JPH0543544A - Indole derivative and anticancer agent resistance overcomer containing the same as active ingredient - Google Patents

Abstract

PURPOSE:To obtain a new indole derivative capable of powerfully suppressing function of p-glycoprotein without any side effects such as hypotensive action and an acid addition salt with a pharmacologically permissible acid. CONSTITUTION:An indole derivative expressed by formula I [R<1> is H, formula II (R is H, lower alkyl, lower alkoxy, halogen or nitro; X is wCH2, SO2 or CO); R<2> is H, formula III, IV, V, etc,; R<3> is dibenzylaminoethyl or (CH2)l- Ym(CH2)n-Py (Y is O, SNH, NMe, etc.; Py is pyridyl or pyridonyl; l is 1-3; m and n are 0 or 1)] and its acid addition salt with a pharmacologically permissible acid, e.g. 1-phenylsulfonyl-3-[2-(2-pyridyl)ethyl]indole. The exemplified compound in formula I is obtained by reacting indole with 2-vinylpyidine, providing 3-[2-(2-pyridyl)ethyl]indole and then reacting the resultant compound with phenylsulfonyl chloride.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel indole derivative, a pharmaceutically acceptable salt thereof with an acid, and an anticancer agent and an anticancer activity enhancer containing them as an active ingredient.

[0002]

[Prior Art and Problems to be Solved by the Invention] Recently,
Various anticancer agents or anticancer agents for leukemia, malignant lymphoma, etc. have been developed. However, neither drug completely cures cancer.

[0003] For example, adriamycin is characterized by its broad anti-cancer spectrum, and is characterized by breast cancer, bladder cancer, lung cancer,
Antitumor effect against testicular tumor, malignant lymphoma and acute leukemia is known. However, these drugs also have limitations, and the problem of drug resistance, that is, cancer cells that show resistance to the used adriamycin, begins to develop, and troublesomely, these adriamycin-resistant cancer cells are Problems such as showing resistance to drugs (multi-drug resistance) arise. Such a problem is not limited to adriamycin, and is similar to other drugs.

This multidrug resistance is associated with reduced drug accumulation due to increased efflux of chemotherapeutic agents. This action is 170
This is due to overexpression of a membrane protein called K-dalton p-glycoprotein. p-glycoprotein is the anti-cancer drug binding site and A
It has a TP binding site and functions as a pump that effluxes the anticancer drug to the outside of the cell by active efflux. This p
-As compounds that suppress the function of glycoproteins, calcium antagonists such as verapamil and nifedipine, calmodulin inhibitors such as trifluoperazine, alkaloids such as cepharanthin and reserpine are known. The mechanism of action is that these compounds bind to the anticancer drug binding site of p-glycoprotein, thereby suppressing the binding of the anticancer drug to p-glycoprotein.

As a means for overcoming the resistance to the anticancer drug, an attempt has been made to simultaneously administer the anticancer drug and the above compound. For example, by administering verapamil at the same time as an anti-cancer agent, the active excretion function of the anti-cancer agent of resistant cancer cells is inhibited, and the concentration of the anti-cancer agent in the cancer cells is increased to try to overcome the resistance of the cancer cells.

However, in the combination therapy of an anticancer drug and a calcium antagonist such as verapamil, the hypotensive action, which is the main action of the calcium antagonist, appears as a side effect, and neither compound has a p-glycoprotein inhibitory action. Sufficient and weak to overcome its resistance has severely limited clinical use.

[0007]

[Means for Solving the Problems] In order to solve the above-mentioned problems, as a result of earnest research to find a compound which has no side effect such as an antihypertensive effect and strongly suppresses the function of P-glycoprotein, the results are as follows. The inventors have found that the indole derivative has an action of strongly suppressing the function of p-glycoprotein, and completed the present invention.

The present invention relates to a novel indole derivative represented by the following general formula (I) and its addition salt with a pharmacologically acceptable acid.

[0009]

[Chemical 4] (In the formula, R ¹ is hydrogen or the following formula:

[Chemical 5] Wherein R is hydrogen, lower alkyl, lower alkoxy, halogen atom or nitro group,
X is -CH ₂ -, - SO ₂ - or -CO- represents, R
² is hydrogen and a group of the formula:

[Chemical 6] A group selected from the group consisting of, R ³ is dibenzylamino-ethyl or the following formula _{:-( CH 2) l -Y m -} (CH 2) n
A group represented by -Py, wherein Y is -O-,-
S -, - NH -, - NMe- or -N (CO ₂ Et) - a and, Py is pyridyl or pyridonyl group, l is 1, 2 or 3, m is 0 or 1, n is 0 or 1 And Me represents methyl and Et represents ethyl).

