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    • 专利摘要:
    The present invention relates to an indole quinone derivative represented by the following formula (1) and a preparation method thereof. Indole quinone derivative of the present invention introduces a variety of substituents to the indole quinone as a nucleus, in particular a halogen element introduced to C5 or C6, showing a more selective and less toxic anti-cancer activity, thereby reducing cancer toxicity and side effects It can be usefully used as. Formula 1 (Wherein R 1 , R 2 , R 3 and R 4 are as described in the specification).
    公开号:KR20040043773A
    申请号:KR1020020072164
    申请日:2002-11-20
    公开日:2004-05-27
    发明作者:신재연；박진일；권오령；지대윤；홍동호
    申请人:주식회사 켐온；
    IPC主号:
    专利说明:

    Indole quinone derivatives having anticancer activity and a method of preparing the same {AN INDOLEQUINONE DERIVATIVE HAVING ANTICANCER ACTIVITY AND A PROCESS FOR THE PREPARATION THEREOF}
    [1] The present invention relates to an indolquinone derivative having anticancer activity and a method for preparing the same, wherein the indolequinone derivative of the present invention is activated by a hypoxic physiological state of cancer cells and DT-Diaphorase overexpressed in specific cancer cells By using the mechanism of alkylation or cross-linking to the DNA to show anti-cancer effect, it can be usefully used as a cancer disease treatment agent with less toxicity and side effects.
    [2] According to a recent domestic press release, the incidence of chronic diseases such as cancer, hypertension, cerebrovascular disease, diabetes, etc. continues to increase, and economic losses from these diseases account for about 37 trillion won, or 8% of GDP. We analyze that it comes to. In particular, the number one mortality rate due to disease in Korea is gastric cancer, and the mortality rate of lung cancer is increasing rapidly. Unlike other diseases, cancer, especially lung cancer, pancreatic cancer, esophageal cancer, gastric cancer, etc., have a very low survival rate, and pain from cancer has a significant effect on mental loss as well as economic cost.
    [3] However, due to the progress of cancer treatment, the number of deaths from cancer has been steadily decreasing, but the continuous increase in the number of cancer patients themselves and the duration of administration of therapeutic drugs are prolonged. Thus, the market for anticancer drugs in 2001 is about $ 12 billion, and in 2010, the global anticancer drug market is expected to reach $ 35 billion with an annual growth rate of about 10%.
    [4] Currently, about 30% of chemotherapy-based anticancer drugs are used in chemotherapy. For example, 40 to 50 species including prostate cancer, loopron, ovarian cancer, taxol, and breast cancer, zoladex, etc. Other anti-cancer therapies include immunotherapy that treats breast cancer or herceptin using therapeutic vaccines or single antibodies, antisense anticancer agents using gene therapy, neovascular inhibitors, protein inhibitors related to signaling within cancer cells, and natural cancer cells. More than 400 anticancer drugs are being developed using death. The purpose of the development of anticancer drugs using the various therapies is to overcome the cancer at the same time more selective and fundamentally, and overcome the side effects, induction of resistance and recurrence due to toxicity.
    [5] Various cyclic compounds derived from natural products are widely used as therapeutic agents such as antibiotics, antibacterial agents, anticancer agents by using natural products or fractions of active substances or synthesizing presynthetic or analogous substances.
    [6] In particular, in the case of anticancer agents, as representative quinolinedione-based compounds derived from natural products, doxorubicin and streptonigrin are known as representative drugs that act on DNA. However, due to the low selectivity of these compounds for tumor tissues, side effects due to toxicity, as well as excellent anti-cancer and anti-tumor effects, have emerged as a problem, and therefore special care is required for clinical use.
    [7] Recently, the development of anticancer drugs is looking for ways to increase the selectivity of tumor tissue. As an example, cell cycle-related inhibitors, intracellular signaling-related protein inhibitors, and neovascular inhibitors have been actively studied. In particular, hypoxic properties of tumor tissues and DT-diaphorase overexpressed in certain solid cancers
    [8] Drugs that are antireactive (bioreductive alkylating) have been developed. Typical drugs include mitomycin C, a quinone compound used clinically, and indolequinone compound EO-9 (3-Hydroxymethyl-5-Aziridinyl-1-methyl-2- [1 H -indole-) under clinical trial. 4,7-dione] prop-β-en-α-ol), tirapazamine of the N-oxide family, alkylaminoanthraquinone N-oxide (AQ4N), and nitrogen mustard. , Nitroarene, and benzoquinone compounds.
    [9] Indole-based compounds, in particular, have various physiological activities derived from natural products, and are one of important cyclic compounds that exist in vivo and regulate physiological functions in cells such as serotonin and L-tryptophan. Therefore, using indole compounds, Parkinson's, Alzheimer's drug development, depression, anxiety, vomiting central nervous system drugs related to vomiting, and in particular the indole compound as a nucleus mitomycin analogues, mitonesnes (mitosenes) as well as Indoquinone compounds having various structures and structural activities have been developed.
    [10] Currently, the indolequinone compound EO-9, developed by Speckman and Oosteen, does not show any clear anticancer activity in clinical trials. Therefore, it is attempting to combine radiation therapy with other chemotherapy agents. In addition, the aziridinylindolequinone-based compounds developed by Skibo et al. Have relatively secured structural diversity, but the preparation method of indolequinone is expensive using an expensive oxidizing agent, Fremy's salt, multi-step manufacturing process and various substituents at C5 or C6 positions. The introduction of is still insufficient.
