JP2833821B2 - Anticancer drug - Google Patents

Description

The present invention relates to an indole derivative represented by the following formulas (I) to (V) and an addition salt thereof with a pharmaceutically acceptable salt thereof. The present invention relates to an anticancer and an anticancer activity enhancer contained as an active ingredient.

(Problems to be Solved by Conventional Techniques and Inventions) Recently, various anticancer agents or anticancer agents for leukemia, malignant lymphoma and the like have been developed. However, neither drug completely cures cancer.

For example, adriamycin is characterized by its broad anticancer spectrum, including breast, bladder, lung, testicular,
Antitumor effects against malignant lymphoma and acute leukemia are known. However, these drugs also have limitations, and the problem of drug resistance, i.e., the development of cancer cells that are resistant to the adriamycin used, has begun to develop. Problems such as resistance to drugs (multidrug resistance) also arise. Such a problem is not limited to adriamycin, but also applies to other drugs.

The present inventors have studied compounds effective against such drug-resistant tumor cells, and as a result, the following formulas (I) to (V)
Found that the indole derivative has an anticancer activity of an anticancer drug such as adriamycin or vincristine, particularly an action to enhance the drug efficacy against cancer cells having drug resistance, and completed the present invention.

(Means for Solving the Problem) That is, the present invention relates to formulas (I) to (V) An anti-cancer agent comprising an indole derivative of the above as an active ingredient.

The compounds of the formulas (I) to (V) are compounds known per se, for example, the compounds of the formulas (I) and (II) are represented by the chemical pharmacodynamic bletein (Chem.
rm.Bull.) 21 (8) 1783-1798 (1973), the formula (III)
The compound of formula (IV) is represented by Chemical Pharmaceutical Bultein (Chem. Pharm. Bull.) 232805 (1975), and the compound of formula (IV) is represented by Tetrahedron 29 2015-2021
(1973), the compound of formula (V) is described in Pharmaceutical Journal (97 (3) 30
9-319 (1977)), but is not yet known for applications such as the present invention.

The present invention further provides an anticancer activity enhancer containing, as an active ingredient, an indole derivative of the formula (I) to the formula (V) or an addition salt thereof with a pharmaceutically acceptable acid, In particular, an object of the present invention is to provide an anticancer agent adjusted by blending the compound with another anticancer agent.

The present invention is particularly directed to the fact that the compounds of formulas (I) to (V) show excellent effects at low doses and show effective anticancer activity against specific drug-resistant tumor cells and multidrug-resistant tumor cells. It is unique in that its combined use with an anticancer agent significantly enhances its anticancer activity.

According to the present invention, there is provided an agent for overcoming cancer multidrug resistance comprising the indole derivative of the above formulas (I) to (V) as an active ingredient.

The compounds represented by the formulas (I) to (V) of the present invention are shown in the tests described below to exhibit anticancer and anticancer activity enhancing effects. Therefore, the compounds represented by formulas (I) to (V) are useful as anticancer and anticancer activity enhancers.
See the examples below for details on bioactivity.

According to the present invention, these indole derivatives can be administered alone or in combination with other anticancer agents, in which case the daily dose can be appropriately increased or decreased depending on the administration method and the target disease, Generally, the amount will be in the range of 1.0 mg to 2 g / day. In particular, when the compound of formula (I) or (II) is orally administered alone as an anticancer agent, about 4 m
g to 1 g / day is appropriate. When used in combination with another anti-cancer agent, the dose of the other anti-cancer agent is a normal dose, and generally the dose of the compound of formula (I) or (II) is different depending on the type of the anti-cancer agent. The dose can be lower than in the case of single administration described above.

The above-mentioned indole derivatives exert their effects alone or in combination with other anticancer agents as described below. In particular, when combined with other anti-cancer agents, the effect of each is enhanced. Specific examples of anticancer agents that can be used in combination with the indole derivatives of the formulas (I) to (V) include vincristine, adriamycin, sarcomycin, carcinofiline, mitomycin A, mitomycin B, mitomycin C, chromomycin, bleomycin, daunomycin. 5-fluorouracil and the like can be mentioned.

Next, the in vitro efficacy of the anticancer agent and the anticancer activity enhancer of the present invention will be described.

Example 1 × 10 ⁵ drug-resistant strains (KB-C-2) of human nasal epidermis-derived tumor cells (KB-3-1) were cultured in a 60 mm diameter dish in an Eagle medium for 18 hours, and the expression The indole derivative represented by (I) was added at various concentrations to give an additional 2
Cultured for days. 0.25 cells grown on the bottom of the container
% Trypsin to give a cell suspension, the cell count is calculated with a hemocytometer, and the concentration (IC
₅₀ ) was calculated. As a result, all the indole derivatives represented by the formulas (I) to (V) were found to have a cancer cell growth inhibitory effect.