A compound represented by the general formula (I) of the present invention,
It is shown in the test described later that the compound and its pharmacologically acceptable salt with an acid exhibit an anticancer activity and an anticancer activity enhancing activity. Therefore, the compound represented by the formula (I) is useful as an anticancer agent and an anticancer activity enhancer. Details regarding physiological activity are described in Examples below.

The compound represented by the general formula (I) of the present invention can be synthesized by various methods depending on the kinds of the substituents R ¹ , R ² and R ³ on the indole ring,
Typical examples of synthetic routes are shown in Scheme 1 and Scheme 2 below.
Can be shown with).

Scheme 1

[Chemical 7]

[In the above formula, R'and R "are hydrogen, M
e, n-Bu, Ph,

[Chemical 8] And —COOMe, R ″ ″ is Ac, —C
Is a H ₂ -S-Me. ]

Scheme 2

[Chemical 9] [In the above formula, l, m, Y and Py are as defined above. ]

The compound represented by the general formula (I) of the present invention can be optionally converted into a pharmaceutically acceptable addition salt with an acid, and these acid addition salts are also included in the scope of the present invention. It is something. Examples of acid addition salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, succinic acid, butyric acid, oxalic acid, malic acid, fumaric acid, maleic acid, stearic acid, and citric acid. Examples thereof include salts of organic acids such as acids, tartaric acid and lactic acid.

When the compound represented by the general formula (I) is used as a medicine, it can be made into various dosage forms. That is, this preparation is orally tablets, dragees, hard capsules, soft capsules, solvents,
It can be administered in the form of solutions in the form of emulsions or suspensions. In the case of parenteral administration, it is administered in the form of injection solution. In preparing these formulations, well-known additives for formulation, such as excipients, stabilizers, preservatives, solubilizers, wetting agents, emulsifiers, lubricants, sweeteners, coloring agents, flavoring agents, A tonicity adjusting agent, a buffering agent, an antioxidant and the like can be added to prepare a formulation.

The administration method and dose of the anticancer agent and the anticancer activity enhancer of the present invention are not particularly limited and may be appropriately selected depending on various preparation forms, sex of patients and degree of disease. The dose is preferably 1 mg to 2000 mg.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is merely illustrative of the present invention, and the description of the Examples does not limit the present invention in any way.

Example 1 1-Phenylsulfonyl-3- (2- (2-pyridyl))
Ethyl) indole

[Chemical 10]

I) Preparation of 3- (2- (2-pyridyl) ethyl) indole

[Chemical 11] Indole (23.4 g) and 2-vinylpyridine (23.1 g) were dissolved in acetic acid and heated under reflux for 8 hours.
After acetic acid was distilled off under reduced pressure, the residue was dissolved in chloroform and
The organic layer was washed with 0% aqueous sodium hydroxide solution and dried (anhydrous sodium sulfate), and then the solvent was distilled off. After purification by silica gel column chromatography, the obtained crude crystals were recrystallized from dichloromethane-n-hexane to obtain the title compound (26.8 g).

Ii) 1-phenylsulfonyl-3- (2
Preparation of-(2-pyridyl) ethyl) indole 3- (2- (2-pyridyl) ethyl) indole (20 g) obtained in i) above was dissolved in benzene (150 ml) and tetra-n-butyl hydrogen sulfate was added. Ammonium (2
g) was added, and then an aqueous sodium hydroxide solution (50%, 50 ml) and phenylsulfonyl chloride (24 g) were added dropwise with vigorous stirring under ice cooling. After reacting for 2 hours at room temperature, water was added to separate the organic layer, which was dried (anhydrous sodium sulfate) and the solvent was distilled off to obtain a residue, which was purified by silica gel column chromatography. Recrystallization from ether-n-hexane gave the title compound (31 g).

Mp. 88.0 ° IR (cm ^-1 , nujol) 1590, 1185, 1180, 1120, 980, 755,
720 ¹ H-NMR (CDCl ₃ , δ) 3.14 (br, 4H), 7.03 (d, 1H), 7.0
5-7.55 (9H), 7.78 (m, 2H), 7.98 (d, 1H), 8.57 (d, 1H)

Example 2 1- (4-methylphenylsulfonyl) -3- (2-
(2-pyridyl) ethyl) indole

[Chemical formula 12] The procedure of Example 1 was repeated except that 4-methylphenylsulfonyl chloride was used in place of phenylsulfonyl chloride in step ii) to give the title compound in 9% yield.
Obtained at 2%.

Example 3 1- (4-methoxyphenylsulfonyl) -3- (2-
(2-pyridyl) ethyl) indole

[Chemical 13] The procedure of Example 1 was repeated except that 4-methoxyphenylsulfonyl chloride was used instead of phenylsulfonyl chloride in step ii) to obtain the title compound in a yield of 94%.

