JP2807537B2 - Indole derivatives and anticancer agents containing them as active ingredients - Google Patents

Description

The present invention relates to novel indole derivatives, their salts with pharmacologically acceptable acids, and anticancer and anticancer activities containing them as active ingredients. Related to enhancers.

(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 limpoma 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.

(Means for Solving the Problems) As described above, known drugs have drawbacks such as limitations on the efficacy of the drugs and limitations on the method of use due to problems such as drug resistance. The present inventors have conducted intensive studies based on these findings, and as a result, have found that the indole derivative of the following formula (I) has a remarkable anticancer and anticancer activity enhancer effect, and have completed the present invention. .

The present invention relates to a novel indole derivative represented by the following formula (I), and an addition salt thereof with a pharmaceutically acceptable acid.

It is shown in the test described later that the compound represented by the formula (I) of the present invention and a salt thereof with a pharmacologically acceptable acid show anticancer and anticancer activity enhancing action. Therefore, the compound represented by the formula (I) is useful as an anticancer and an anticancer activity enhancer. Details of the physiological activity are described in the examples below.

The compound of the formula (I) can be synthesized by a condensation reaction between the compound of the formula (III) and 2-pyridone according to the method shown in the following scheme 1. That is, in the formula (III), X represents a halogen such as a methanesulfonyl group, a benzenesulfonyl group, or bromo, and a metal hydride such as sodium hydride or potassium hydride is used as a base. Can be. As the reaction solvent, an aprotic solvent such as benzene or dimethylformamide can be used.
The reaction can also be activated by adding a crown ether such as 18-crown-6.

The starting compound of the formula (III) is synthesized by the route shown in the following scheme 2, and these are already known methods (JACS94 6190 (1972), Synthesis 13).
6 (1979), Tetrahedron Lett. 165 (1976)). That is, the following formulas were obtained after sequentially performing o-silylation, N-benzenesulfonylation, condensation reaction of indole with methyl pyruvate, o-methylthiomethylation, and desilylation using tryptophthal as a starting material. Sulfonylation or halogenation of the compound of formula (II) gives the compound of formula (III).

The compound represented by formula (I) of the present invention can be converted into an addition salt with a pharmacologically acceptable acid if desired, and these acid addition salts are also included in the scope of the present invention. . Examples of the acid addition salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, acetic acid, succinic acid, butyric acid, oxalic acid, malic acid, fumaric acid, maleic acid, stearic acid, and citrate. Salts of organic acids such as acid, tartaric acid, lactic acid and the like can be mentioned.

When the compound represented by the general formula (I) is used for a drug, it can be prepared into various dosage forms. Thus, the preparation can be administered orally in the form of tablets, dragees, hard capsules, soft capsules, solutions, emulsions or suspensions. In the case of parenteral administration, it is administered in the form of an injection solution. In preparing these preparations, well-known additives for preparation such as excipients, stabilizers, preservatives, dissolving agents, wetting agents, emulsifiers, lubricants, sweeteners, coloring agents, flavoring agents, The preparation can be prepared by adding a tonicity adjusting agent, a buffer, an antioxidant and the like.

The administration method and dosage of the anticancer and anticancer activity enhancer of the present invention are not particularly limited, and are appropriately selected depending on the form of the preparation, the sex of the patient, and the degree of the disease. Is preferably 1 mg to 2000 mg.

The cytotoxicity of this compound against KB-C-2 cells is an IC ₅₀ value of 52 μg / ml.

Hereinafter, the present invention will be described in more detail by way of examples, which merely illustrate the present invention.
The description of the examples does not limit the present invention in any way.

Example 1 Synthesis of compound of formula (I) a 1531 mg of compound of formula (II) and 0.1% of triethylamine
To a dichloromethane solution containing 58 ml, methanesulfonyl chloride (0.32 ml) was added dropwise under cooling with ice water, and stirring was continued for 1 hour. The reaction solution was washed with diluted hydrochloric acid, dried over sodium sulfate, evaporated, and crystallized from ethyl acetate-n-hexane to obtain 1515 mg of a compound of the formula (III) (X: methanesulfonyl).