    [11] Accordingly, the present inventors introduced various substituents to indole quinone in the mother nucleus, in particular to introduce a halogen element into C5 or C6, in order to develop a new therapeutic agent through research on various structures of the indole quinone derivatives and their activities. The present invention was completed by confirming that the indolequinone derivative was more selective and less toxic.
    [12] An object of the present invention is to provide an indolquinone derivative represented by the formula (1) and a pharmaceutically acceptable salt thereof.
    [13] Another object of the present invention is to provide a method for preparing an indolequinone derivative represented by the formula (1).
    [14] Still another object of the present invention is to provide a new indolquinone derivative represented by the formula (1) and a pharmaceutically acceptable salt thereof as an active ingredient for treating cancer diseases or radiotherapy aids.
    [15] In order to achieve the above object, the present invention provides an indolquinone derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof.
    [16]
    [17] (Wherein R 1 is hydrogen or an alkyl group of C 1 to C 3 ;
    [18] R 2 is Wherein R a is C 1 to C 4 straight or branched alkyl, or aryl; Cyclo C 3 to C 6 carbonyl or 1-hydroxy C 1 to C 3 alkyl group;
    [19] R 3 and R 4 are each independently hydrogen, C 1 -C 6 straight or branched alkyl amino, cyclo C 3 -C 6 alkyl amino, piperidinyl, 2-methylaziridinyl, N-phenylamino, N- (4-halophenyl) amino or halogen.
    [20] More preferably in the compound of Formula 1
    [21] R 1 is hydrogen, methyl, or an ethyl group;
    [22] R 2 is an acetyl, isopropanecarbonyl, benzoyl, cyclopropanecarbonyl, cyclohexanecarbonyl, 1-hydroxyethyl group;
    [23] R 3 and R 4 are each independently hydrogen, methylamino, dimethylamino, propylamino, cyclopropylamino, cyclohexylamino, 2-methylaziridinyl, piperidinyl, N-phenylamino, N- (4- Halophenyl) amino, or bromine atom.
    [24] Preferred compounds among the compounds of Formula 1 are specifically as shown in Tables 1a to 1c .
    [25]
    [26]
    [27]
    [28] The most preferable compound among the above compounds is as follows.
    [29] 1) 3-acetyl-6-bromo-5- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione;
    [30] 3) 3-acetyl-6-bromo-5- (2-methylaziridin-1-yl) -1-ethyl-2-methylindole-4,7-dione;
    [31] 5) 3-acetyl-5- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione;
    [32] 6) 3-acetyl-5- (2-methylaziridin-1-yl) -1-ethyl-2-methylindole-4,7-dione;
    [33] 14) 3-acetyl-6-bromo-1,2-dimethyl-5-piperazin-1-ylindole-4,7-dione;
    [34] 17) 3-acetyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione;
    [35] 34) 3-acetyl-6- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione;
    [36] 37) 3-acetyl-5- (2-methylaziridin-1-yl) -1,2-dimethylindol-4,7-dione;
    [37] 41) 3-benzoyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindol-4,7-dione;
    [38] 46) 3-isopropanecarbonyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione;
    [39] 47) 3-isopropanecarbonyl-6-bromo-5- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione;
    [40] 48) 3-cyclopropanecarbonyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindol-4,7-dione;
    [41] 49) 3-cyclopropanecarbonyl-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione;
    [42] 50) 3-benzoyl-5- (2-methylaziridin-1-yl) -1,2-dimethylindol-4,7-dione;
    [43] 52) 3-cyclohexanecarbonyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindol-4,7-dione;
    [44] 53) 3-isopropanecarbonyl-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione.
    [45] The present invention includes both indolequinone derivatives represented by the formula (1) and pharmaceutically acceptable salts thereof, as well as possible solvates and hydrates that can be prepared therefrom.
    [46] The compound of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Organic acids and inorganic acids may be used as the free acid, and hydrochloric acid, hydrogen bromide, phosphoric acid, sulfuric acid, sodium hydrogen sulfate, nitric acid, carbonic acid, or tartaric acid may be used as the inorganic acid, and formic acid and gestice may be used as the organic acid. Acids, lactobionic acid, salicylic acid, acetylsalicylic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid ), Citric acid, lactic acid, glycolic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, Aspartic acid, ascorbic acid, carbonic acid, vanic acid, or hydroiodic acid can be used.
    [47] The acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving the compound of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, for example methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.
    [48] An equivalent amount of the compound of formula 1 and an acid or alcohol (glycol monomethyl ether) in water may be heated and then the mixture is evaporated to dryness or the precipitated salt is filtered off with suction.
    [49] Bases can also be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).
    [50] In another aspect, the present invention provides a method for producing an indolquinone derivative represented by the formula (1).
    [51] More specifically, the manufacturing method of the indole quinone derivative of the present invention
    [52] 1) introducing a carbonyl group (R 2 ) at the C 3 position of 2-methyl-4,7-dimethoxyindole;
    [53] 2) protecting (R 1 ) nitrogen of 2-methyl-4,7-dimethoxyindole having the carbonyl group introduced therein;
    [54] 3) oxidizing and deacetylating the 2-methyl-4,7-dimethoxyindole; And
    [55] 4) step 4 of introducing a substituent to the C5 and C6 of the deacetylated indolequinone derivative using a competitive reaction, as shown in Scheme 1.