Example 4 1- (4-chlorophenylsulfonyl) -3- (2-
(2-pyridyl) ethyl) indole

[Chemical 14] The procedure of Example 1 was repeated except that 4-chlorophenylsulfonyl chloride was used instead of phenylsulfonyl chloride in step ii) to give the title compound in a yield of 8
Obtained at 8%.

Example 5 1- (4-Bromophenylsulfonyl) -3- (2-
(2-pyridyl) ethyl) indole

[Chemical 15] The procedure of Example 1 was repeated except that 4-bromophenylsulfonyl chloride was used instead of phenylsulfonyl chloride in step ii) to give the title compound in a yield of 5
Obtained at 5%.

Example 6 1- (4-fluorophenylsulfonyl) -3- (2-
(2-pyridyl) ethyl) indole

[Chemical 16] The procedure of Example 1 was repeated except that 4-fluorophenylsulfonyl chloride was used instead of phenylsulfonyl chloride in step ii) to obtain the title compound in a yield of 57%.

Example 7 1- (4-Nitrophenylsulfonyl) -3- (2-
(2-pyridyl) ethyl) indole

[Chemical 17] The procedure of Example 1 was repeated except that 4-nitrophenylsulfonyl chloride was used instead of phenylsulfonyl chloride in step ii) to give the title compound.

Example 8 1-Benzyl-3- (2- (2-pyridyl) ethyl) indole

[Chemical 18] 3- (2- (2) obtained by the operation of i) of Example 1
-Pyridyl) ethyl) indole (0.7 g) was dissolved in dry dimethylformamide, and 60% sodium hydride (0.14 g) and benzyl chloride (0.8 g) were added and the reaction was carried out at room temperature for 2 hours. After completion of the reaction, the mixture was poured into benzene, washed with water, dried (anhydrous sodium sulfate), and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain the desired product (0.9 g) (yield 92%). It was

Example 9 1-Benzoyl-3- (2- (2-pyridyl) ethyl)
Indole

[Chemical 19] The procedure of Example 8 was repeated except that benzoyl chloride was used instead of benzyl chloride to obtain the title compound in a yield of 88%.

The physical properties of the compounds obtained in the above Examples 2 to 9 are collectively shown in Table 1 below.

[0032]

[Table 1]

Example 10 1-Phenylsulfonyl-3- (2- (4-pyridyl)
Ethyl) indole

[Chemical 20]

I) Preparation of 3- (2- (4-pyridyl) ethyl) indole The reaction of Example 1 except that 4-vinylpyridine was used in place of 2-vinylpyridine in the reaction procedure i) of Example 1. The operation was repeated to give the title compound.

Mp. 149.5 ° IR (cm ^-1 , KBr) 3160, 1610, 1420, 1350, 1220, 1010,
810, 745 ¹ H-NMR (CDCl ₃ , δ) 3.02 (m, 2H), 3.10 (m, 2H), 6.88
(s, 1H), 7.07-7.26 (4H), 7.37 (d, 1H), 7.61 (d, 1H),
8.09 (br, 1H), 8.48 (m, 2H)

Ii) 1-phenylsulfonyl-3- (2
Production of-(4-pyridyl) ethyl) indole The 3- (2- (4-pyridyl) ethyl) indole obtained by the reaction operation of i) above was subjected to the reaction operation of ii) of Example 1 to give the title compound. Obtained.

Mp. 112.5 ° IR (cm ^-1 , KBr) 1610, 1450, 1365, 1180, 1130, 981, 7
55,580 ¹ H-NMR (CDCl ₃ , δ) 3.00 (s, 4H), 7.03 (m, 2H), 7.20-
7.60 (7H), 7.77 (m, 2H), 7.99 (d, 1H), 8.40 (m, 2H)

Example 11 1-Phenylsulfonyl-2- (hydroxy- (3-pyridyl) methyl) -3- (2- (2-pyridyl) ethyl) indole

[Chemical 21] 1-phenylsulfonyl-3- (2-
(2-Pyridyl) ethyl) indole (2.0 g) was dissolved in dry tetrahydrofuran (10 ml) and n- was added at room temperature.
Butyl lithium (1.5 M, 5.5 ml) was added dropwise and reacted for 5 minutes. After cooling to −78 ° C., pyridine-3-aldehyde (0.89 g) was added dropwise, and the temperature was gradually returned to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction solution, the solvent was distilled off, the residue was extracted with ethyl acetate, washed with water, dried (anhydrous sodium sulfate), and the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography. The title compound was obtained as crystals (1.40 g).

Example 12 1-Phenylsulfonyl-2- (hydroxy- (phenyl) methyl) -3- (2- (2-pyridyl) ethyl) indole

[Chemical formula 22] The reaction procedure of Example 11 was repeated except that benzaldehyde was used instead of pyridine-3-aldehyde to obtain the title compound in a yield of 42%.

