JP3223193B2 - Indole derivatives and anticancer drug resistance overcoming substances containing them as active ingredients - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

2. Description of the Related Art Problems to be solved by the prior art and the present invention
Various anticancer drugs or anticancer drugs for leukemia, malignant lymphoma and the like have been developed. However, neither drug completely cures cancer.

[0003] For example, adriamycin is characterized by its broad anticancer spectrum, such as breast cancer, bladder cancer, lung cancer,
Antitumor effects against testicular tumors, malignant lymphomas and acute leukemias 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) arise. Such a problem is not limited to adriamycin, but also applies to other drugs.

[0004] This multidrug resistance is associated with a decrease in drug accumulation due to increased efflux of chemotherapeutic agents. This effect is 170
This is due to overexpression of a membrane protein called K-dalton p-glycoprotein. p-glycoprotein binds to the anticancer drug binding site and A
It has a TP binding site, and functions as a pump that discharges anticancer drugs out of cells by active elimination. This p
-Known compounds that suppress the function of glycoproteins include calcium antagonists such as verapamil and nifedipine, calmodulin inhibitors such as trifloperazine, and alkaloids such as cepharanthin and reserpine. The mechanism of action is that these compounds bind to the anticancer drug binding site of p-glycoprotein, thereby inhibiting the binding of the anticancer drug to p-glycoprotein.

[0005] As a means for overcoming the resistance to the anticancer drug, attempts have been made to simultaneously administer the anticancer drug and the above-mentioned compound. For example, by administering verapamil simultaneously with an anticancer drug, the active elimination function of the anticancer drug in the resistant cancer cells is inhibited, and the concentration of the anticancer drug in the cancer cells is increased 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 antihypertensive effect, which is the main effect of the calcium antagonist, appears as a side effect. Sufficient and poor resistance overcoming 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 for finding a compound which does not have side effects such as blood pressure lowering action and strongly suppresses the function of P-glycoprotein, The inventors have found that an indole derivative has an action of strongly suppressing the function of p-glycoprotein, and have 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]

Embedded image Wherein R ¹ is hydrogen or the following formula:

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

Embedded image 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) —, Py is a pyridyl or pyridonyl group, 1 is 1, 2 or 3, m is 0 or 1, n is 0 or 1. And Me represents methyl and Et represents ethyl).

The compound of the present invention represented by the general formula (I),
And a salt thereof with a pharmacologically acceptable acid are shown to exhibit anticancer and anticancer activity-enhancing activity in a test described later. 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 represented by the general formula (I) of the present invention can be synthesized by various methods depending on the types of the substituents R ¹ , R ² and R ³ on the indole ring.
Typical examples of the synthetic route are the following Schemes 1 and 2.
Can be shown).

Scheme 1

Embedded image

[Wherein R ′ and R ″ are hydrogen, M
e, n-Bu, Ph,

Embedded image And -COOMe, wherein R "" is Ac, -C
H ₂ -S-Me. ]

Scheme 2

Embedded image [Where l, m, Y, and Py are as defined above. ]

The compound represented by the general 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. Things. 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 medicament, it can be formulated into various dosage forms. That is, this preparation is orally administered as tablets, dragees, hard capsules, soft capsules, solvents,
It can be administered in the form of a solution in the form of an emulsion or suspension. 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.

Hereinafter, the present invention will be described in more detail by way of examples. However, this is merely for explanation 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

Embedded image

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

Embedded image Indole (23.4 g) and 2-vinylpyridine (23.1 g) were dissolved in acetic acid and heated under reflux for 8 hours.
After the acetic acid was distilled off under reduced pressure, the residue was dissolved in chloroform.
After washing with a 0% aqueous sodium hydroxide solution and drying (anhydrous sodium sulfate), 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) was dissolved in benzene (150 ml), and tetra-n-butyl hydrogen sulfate was dissolved. Ammonium (2
After adding g), an aqueous solution of sodium hydroxide (50%, 50 ml) and phenylsulfonyl chloride (24 g) were added dropwise with vigorous stirring under ice cooling. After reacting at room temperature for 2 hours, water was added, the organic layer was separated, dried (anhydrous sodium sulfate), and the residue obtained by evaporating the solvent 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

Embedded image 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 a yield of 9
Obtained at 2%.