    [56]
    [57] (Wherein R 1 , R 2 , R 3 and R 4 are the same as mentioned in Formula 1 above)
    [58] In the above scheme, 2-methyl-4,7-dimethoxyindole, which is a starting material in step 1, reacts 1,4-dimethoxybenzene with concentrated nitric acid to introduce a nitro group at the C2 position, and isopropenylmagnesium bromide Prepared by reaction with
    [59] At this time, the nitric acid used is 1.0-2.0 equivalent, Preferably it is 1.2-1.5 equivalent, and isopropenyl magnesium bromide uses 1.5-3.5 equivalent. More preferably, 2.2-2.5 equivalent is used, and reaction temperature is -65-70 degreeC, and it reacts under nitrogen atmosphere.
    [60] Step 1 is a compound containing a carbonyl group (R 2 ) by dissolving the starting material 2-methyl-4,7-dimethoxyindole in a solvent at room temperature and then slowly adding 1.3-1.5 equivalents of diethylaluminum chloride solution. Reaction is carried out.
    [61] R 2 is Wherein R a is C 1 to C 4 straight or branched alkyl, or aryl; Cyclo C 3 to C 6 carbonyl or alkyl groups of 1-hydroxy C 1 to C 3 are used. As a specific example thereof, R 2 is preferably selected from the group consisting of acetyl chloride, isopropylcarbonyl chloride, benzoyl chloride, cyclopropylcarbonyl chloride and cyclohexylcarbonyl chloride. In addition, preferable usage-amount adds 1.2-1.5 equivalent.
    [62] In step 1, 3-acyl-2-methyl-4,7-dimethoxyindole having a carbonyl group introduced therein is reacted with RI under NaH conditions to protect nitrogen of 2-methyl-4,7-dimethoxyindole (R 1 ) In this case, NaH used is 1.2-2.2 equivalents, RI is selected from methane iodide or ethane iodide, and acetyl chloride may be used. In addition, it is preferable to use 1.2-1.5 equivalents.
    [63] In the above method, step 3 is a deacetylation reaction by oxidizing 3-acyl-1-alkyl or 3-acyl-1-acetyl-2-methyl-4,7-dimethoxyindole of step 2. In this case, the oxidation may be performed using an oxidizing agent that is commonly used, and most preferably 3.5 to 5.5 equivalents of ammonium cerium (IV) nitrate is used. After the reaction is completed, 5.0-20 equivalents of potassium carbonate, more preferably 15-20 equivalents, are used.
    [64] In step 4 of introducing a substituent to the C5 and C6 of the deacetylated indolequinone derivative using a competitive reaction, the substituents R 3 and R 4 are each independently, hydrogen, C 1 to C 6 linear or pulverized Alkyl amino, cyclo C 3 to C 6 alkyl amino, piperidinyl, 2-methylaziridinyl, N-phenylamino, N- (4-halophenyl) amino or halogen are introduced.
    [65] More preferred R 3 and R 4 are each independently hydrogen, methylamino, dimethylamino, propylamino, cyclopropylamino, cyclohexylamino, 2-methylaziridinyl, N-phenylamino, piperidinyl, N- ( 4-chlorophenyl) amino, or bromine atom.
    [66] Indole quinone may be carried out as in Scheme 2 in order to prepare indole quinone derivatives in which various substituents are introduced into the mother nucleus, and in particular a halogen element is introduced into C5 or C6. In this case, the halogen will be described as bromine as an example.
    [67] In particular, halogen is substituted with dibromo indolquinone for C5 and C6 by primary or secondary amine using a bromination reaction as in Scheme 2 below.
    [68]
    [69] (Wherein R 1 and R 2 are the same as mentioned in Formula 1 above)
    [70] Br 2 used in the bromination reaction is used in 4.0 to 6.0 equivalents, preferably 4.5 to 5.5 equivalents.
    [71] In order to obtain the target compound of the present invention, an indolequinone derivative is prepared using a primary amine or a secondary amine. In this case, the compounds introduced at the C5 and C6 positions can be obtained at the same time, and the target compound substituted at the ratio of 60:40 or 70:30 at the C5 and C6 positions, respectively, can be obtained by a conventional organic chemical separation and purification method. .
    [72] In addition, in order to introduce R 3 and R 4 which may be substituted in addition to halogen, it may be performed as in Scheme 3 below. As an example thereof, explanation will be made using 2-methylaziridine.
    [73]
    [74] (Wherein R 1 and R 2 are the same as mentioned in Formula 1 above)
    [75] Zinc chloride is used in 5.0-10 equivalents, More preferably, 5.0-5.5 equivalents is used. At this time, as a result of the reaction in the presence of zinc chloride, the compound introduced at the C5 and C6 position can be obtained at the same time, the target compound substituted at 60:40 or 70:30 ratio in the C5 and C6 position, respectively, and the conventional organic chemical separation and It can obtain by a purification method.
    [76] The present invention provides a new indolquinone derivative represented by the general formula (1) and a pharmaceutically acceptable salt thereof as an active ingredient, a cancer disease therapeutic agent.
    [77] Indole quinone derivatives of the present invention are lung cancer cell line, melanoma cell line, colon cancer cell line, prostate cancer cell line, breast cancer and breast cancer - excellent anticancer of adriamycin results of testing the anti-cancer activity against resistant cancer cell lines, and the average GI 50 is 5 ug / ml or less Active
    [78] In particular, 3-acetyl-6-bromo-5- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione, a compound of Formula 1 of the present invention, 3 -Acetyl-5- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione, and 3-acetyl-6-bromo-5- (2-methylaziri as a compound of formula 5 Din-1-yl) -1,2-dimethylindole-4,7-dione showed excellent anticancer activity of 1 ug / ml or less.