Example 13 1-Phenylsulfonyl-2- (hydroxy- (2-thienyl) methyl) -3- (2- (2-pyridyl) ethyl) indole

[Chemical formula 23] The reaction procedure of Example 11 was repeated except that 2-thiophene aldehyde was used instead of pyridine-3-aldehyde to give the title compound in a yield of 39%.

Example 14 1-Phenylsulfonyl-2- (hydroxy- (4-quinolinyl) methyl) -3- (2- (2-pyridyl) ethyl) indole

[Chemical formula 24] The reaction procedure of Example 11 was repeated except that quinoline-4-aldehyde was used instead of pyridine aldehyde to obtain the title compound in a yield of 38%.

Example 15 1-Phenylsulfonyl-2- (hydroxy- (4-pyridyl) methyl) -3- (2- (2-pyridyl) ethyl) indole

[Chemical 25] The reaction procedure of Example 11 was repeated except that 4-pyridinealdehyde was used instead of 3-pyridinealdehyde to obtain the title compound in a yield of 62%.

Example 16 1-Phenylsulfonyl-2- (1-methoxycarbonyl-1-hydroxy) ethyl-3- (2- (2-pyridyl) ethyl) indole

[Chemical formula 26] The reaction procedure of Example 11 was repeated except that methyl acetoformate was used instead of pyridine aldehyde to give the title compound
Obtained in a yield of 5%.

Example 17 1-Phenylsulfonyl-2- (1-hydroxy) pentyl-3- (2- (2-pyridyl) ethyl) indole

[Chemical 27] The reaction procedure of Example 11 was repeated except that pentylaldehyde was used instead of pyridinealdehyde to obtain the title compound in a yield of 53%.

Example 18 1-Phenylsulfonyl-2- (acetoxy- (3-pyridyl) methyl) -3- (2- (2-pyridyl) ethyl) indole

[Chemical 28] 1-Phenylsulfonyl-2- (hydroxy- (3-pyridyl) methyl) -3- (2- (2-pyridyl) ethyl) indole (0.5 g) was dissolved in pyridine and acetic anhydride (0.13 g) was added. In addition, the reaction was carried out at room temperature overnight. After the solvent was distilled off, the residue was dissolved in ethyl acetate, washed with saturated brine, dried (anhydrous sodium sulfate), and the solvent was distilled off. The residue was purified by silica gel column chromatography to give the title compound (0.40 g).

Example 19 1-Phenylsulfonyl-2- (1-acetoxy) pentyl-3- (2- (2-pyridyl) ethyl) indole

[Chemical 29] 1-Phenylsulfonyl-2- (1-hydroxy) pentyl-3- (2- (2-pyridyl) ethyl) indole was reacted in the same manner as in Example 18 to introduce an acetyl group to give 61% of the title compound. Obtained in yield.

Example 20 1-Phenylsulfonyl-2- (1-methoxycarbonyl-1-methylthiomethoxy) ethyl-3- (2- (2
-Pyridyl) ethyl) indole

[Chemical 30] 1-Phenylsulfonyl-2- (1-methoxycarbonyl-1-hydroxy) ethyl-3- (2- (2-pyridyl) ethyl) indole (N-3630) (0.5 g)
Was dissolved in dimethylsulfoxide (5 ml), acetic anhydride (6 ml) was added, and the mixture was left at room temperature overnight. The reaction solution was dissolved in chloroform, washed with 30% aqueous potassium carbonate solution, dried (anhydrous sodium sulfate), and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give the title compound (. 31 g) was obtained.

Example 21 1-Phenylsulfonyl-2- (1-oxo) pentyl-3- (2- (2-pyridyl) ethyl) indole

[Chemical 31] 1-Phenylsulfonyl-2-obtained in Example 17
(1-Hydroxy) pentyl-3- (2- (2-pyridyl) ethyl) indole (0.4 g) was dissolved in dimethylsulfoxide (5 ml) and acetic anhydride (6 ml) was added,
It was left at room temperature overnight. The reaction solution was dissolved in chloroform, washed with 30% aqueous potassium carbonate solution, dried (anhydrous sodium sulfate), and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give the title compound (. 16 g) was obtained.

The physical properties of the compounds obtained in the above Examples 11 to 21 are collectively shown in Tables 2 and 3.

[0050]

[Table 2]

[0051]

[Table 3]

Example 22 1-Phenylsulfonyl-3- (2- (2-pyridyloxy) ethyl) indole

[Chemical 32] 2- (3-Indole) ethanol (0.5 g) was dissolved in benzene (50 ml), tetra-n-butylammonium hydrogensulfate (0.5 g) was added, and 50% sodium hydroxide was added under vigorous stirring under ice cooling. Aqueous solution (25 ml) and phenylsulfonyl chloride (11.2 g) were added dropwise. After reacting at room temperature for 30 minutes, water was added to separate the organic layer, which was dried (anhydrous sodium sulfate) and the solvent was distilled off. The obtained residue was recrystallized from ether-n-hexane to give 1-phenyl. Sulfonyl-3- (2-phenylsulfonyloxy) ethylindole (12.2 g) was obtained.

