JP2004307487A - Indolylmaleimides - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a compound capable of blocking a protein kinase, inhibiting neovascularization and blocking topoisomerase, so as to have anticancer activity, and therefore, useful as a prophylactic or therapeutic agent for cancer. <P>SOLUTION: The subject compound expressed by formula (I) (R<SP>1</SP>is a substituent positioned on one of nitrogen atoms of imidazole ring, and is H, an alkyl or an alkoxyalkyl; and R<SP>2</SP>is H, an alkyl or an alkoxyalkyl), its salt, a solvate of the same and a pharmaceutical containing the same are provided, respectively. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention has excellent inhibitory activity on the tyrosine kinase of Flt (fms-like tyrosine kinase) -1, which is one of the vascular endothelial cell growth factor (VEGF) receptors, The present invention relates to novel indolylmaleimides having a newborn inhibitory effect and an anticancer effect, and a medicament containing the same as an active ingredient.

  Since cancer cells have a strong proliferation ability, they have a strong angiogenesis effect to obtain nutrition and oxygen. Cancer cells have the ability to produce VEGF. The VEGF binds to Flt-1, which is a receptor present in vascular endothelial cells, thereby activating the Flt-1 protein kinase. As a result, the intracellular signal transduction system acts to proliferate vascular endothelial cells. And angiogenesis occurs. Therefore, compounds having protein kinase inhibitory activity, such as tyrosine kinase, inhibit angiogenesis and are expected as excellent cancer therapeutics.

  On the other hand, a granulatimide (Formula (A)) containing an indole-imidazole-maleimide ring found from the Brazilian sea shell (Brazilian ascidian) and a bis-indolyl found from a pigment component containing slime mold (Slime mold) Arcyriacyanin A (Formula (B)), which is one of maleimides, is known to have a G2 checkpoint inhibitory action on the cell cycle (Non-Patent Documents 1 to 3). However, the protein kinase inhibitory action and the angiogenesis inhibitory action of these compounds are not known at all.

Cancer Res., 58 (24), 5701-5706 (1998) Chem. Pharm. Bull., 48, 81 (2000) Chem. Pharm. Bull., 50, 872 (2002)

  An object of the present invention is to provide a compound useful as a cancer preventive and therapeutic drug having an anticancer effect by inhibiting protein kinase and inhibiting angiogenesis and inhibiting topoisomerase.

  Thus, the present inventors have chemically synthesized a compound having an indolylmaleimide skeleton and studied its pharmacological action. As a result, the compound represented by the following general formula (1) showed an excellent inhibitory effect on Flt-1 tyrosine kinase and The present inventors have found that the compound has a topoisomerase inhibitory activity and has an anticancer activity, and is therefore useful as a cancer preventive / remedy, thereby completing the present invention.

  That is, the present invention provides the following general formula (1)

(Wherein, R ¹ is a substituent on one nitrogen atom of the imidazole ring and represents a hydrogen atom, an alkyl group or an alkoxyalkyl group, and R ² represents a hydrogen atom, an alkyl group or an alkoxyalkyl group)
And a salt thereof or a solvate thereof, and a method for producing the compound.

  Further, the present invention provides the following general formula (2-1) or (2-2), which is useful as a synthetic intermediate for the above-mentioned indolylmaleimides.

(In the formula, R ⁴ represents an alkyl group or an alkoxyalkyl group, R ³ represents a hydrogen atom or an amino protecting group, and a broken line indicates that this portion may be a double bond.)
Or a salt thereof or a solvate thereof.
The present invention also provides a Flt-1 kinase inhibitor containing the compound represented by the general formula (1), a salt thereof, or a solvate thereof.
The present invention also provides an angiogenesis inhibitor containing the compound represented by the above general formula (1), a salt thereof, or a solvate thereof.
The present invention also provides a topoisomerase inhibitor containing the compound represented by the above general formula (1), a salt thereof, or a solvate thereof.

  The present invention also provides a medicine comprising a compound represented by the above general formula (1), a salt thereof or a solvate thereof as an active ingredient.

  ADVANTAGE OF THE INVENTION According to this invention, the compound which has an excellent tyrosine kinase inhibitory effect of Flt-1 and which is useful as a cancer preventive and therapeutic agent based on an angiogenesis inhibitory effect and a topoisomerase inhibitory effect can be provided.

In the general formula (1), as the alkyl group represented by R ¹ and R ² , a linear or branched alkyl group having 1 to 6 carbon atoms is preferable, and a linear or branched alkyl group having 1 to 4 carbon atoms is particularly preferable. Alkyl groups are preferred. Specific examples of these alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. As the alkoxyalkyl group, a C _1-6 alkoxy-C _1-6 alkyl group is preferable, and a C _1-4 alkoxy-C _1-4 alkyl group is particularly preferable. Specific examples of these alkoxyalkyl groups include a methoxymethyl group and an ethoxyethyl group.

In the general formula (1), R ¹ is a substituent on one nitrogen atom of the imidazole ring and has a partial structure

Represents an imidazole ring. Therefore, the compound of the general formula (1) has the following two structures depending on the substitution position of R ¹ .

(Wherein R ¹ and R ² are the same as described above)

In the formula (1), a compound in which R ¹ and R ² are the same or different and each is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms is more preferable. Further, in the general formula (1), a compound in which R ¹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms and R ² is a hydrogen atom is more preferable.

  Examples of the salt of the compound (1) of the present invention include mineral salts such as hydrochloride, sulfate and nitrate, and organic acid salts such as acetate, succinate and maleate.

The compound (1) of the present invention may have various isomers depending on the types of the substituents of R ¹ and R ² , and the present invention includes these various isomers and mixtures thereof. The compound (1) of the present invention or a salt thereof also includes a solvate such as a hydrate.

  The compound (1) of the present invention or a salt thereof can be produced, for example, according to the following method.

(In the formula, R ⁴ represents an alkyl group or an alkoxyalkyl group, X ¹ , X ² and X ³ represent a halogen atom, and R ² and R ³ are the same as described above.)

  That is, the imidazole (3) and the tetrahydroindole (4) are subjected to a Grignard reaction to give a compound (5), which is subjected to a dehydration reaction to obtain a compound (6), which is oxidized to give a compound (6). The compound (8) is obtained by removing the amino protecting group from the compound (7). The compound (8) is reacted with an alkyl magnesium halide and then with the compound (9) to produce the compound (1a) of the present invention.

The Grignard reaction between the imidazoles (3) and the tetrahydroindoles (4) is carried out, for example, by reacting the imidazoles (3) with an alkylmagnesium halide such as ethylmagnesium bromide to give imidazole magnesium halides, and then adding the tetrahydroindoles ( This is carried out by reacting 4). X ³ in the formula (3) is preferably an iodine atom. In formula (4), the amino-protecting group represented by R ³ is preferably a group capable of leaving by a hydrolysis reaction such as a sulfonyl-protecting group such as a p-toluenesulfonyl group and a methanesulfonyl group. Examples of the alkyl magnesium halide used for the Grignard reaction include methyl magnesium bromide, ethyl magnesium bromide and the like. This Grignard reaction can be carried out according to the usual reaction between a Grignard reagent and a ketone.

  The dehydration reaction of compound (5) is performed, for example, by reacting compound (5) with an acid such as hydrochloric acid. The reaction is easily carried out, for example, by adding an acid in a solvent such as dichloromethane and stirring. The Grignard reaction and the dehydration reaction are preferably performed continuously without isolating the compound (5).

  The oxidation reaction of compound (6) is performed, for example, by reacting compound (6) with a dehydrogenating reagent such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and activated manganese dioxide. It is. The reaction may be performed in a solvent such as benzene at a temperature of 0 ° C to 100 ° C for 30 minutes to 3 hours.