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

Embedded image The procedure of Example 1 was repeated except that 4-methoxyphenylsulfonyl chloride was used in place of phenylsulfonyl chloride in step ii), to give the title compound in a yield of 94%.

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

Embedded image The procedure of Example 1 was repeated except that 4-chlorophenylsulfonyl chloride was used in place 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

Embedded image The procedure of Example 1 was repeated except that 4-bromophenylsulfonyl chloride was used in place 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

Embedded image The procedure of Example 1 was repeated except that 4-fluorophenylsulfonyl chloride was used in place of phenylsulfonyl chloride in step ii), to give the title compound in a yield of 57%.

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

Embedded image The title compound was obtained by repeating the procedure of Example 1 except that 4-nitrophenylsulfonyl chloride was used in place of phenylsulfonyl chloride in step ii).

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

Embedded image 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) was added, followed by benzyl chloride (0.8 g), and the mixture was reacted 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 resulting residue was purified by silica gel column chromatography to obtain the desired product (0.9 g) (yield 92%). Was.

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

Embedded image The procedure of Example 8 was repeated, except that benzoyl chloride was used instead of benzyl chloride, to give the title compound in a yield of 88%.

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

[0032]

[Table 1]

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

Embedded image

I) Preparation of 3- (2- (4-pyridyl) ethyl) indole The reaction of Example 1 was repeated except that 4-vinylpyridine was used instead of 2-vinylpyridine in the reaction procedure i) of Example 1. The procedure 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 reaction compound of ii) of Example 1 was repeated on 3- (2- (4-pyridyl) ethyl) indole obtained by the reaction operation of i) 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

Embedded image In a stream of argon, 1-phenylsulfonyl-3- (2-
(2-Pyridyl) ethyl) indole (2.0 g) was dissolved in dry tetrahydrofuran (10 ml) and n-
Butyllithium (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 ammonium chloride solution was added to the reaction solution, the solvent was distilled off, and the mixture was extracted with ethyl acetate, washed with water, dried (anhydrous sodium sulfate), and the solvent was distilled off. 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

Embedded image The reaction procedure of Example 11 was repeated except that benzaldehyde was used instead of pyridine-3-aldehyde, to give the title compound in a yield of 42%.

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

Embedded image The reaction procedure of Example 11 was repeated except that 2-thiophenaldehyde 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

Embedded image The reaction procedure of Example 11 was repeated except that quinoline-4-aldehyde was used instead of pyridine aldehyde to give the title compound in a yield of 38%.

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

Embedded image The reaction procedure of Example 11 was repeated except that 4-pyridinealdehyde was used instead of 3-pyridinealdehyde, to give the title compound in a yield of 62%.

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

Embedded image The same procedure as in Example 11 was repeated except that methyl acetoformate was used instead of pyridine aldehyde to give the title compound as 3
Obtained in 5% yield.

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

Embedded image The reaction procedure of Example 11 was repeated except that pentylaldehyde was used instead of pyridinealdehyde, to give the title compound in a yield of 53%.

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

Embedded image 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 evaporating the solvent, the residue was dissolved in ethyl acetate, washed with saturated saline, dried (anhydrous sodium sulfate), and evaporated. 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

Embedded image 1-phenylsulfonyl-2- (1-hydroxy) pentyl-3- (2- (2-pyridyl) ethyl) indole was subjected to the same reaction 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

Embedded image 1-phenylsulfonyl-2- (1-methoxycarbonyl-1-hydroxy) ethyl-3- (2- (2-pyridyl) ethyl) indole (N-3630) (0.5 g)
Was dissolved in dimethyl sulfoxide (5 ml), acetic anhydride (6 ml) was added, and the mixture was allowed to stand at room temperature overnight. The reaction solution was dissolved in chloroform, washed with a 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 (0.1%). 31 g) was obtained.