2-Hydroxypyridine (0.7 g) and 60% sodium hydroxide (0.30 g) were added to dry dimethylformamide and stirred at room temperature for 10 minutes, and then 1-phenylsulfonyl-3- (2-phenylsulfonyloxy). ) Add ethylindole (2.8g) and add 1 at 60 ° C.
Reacted for hours. The reaction solution was poured into benzene, washed with water, dried (anhydrous sodium sulfate), the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography and recrystallized from ether to obtain the title compound (0.95 g). It was

Mp. 123 ° IR (cm ^-1 , nujol) 1610, 1600, 1285, 1180, 1025, 75
0 ¹ H-NMR (CDCl ₃ , δ) 3.15 (t, 2H), 4.57 (t, 1H), 6.72
(d, 1H), 6.88 (dd, 1H), 7.24-7.6 (8H), 7.84 (m, 2H),
7.98 (d, 1H), 8.15 (d, 1H)

Simultaneously with the above reaction, 1-phenylsulfonyl-3- (2- (1- (2-pyridonyl)))
Ethyl) indole (Compound of Example 22-2) (0.9)
7%).

[0056]

[Chemical 33] mp. 114.8 ° IR (cm ^-1 ,, nujol) 1670, 1600, 1190, 1125, 990, 78
0, 755 ¹ H-NMR (CDCl ₃ , δ) 3.14 (t, 2H), 4.17 (t, 2H), 5.88
(t, 1H), 6.58 (d, 1H), 6.81 (dd, 1H), 7.20-7.58 (8H),
7.84 (m, 2H), 8.00 (d, 1H)

Example 23 1-Phenylsulfonyl-3- (2- (2-pyridylthio) ethyl) indole

[Chemical 34] The reaction procedure of Example 22 was repeated except that 2-mercaptopyridine was used instead of 2-hydroxypyridine to obtain the title compound.

Mp. 78.3 ° IR (cm ^-1 , KBr) 1590, 1455, 1370, 1180, 1130, 75
0, 605 ¹ H-NMR (CDCl ₃ , δ) 3.09 (t, 2H), 3.46 (t, 2H), 6.99 (d
d, 1H), 7.17 (d, 1H), 7.2-7.55 (7H), 7.63 (d, 1H), 7.8
6 (m, 2H), 7.98 (d, 1H), 8.46 (d, 1H)

Example 24 1-Phenylsulfonyl-3-((2- (N-ethoxycarbonyl-N- (2-pyridyl)) amino) ethyl)
Indole

[Chemical 35] The reaction procedure of Example 22 was repeated except that N-ethoxycarbonyl-2-aminopyridine was used instead of 2-hydroxypyridine to obtain the title compound.

Mp. Oily IR (cm ^-1 , neat) 1720, 1595, 1450, 1380, 1280, 11
80, 980, 750 ¹ H-NMR (CDCl ₃ , δ) 1.21 (t, 3H), 3.06 (t, 2H), 4.15
(q, 2H), 4.26 (t, 2H), 7.02 (t, 1H), 7.2-7.64 (9H), 7.8
6 (m, 2H), 7.96 (d, 1H), 8.39 (d, 1H)

Example 25 1-Phenylsulfonyl-3- (3- (2-pyridyloxy) propyl) indole

[Chemical 36] 3- (3- instead of 2- (3-indole) ethanol
The reaction procedure of Example 22 was repeated except that indole) propanol was used to obtain the title compound.

Mp. 76.8 ° IR (cm ^-1 , KBr) 1600, 1570, 1480, 1365, 1275, 11
80, 790, 750 ¹ H-NMR (CDCl ₃ , δ) 2.17 (m, 2H), 2.84 (t, 2H), 4.34
(t, 2H), 6.75 (d, 1H), 6.88 (m, 1H), 7.20-7.65 (8H), 7.
85 (m, 2H), 7.99 (d, 1H), 8.16 (m, 1H)

Simultaneously with the above reaction, 1-phenylsulfonyl-3- (3- (1- (2-pyridonyl))
Propyl) indole

[Chemical 37] Got

Mp. 136.0 ° IR (cm ^-1 , KBr) 1660, 1595, 1450, 1380, 1180, 11
35, 980, 730 ¹ H-NMR (CDCl ₃ , δ) 2.17 (m, 2H), 2.73 (t, 2H), 3.98
(t, 2H), 6.14 (t, 1H), 6.58 (d, 1H), 7.15-7.52 (9H), 7.
86 (m, 2H), 7.99 (d, 1H)

Example 26 1-Phenylsulfonyl-3- (3- (2-pyridylthio) propyl) indole

[Chemical 38] 3- (3- instead of 2- (3-indole) ethanol
The reaction procedure of Example 23 was repeated except that indole) propanol was used to obtain the title compound.