    [79] The compound of Formula 1 may be administered in various oral and parenteral formulations during clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc., which are commonly used, may be used. It is manufactured by.
    [80] Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.
    [81] Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.
    [82] Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.
    [83] In addition, the indolequinone derivatives and pharmaceutically acceptable salts thereof prepared in the present invention have acute toxicity test results in experimental mice, and the minimum lethal dose (LD 10 ) upon oral administration is 500 mg / kg or more. It can be appreciated that the indolequinone derivatives and pharmaceutically acceptable salts thereof of the present invention can be safely administered to a living body.
    [84] Therefore, the indolequinone derivative of the present invention can be usefully used as a cancer disease treatment agent by identifying anticancer activity that is more selective and less toxic than conventional anticancer agents.
    [85] The dosage of the compound represented by Chemical Formula 1 to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally based on an adult patient having a weight of 70 kg. 0.01 to 3,000 mg / day, preferably 0.1 mg to 1,000 mg / day, and may be administered once or several times a day at regular intervals according to the judgment of a doctor or pharmacist.
    [86] Hereinafter, the present invention will be described in more detail with reference to Examples.
    [87] However, the following examples are illustrative of the present invention, and the content of the present invention is not limited by the examples.
    [88] Preparation Example 1 Preparation of 4,7-dimethoxy-2-methylindole
    [89]
    [90] Step 1: Preparation of 2-nitro-1,4-dimethoxybenzene
    [91] 60 g (0.43 mol) of dimethoxybenzene was dissolved in 380 ml of acetic acid, and 48.7 ml (1.5 equivalents) of concentrated nitric acid was added slowly, followed by reaction at room temperature for 1 hour. 1500 ml of distilled water was added to the reaction product to precipitate the product, and the precipitate was filtered, washed with 500 ml of water, and dried under reduced pressure with P 2 O 5 for 12 hours to give 2-nitro-1,4 as a yellow solid product. 75.6 g (95%) of dimethoxybenzene was obtained.
    [92] Melting point; 70-71 ° C (TCI standard 72 ° C), 1 H-NMR (300 MHz, CDCl 3 ) δ 7.40 (S, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 3H)
    [93] Step 2: Preparation of 4,7-dimethoxy-2-methylindole
    [94] 4.5 g (24.5 mmol) of 2-nitro-1,4-dimethoxybenzene obtained in the above step was dissolved in 30 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere, cooled to −70 ° C., and then isopropenylmagnesium 98.3 ml (0.5 M, 2.0 equiv) of bromide was added slowly and stirred for 30 minutes. The reaction was terminated by slowly adding 150 ml of saturated ammonium chloride solution to the mixture, extracted with 200 ml of ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate, distilled under reduced pressure with silica gel (230-400 mesh), and purified by column chromatography (ethyl acetate / hexane = 20/80) to give a pale yellow solid, 4,7-dimethoxy-2-. 750 mg (16%) of methylindole were obtained.
    [95] Melting point; 117-118 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ6.45 (d, J = 8.5 Hz, 1H), 6.35 (d, J = 8.4 Hz, 1H), 6.28 (s, 1H), 3.89 (s, 6H), 2.42 (s, 3H)
    [96] Example 1 Preparation of 3-acetyl-4,7-dimethoxy-2-methylindole
    [97] In a nitrogen atmosphere, 3.16 g (16.5 mmol) of 4,7-dimethoxy-2-methylindole was dissolved in 50 ml of dichloromethane and cooled to 0 ° C. 24.8 ml (1.5 equiv) of 0.95 M diethylaluminum chloride were added slowly, followed by stirring for 30 minutes, and a solution of 1.76 ml (1.5 equiv) of acetylchloride diluted in 36 ml of dichloromethane was added slowly. The reaction was stirred for 2 hours and then carefully terminated with 150 ml of cooling water. Successively extracted with 200 ml of ethyl acetate, washed with water and brine and dried over sodium sulfate. 2.74 g (71%) of 3-acetyl-4,7-dimethoxy-2-methylindole as a white solid was obtained using column chromatography (ethyl acetate / hexane = 30/70).
    [98] Melting point; 141-142 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ6.57 (d, J = 8.5 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 3.87 ( s, 3H), 2.67 (s, 3H), 2.57 (s, 3H)
    [99] Example 2 Preparation of 3-isopropanecarbonyl-4,7-dimethoxy-2-methylindole
    [100] Except for using isobutyryl chloride instead of acetyl chloride was carried out in the same manner as in Example 1, to give a compound in a yield of 44%.
    [101] 1 H-NMR (300 MHz, CDCl 3 ) δ6.54 (d, J = 8.5 Hz, 1H), 6.46 (d, J = 8.3 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H) , 3.73-3.75 (m, 1 H). 2.49 (s, 3H), 1.12 (d, J = 6.9 Hz, 6H)
    [102] Example 3 Preparation of 3-benzoyl-4,7-dimethoxy-2-methylindole
    [103] The compound was obtained in the same manner as in Example 1, except that benzoyl chloride was used instead of acetyl chloride, in a yield of 42%.
    [104] 1 H-NMR (300 MHz, CDCl 3 ) δ7.78 (d, J = 7.0, 2H), 7.46 (d, J = 7.3, 1H), 7.38 (d, J = 7.0, 2H), 6.53 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H), 3.28 (s, 3H), 2.54 (s, 3H)
    [105] Example 4 Preparation of 3-cyclopropanecarbonyl-4,7-dimethoxy-2-methylindole
    [106] Except for using cyclopropylcarbonyl chloride instead of acetyl chloride was carried out in the same manner as in Example 1, to give a compound in a yield of 52%.