NMR (δ, CDCl ₃ ) 2.10 (3H, s), 2.20 (3H, s), 2.81 (3
H, s), 3.52 (3H, t), 3.75 (3H, t), 4.57 (3H, t), 4.65
(1H, d), 4.72 (1H, d), 7.07-7.81 (9H, m) MASS (m / z,%) 326 (100), 185 (93) Next, sodium hydride 25 mg (50% oily) including
52 mg of 2-pyridone in DMF (dimethylformamide) solution
And the solution stirred at room temperature for 30 minutes is added with the above formula (II)
A DMF solution of 90 mg of the compound of I) was added, and the mixture was stirred at 50 ° C for 12 hours. Ethyl acetate was added to the reaction solution, washed with water, dried over sodium sulfate and evaporated, and purified by a silica gel column.
37 mg of the compound of formula (I) were obtained.

Crystallization from ethanol NMR (δ, CDCl ₃ ) 2.18 (3H, s), 2.19 (3H, s), 3.44
(1H, m), 3.70 (1H, m), 3.78 (3H, s), 4.56-4.62 (2H,
m), 4.60 (1H, m), 4.70 (1H, m), 6.64 (1H, d), 6.85 (1
H, t), 7.14-7.74 (10H, m), 8.15 (1H, dd) IR (cm- ¹ , KBr) 1730,1370,1170 MASS (m / z, (%)) 399 (M ⁺ , 100) Example 2 Synthesis b of compound of formula (I) b To a benzene solution containing 560 mg of potassium hydride (30%, oily) was added 406 mg of 2-pyridone at room temperature to give 30.
The mixture was stirred for minutes. After adding thereto 40 mg of 18-crown-6 and then 735 mg of the compound of the formula (III) obtained in Example 1,
Heating and stirring were continued at 50 ° C. for 45.5 hours. Chloroform was added to the reaction solution, washed with water, dried over sodium sulfate and evaporated, and purified by a silica gel column to obtain 297 mg of the compound of the formula (I).

Production Example Synthesis of Compound of Formula (II) To a solution of tryptophor 4004 mg in DMF was added imidazole 4
225 mg, and t-butyldimethylsilyl chloride 450
After sequentially adding 1 mg, the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. Ether was added to the reaction solution, washed with water, dried over sodium sulfate and evaporated to give crude 3- (2-t-butyldimethylsilyloxyethyl) indole (Compound IV).
79 mg were obtained.

NMR (δ, CDCl ₃ ) 0.03 (6H, s), 0.90 (9H, s), 2.99
(2H, d), 3.88 (2H, d), 7.02-7.62 (5H, m), 7.94 (1H,
brs) MASS (m / z,%) 275 (M ⁺ , 4), 218 (100) To a benzene solution containing 7179 mg of this compound IV, 13 ml of a 50% aqueous NaOH solution, and 886 m of tetra-n-butylammonium hydrogen sulfate were added.
g was added. Under vigorous stirring of this solution, benzenesulfonyl chloride was further added, and then stirring was continued at room temperature for 30 minutes. The benzene layer was washed with water, dried over sodium sulfate, and evaporated. The residue was crystallized from ethanol to give 9675
mg of 1-benzenesulfonyl 3- (2-t-butyldimethylsilyloxyethyl) indole (Compound V) was obtained.

Melting point 62-64 ° C NMR (δ, CDCl ₃ ) 0.00 (6H, s), 0.89 (9H, s), 2.88
(2H, d), 3.88 (2H, d), 7.21-8.01 (9H, m) MASS (m / z,%) 358 (42), 199 (100) Under an argon atmosphere, compound V2084 mg was added to lithium diisopropylamide. It was added dropwise to a dry tetrahydrofuran solution containing 7 mmol at -73 ° C, and the mixture was stirred for 1 hour. Separately, the above solution was added dropwise to a solution of a dry tetrahydrofuran solution containing 3.9 ml of methyl pyruvate cooled to -73 ° C, and after 1 hour, the temperature was returned to room temperature and stirred for 30 minutes. The reaction solution was poured into a saturated ammonium chloride solution and extracted with ethyl acetate. Purification is performed on a silica gel column.
2233 mg of compound VI were obtained.