Mp. Oily IR (cm ^-1 , neat) 1585, 1455, 1420, 1375, 1180, 11
30, 990, 760 ¹ H-NMR (CDCl ₃ , δ) 2.11 (m, 2H), 2.82 (t, 2H), 3.19
(t, 2H), 6.98 (m, 1H), 7.15-7.51 (9H), 7.85 (m, 2H), 7.
99 (d, 1H), 8.45 (m, 1H)

Example 27 1-Phenylsulfonyl-3- (2- (N- (2-pyridyl) amino) ethyl) indole

[Chemical Formula 39] 1-phenylsulfonyl-3-((2- (N-ethoxycarbonyl-N- (2-pyridyl)) amino) ethyl)
Indole (N-3625) (2.8 g) was dissolved in dry tetrahydrofuran (50 ml), lithium aluminum hydride (0.48 g) was added, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, water (0.5 g), 15% aqueous sodium hydroxide solution (0.5 ml) and water (1.5 ml) were added successively, the purified precipitate was filtered off and the solvent was distilled off to obtain a residue. The product was purified by silica gel column chromatography and recrystallized from ether to give the title compound (1.20 g).

Mp. 121.5 ° IR (cm ^-1 , KBr) 3430, 1610, 1510, 1450, 1360, 11
75, 985, 745, 605 ¹ H-NMR (CDCl ₃ , δ) 2.98 (t, 2H), 3.63 (q, 2H), 4.50 (b
r, 1H), 6.33 (d, 1H), 6.58 (m, 1H), 7.13-7.53 (8H), 7.
85 (m, 2H), 8.00 (d, 1H), 8.10 (d, 1H)

Example 28 1-Phenylsulfonyl-3- (2-pyridylthio) methylindole

[Chemical 40] 2-Mercaptopyridine (0.35 g) and sodium hydride (0.13 g) were dissolved in dry dimethylformamide and reacted at room temperature for 10 minutes, and then 1-phenylsulfonyl-3-chloromethylindole (0.90 g) was added. The reaction was continued for 30 minutes. Pour the reaction solution into benzene,
The residue obtained by washing with water, drying (anhydrous sodium sulfate) and evaporating the solvent was purified by silica gel column chromatography and recrystallized from ether to give the title compound (0.80).
g) was obtained.

Mp. 94.8 ° IR (cm ^-1 , KBr) 1585, 1420, 1380, 1190, 1125, 98
5, 755, 610 ¹ H-NMR (CDCl ₃ , δ) 4.52 (s, 2H), 7.02 (m, 1H), 7.12
(d, 1H), 7.20-7.61 (8H), 7.76 (m, 2H), 7.95 (d, 1H),
8.50 (d, 1H)

Example 29 1-Phenylsulfonyl-3- (1- (2-pyridonyl) methylindole

[Chemical 41] The reaction procedure of Example 28 was repeated except that 2-hydroxypyridine was used instead of 2-mercaptopyridine to obtain the title compound.

Mp. 145.3 ° IR (cm ^-1 , KBr) 1670, 1550, 1450, 1370, 1175, 97
5, 770, 610 ¹ H-NMR (CDCl ₃ , δ) 5.27 (s, 2H), 6.11 (t, 1H), 6.62
(d, 1H), 7.20-7.63 (9H), 7.89 (m, 2H), 7.97 (d, 1H)

Example 30 1-Phenylsulfonyl-3- (2-pyridyl) methylthiomethylindole

[Chemical 42] The reaction procedure of Example 28 was repeated except that 2- (mercaptomethyl) pyridine was used instead of 2-mercaptopyridine to obtain the title compound.

Mp. Oily IR (cm ^-1 , neat) 1600, 1455, 1380, 1180, 1130, 98
0, 750 ¹ H-NMR (CDCl ₃ , δ) 3.68 (s, 2H), 3.78 (s, 2H), 7.15-
7.65 (10H), 7.90 (m, 2H), 7.98 (d, 1H), 8.57 (d, 1H)

Example 31 1-Phenylsulfonyl-3- (N-methyl-N- (2
-Pyridyl) amino) methylindole

[Chemical 43] 2- (methylamino) pyridine (0.7 g) and 1-
Phenylsulfonyl-3-chloromethylindole (1.0 g) was dissolved in acetonitrile, anhydrous potassium carbonate (0.5 g) was added, and the mixture was reacted at 70 ° C for 2 hours. After completion of the reaction, the solvent was distilled off, the residue was dissolved in chloroform, washed with water, dried (anhydrous sodium sulfate), and the solvent was distilled off. It was purified by silica gel column chromatography and recrystallized from ether to give the title compound (0.42 g).

