumors in humans or animals.

 

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3 ex

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