The elimination reaction of the amino protecting group represented by R ³ of the compound (7) is preferably a hydrolysis reaction. The hydrolysis reaction is preferably performed in the presence of an alkali such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like.

  The reaction of the compound (8) with the alkylmagnesium halide and the compound (9) is carried out, for example, by adding the alkylmagnesium halide to the compound (8) and then adding the compound (9) in a solvent such as tetrahydrofuran, diethyl ether, benzene or toluene. The stirring may be performed at a temperature of 0 ° C to 100 ° C for 2 hours to 24 hours.

(Wherein, R ² , R ³ , R ⁴ , X ¹ and X ² are the same as described above)

That is, an imidazole (10) is reacted with an alkyl lithium and then a tetrahydroindole (4) to give a compound (11), which is subjected to a dehydration reaction to obtain a compound (12), which is oxidized. Thus, the compound (13) is obtained, and by removing the amino protecting group from the compound (13), the compound (15) is obtained. The compound (15) is reacted with an alkylmagnesium halide, and then reacted with the compound (9) to obtain a compound (16), which is reduced to produce the compound (1b) of the present invention.
Compound (15) can also be obtained by removing the amino protecting group of compound (12) and then oxidizing it.

  Examples of the alkyl lithium include butyl lithium, sec-butyl lithium, and tert-butyl lithium. The reaction between the imidazoles (10) and the alkyl lithium is carried out in a solvent such as n-hexane, tetrahydrofuran, n-pentane, cyclohexane or the like at a low temperature of -80 to -50 ° C. Further, the subsequent reaction with tetrahydroindoles may be performed in a solvent such as tetrahydrofuran, n-pentane, cyclohexane or the like at a temperature of room temperature to 100 ° C.

  The dehydration reaction of compound (11), the oxidation reaction of compound (12) and compound (14), and the elimination reaction of the amino protecting group of compound (12) and compound (13) can be carried out in the same manner as described above. . Further, the reaction between compound (15) and compound (9) is preferably carried out by heating to 50 to 200 ° C. in an alcohol such as methanol, ethanol or butanol after the same reaction as described above.

  The reduction reaction of compound (16) is performed using a Raney nickel catalyst or the like. For example, the reaction may be performed in a solvent such as methanol or ethanol in the presence of a Raney nickel catalyst.

Further, in the formula (1), the compound (1d) in which R ¹ is a hydrogen atom can be produced according to the following reaction formula.

(Wherein, R ^2a represents a hydrogen atom or an alkyl group, R ^4a is a substituent on one nitrogen atom of an imidazole ring, and represents an alkoxyalkyl group)

  That is, the compound (1d) can be produced by hydrolyzing the compound (1c). This reaction is preferably performed in the presence of a mineral acid such as hydrochloric acid or sulfuric acid.

  In the above reaction, in order to isolate the target substance from the reaction mixture, ordinary means such as washing, recrystallization and various types of chromatography can be used.

  As is clear from the above reaction formula, the indolylimidazoles or salts thereof represented by the general formulas (2-1) and (2-2) are synthesized intermediates of the compound (1) of the present invention or a salt thereof. Useful as

  The compound (1) of the present invention or a salt thereof has a tyrosine kinase inhibitory effect of Flt-1, a receptor present on vascular endothelial cells, and is useful as a Flt-1 kinase inhibitor and an angiogenesis inhibitor. Further, the compound (1) of the present invention or a salt thereof also has a cancer cell growth inhibitory action. Therefore, the compound (1) of the present invention or a salt thereof is useful as an agent for preventing and / or treating cancer in animals including humans.

  When the compound of the present invention is used as a medicament for human body, the dose is 1 mg to 1 g, preferably 10 mg to 300 mg per day for an adult. The dosage for animals may vary depending on the purpose of the administration (treatment or prevention), the type and size of the animal to be treated, the type and extent of the infected pathogen, but is generally regarded as a daily dose, and is generally the weight of the animal. The range is 0.1 mg to 200 mg, preferably 0.5 mg to 100 mg per kg. This daily dose is administered once a day or divided into 2 to 4 times. The daily dose may exceed the above-mentioned amount if necessary.

  The pharmaceutical composition containing the compound of the present invention can be prepared by selecting an appropriate preparation according to the administration method and preparing various commonly used preparations. As the dosage form of the pharmaceutical composition containing the compound of the present invention as a main component, for example, tablets, powders, granules, capsules, liquids, syrups, elixirs, oily or aqueous suspensions and the like can be exemplified as oral preparations. .

  Injectables may use stabilizers, preservatives, and solubilizing agents in the formulation.After storing solutions that may contain these adjuvants in containers, freeze-dry etc. to prepare them as solid preparations at the time of use. It may be a formulation. Further, a single dose may be stored in one container, or a multi-dose may be stored in one container.

  The solid preparation contains a pharmaceutically acceptable additive together with the compound of the present invention, and includes, for example, a filler, a bulking agent, a binder, a disintegrant, a dissolution promoter, a wetting agent, a lubricant and the like. They can be selected and mixed as needed to form a formulation.

  Liquid preparations include solutions, suspensions, emulsions, and the like, and may also contain suspending agents, emulsifiers, and the like as additives.

  Next, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

Example 1
(1) 4- (1-Tosyl-6,7-dihydroindol-4-yl) -1- (methoxymethyl) imidazole 144 mg of magnesium and 1.3 g of ethyl bromide were added to 3 mL of tetrahydrofuran, and the mixture was stirred at room temperature under a nitrogen atmosphere. Thus, an ethyl magnesium bromide solution was prepared. A solution of 1.19 g of 4-iodo-1-methoxymethylimidazole in methylene chloride (5 mL) was added to the above ethylmagnesium bromide solution, and the mixture was stirred for 5 minutes. A solution of 1.44 g of 4-oxo-1-tosyl-4,5,6,7-tetrahydroindole in methylene chloride (5 mL) was added dropwise thereto, and the mixture was stirred overnight. A 10% aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic phase was washed with saline and concentrated to dryness. The residue was subjected to silica gel chromatography (ethyl acetate) and recrystallized from ethyl acetate to obtain 1.58 g (yield 82%) of the title compound as a white powder.

mp 162-164 ℃
IR (KBr) cm ^-1 : 3434, 3088, 2946, 2590, 1451, 1371, 1173, 1130, 1087, 1059, 852, 814, 690, 664, 611, 572, 535.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.40 (3H, s, Ts-Me), 2.45 (2H, dt, J = 4.8 Hz, 9.2 Hz, -CH _2- ), 2.91 (2H, t, J = 9.2Hz, -CH _2- ), 3.28 (3H, s, O-Me), 5.22 (2H, s, N-CH _2- ), 6.19 (1H, t, J = 4.8Hz, Indole olefin-H) , 6.54 (1H, d, J = 3.5Hz, Indole H-3), 7.11 (1H, s, imidazole H-5), 7.21 (1H, d, J = 3.5Hz, Indole H-2), 7.28 (2H , d, J = 8.5Hz, Ts Ar-H), 7.59 (1H, s, imidazole H-2), 7.70 (2H, d, J = 8.5Hz, Ts Ar-H).
¹³ C-NMR (CDCl ₃ , 75.45 MHz) δ: 20.6, 21.6, 23.9, 56.2, 77.8, 109.8, 114.9, 118.9, 120.4, 122.3, 126.8 (x2), 127.1, 129.5, 130.0 (x2), 136.2, 137.1 , 141.3, 144.9.
LR-MS m / z: 383 [M ⁺ ].
HR-MS m / z: 383.1330 [M +] (Calcd for C 20 H 21 N 3 O 3 S, 383.1298).