    [107] 1 H-NMR (300 MHz, CDCl 3 ) δ6.56 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 8.5 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H) , 2.80-2.82 (m, 1H), 2.54 (s, 3H), 1.20-1.22 (m, 2H), 0.91-0.94 (m, 2H)
    [108] Example 5 Preparation of 3-cyclohexanecarbonyl-4,7-dimethoxy-2-methylindole
    [109] A compound was obtained in the same manner as in Example 1 except that cyclohexylcarbonyl chloride was used instead of acetyl chloride in a yield of 37%.
    [110] 1 H-NMR (300 MHz, CDCl 3 ) δ6.54 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H) , 3.45-3.47 (m, 1H), 2.49 (s, 3H), 1.89-1.24 (m, 10H)
    [111] Example 6 Preparation of 3-acetyl-4,7-dimethoxy-1,2-dimethylindole
    [112] 2.74 g (11.7 mmol) of 3-acetyl-4,7-dimethoxy-2-methylindole was dissolved in 45 ml of DMF (Dimethylformamide) under nitrogen atmosphere, and then cooled to 0 ° C. 1.0 g (2.2 equiv) of 60% NaH was added slowly, then stirred for 30 minutes, and 1.46 ml (2.0 equiv) of methane iodide were added slowly. The reaction was stirred for 1 hour and then the reaction was terminated with 100 ml of water. Extracted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. After distilling the dried organic layer under reduced pressure, hexane was added to the product to obtain 2.5 g (86%) of 3-acetyl-4,7-dimethoxy-1,2-dimethylindole as a white solid.
    [113] Melting point; 114-115 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ6.56 (d, J = 8.5 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 2.58 (s, 3H), 2.47 (s, 3H)
    [114] Example 7 3-isopropanecarbonyl-4,7-dimethoxy-1,2-dimethylindole
    [115] Using 3-isopropanecarbonyl-4,7-dimethoxy-2-methylindole, which is a compound of Example 2, was carried out in the same manner as in Example 6, with 3-isopropanecarbonyl in a yield of 90%. -4,7-dimethoxy-1,2-dimethylindole was obtained.
    [116] 1 H-NMR (300 MHz, CDCl 3 ) δ6.53 (d, J = 8.4 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.88 (s, 3H) , 3.83 (s, 3H), 3.53-3.55 (m, 1H), 2.38 (s, 3H), 1.11 (d, J = 7.2 Hz, 6H)
    [117] Example 8 3-Benzoyl-4,7-dimethoxy-1,2-dimethylindole
    [118] 3-benzoyl-4,7-dimethoxy-2-methylindole, which is a compound of Example 3, was used in the same manner as in Example 6 to obtain 3-benzoyl-4,7-dimethine in a yield of 95%. Toxoxy-1,2-dimethylindole was obtained.
    [119] 1 H-NMR (300 MHz, CDCl 3 ) δ 7.74 (d, J = 7.0, 2H), 7.44 (d, J = 7.4, 1H), 7.34 (d, J = 7.5, 2H), 6.53 (d, J = 8.5 Hz, 1H), 6.31 (d, J = 8.5 Hz, 1H), 4.02 (s, 3H), 3.90 (s, 3H), 3.23 (s, 3H), 2.46 (s, 3H)
    [120] Example 9 3-cyclopropanecarbonyl-4,7-dimethoxy-1,2-dimethylindole
    [121] 3-cyclopropanecarbonyl-4,7-dimethoxy-2-methylindole, which is a compound of Example 4, was used in the same manner as in Example 6 to obtain 3-cyclopropanecarbonyl in a yield of 90%. -4,7-dimethoxy-1,2-dimethylindole was obtained.
    [122] 1 H-NMR (300 MHz, CDCl 3 ) 66.56 (d, J = 8.6 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.89 (s, 3H) , 3.84 (s, 3H), 2.59-2.61 (m, 1H), 2.44 (s, 3H), 1.17-1.19 (m, 2H), 0.90-0.92 (m, 2H)
    [123] Example 10 3-cyclohexanecarbonyl-4,7-dimethoxy-1,2-dimethylindole
    [124] 3-cyclohexanecarbonyl-4,7-dimethoxy-2-methylindole, which is a compound of Example 5, was used in the same manner as in Example 6 to obtain 3-cyclohexanecarbonyl in a yield of 85%. -4,7-dimethoxy-1,2-dimethylindole was obtained.
    [125] 1 H-NMR (300 MHz, CDCl 3 ) δ6.54 (d, J = 8.7 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H) , 3.84 (s, 3H), 3.23-3.25 (m, 1H), 2.37 (s, 3H), 1.85-1.23 (m, 10H)
    [126] Example 11 Preparation of 3-acetyl-4,7-dimethoxy-1-ethyl-2-methylindole
    [127] Except for using 3-acetyl-4,7-dimethoxy-2-methylindole of Example 1 and using ethane iodide instead of methane iodide, it was carried out in the same manner as in Example 6, 80% yield 3-acetyl-4,7-dimethoxy-1-ethyl-2-methylindole was obtained.