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

Embedded image 1-phenylsulfonyl-2- obtained in Example 17
(1-Hydroxy) pentyl-3- (2- (2-pyridyl) ethyl) indole (0.4 g) was dissolved in dimethyl sulfoxide (5 ml) and acetic anhydride (6 ml) was added.
Left at room temperature overnight. The reaction solution was dissolved in chloroform, washed with a 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 (0.1%). 16 g) were obtained.

The physical properties of the compounds obtained in 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

Embedded image 2- (3-indole) ethanol (0.5 g) was dissolved in benzene (50 ml), tetra-n-butylammonium hydrogen sulfate (0.5 g) was added, and 50% sodium hydroxide was added under vigorous stirring under ice-cooling. An aqueous solution (25 ml) and phenylsulfonyl chloride (11.2 g) were added dropwise. After reacting at room temperature for 30 minutes, water was added, the organic layer was separated, dried (anhydrous sodium sulfate) and the solvent was distilled off. The residue obtained 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) was added. ) Ethyl indole (2.8 g)
Allowed to react for hours. The reaction mixture was poured into benzene, washed with water, dried (anhydrous sodium sulfate) and evaporated, and the obtained residue was purified by silica gel column chromatography and recrystallized from ether to give the title compound (0.95 g). 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)

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

[0056]

Embedded image 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

Embedded image The title compound was obtained by repeating the reaction procedure of Example 22 except that 2-mercaptopyridine was used instead of 2-hydroxypyridine.

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

Embedded image The title compound was obtained by repeating the reaction procedure of Example 22 except that N-ethoxycarbonyl-2-aminopyridine was used instead of 2-hydroxypyridine.

Mp. Oil 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

Embedded image Instead of 2- (3-indole) ethanol, 3- (3-indole)
The title compound was obtained by repeating the reaction procedure of Example 22 except that indole) propanol was used.

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)

By the above reaction, simultaneously, 1-phenylsulfonyl-3- (3- (1- (2-pyridonyl))
Propyl) indole

Embedded image I 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

Embedded image Instead of 2- (3-indole) ethanol, 3- (3-indole)
The title compound was obtained by repeating the reaction procedure of Example 23 except that indole) propanol was used.

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

Embedded image 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), a 15% aqueous sodium hydroxide solution (0.5 ml) and water (1.5 ml) were sequentially added, and the purified precipitate was separated by filtration 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

Embedded image 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 mixture was reacted for 30 minutes. Pour the reaction solution into benzene,
The residue obtained by washing with water, drying (anhydrous sodium sulfate) and distilling off 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

Embedded image The title compound was obtained by repeating the reaction procedure of Example 28 except that 2-hydroxypyridine was used instead of 2-mercaptopyridine.

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

Embedded image The title compound was obtained by repeating the reaction procedure of Example 28 except that 2- (mercaptomethyl) pyridine was used instead of 2-mercaptopyridine.

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

Embedded image 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. Purification by silica gel column chromatography and recrystallization from ether gave 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

Embedded image The title compound was obtained by repeating the reaction procedure of Example 31 except that 2- (aminomethyl) pyridine was used instead of 2- (methylamino) pyridine.

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

Embedded image 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. I let it.
The solvent was distilled off, the residue was dissolved in chloroform, washed with water, dried (anhydrous sodium sulfate), and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography to obtain the title compound (0.25 g). 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

Embedded image In an argon stream, 1- (4-methylphenylsulfonyl) -3- (2- (2-pyridyl) ethyl) indole (2.0 g) was dissolved in dry tetrahydrofuran (10 ml), and n-butyllithium (1 5.5M, 5.5ml)
Was added dropwise 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 ammonium chloride solution was added to the reaction solution, the solvent was distilled off, and the mixture 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

Embedded image 1- (4-methylphenylsulfonyl) -3- (2-
Instead of (2-pyridyl) ethyl) indole, 1-
The title compound was obtained by repeating the reaction procedure of Example 34 except that (4-methylphenylsulfonyl) -3-dibenzylaminoethyl-indole was used.