(2) 4- (1-tosylindol-4-yl) -1- (methoxymethyl) imidazole 4- (1-tosyl-6,7-dihydroindol-4-yl) -1- (methoxymethyl) imidazole 1 0.53 g and 1.0 g of 97% DDQ were stirred in 30 mL of dry benzene at room temperature for 1 hour. After adding a 10% aqueous solution of NaOH, the mixture was extracted with methylene chloride. The extract was dried over Na ₂ SO ₄ and evaporated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate) to give 1.31 g (yield 86%) of the title compound as a colorless oil.

IR (KBr) cm ^-1 : 3124, 2934, 1595, 1365, 1175, 1127, 1108, 753, 675, 557.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.32 (3H, s, Ts-Me), 3.32 (3H, s, O-Me), 5.28 (2H, s, N-CH _2- ), 7.19 (2H , d, J = 8.6Hz, Ts Ar-H), 7.28 (1H, dd, J = 0.7Hz, 3.7Hz, Indole H-3), 7.32 (1H, t, J = 7.9Hz, indole Ar-H) , 7.37 (1H, d, J = 1.3Hz, imidazole H-5), 7.59 (1H, dd, J = 0.9Hz, 7.9Hz, indole Ar-H), 7.61 (1H, d, J = 3.7Hz, indole H-2), 7.72 (1H d, J = 1.3Hz, imidazole H-2), 7.75 (2H, d, J = 8.6Hz, Ts Ar-H), 7.92 (1H, d, J = 8.3Hz, indole Ar-H).
¹³ C-NMR (CDCl ₃ , 75.45 MHz) δ: 21.5, 56.3, 78.0, 109.3, 112.4, 116.0, 121.1, 124.7, 126.4, 126.7 (x2), 126.8, 127.8, 129.8 (x2), 135.2, 135.5, 137.4 , 141.8, 144.9.
LR-MS m / z: 381 [M ⁺ ].
HR-MS m / z: 381.1181 [M +] (Calcd for C 20 H 19 N 3 O 3 S, 381.1142).

(3) 4- (1H-indol-4-yl) -1- (methoxymethyl) imidazole 1.31 g of 4- (1-tosylindol-4-yl) -1- (methoxymethyl) imidazole and K ₂ CO ₃ 1.42 g was added to a solution of methanol (35 mL) -water (15 mL), and the mixture was heated under reflux for 24 hours. The reaction mixture was concentrated, the residual solid was filtered, washed with water, dried and recrystallized from ethyl acetate to obtain 740 mg (yield 95%) of the title compound as a white powder.

mp 210-211 ℃
IR (KBr) cm ^-1 : 3090, 2912, 1502, 1437, 1390, 1342, 1271, 1201, 1185, 1105, 1081, 1029, 985, 921, 888, 813, 788, 748, 731, 629.
¹ H-NMR (DMSO-d ₆ , 500 MHz) δ: 3.27 (3H, s, O-Me), 5.37 (2H, s, N-CH _2- ), 6.93-6.94 (1H, m, indole H-3 ), 7.10 (1H, t, J = 7.6Hz, Indole Ar-H), 7.30 (1H, d, J = 7.9Hz, Indole Ar-H), 7.38 (1H, t, J = 2.8Hz, Indole H- 2), 7.56 (1H, dd, J = 0.9Hz, 7.3Hz, Indole Ar-H), 7.82 (1H, d, J = 1.2Hz, imidazole H-5), 7.90 (1H, d, J = 1.2Hz) , Imidazole H-2), 11.13 (1H, s, indole NH).
¹³ C-NMR (DMSO-d ₆ , 125.65 MHz) δ: 55.5, 76.8, 101.3, 109.9, 116.0, 116.6, 120.8, 123.9, 125.1, 125.8, 136.5, 137.8, 141.2.
LR-MS m / z: 227 [M ⁺ ].
HR-MS m / z: 227.1067 [M +] (Calcd for C 13 H 13 N 3 O, 227.1056).

(4) 4- (methoxymethyl) -imidazo [4 ″, 5 ″: 4,5] pyrrolo [3 ′, 4 ′: 6,7] cyclohept [1,2,3-cd] indole-1,3- Dione (in the formula (1), R ¹ = —CH ₂ OCH ₃ , R ² = H)
To a solution of 113 mg of 4- (1H-indol-4-yl) -1- (methoxymethyl) imidazole, 36 mg of Mg and 5 mL of tetrahydrofuran was added 327 mg of ethyl bromide, and the mixture was stirred until Mg was dissolved. A mixture of 127 mg of 3,4-dibromomaleimide and 2 mL of tetrahydrofuran was added dropwise thereto, and the mixture was stirred overnight. An aqueous ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with a saline solution, and evaporated to dryness. The residue was subjected to column chromatography (ethyl acetate) and recrystallized from acetone-n-hexane to obtain 73 mg (yield 46%) of the title compound as a blue powder.

mp> 300 ℃
IR (KBr) cm ^-1 : 3202, 1754, 1701, 1585, 1483, 1347, 1186, 1098, 740.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 3.19 (3H, s, O-Me), 5.68 (2H, s, -CH _2- ), 6.85-6.95 (2H, m, indole Ar-H) , 7.15 (1H, dd, J = 6.9Hz, 1.3Hz, Indole Ar-H), 7.76 (1H, d, J = 2.8Hz, Indole H-2), 7.93 (1H, s, Imidazole H-2), 10.94 (1H, br, CO-NH-CO), 11.55 (1H, br, Indole NH).
¹³ C-NMR (DMSO-d ₆ , 75.45 MHz) δ: 55.3, 79.1, 109.7, 110.9, 114.7, 120.0, 121.5, 124.5 (x2), 130.2, 130.5, 135.1, 137.4, 144.0, 145.1, 169.9, 170.2.
LR-MS m / z: 320 [M ⁺ ].
HR-MS m / z: 320.0932 [M +] (Calcd for C 17 H 12 N 4 O 3, 320.0907).

Example 2
2-methyl-4- (methoxymethyl) -imidazo [4 ″, 5 ″: 4,5] pyrrolo [3 ′, 4 ′: 6,7] cyclohept [1,2,3-cd] indole-1,3 -Dione (in the formula (1), R ¹ = —CH ₂ OCH ₃ , R ² = CH ₃ )
Using 56 mg of 4- (1H-indol-4-yl) -1- (methoxymethyl) imidazole and 67 mg of N-methyl-3,4-dibromomaleimide, the reaction was carried out in the same manner as in Example 1 (4) to give acetone-. Recrystallization from n-hexane gave 34 mg (yield 41%) of the title compound as a blue powder.

mp> 300 ℃
IR (KBr) cm ^-1 : 3196, 1754, 1692, 1583, 1483, 1438, 1385, 1184, 1103, 1076, 975, 716.
^{1 H-NMR (DMSO-d} 6, 300MHz) δ: 2.88 (3H, s, N-Me), 3.12 (3H, s, O-Me), 5.63 (2H, s, N-CH 2 -), 6.78 -6.88 (2H, m, Indole Ar-H), 7.08 (1H, dd, J = 7.0Hz, 1.3Hz, Indole Ar-H), 7.72 (1H, d, J = 2.9Hz, Indole H-2), 7.86 (1H, s, imidazole H-2), 11.50 (1H, br, indole NH).
¹³ C-NMR (DMSO-d ₆ , 75.45 MHz) δ: 23.7, 55.3, 79.1, 109.9, 111.0, 114.7, 119.2, 121.6, 124.6 (x2), 130.2, 130.5, 134.7, 137.5, 144.1, 145.0, 168.6, 169.0.
LR-MS m / z: 334 [M ⁺ ].
HR-MS m / z: 334.1048 [M +] (Calcd for C 18 H 14 N 4 O 3, 334.1063).