NMR (δ, CDCl ₃ ) 0.01 (6H, s), 0.84 (9H, s), 2.06
(3H, s), 3.27 (1H, m), 3.48 (1H, m), 3.74 (3H, s), 3.
92 (2H, m), 5.66 (1H, s), 7.17-7.74 (9H, m) MASS (m / z,%) 309 (100), 214 (62) 2233 mg of compound VI in dimethyl sulfoxide solution ,
26 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 41 hours under an argon atmosphere. The reaction solution was neutralized by adding a 30% aqueous potassium carbonate solution, and extracted with chloroform. Purification was performed on a silica gel column to give 2320 mg of compound VII.

NMR (δ, CDCl ₃ ) 2.12 (3H, s), 0.13 (3H, s), 0.99
(9H, s), 2.27 (3H, s), 2.34 (3H, s), 3.35−3.50 (2H,
m), 3.91 (3H, s), 3.99−4.06 (2H, m), 3.72 (1H, d) 4.
80 (1H, d), 7.17-7.74 (9H, m) MASS (m / z,%) 520 (6), 442 (54), 61 (100) 1903 mg of compound VII was dissolved in 13.5 ml of acetic acid, and water 4.5
ml was added and the mixture was stirred at room temperature for 12 hours. After the reaction solution was distilled off under reduced pressure, chloroform was added, and this was washed with an aqueous sodium carbonate solution. Purification was performed using a silica gel column to obtain 1343 mg of oily compound II.

NMR (δ, CDCl ₃ ) 2.13 (3H, s), 2.24 (3H, s), 2.42
(1H, s), 3.80 (3H, s), 3.85-3.92 (2H, m), 4.60 (1H,
d), 4.71 (1H, d), 7.13-7.76 (9H, m) MASS (m / z,%) 463 (M ⁺ , 2), 322 (32), 61 (100) The anticancer and anticancer activity enhancer effects of the compounds of the present invention were evaluated by the following methods.

Example 3 Anticancer and Anticancer Activity Enhancing Activity Drug-resistant strain of human nasal epidermis-derived tumor cells (KB) (KB-
C-2) After culturing 1 × 10 ⁵ cells in a 60 mm diameter dish in an Eagle medium for 18 hours, the indole derivative represented by the formula (I) was added at various concentrations, and the cells were further cultured for 2 days. The cells adhered and grown on the bottom of the container were treated with 0.25% trypsin to prepare a cell suspension, and the number of cells was calculated using a hemocytometer, and the concentration (IC ₅₀ ) that inhibited cell growth by 50% was calculated. . As a result, the inhibitory effect of cancer cells on the growth of cancer cells was observed with the involute derivative represented by formula (I).

Table I IC ₅₀ value of the indole derivative represented by the formula (I) against the anticancer compound KB-C-2 (μg / ml) (I) 52 Furthermore, 1 × 10 ⁵ KB-C-2 cells were cultivated with a diameter of 60 mm. After culturing in an Eagle's medium for 18 hours in adhering medium, adriamycin, vincristine and the indole derivative represented by the formula (I) were added at 2 μg / ml, 0.5 μg / ml and 10 μg / m 2 respectively.
1 or in combination, and cultured for another 2 days. 0.25% of cells that adhered to the bottom of the container and proliferated
After treatment with trypsin to obtain a cell suspension, the number of cells 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. The above results are shown in the table.
Illustrated in II.

────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Toshihiro Takahashi 1-25-25 Kishimachi, Kawagoe-shi, Saitama 53 (58) Field surveyed (Int.Cl. ⁶ , DB name) C07D 401/12 CA, REGISTRY (STN )

Claims (2)

(57) [Claims] 1. An indole derivative represented by the following formula (I) and an addition salt thereof with a pharmacologically acceptable acid. 2. An indole derivative represented by the formula (I):
Or an anticancer agent comprising an addition salt thereof with a pharmacologically acceptable acid as an active ingredient.