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 with reference to the examples. Next, the function of the compound of the present invention for suppressing the function of p-glycoprotein and for enhancing the anticancer activity will be described. This will be specifically described in an example.

Example 36 Inhibitory Action of p-Glycoprotein p-Glycoprotein has an anticancer drug binding site, and actively excretes after binding the intracellular anticancer drug. The effect of suppressing the binding of the anticancer drug to p-glycoprotein was examined by the following method.

The drug-resistant strain (KB-C2) of human nasal epidermis-derived tumor cells (KB) was 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 as described by Akiyama et al. (Akiyama,
S. et al, Mol. Pharmacol. 33: 144-147, 1
988).

The function-suppressing action of p-glycoprotein on cell membrane vesicles has been confirmed to bind to the binding site of p-glycoprotein to an anticancer drug. Binding of [ ³ H] azidopine to p-glycoprotein Was examined in terms of the effect of suppressing

The cell membrane vesicles were reacted with 0.7 μM [ ³ H] azidopine (53 Ci / mmol) for 15 minutes at room temperature in the presence or absence of a drug. After that, light of 366 nm
Irradiated at 5 ° C for 20 minutes to bind to p-glycoprotein [ ³
H] Azidopine was irreversibly bound to p-glycoprotein.
Thereafter, the method of Yoshimura et al. (Yoshimura, A. et al. JBC.
264, 16282-16291, 1989), the reaction solution is subjected to SDS-polyacrylamide gel electrophoresis, followed by autoradiogram for 4 days, and the density of the band derived from p-glycoprotein on the autoradiogram is measured. Accordingly, the amount of [ ³ H] azidopine bound to p-glycoprotein was measured. The inhibition of binding of ^[3 H] Ajidopin of p- glycoprotein was calculated by the following equation.

[0090]

(Equation 1)

The results are as shown in Table 4.

[0092]

[Table 4]

Example 37 Enhancing activity of anticancer activity Drug-resistant strain KB- of human nasal epidermis-derived tumor cells (KB)
After culturing 1 × 10 ⁵ C-2 cells in a 60 mm diameter Petri dish in an Eagle's medium for 18 hours, vincristine and the indole derivative of the present invention were each 0.1 μg / ml,
It was added alone or in combination at a concentration of 3 μg / ml and cultured for another 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 cell count was calculated using a hemocytometer. As a result, cell growth was not inhibited by adriamycin, vincristine or the indole derivative of the present invention alone. In contrast, it was found 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 results are shown in Table 5.

[0094]

[Table 5]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07D 401/14 C07D 401/14 409/14 409/14 (72) Inventor Toshihiro Takahashi 1-25-25 Kishimachi, Kawagoe-shi, Saitama 53 (72) Inventor Masanori Sugita 50-16 Sanmitsu-cho, Sakado-shi, Saitama (72) Inventor Chikako Suzuki 2-23-22 Yamamuro, Fujimi-shi, Saitama (58) Field surveyed (Int.Cl. ⁷ , DB name) C07D 401/06 C07D 401/12 C07D 401/14 C07D 409/14 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. The following general formula (I): And an addition salt thereof with a pharmacologically acceptable acid. In the above formula, R ¹ is the following formula: Wherein R is hydrogen, lower alkyl, lower alkoxy, a halogen atom or a nitro group,
X represents —SO ₂ —, R ² represents hydrogen and a group of the following formula: 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 Wherein 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 is methyl, Et.
Represents ethyl. Provided that R is hydrogen and R ² is R ³ is Except in the case of. 2. In the formula (I), R ² is hydrogen. R ³ is The indole derivative according to claim 1, which is represented by the formula: 3. A general formula according to claim 1 or 2.
An anticancer agent comprising, as an active ingredient, the indole derivative represented by (I) or an addition salt thereof with a pharmacologically acceptable acid.