Example 3
1H-imidazo [4 ″, 5 ″: 4,5] pyrrolo [3 ′, 4 ′: 6,7] cyclohept [1,2,3-cd] indole-1,3-dione (in the formula (1) R ¹ = R ² = H)
To 32 mg of the compound obtained in Example 1 (4) was added 4 mL of a 10% aqueous hydrochloric acid solution, and the mixture was heated to 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature, and the aqueous solution was made basic by addition of an aqueous solution of NaHCO ₃ . The remaining solid was collected and recrystallized from acetone-n-hexane to give 24 mg (yield 87%) of the title compound as a blue powder.

mp> 300 ℃
IR (KBr) cm ^-1 : 3356, 1749, 1697, 1632, 1523, 1353, 1334, 1177, 1104, 739, 529.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 6.73-6.82 (2H, m, indole Ar-H), 7.00 (1H, dd, J = 6.6 Hz, 1.5 Hz, indole Ar-H), 7.48 ( 1H, s, imidazole H-2), 7.55 (1H, d, J = 2.6Hz, indole H-2), 10.80 (1H, s, CO-NH-CO), 11.35 (1H, s, indole NH), 11.73 (1H, s, imidazole NH).
¹³ C-NMR (DMSO-d ₆ , 75.45 MHz) δ: 110.5, 110.8, 113.5, 118.8, 120.9, 122.8, 124.5, 129.4, 130.4, 130.6, 137.9, 139.4, 142.7, 170.9, 171.3.
LR-MS m / z: 276 [M ⁺ ].
HR-MS m / z: 276.0668 [M +] (Calcd for C 15 H 8 N 4 O 2, 276.0646).

Example 4
2-methyl-1H-imidazo [4 ″, 5 ″: 4,5] pyrrolo [3 ′, 4 ′: 6,7] cyclohept [1,2,3-cd] indole-1,3-dione (formula ( 1), where R ¹ = H, R ² = CH ₃ )
23 mg of the compound obtained in Example 3 was treated with a 10% aqueous hydrochloric acid solution (2 mL) in the same manner as in Example 3, and recrystallized from acetone-n-hexane to obtain 17 mg (yield: 85%) of the title compound as a blue powder. Was.

mp> 300 ℃
IR (KBr) cm ^-1 : 3356, 1751, 1690, 1631, 1438, 1383, 1328, 1175, 1102, 737.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 2.88 (3H, s, N-Me), 6.73-6.81 (2H, m, indole Ar-H), 7.00 (1H, d, J = 6.8 Hz, Indole Ar-H), 7.49 (1H, s, imidazole H-2), 7.56 (1H, s, indole H-2), 11.35 (1H, s, indole NH), 11.76 (1H, s, imidazole NH).
¹³ C-NMR (DMSO-d ₆ , 75.45 MHz) δ: 23.4, 110.6, 110.8, 113.5, 118.2, 120.9, 122.7, 124.6, 129.4, 129.9, 130.6, 138.0, 139.5, 142.6, 169.6, 169.9.
LR-MS m / z: 290 [M ⁺ ].
HR-MS m / z: 290.0785 [M +] (Calcd for C 16 H 10 N 4 O 2, 290.0802).

Example 5
(1) 4- (1-Tosyl-6,7-dihydroindol-4-yl) -1-methylimidazole As in Example 1 (1), 3.56 g of 4-iodo-1-methylimidazole was treated with ethyl magnesium bromide. And then reacted with 4.91 g of 4-oxo-1-tosyl-4,5,6,7-tetrahydroindole and recrystallized from ethyl acetate to give the title compound as a white powder, 5.42 g (yield). 90%).

mp 136-137 ℃
IR (KBr) cm ^-1 : 3352, 3116, 1632, 1594, 1361, 1173, 1125, 813, 698, 666, 615, 574, 536.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.39 (3H, s, Ts-Me), 2.42 (2H, dt, J = 9.2 Hz, 4.8 Hz, -CH _2- ), 2.89 (2H, t, J = 9.2Hz, -CH _2- ), 3.67 (3H, s, N-Me), 6.11 (1H, t, J = 4.8Hz, indole olefin-H), 6.53 (1H, d, J = 3.4Hz, indole H-3), 6.93 (1H, s, imidazole H-5 '), 7.20 (1H, d, J = 3.4Hz, Indole H-2), 7.28 (2H, d, J = 8.2Hz, Ts Ar-H ), 7.40 (1H, s, imidazole H-2), 7.69 (2H, d, J = 8.2Hz, Ts Ar-H).
¹³ C-NMR (CDCl ₃ , 75.45 MHz) δ: 20.6, 21.6, 23.9, 33.4, 109.9, 116.4, 118.2, 120.4, 122.6, 126.8 (x2), 127.4, 129.4, 129.9 (x2), 136.2, 137.4, 140.7 , 144.8.
LR-MS m / z: 353 [M ⁺ ].
HR-MS m / z: 353.1198 [M ⁺ ] (Calcd for C ₁₉ H ₁₉ N ₃ O ₂ S, 353.1193).

(2) 4- (1-Tosylindol-4-yl) -1-methylimidazole As in Example 1 (2), 1.06 g of the compound obtained in Example 5 (1) was reacted with 749 mg of DDQ. Thus, 825 mg (yield 78%) of the title compound was obtained as an oil.

IR (KBr) cm ^-1 : 3124, 2946, 1595, 1365, 1181, 1127, 752, 674, 577.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.31 (3H, s, Ts-Me), 3.73 (3H, s, N-Me), 7.18 (2H, d, J = 7.5 Hz, Ts Ar-H) , 7.20 (1H, s, imidazole H-5), 7.28 (1H, dd, J = 3.7Hz, 0.7Hz, indole H-3), 7.30 (1H, t, J = 7.9Hz, indole Ar-H), 7.52 (1H, s, imidazole H-2), 7.55 (1H, dd, J = 7.5Hz, 0.9Hz, indole Ar-H), 7.60 (1H, d, J = 3.7Hz, indole H-2), 7.74 (2H, d, J = 8.3Hz, Ts Ar-H), 7.90 (1H, d, J = 8.3Hz, indole Ar-H).
¹³ C-NMR (CDCl ₃ , 75.45 MHz) δ: 21.5, 33.5, 109.4, 112.1, 117.5, 120.9, 124.7, 126.3, 126.8 (x2), 127.48, 127.8, 129.8 (x2), 135.2, 135.5, 137.8, 141.3 , 114.8.
LR-MS m / z: 351 [M ⁺ ].
HR-MS m / z: 351.1055 [M ⁺ ] (Calcd for C ₁₉ H ₁₇ N ₃ O ₂ S, 351.1037).

(3) 4- (1H-indol-4-yl) -1-methylimidazole In the same manner as in Example 1 (3), 952 mg of K ₂ CO ₃ was reacted with 819 mg of the compound obtained in Example 5 (2). Recrystallization from ethyl acetate gave 420 mg (93% yield) of the title compound as colorless needles.

mp 283-285 ℃
IR (KBr) cm ^-1 : 3140, 2916, 1510, 1418, 1342, 1220, 1078, 990, 889, 823, 748, 619.
^{1 H-NMR (DMSO-d} 6, 500MHz) δ: 3.72 (3H, s, N-Me), 6.91-6.92 (1H, m, indole H-3), 7.08 (1H , t, J = 7.9Hz, Indole Ar-H), 7.26 (1H, d, J = 7.9Hz, Indole Ar-H), 7.35 (1H, t, J = 2.8Hz, Indole H-2), 7.50 (1H, d, J = 7.6Hz) , Indole Ar-H), 7.65 (1H, s, imidazole H-5), 7.66 (1H, s, imidazole H-2), 11.10 (1H, s, indole NH).
¹³ C-NMR (DMSO-d ₆ , 125.65 MHz) δ: 32.9, 101.4, 109.5, 115.7, 117.7, 120.8, 123.8, 124.9, 126.3, 136.5, 137.7, 140.8.
LR-MS m / z: 197 [M ⁺ ].
HR-MS m / z: 197.0956 [M +] (Calcd for C 12 H 11 N 3, 197.0951).