Mp. 123.0 ° IR (cm ^-1 , KBr) 1600, 1500, 1430, 1365, 1180, 98
^{0, 770, 610 1 H-} NMR (CDCl 3, δ) 2.98 (s, 3H), 4.90 (s, 2H), 6.50
(d, 1H), 6.61 (dd, 1H), 7.19 (t, 1H), 7.30 (t, 1H), 7.
37-7.53 (6H), 7.79 (m, 2H), 7.97 (d, 2H), 8.22 (d, 1H)

Example 32 1-Phenylsulfonyl-3- (2-pyridyl) methylaminomethylindole

[Chemical 44] The reaction procedure of Example 31 was repeated except that 2- (aminomethyl) pyridine was used instead of 2- (methylamino) pyridine to obtain the title compound.

Mp. Oily IR (cm ^-1 , neat) 3340, 1600, 1455, 1370, 1180, 11
30, 980, 750 ¹ H-NMR (CDCl ₃ , δ) 3.94 (s, 2H), 3.96 (s, 2H), 7.15-
7.67 (10H), 7.87 (m, 2H), 7.99 (d, 1H), 8.57 (d, 1H)

Example 33 1-Phenylsulfonyl-3- (2-pyridyl) methylthiomethylindole

[Chemical 45] 2- (Mercaptomethyl) pyridine (0.40 g) and 1-phenylsulfonyl-3-chloromethylindole (0.8 g) were dissolved in ethanol, sodium ethoxide (0.2 g) was added, and the mixture was reacted at room temperature for 3 hours. Let
The solvent was distilled off, the residue was dissolved in chloroform, washed with water, dried (anhydrous sodium sulfate), and the residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain the title compound (0.25 g). It was

Mp. Oily IR (cm ^-1 , neat) 1600, 1455, 1380, 1180, 1130, 98
0, 750 ¹ H-NMR (CDCl ₃ , δ) 3.68 (s, 2H), 3.78 (s, 2H), 7.15-
7.65 (10H), 7.90 (m, 2H), 7.98 (d, 1H), 8.57 (d, 1H)

Example 34 1- (4-methylphenylsulfonyl) -2- (hydroxy- (4-quinolinyl) methyl) -3- (2- (2-
Pyridyl) ethyl) indole

[Chemical 46] In a stream of argon, 1- (4-methylphenylsulfonyl) -3- (2- (2-pyridyl) ethyl) indole (2.0 g) was dissolved in dry tetrahydrofuran (10 ml), and n-butyllithium (1 0.5M, 5.5ml)
Was dropped and reacted for 5 minutes. After cooling to −78 ° C., quinoline-4-aldehyde (1.44 g) was added dropwise, and the temperature was gradually returned to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction solution, the solvent was distilled off, the residue was extracted with ethyl acetate, washed with water, dried (anhydrous sodium sulfate), and the solvent was distilled off. Was obtained.

Amorphous powder IR (KBr) 1593, 1453, 1367, 1172, 749, 669, 578 ¹ H-NMR (CDCl ₃ , δ) 2.29 (3H, s), 2.84 (1H, m), 2.9-3.1
(3H, m), 6.80 (1H, d, J = 7.8Hz), 6.91 (1H, t-like, J =
6.1Hz), 7.03 (2H, d, J = 8.3Hz), 7.23 (1H, t, J = 7.3Hz),
7.3-7.5 (6H, m), 7.6-7.7 (3H, m), 7.94 (1H, d, J = 8.3
Hz), 8.04 (1H, d, J = 4.9Hz), 8.09 (1H, d, J = 8.3Hz), 8.
23 (1H, d, J = 8.3Hz), 8.68 (1H, d, J = 4.4Hz)

Example 35 1- (4-Methylphenylsulfonyl) -2- (hydroxy- (4-quinolinyl) methyl) -3-dibenzylaminoethyl-indole

[Chemical 47] 1- (4-methylphenylsulfonyl) -3- (2-
Instead of (2-pyridyl) ethyl) indole, 1-
The reaction procedure of Example 34 was repeated except that (4-methylphenylsulfonyl) -3-dibenzylaminoethyl-indole was used to obtain the title compound.

Amorphous powder IR (KBr) 3398, 1454, 1367, 1193, 747, 669, 580 ¹ H-NMR (CDCl ₃ , δ) 2.24 (5H, br.s), 2.48 (2H, m), 3.2
7 (2H, d, J = 13.2Hz), 3.46 (2H, d, J = 13.2Hz), 6.97 (3H,
m), 7.16 (11H, m), 7.26 (2H, m), 7.33 (2H, m), 7.52 (2
H, d, J = 8.3Hz), 7.67 (1H, m), 7.79 (1H, d, J = 8.3Hz),
8.10 (1H, d, J = 8.3Hz), 8.23 (1H, d, J = 8.8Hz), 8.67 (1
(H, d, J = 4.4Hz)

The method for synthesizing the compound of the present invention and its physical properties have been described in detail above with reference to Examples. Next, the inhibitory action on the function of p-glycoprotein possessed by the compound of the present invention and the anticancer activity enhancing action will be carried out. A concrete description will be given in the example.