    [128] Melting point; 88-89 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ6.57 (d, J = 8.5 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H), 4.40 (q, J = 7.1, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 2.58 (s, 3H), 2.49 (s, 3H), 1.32 (t, J = 7.0, 3H)
    [129] Example 12 Preparation of 1,3-Diacetyl-4,7-dimethoxy-2-methylindole
    [130] Same as Example 6 above, except that 3-acetyl-4,7-dimethoxy-2-methylindole of Example 1 was used, acetyl chloride was used instead of methane iodide, and the amount of NaH was adjusted to 1.2 equivalents. The method was carried out to obtain 1,3-diacetyl-4,7-dimethoxy-2-methylindole in a yield of 85%.
    [131] Melting point; 163-164 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ6.67 (d, J = 8.6 Hz, 1H), 6.60 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.59 (s, 3H), 2.54 (s, 3H), 2.44 (s, 3H)
    [132] Example 13 Preparation of 3-acetyl-1,2-dimethylindole-4,7-dione
    [133] 1.26 g (5.1 mmol) of 3-acetyl-4,7-dimethoxy-1,2-dimethylindole, which is a compound of Example 6, was dissolved in 60 ml of acetonitrile, followed by 15.4 g (5.5) of ammonium cerium (IV) nitrate. Equivalent) aqueous solution was added slowly. The reaction was terminated with excess 20% aqueous sodium bicarbonate solution for 30 minutes at room temperature. Extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate and filtered. The organic layer was distilled under reduced pressure with silica gel, separated and purified by column chromatography (ethyl acetate / hexane = 30/70) to give 3-acetyl-1,2-dimethyl-indole-4,7-dione as an orange solid 0.7. g (63%) was obtained.
    [134] Melting point; 134-135 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ6.63-6.65 (m, 2H), 3.93 (s, 3H), 2.65 (s, 3H), 2.40 (s, 3H)
    [135] Example 14 Preparation of 3-acetyl-1-ethyl-2-methylindole-4,7-dione
    [136] 3-acetyl-4,7-dimethoxy-1-ethyl-2-methylindole, which is a compound of Example 11, was carried out in the same manner as in Example 13 to obtain a compound in a yield of 40%.
    [137] 1 H-NMR (300 MHz, CDCl 3 ) δ6.57 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 4.42 (q, J = 7.0, 3H), 2.65 ( s, 3H), 2.42 (s, 3H), 1.35 (t, J = 7.0, 3H)
    [138] Example 15 Preparation of 3-isopropanecarbonyl-1,2-dimethylindole-4,7-dione
    [139] 3-isopropanecarbonyl-4,7-dimethoxy-2-dimethylindole, which is a compound of Example 7, was carried out in the same manner as in Example 13 to obtain a compound in a yield of 55%.
    [140] 1 H-NMR (300 MHz, CDCl 3 ) δ6.55 (s, 2H), 3.93 (s, 3H), 3.51-3.53 (m, 1H), 2.31 (s, 3H), 1.13 (d, J = 6.8 Hz, 6H)
    [141] Example 16 Preparation of 3-benzoyl-1,2-dimethylindole-4,7-dione
    [142] 3-benzoyl-4,7-dimethoxy-1,2-dimethylindole, which is a compound of Example 8, was carried out in the same manner as in Example 13 to obtain a compound in a yield of 30%.
    [143] 1 H-NMR (300 MHz, CDCl 3 ) δ 7.82 (d, J = 7.1, 2H), 7.54 (d, J = 7.4, 1H), 7.42 (d, J = 7.6, 2H), 6.54 (d, J = 9.9 Hz, 1H), 6.43 (d, J = 10.2 Hz, 1H), 3.98 (s, 3H), 2.32 (s, 3H)
    [144] Example 17 Preparation of 3-cyclopropanecarbonyl-1,2-dimethylindole-4,7-dione
    [145] 3-cyclopropanecarbonyl-4,7-dimethoxy-1,2-dimethylindole, which is a compound of Example 9, was carried out in the same manner as in Example 13 to obtain a compound in a yield of 41%.
    [146] 1 H-NMR (300 MHz, CDCl 3 ) δ6.57 (s, 2H), 3.94 (s, 3H), 2.56-2.58 (m, 1H), 2.38 (s, 3H), 1.23-1.25 (m, 2H ), 1.04-1.05 (m, 2H)
    [147] Example 18 Preparation of 3-cyclohexanecarbonyl-1,2-dimethylindole-4,7-dione
    [148] 3-cyclohexanecarbonyl-4,7-dimethoxy-1,2-dimethylindole, which is a compound of Example 10, was carried out in the same manner as in Example 13 to obtain a compound.
    [149] 1 H-NMR (300 MHz, CDCl 3 ) δ6.60 (s, 2H), 3.90 (s, 3H), 3.09-3.11 (m, 1H), 2.28 (s, 3H), 1.90-1.23 (m, 10H )
    [150] Example 19 Preparation of 3-acetyl-2-methylindole-4,7-dione
    [151] Oxidation reaction was carried out in the same manner as in Example 13 using 1.0 g (3.63 mmol) of 1,3-diacetyl-4,7-dimethoxy-2-methylindole, which is a compound of Example 12, and then to the reaction product. 7.7 g (20 equivalents) of potassium carbonate was added and reacted for 30 minutes. After the reaction, excess potassium carbonate was filtered, extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate and filtered. The organic layer was distilled under reduced pressure with silica gel, and then purified by column chromatography (hexane / ethyl acetate = 60/40) to give 440 mg (60%) of 3-acetyl-2-methylindole-4,7-dione as an orange solid. Got.