(4) 4-methyl-imidazo [4 ″, 5 ″: 4,5] pyrrolo [3 ′, 4 ′: 6,7] cyclohept [1,2,3-cd] indole-1,3-dione (formula (1), R ¹ = CH ₃ , R ² = H)
Similarly to Example 1 (4), 49 mg of the compound obtained in Example 5 (3) was reacted with ethylmagnesium bromide, followed by 63 mg of 3,4-dibromomaleimide, and recrystallized from acetone-n-hexane. Thus, 15 mg (yield 21%) of the title compound was obtained as a blue powder.

mp> 300 ℃
IR (KBr) cm ^-1 : 3182, 2922, 1756, 1707, 1584, 1489, 1464, 1342, 1183, 736.
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 3.76 (3H, s, N-Me), 6.83-6.92 (2H, m, indole Ar-H), 7.13 (1H, dd, J = 1.5 Hz, 6.6Hz, Indole Ar-H), 7.70 (1H, d, J = 1.8Hz, Imidazole H-2), 7.76 (1H, d, J = 2.6Hz, Indole H-2), 10.88 (1H, s, CO -NH-CO), 11.50 (1H, s, Indole NH).
¹³ C-NMR (DMSO-d ₆ , 75.45 MHz) δ: 35.9, 109.9, 110.5, 114.3, 119.9, 123.3, 124.1, 124.4, 130.3, 130.5, 134.9, 137.3, 144.1, 170.06, 170.09.
LR-MS m / z: 290 [M ⁺ ].
HR-MS m / z: 290.0815 [M ⁺ ] (Calcd for C ₁₆ H ₁₀ N ₄ O ₂ , 290.0802).

Example 6
2,4-dimethyl-imidazo [4 ", 5": 4,5] pyrrolo [3 ', 4': 6,7] cyclohept [1,2,3-cd] indole-1,3-dione (formula ( 1), where R ¹ = R ² = CH ₃ )
Similarly to Example 1 (4), 49 mg of the compound obtained in Example 5 (3) was reacted with ethylmagnesium bromide, and then reacted with 67 mg of N-methyl-3,4-dibromomaleimide to give acetone-n-hexane. To give 26 mg (34% yield) of the title compound as a blue powder.

mp 246-248 ℃
IR (KBr) cm ^-1 : 3160, 2896, 1757, 1697, 1586, 1439, 1385, 1180, 1071, 736.
^{1 H-NMR (DMSO-d} 6, 500MHz) δ: 2.89 (3H, s, CO-NMe-CO), 3.71 (3H, s, NMe), 6.80 (1H, d, J = 8.2Hz, indole Ar-H), 6.84 (1H, t, J = 8.2Hz, indole Ar-H), 7.06 (1H, d, J = 7.3Hz, indole Ar-H), 7.66 (1H, s, imidazole H-2) , 7.73 (1H, s, Indole H-2), 11.48 (1H, s, Indole NH).
¹³ C-NMR (DMSO-d ₆ , 125.65 MHz) δ: 23.6, 35.9, 110.0, 110.5, 114.2, 119.1, 123.3, 124.1, 124.5, 130.2, 130.4, 134.3, 137.4, 144.0, 144.1, 168.8, 168.9.
LR-MS m / z: 304 [M ⁺ ].
HR-MS m / z: 304.0997 [M +] (Calcd for C 17 H 12 N 4 O 2, 304.0958).

Example 7
(1) 1-Methyl-2- (phenylthio) imidazole In a nitrogen atmosphere at -78 ° C, an n-hexane solution of n-butyllithium (2.6 M, 40 mL) was added to tetrahydrofuran (8.2 g) of 1-methylimidazole (8.2 g). 100 mL) solution and stirred for 30 minutes. Then, a solution of diphenyl disulfide (24 g) in tetrahydrofuran was added, and the mixture was slowly warmed to room temperature and stirred overnight. An aqueous NH ₄ Cl solution was added to the reaction mixture, extracted with ethyl acetate, washed with a physiological saline solution, and then dried by evaporation. The residue was subjected to silica gel column chromatography (acetone: n-hexane = 1: 2) to give 17.2 g (yield 90%) of the title compound as a colorless oil.

IR (KBr) cm ^-1 : 2948, 1476, 1454, 1278, 1121, 1079, 686.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 3.62 (3H, s, N-Me), 7.07 (1H, d, J = 1.1 Hz, H-5), 7.11-7.28 (5H, m, SPh-H ), 7.18 (1H, d, J = 1.3Hz, H-4).
¹³ C-NMR (CDCl ₃ , 75.45 MHz) δ: 33.8 (N-Me), 123.8 (C-5), 126.4 (SPh-C), 127.8 (SPh-C), 129.1 (SPh-C), 130.1 ( C-4), 134.8 (SPh-C), 137.9 (C-2).
LR-MS m / z: 190 [M ⁺ ].
HR-MS m / z: 190.0596 [M ⁺ ] (Calcd for C ₁₀ H ₁₀ N ₂ S, 190.0566).

(2) 5- (4-Hydroxy-1-tosyl-4,5,6,7-tetrahydroindol-4-yl) -1-methyl-2- (phenylthio) imidazole 1-78 ° C. under nitrogen atmosphere To a solution of methyl-2- (phenylthio) imidazole (19 g) in tetrahydrofuran (100 mL) was added a solution of n-butyllithium in n-hexane (2.5 M, 40 mL), and the mixture was stirred for 15 minutes. To this was added dropwise a solution of 4-oxo-1-tosyl-4,5,6,7-tetrahydroindole (28.9 g) in tetrahydrofuran (100 mL), and the mixture was slowly warmed to room temperature and stirred overnight. An aqueous NH ₄ Cl solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saline and evaporated to dryness. The residue was recrystallized from methanol to give the title compound (33.1 g, yield 69%) as a white solid.

mp 116-118 ℃
IR (KBr) cm ^-1 : 3210, 3128, 2936, 1443, 1367, 1175, 1123, 1094, 701, 677, 659, 577.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.69-1.71 (2H, m, -CH _2- ), 1.93-1.98 (2H, m, -CH _2- ), 2.40 (3H, s, Ts-Me) , 2.60 (1H, dt, J = 5.9Hz, 17.3Hz, -CH _2- ), 2.79 (1H, dt, J = 5.9Hz, 17.2Hz, -CH _2- ), 3.56 (3H, s, N-Me ), 6.19 (1H, d, J = 3.5Hz, indole H-3), 6.60 (1H, s, imidazole H-4), 7.07-7.25 (6H, m, indole H-2 and SPh-H), 7.29 (2H, d, J = 8.3Hz, Ts Ar-H), 7.67 (2H, d, J = 8.3Hz, Ts-Ar-H).
¹³ C-NMR (CDCl ₃ , 75.45 MHz) δ: 19.6, 21.6, 22.7, 32.9, 36.7, 69.2, 109.8, 121.8, 126.6, 126.7, 126.8 (SPh-C), 128.0 (SPh-C), 129.2 (Ts -C), 129.7, 130.1 (Ts-C), 131.0, 134.7, 135.9, 138.5, 139.8, 145.3.
LR-MS m / z: 461 [M-OH ₂ ] ⁺ .
FAB-MS m / z: 480 [M + H] ⁺ .
HR-FAB-MS m / z: 480.1398 [M + H] ⁺ (Calcd for C ₂₅ H ₂₆ N ₃ O ₃ S ₂ , 480.1418).