Example 36 Function-suppressing action of p-glycoprotein p-glycoprotein has an anticancer drug-binding site, and after intracellular anticancer drug is bound, it is actively excreted. The effect of suppressing the binding of the anticancer drug to p-glycoprotein was examined by the following method.

Human nasal epidermis-derived tumor cell (KB) drug-resistant strain (KB-C2) cells were cultured in a 24 × 24 cm dish (GIBCO) as reported by Akiyama et al. (Akiyama, S. et al, Somatic Cell Mol. Genet. 1
1: 117-126, 1985), cells were collected and cell membrane vesicles were prepared by the method reported by Akiyama et al. (Akiyama,
S. et al, Mol. Pharmacol. 33: 144-147, 1
988).

It has been confirmed that the function-suppressing action of p-glycoprotein on cell membrane vesicles binds to the anti-cancer agent binding site of p-glycoprotein. Binding of [ ³ H] azidopine to p-glycoprotein The effect of suppressing

Cell membrane vesicles were reacted with 0.7 μM [ ³ H] azidopine (53 Ci / mmol) at room temperature for 15 minutes in the presence or absence of a drug. Then 2 366nm light
Irradiate at 5 ° C for 20 minutes to bind to p-glycoprotein [ ³
[H] azidopine was irreversibly bound to p-glycoprotein.
After that, the method of Yoshimura et al. (Yoshimura, A. et al. JBC.
264, 16282 to 16291, 1989), and after subjecting the reaction solution to SDS-polyacrylamide gel electrophoresis, autoradiogram is carried out for 4 days to measure the density of bands derived from p-glycoprotein on the autoradiogram. Then, the amount of [ ³ H] azidopine bound to p-glycoprotein was measured. The inhibition rate of [ ³ H] azidopine binding to p-glycoprotein was calculated by the following formula.

[0090]

[Equation 1]

The results are shown in Table 4.

[0092]

[Table 4]

Example 37 Anticancer activity enhancing action Drug-resistant strain KB- of human nasal epidermis-derived tumor cell (KB)
After culturing 1 × 10 ⁵ C-2 cells in a petri dish having a diameter of 60 mm in an Eagle medium for 18 hours, vincristine and the indole derivative of the present invention were each added at 0.1 μg / ml,
The cells were added alone or in combination at a concentration of 3 μg / ml, and further cultured for 2 days. The cells grown by adhering to the bottom of the container were treated with 0.25% trypsin to give a cell suspension, and the number of cells was calculated with a hemocytometer. As a result, cell growth inhibition was not observed with adriamycin, vincristine and the indole derivative of the present invention alone. On the other hand, it was confirmed that the combination of the indole derivative of the present invention and adriamycin or vincristine enhanced the cell growth inhibitory effect of these compounds on drug resistant cells. The above results are shown in Table 5.

[0094]

[Table 5]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location C07D 401/06 209 8829-4C 401/12 209 8829-4C 401/14 209 8829-4C 409/14 213 8829-4C (72) Toshihiro Takahashi 1-25, Kishimachi, Kawagoe City, Saitama 53 (72) Masanori Sugita 50 50, Sanko-cho, Sakado City, Saitama Prefecture Inventor Chikako Suzuki Fujimi City, Saitama Prefecture Yamamuro 2 chome 23-22

Claims (2)

[Claims] 1. The following general formula (I): (Wherein R ¹ is hydrogen or the following formula: Wherein R is hydrogen, lower alkyl, lower alkoxy, halogen atom or nitro group,
X represents —CH ₂ —, —SO ₂ — or —CO—, R ² is hydrogen and a group of the following formula: R ³ is a group selected from the group consisting of: R ³ is dibenzylaminoethyl or the following formula: — (CH ₂ ).
a (CH ₂₎ a group represented by _n -Py, wherein, Y is _{-O - - l -Y m, -} S -, - NH -, - NMe- or -N (CO ₂ Et) - in And Py is a pyridyl or pyridonyl group, l is 1, 2 or 3, m is 0 or 1, n is 0 or 1
And Me represents methyl and Et represents ethyl).
The indole derivative represented by and its addition salt with a pharmacologically acceptable acid. 2. An anticancer agent containing the indole derivative represented by the general formula (I) or the pharmaceutically acceptable addition salt thereof with an acid according to claim 1 as an active ingredient.