    [152] Melting point; 189-190 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ6.63-6.65 (m, 2H), 2.72 (s, 3H), 2.56 (s, 3H)
    [153] Example 20 Preparation of 3-isopropanecarbonyl-2-methylindole-4,7-dione
    [154] Example 19, except that 3-isopropanecarbonyl-4,7-dimethoxy-2-methylindole was used instead of 1,3-diacetyl-4,7-dimethoxy-2-methylindole. The same procedure was followed to obtain a compound in 30% yield.
    [155] 1 H-NMR (300 MHz, CDCl 3 ) δ6.62 (s, 2H), 3.75-3.76 (m, 1H), 2.47 (s, 3H), 1.14 (d, J = 7.0 Hz, 6H)
    [156] Example 21 Preparation of 3-acetyl-5,6-dibromo-2-methylindole-4,7-dione
    [157] 0.5 g (2.46 mmol) of 3-acetyl-2-methylindole-4,7-dione was dissolved in acetic acid (15 ml), followed by addition of 1.6 g (8.0 equiv) of NaOAc and 0.26 ml (2.0 equiv) of bromine Dropped at After 6 hours of reaction, 0.26 ml (2.0 equiv) of bromine was added dropwise again and reacted for 12 hours. 0.13 ml (1.0 equiv) of bromine was finally added dropwise and then stirred for 12 hours. The reaction was terminated by TLC (ethyl acetate / hexane = 20/80), and the reaction was terminated with 20 ml of water. Extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, distilled under reduced pressure and separated and purified by column chromatography (ethyl acetate / hexane = 20/80) to give 3-acetyl-5,6-di as a red solid. 700 mg (79%) of bromo-2-methylindole-4,7-dione was obtained.
    [158] Melting point; 183 ° C decomposition, 1 H-NMR (300 MHz, CDCl 3 ) δ 2.49 (s, 3H), 2.30 (s, 3H)
    [159] Example 22 Preparation of 3-Isopropanecarbonyl-5,6-dibromo-2-methylindole-4,7-dione
    [160] The same procedure as in Example 21 was repeated except that 3-isopropanecarbonyl-2-methylindole-4,7-dione was used instead of 3-acetyl-2-methylindole-4,7-dione. The compound was obtained.
    [161] 1 H-NMR (300 MHz, CDCl 3 ) δ3.63-3.65 (m, 1H), 2.47 (s, 3H), 1.14 (d, J = 6.8, 6H)
    [162] Example 23 Preparation of 3-acetyl-5,6-dibromo-1,2-dimethylindole-4,7-dione
    [163] The compound was prepared in the same manner as in Example 21, except that 3-acetyl-1,2-dimethylindole-4,7-dione was used instead of 3-acetyl-2-methylindole-4,7-dione. Got.
    [164] 1 H-NMR (300 MHz, CDCl 3 ) δ 3.95 (s, 3H), 2.63 (s, 3H), 2.40 (s, 3H)
    [165] Example 24 Preparation of 3-Isopropanecarbonyl-5,6-dibromo-1,2-dimethylindole-4,7-dione
    [166] In the same manner as in Example 21, except that 3-isopropanecarbonyl-1,2-dimethylindole-4,7-dione was used instead of 3-acetyl-2-methylindole-4,7-dione. The compound was obtained to obtain a compound.
    [167] 1 H-NMR (300 MHz, CDCl 3 ) δ 3.95 (s, 3H), 3.64-3.66 (m, 1H), 2.38 (s, 3H), 1.13 (d, J = 6.8, 6H)
    [168] Example 25 Preparation of 3-benzoyl-5,6-dibromo-1,2-dimethylindole-4,7-dione
    [169] A compound prepared by the same method as Example 21, except that 3-benzoyl-1,2-dimethylindole-4,7-dione was used instead of 3-acetyl-2-methylindole-4,7-dione. Got.
    [170] 1 H-NMR (300 MHz, CDCl 3 ) δ 7.82 (d, J = 7.1, 2H), 7.53 (d, J = 7.3, 1H), 7.43 (d, J = 7.6, 2H), 4.00 (s, 3H), 2.32 (s, 3H)
    [171] Example 26 Preparation of 3-cyclopropanecarbonyl-5,6-dibromo-1,2-dimethylindole-4,7-dione
    [172] In the same manner as in Example 21, except that 3-cyclopropanecarbonyl-1,2-dimethylindole-4,7-dione was used instead of 3-acetyl-2-methylindole-4,7-dione. The compound was obtained to obtain a compound.
    [173] 1 H-NMR (300 MHz, CDCl 3 ) δ 3.95 (s, 3H), 2.44-2.55 (m, 1H), 2.37 (s, 3H), 1.24-1.26 (m, 2H), 1.07-1.09 (m , 2H)
    [174] Example 27 Preparation of 3-cyclohexanecarbonyl-5,6-dibromo-1,2-dimethylindole-4,7-dione
    [175] In the same manner as in Example 21, except that 3-cyclohexanecarbonyl-1,2-dimethylindole-4,7-dione was used instead of 3-acetyl-2-methylindole-4,7-dione. The compound was obtained to obtain a compound.
    [176] 1 H-NMR (300 MHz, CDCl 3 ) δ3.93 (s, 3H), 3.11-3.13 (m, 1H), 2.29 (s, 3H), 1.91-1.25 (m, 10H)
    [177] Example 28 Preparation of 3-acetyl-5,6-dibromo-1-ethyl-2-methylindole-4,7-dione
    [178] The procedure was carried out in the same manner as in Example 21, except that 3-acetyl-1-ethyl-2-methylindole-4,7-dione was used instead of 3-acetyl-2-methylindole-4,7-dione. The compound was obtained.