(3) 5- (1-tosyl-6,7-dihydroindol-4-yl) -1-methyl-2- (phenylthio) imidazole 5- (4-hydroxy-1-tosyl-4,5,6,7 -Tetrahydroindol-4-yl) -1-methyl-2- (phenylthio) imidazole (4.79 g) and p-toluenesulfonic acid (17 mg) were added to benzene (100 mL), and the mixture was added in a Dean-Stark tube under a nitrogen atmosphere. Heated to reflux for hours. Then, the solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate. The organic layer was washed with saline and evaporated to dryness. The residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain 4.25 g (yield 92%) of the title compound as an oil.

IR (KBr) cm ^-1 : 2948, 1594, 1477, 1442, 1370, 1175, 1127, 1087, 1002, 812, 743, 696, 666, 614, 572, 537.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.42 (3H, s, Ts-Me), 2.50 (2H, dt, J = 9.4 Hz, 4.6 Hz, indole H-6 -CH _2- ), 2.96 (2H , t, J = 9.4Hz, Indole H-7 -CH _2- ), 3.41 (3H, s, N-Me), 5.70 (1H, t, J = 4.6Hz, Indole H-5 Olefin-H), 5.93 (1H, d, J = 3.3Hz, indole H-3), 7.09 (1H, s, imidazole H-4), 7.14-7.30 (6H, m, indole, H-2 and SPh-H), 7.32 (2H , d, J = 8.1Hz, Ts Ar-H), 7.72 (2H, d, J = 8.4Hz, Ts Ar-H).
¹³ C-NMR (CDCl ₃ , 75.45 MHz) δ: 20.4, 21.6, 24.2, 32.4, 108.9, 120.9, 122.5, 123.9, 124.3, 126.6, 126.8 (SPh-C), 128.0 (SPh-C), 128.6, 128.9 , 129.2 (Ts-C), 130.1 (Ts-C), 134.4, 134.9, 135.9, 138.4, 145.2.
LR-MS m / z: 461 [M ⁺ ].
HR-MS m / z: 461.1249 [M ⁺ ] (Calcd for C ₂₅ H ₂₃ N ₃ O ₂ S ₂ , 461.1234).

(4) 5- (1-tosylindol-4-yl) -1-methyl-2- (phenylthio) imidazole 5- (1-tosyl-6,7-dihydroindol-4-yl) -1-methyl-2 -(Phenylthio) imidazole (1.84 g) and DDQ (1.09 g) were added in benzene (50 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, and the organic layer was washed with a 5% aqueous K ₂ CO ₃ solution and evaporated to dryness. The residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 2: 1) to give 1.3 g (yield 70%) of the title compound as an oil.

IR (KBr) cm ^-1 : 2952, 1954, 1475, 1442, 1371, 1288, 1210, 1188, 1166, 1129, 1087, 999, 812, 753, 673, 573.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.35 (3H, s, Ts-Me), 3.48 (3H, s, N-Me), 6.55 (1H, d, J = 3.7 Hz, indole H-3) , 7.16 (1H, d, J = 7.5Hz, Indole H-5), 7.20-7.32 (8H, m, Ts Ar-H, SPh-H and imidazole H-4), 7.37 (1H, dd, J = 7.5 Hz, 8.3Hz, Indole H-6), 7.62 (1H, d, J = 3.7Hz, Indole H-2), 7.80 (2H, d, J = 8.5Hz, Ts Ar-H), 8.03 (1H, d , J = 8.5Hz, Indole H-7).
¹³ C-NMR (CDCl ₃ , 75.45 MHz) δ: 21.6, 32.5, 107.7, 113.7, 122.7, 124.2, 124.5, 126.8, 126.9 (SPh-C), 127.1, 128.3 (SPh-C), 129.3 (Ts-C ), 129.8, 130.0 (Ts-C), 130.1, 134.0, 134.5, 134.9, 135.1, 139.3, 145.2.
LR-MS m / z: 459 [M ⁺ ].
HR-MS m / z: 459.1089 [M ⁺ ] (Calcd for C ₂₅ H ₂₁ N ₃ O ₂ S ₂ , 459.1077).

This compound was also obtained by the following method.
Specifically, using 2.4 g of 5- (4-hydroxy-1-tosyl-4,5,6,7-tetrahydroindol-4-yl) -1-methyl-2- (phenylthio) imidazole and 1.36 g of DDQ. The mixture was heated and refluxed in a Dean Stark tube in 100 mL of benzene in a nitrogen atmosphere for 2 hours. Thereafter, the same treatment as above was carried out to obtain 1.06 g (yield 46%) of the title compound.

(5) 5- (1H-indol-4-yl) -1-methyl-2- (phenylthio) imidazole 5- (1-tosylindol-4-yl) -1-methyl-2- (phenylthio) imidazole3. 12g and K ₂ CO ₃ (3.75g) in methanol (80 mL) - was added to water (32 mL) mixture was heated at reflux overnight. The solvent was distilled off, and the residue was collected. The obtained solid was subjected to column chromatography (ethyl acetate) and recrystallized from methanol to obtain 1.55 g (yield 75%) of the title compound as colorless needles.

mp 162-164 ℃
IR (KBr) cm ^-1 : 3422, 3178, 1442, 1399, 1340, 1107, 895, 752, 738, 684, 585.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 3.55 (3H, s, N-Me), 6.39-6.41 (1H, m, indole H-3), 7.06 (1H, dd, J = 0.9Hz, 7.4Hz) , Indole H-5), 7.17-7.32 (7H, m, Indole, H-6 and SPh-H), 7.38 (1H, s, imidazole H-4), 7.46 (1H, d, J = 8.3Hz, Indole H-7), 9.17 (1H, br, NH).
¹³ C-NMR (CDCl ₃ , 75.45 MHz) δ: 32.6, 101.6, 111.8, 121.0, 121.66, 121.73, 125.3, 126.6, 127.3, 127.9 (SPh-C), 129.3 (SPh-C), 129.4, 135.2, 136.0 , 136.1, 138.3.
LR-MS m / z: 305 [M ⁺ ].
HR-MS m / z: 305.0980 [M +] (Calcd for C 18 H 15 N 3 S, 305.0989).

  This compound was also obtained by the following method. 1.53 g of 5- (6,7-dihydro-1H-indol-4-yl) -1-methyl-2- (phenylthio) imidazole described later and 1.36 g of DDQ were stirred in benzene at room temperature for 6 hours. Thereafter, post-treatment was carried out in the same manner as in the above (4) to obtain 794 mg (yield: 50%) of the title compound as colorless needles.