Table The IC ₅₀ values for anti-cancer activity Compound KB-C-2 of the I indole derivatives (μg / ml) (I) 26 (II) 15 (III) 6.8 (IV) 7.6 (V) 6.6 Furthermore KB-C-2 After culturing 1 × 10 ⁵ cells in a 60 mm diameter dish in an Eagle's medium for 18 hours, adriamycin, vincristine and the indole derivative represented by the formula (I) were added at 2.0 μg / ml, 0.5 μg / ml, and 1.0 μg, respectively.
/ ml, at a concentration of 3.0 μg / ml, alone or in combination, and further cultured for 2 days. The cells that adhered and proliferated to the bottom of the container were treated with 0.25% trypsin to form a cell suspension, and the cell count was calculated using a hemocytometer. As a result, cell growth was not inhibited by adriamycin, vincristine and the indole derivative represented by the formula (I) alone. In contrast, it was found that the combination of the indole derivative represented by the formula (I) and adriamycin or vincristine enhanced the cell growth inhibitory effect of these compounds on drug-resistant cells.
Similar results were obtained for the compounds of formulas (II) to (V), and the results are collectively shown in Table II.

Table II Compounds for overcoming cancer multidrug resistance of indole derivatives (concentration μg / ml) Specific cell growth rate (%) Control 100 Adriamycin (2.0) 100 Vincristine (0.5) 100 Compound of formula (I) (1.0) 100 Formula (I) ) Compound (1.0) + Adriamycin (2.0) 31 Compound (1.0) + Vincristine (0.5) 26 Compound (1.0) 95 Compound (1.0) of Formula (II) + Adriamycin (2.0) 25) Compound of formula (II) (1.0) + vincristine (0.5) 24 Compound of formula (III) (1.0) 100 Compound of formula (III) (1.0) + adriamycin (2.0) 4 Compound of formula (III) (1.0 ) + Vincristine (0.5) 4 Compound of formula (IV) (1.0) 100 Compound of formula (IV) (1.0) + Adriamycin (2.0) 20 Compound of formula (IV) (1.0) + Vincristine (0.5) 18 Formula (V ) Compound (1.0) 100 Compound (1.0) of formula (V) + ad Amaishin (2.0) 7 Compounds of formula (V) (1.0) + vincristine (0.5) 0 below shows formulation examples of medicament comprising an anticancer agent or anti-cancer activity enhancing agents of the present invention.

Formulation Example 1 Capsule [Formulation] Compound of formula (V) 20.0 mg Corn starch 128.5 mg Magnesium stearate 1.5 mg Total amount (per capsule) 150.0 mg Corn compound is added to the compound of formula (V),
Powder or granules were added, and then magnesium stearate was added and mixed evenly, and then filled into hard capsules.

Formulation Example 2 Capsule [Formulation] Compound of formula (V) 50 mg Vincristine 10 mg Corn starch 138 mg Magnesium stearate 2 mg Total (per capsule) 200 mg Compound of formula (V) and vincristine are added with corn starch to form granules. , Magnesium stearate was added and mixed evenly, and the mixture was filled into hard capsules.

In addition, capsules used in combination with other anticancer agents were produced in the same manner.

Formulation Example 3 Injection 5 g of the compound of the formula (I), an appropriate amount of peanut oil and 1 g of benzyl alcohol were mixed, and the total amount was made up to 100 cc using peanut oil. This solution is added to the ampoule by aseptic operation.
cc was dispensed and sealed.

Formulation Example 4 Injection 5 g of the compound of the formula (I), 5 g of vincristine, an appropriate amount of peanut oil and 1 g of benzyl alcohol were mixed, and the total amount was adjusted to 100 cc using peanut oil. This solution was dispensed in 1 cc into an ampule by aseptic operation and sealed.

Injections using other anti-cancer drugs were also produced in the same manner.

Formulation Example 5 Fat Emulsion 4 g of the compound of the formula (I) was added to 20 g of soybean oil in Japan and dissolved by heating, and 2.4 g of purified soybean phospholipid and 5 g of glycerin were added thereto. After dissolution, an appropriate amount of distilled water was added, and the mixture was stirred with a Polytron homogenizer to prepare a coarse emulsion. This coarse emulsion was further emulsified with a Manton-Gaurin homogenizer under high pressure, and distilled water was added to 200 ml to obtain a very fine fat emulsion.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) A61K 31/395-31/49 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) An anticancer agent comprising, as an active ingredient, at least one of an indole derivative represented by the following formula (I) and a pharmacologically acceptable acid.