(6) 5- (6,7-dihydro-1H-indol-4-yl) -1-methyl-2- (phenylthio) imidazole 5- (4-hydroxy-1-tosyl-4,5,6,7- 9.58 g of tetrahydroindol-4-yl) -1-methyl-2- (phenylthio) imidazole and 11 g of K ₂ CO ₃ were heated under reflux for 3 days in a mixture of methanol (100 mL) and water (40 mL). The reaction mixture was concentrated, and a solid was collected to obtain 5.32 g (yield 86%) of the title compound as colorless needles.

mp 154-156 ℃
IR (KBr) cm ^-1 : 3100, 2952, 2892, 1577, 1475, 1436, 1070, 897, 832, 794, 736, 683.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.55 (2H, td, J = 4.6 Hz, 8.5 Hz, indole H-6-CH _2- ), 2.77 (2H, t, J = 8.6 Hz, indole H- 7-CH _2- ), 3.50 (3H, s, N-Me), 5.59 (1H, t, J = 4.6Hz, Indole H-5 Olefin-H), 5.85 (1H, t, J = 2.6Hz, Indole H-3), 6.58 (1H, t, J = 2.6Hz, Indole H-2), 7.12-7.18 (2H, m, SPh-H), 7.19 (1H, s, imidazole H-4), 7.23-7.30 (3H, m, SPh-H), 8.66 (1H, s, NH).
¹³ C-NMR (CDCl ₃ , 75.45 MHz) δ: 20.9, 24.5, 32.6, 104.9, 115.8, 116.9, 120.9, 125.3, 126.3, 127.6 (SPh-C), 127.7, 128.7, 129.2 (SPh-C), 135.4 , 135.9, 137.7.
LR-MS m / z: 307 [M ⁺ ].
HR-MS m / z: 307.1119 [M +] (Calcd for C 18 H 17 N 3 S, 307.1145).

(7) 2,6-dimethyl-5-phenylthio-imidazo [4 ″, 5 ″: 5,4] pyrrolo [3 ′, 4 ′: 6,7] cyclohept [1,2,3-cd] indole-1 , 3-dione Ethyl bromide (654 mg) and 48 mg of magnesium were added to tetrahydrofuran (2 mL) to prepare an ethylmagnesium bromide solution.
A solution of 305 mg of 5- (1H-indol-4-yl) -1-methyl-2- (phenylthio) imidazole in tetrahydrofuran (3 mL) was added to the ethylmagnesium bromide solution, and the mixture was stirred at room temperature under a nitrogen atmosphere for 15 minutes. Next, a solution of 269 mg of 3,4-dibromo-1-methylmaleimide in tetrahydrofuran (3 mL) was added dropwise thereto, and the mixture was stirred at room temperature overnight. An aqueous NH ₄ Cl solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saline and evaporated to dryness. The residue was dissolved in methanol and heated to 100 ° C. for 3 days. The solvent was distilled off, and the residue was recrystallized from acetone to obtain 89 mg (yield: 22%) of the title compound as a blue powder.

mp 222-224 ℃
IR (KBr) cm ^-1 : 3360, 1754, 1689, 1622, 1513, 1432, 1383, 1189, 1135, 740, 687.
^{1 H-NMR (DMSO-d} 6, 300MHz) δ: 2.84 (3H, s, CO-N-Me), 3.79 (3H, s, N-Me), 6.86 (1H, t, J = 7.7Hz, indole H-6), 6.92 (1H, d, J = 6.8Hz, Indole H-5), 6.97 (1H, d, J = 7.7Hz, Indole H-7), 7.20-7.28 (3H, m, SPh-H ), 7.33-7.39 (2H, m, SPh-H), 7.75 (1H, d, J = 2.8Hz, Indole H-2), 11.55 (1H, s, Indole NH).
¹³ C-NMR (DMSO-d ₆ , 75.45 MHz) δ: 23.4, 36.1, 110.2, 112.3, 115.7, 122.3, 124.0, 124.5, 125.5, 126.7, 127.3 (SPh-C), 129.6 (SPh-C), 130.5 , 132.4, 133.9, 134.6, 136.6, 138.2, 141.7, 167.8, 169.3.
LR-MS m / z: 412 [M ⁺ ].
HR-MS m / z: 412.1010 [M +] (Calcd for C 23 H 16 N 4 O 2 S, 412.0996).

(8) 6-methyl-5-phenylthio-imidazo [4 ″, 5 ″: 5,4] pyrrolo [3 ′, 4 ′: 6,7] cyclohept [1,2,3-cd] indole-1,3 -Dione 5- (1H-indol-4-yl) -1-methyl-2- (phenylthio) imidazole 76 mg was treated with ethyl magnesium bromide and 3,4-dibromomaleimide (63 mg) as in (7). The mixture was dissolved in methanol and heated to 100 ° C. for 3 days. The solvent was distilled off under reduced pressure, and the residue was recrystallized from acetone to obtain 10 mg (yield 10%) of the title compound as a blue powder.

mp> 300 ℃
IR (KBr) cm ^-1 : 3392, 1711, 1629, 1533, 1518, 1441, 1349, 738.
^{1 H-NMR (DMSO-d} 6, 300MHz) δ: 3.79 (3H, s, N-Me), 6.86 (1H, t, J = 7.7Hz, indole H-6), 6.94 (1H , d, J = 6.8Hz, Indole H-5), 6.98 (1H, d, J = 7.2Hz, Indole H-7), 7.19-7.27 (3H, m, SPh-H), 7.33-7.38 (2H, m, SPh-H ), 7.74 (1H, d, J = 2.8Hz, Indole H-2), 10.58 (1H, s, CO-NH-CO), 11.57 (1H, s, Indole NH).
¹³ C-NMR (DMSO-d ₆ , 75.45 MHz) δ: 36.1, 110.0, 112.4, 115.8, 122.8, 124.1, 124.4, 125.4, 126.7, 127.2 (SPh-C), 129.6 (SPh-C), 130.6, 132.9 , 134.0, 134.5, 136.7, 138.1, 141.6, 169.0, 170.6.

(9) 2,6-dimethyl-imidazo [4 ″, 5 ″: 5,4] pyrrolo [3 ′, 4 ′: 6,7] cyclohept [1,2,3-cd] indole-1,3-dione Raney nickel (4 mL) suspended in ethanol was mixed with 2,6-dimethyl-5-phenylthio-imidazo [4 ″, 5 ″: 5,4] pyrrolo [3 ′, 4 ′: 6,7] cyclohept [1,2,2]. 3-cd] indole-1,3-dione (82 mg) in methanol (20 mL) and heated with stirring overnight. The reaction mixture was filtered through celite and washed with DMF. The filtrate was evaporated and the residue was recrystallized from acetone to give 22 mg (36% yield) of the title compound as a blue powder.

mp> 300 ℃
IR (KBr) cm ^-1 : 3410, 3202, 1754, 1690, 1629, 1527, 1437, 1385, 1127, 736, 642.
¹ H-NMR (DMSO-d ₆ , 500 MHz) δ: 2.84 (3H, s, CO-N-Me), 3.81 (3H, s, N-Me), 6.80-6.92 (3H, m, indole H-5 , H-6, H-7), 7.58 (1H, s, imidazole H-2), 7.69 (1H, s, indole H-2), 11.61 (1H, br, indole NH).
¹³ C-NMR (DMSO-d ₆ , 125.65 MHz) δ: 23.4, 36.2, 110.5, 111.9, 114.2, 123.1, 123.4, 124.4, 126.2, 130.3, 131.3, 133.2, 134.0, 138.4, 143.4, 168.1, 169.5.
LR-MS m / z: 304 [M ⁺ ].
HR-MS m / z: 304.0968 [M +] (Calcd for C 17 H 12 N 4 O 2, 304.0962).

(10) 6-methyl-imidazo [4 ", 5": 5,4] pyrrolo [3 ', 4': 6,7] cyclohept [1,2,3-cd] indole-1,3-dione in ethanol The suspended Raney nickel (1 mL) was treated with 6-methyl-5-phenylthio-imidazo [4 ", 5": 5,4] pyrrolo [3 ', 4': 6,7] cyclohept [1,2,3-cd]. The solution was added to a solution of indole-1,3-dione (40 mg) in tetrahydrofuran (40 mL), and the mixture was refluxed overnight. The reaction mixture was filtered through celite and washed with DMF. The filtrate was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate), and recrystallized from methanol to obtain 3.7 mg (yield: 12.7%) of the title compound.

mp> 300 ℃
IR (KBr) cm ^-1 : 3482, 1704, 1562, 1421, 1359, 738.
¹ H-NMR (DMSO-d ₆ , 500 MHz) δ: 3.82 (3H, s, N-Me), 6.81 (1H, t, J = 7.94 Hz, indole H-6), 6.88 (1H, d, J = 7.23Hz, Indole H-5), 6.92 (1H, d, J = 8.24Hz, Indole H-7), 7.58 (1H, s, Imidazole H-2), 7.66 (1H, s, Indole H-2), 10.54 (1H, s, CO-NH-CO), 11.69 (1H, s, indole NH).
¹³ C-NMR (DMSO-d ₆ , 125.65 MHz) δ: 36.2 (N- Me ), 110.2 (indole C-3), 111.7 (indole C-7), 114.2 (indole C-5), 123.1 (indole C) -2), 123.5 (maleimide C-3 or C-4), 124.3 (indole C-6), 126.0 (indole C-4), 130.1 (indole C-3a), 131.8 (maleimide C-3 or C-4) ), 133.2 (imidazole C-5), 133.7 (imidazole C-4), 138.1 (indole C-7a), 143.4 (imidazole C-2), 170.0 (maleimide C-2 or C-5), 170.0 (maleimide C) -2 or C-5), 170.8 (maleimide C-2 or C-5).
LR-MS m / z: 290 [M ⁺ ].
HR-MS m / z: 290.0817 [M ⁺ ] (Calcd for C ₁₆ H ₁₀ N ₄ O ₂ , 290.0804).

Test example 1
Infect insect cells Tn5 with a baculovirus incorporating the Flt-1 gene (produced by Prof. Shibuya, The University of Tokyo), disrupt the cells with a sucrose buffer, enucleate, collect the membrane fractions by ultracentrifugation, and remove the enzyme solution. I do. To this, the sample and [γ- ³² P] ATP are added and reacted at 25 ° C. for 10 minutes. After stopping the reaction, the phosphorylated Flt-1 is analyzed by SDS-PAGE and autoradiography.

  Evaluation of activity: The sample is added to a final concentration of 0.1 mg / mL, and the presence or absence of phosphorylation inhibition and the inhibition pattern are determined.

  As a result, as shown in Table 1, it was found that the compounds of Examples 3 and 5 (4) had an excellent inhibitory action on Flt-1 tyrosine kinase.

Test example 2
The anticancer effect of the human cancer cell panel was assayed. That is, the cancer cells are spread on a 96-well plate, the sample solution is added the next day, and the cells are cultured for 2 days. Then, the cell proliferation is measured by colorimetry using sulforhodamine B. The data is displayed as a Finger Print that visually represents the effective concentration deviation of the drug for each cancer cell. This reveals which cancer cell lines the sample relatively inhibits in growth.

  As a result, as shown in Table 2, the compounds of Examples 3 and 5 (4) exhibited excellent growth inhibitory effects on many human cancer cells.

Test example 3
Using the recombinant human topoisomerase I and topoisomerase IIα, the presence or absence of inhibition of the enzyme activity of the compound of the present invention (the compound of Example 3) was assayed.
Topo I activity is a relaxation reaction of circular plasmid DNA with supercoil (super helix) using camptothecin (camptothecin, CPT) as a positive control, and topo II activity is a cross-linking reaction using ICRF-193 as a positive control. The enzymatic activity was measured by a decatenation reaction of kinetoplast DNA (kDNA) of the protozoan trypanosoma, which is catenated DNA. Samples were added to the reaction solution at concentrations of 300, 100, and 30 μM, and the reaction was performed. After the reaction, the reaction solution was subjected to plate agarose gel electrophoresis, and after staining the gel with Ethidium Bromide (EB), the 50% inhibitory concentration (IC ₅₀ ) was determined from the change in the amount of DNA of the reaction product. The intensity of the enzyme inhibitory activity of the sample was expressed as follows, and the results are shown in Table 3.
_{++: IC 50 ≦ 30 (μM} , hereinafter the _{same); +: 30 <IC 50} ≦ 100; ±: 100 <IC 50 <300; -: IC 50 ≧ 300

Claims (16)

The following general formula (1)

(Wherein, R ¹ is a substituent on one nitrogen atom of the imidazole ring and represents a hydrogen atom, an alkyl group or an alkoxyalkyl group, and R ² represents a hydrogen atom, an alkyl group or an alkoxyalkyl group)
Or a salt thereof, or a solvate thereof. The compound according to claim ^1, wherein R ¹ and R ² are the same or different and each is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, a salt thereof, or a solvate thereof. The compound according to claim 1 or 2, wherein R ¹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ² is a hydrogen atom, or a salt thereof or a solvate thereof. The following general formula (2-1)

(In the formula, R ⁴ represents an alkyl group or an alkoxyalkyl group, R ³ represents a hydrogen atom or an amino protecting group, and a broken line indicates that this portion may be a double bond.)
Or a salt thereof, or a solvate thereof. General formula (2-2)

(In the formula, R ⁴ represents an alkyl group or an alkoxyalkyl group, R ³ represents a hydrogen atom or an amino protecting group, and a broken line indicates that this portion may be a double bond.)
Or a salt thereof, or a solvate thereof. General formula (8)

(Wherein, R ⁴ represents an alkyl group or an alkoxyalkyl group)
Is reacted with an alkyl magnesium halide, and then the compound represented by the general formula (9)

(Wherein, R ² represents a hydrogen atom, an alkyl group or an alkoxyalkyl group, and X ¹ and X ² represent a halogen atom)
Wherein the compound represented by the general formula (1a) is reacted:

(In the formula, R ⁴ represents an alkyl group or an alkoxyalkyl group, and R ² is the same as described above.)
A method for producing a compound represented by the formula: or a salt or solvate thereof. The following general formula (15)

(Wherein, R ⁴ represents an alkyl group or an alkoxyalkyl group)
Is reacted with an alkyl magnesium halide, and then the compound represented by the general formula (9)

Reacting the compound represented by the general formula (16)

(Wherein, R ⁴ is the same as described above)
A compound represented by the general formula (1b):

(Wherein, R ⁴ is the same as described above)
A method for producing a compound represented by the formula: or a salt or solvate thereof. The following general formula (1c)

(Wherein, R ^2a represents a hydrogen atom or an alkyl group, R ^4a is a substituent on one nitrogen atom of an imidazole ring, and represents an alkoxyalkyl group)
Wherein the compound represented by the formula is hydrolyzed:

(Wherein, R ^2a is the same as described above)
A method for producing a compound represented by the formula: or a salt or solvate thereof.   An Flt (fms-like tyrosine kinase) -1 kinase inhibitor comprising the compound according to any one of claims 1 to 3, a salt thereof, or a solvate thereof.   An angiogenesis inhibitor comprising the compound according to any one of claims 1 to 3, a salt thereof, or a solvate thereof.   A topoisomerase inhibitor comprising the compound according to any one of claims 1 to 3, a salt thereof, or a solvate thereof. A prophylactic and / or therapeutic agent for cancer comprising the compound according to claim 1, a salt thereof, or a solvate thereof.   A medicament comprising the compound according to any one of claims 1 to 3, a salt thereof, or a solvate thereof as an active ingredient.   14. The medicament according to claim 13, which is an agent for preventing and / or treating cancer.   14. The medicament according to claim 13, which is an angiogenesis inhibitor.   14. The medicament according to claim 13, which is a topoisomerase inhibitor.