    [179] 1 H-NMR (300 MHz, CDCl 3 ) δ4.41 (q, J = 7.2, 2H), 2.63 (s, 3H), 2.41 (s, 3H), 1.37 (t, J = 7.0, 3H)
    [180] Example 29 Preparation of 3-acetyl-6-bromo-5- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione (1)
    [181] Being the compound of Example 21 0.6 g (1.66 mmol) of 3-acetyl-5,6-dibromo-2-methylindole-4,7-dione was dissolved in tetrahydrofuran (THF) and 0.35 ml (3.0 equiv. Of 2-methylaziridine at room temperature ) Was added slowly and stirred for 1 hour. After completion of the reaction, the organic layer was distilled under reduced pressure with silica gel, purified by column chromatography (ethyl acetate / hexane = 40/60), and 3-acetyl-6-bromo-5- (2) 400 mg (72%) of -methylaziridin-1-yl) -2-methylindole-4,7-dione was obtained.
    [182] Melting point; 188-189 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ 2.69 (s, 3H), 2.65-2.67 (m, 1H), 2.55 (s, 3H), 2.57-2.51 (m, 2H), 1.55 (d, J = 5.3 Hz, 3H), 13 C-NMR (75 MHz, DMSO) δ 196.3, 175.8, 170.6, 155.9, 140.4, 129.2, 120.6, 120.2, 112.3, 37.7, 37.4, 31.1, 17.7, 12.6
    [183] Example 30 Preparation of 3-acetyl-6-bromo-5- (2-methylaziridin-1-yl) -1-ethyl-2-methylindole-4,7-dione (3)
    [184] 150 mg (0.38 mmol) of 3-acetyl-5,6-dibromo-1-ethyl-2-methylindole-4,7-dione are dissolved in THF and 80 ul (3.0 equiv) of 2-methylaziridine at room temperature The same procedure as in Example 29 was carried out except for the addition of 3-acetyl-6-bromo-5- (2-methylaziridin-1-yl) -1 as a purple solid compound of Formula 3 100 mg (71%) of ethyl-2-methylindole-4,7-dione was obtained.
    [185] Melting point; 161-162 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ 4.37 (q, J = 7.1, 2H), 2.60 (s, 3H), 2.58-2.56 (m, 1H), 2.47-2.42 (m , 2H), 2.35 (s, 3H), 1.50 (d, J = 5.4 Hz, 3H), 1.31 (t, J = 7.0, 3H)
    [186] Example 31 Preparation of 3-acetyl-5- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione (5)
    [187] 300 mg (1.47 mmol) of 3-acetyl-2-methylindole-4,7-dione was dissolved in THF and then 300 mg (1.5 equiv) of zinc chloride were added. After stirring for 5 minutes, 0.35 ml (3.0 equiv) of 2-methylaziridine was added slowly and stirred for 2 hours. After the same amount of 2-methylaziridine was further added, the reaction was terminated with water, extracted with ethyl acetate and washed with water and brine. After washing, the separation and purification step was carried out in the same manner as in Example 29, 3-acetyl-5- (2-methylaziridin-1-yl) -2-methylindole- of the violet solid of the compound of formula 5 168 mg (44%) of 4,7-dione was obtained.
    [188] Melting point; 165-166 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ5.81 (s, 1H), 2.72 (s, 3H) 2.52 (s, 3H), 2.44-2.38 (m, 1H), 2.19-2.17 (m, 2H), 1.45 (d, J = 5.3 Hz, 3H), 13 C-NMR (75 MHz, CDCl 3 ) δ 197.6, 178.7, 178.4, 159.0, 140.8, 130.7, 121.5, 121.1, 113.5, 36.6 , 34.7, 31.8, 17.6, 13.5
    [189] Example 32 Preparation of 3-acetyl-5- (2-methylaziridin-1-yl) -1-ethyl-2-methylindole-4,7-dione (6)
    [190] 200 mg (0.86 mmol) of 3-acetyl-1-ethyl-2-methylindole-4,7-dione was dissolved in THF, and then 235 mg (2.0 equiv) of zinc chloride was added and stirred for 5 minutes. After stirring, 0.18 ml (3.0 equiv) of 2-methylaziridine was added slowly and stirred for 2 hours. An equal amount of 2-methylaziridine was further added, the reaction was terminated with water, extracted with ethyl acetate and washed with water and brine. After washing, the separation and purification step was carried out in the same manner as in Example 29, 3-acetyl-5- (2-methylaziridin-1-yl) -1-ethyl-2 of an orange solid as a compound of formula 6 150 mg (61%) of methylindole-4,7-dione was obtained.
    [191] Melting point; 113-114 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ 5.77 (s, 1H), 4.39 (q, J = 7.1, 2H), 2.66 (s, 3H), 2.39 (s, 3H), 2.31-2.27 (m, 1H), 2.12-2.09 (m, 2H), 1.42 (d, J = 5.5 Hz, 3H), 1.34 (t, J = 7.0, 3H)
    [192] Example 33 Preparation of 3-Acetyl-6-bromo-1,2-dimethyl-5-piperazin-1-ylindole-4,7-dione (14)
    [193] 30 mg (0.08 mmol) of 3-acetyl-5,6-dibromo-1,2-dimethylindole-4,7-dione was dissolved in THF and 16.8 mg (2.5 equiv) piperazine dissolved in THF at room temperature Was added slowly and stirred for 1 hour. After completion of the reaction, the organic layer was distilled under reduced pressure with silica gel, separated and purified by column chromatography (ethyl acetate / hexane = 90/10), and 3-acetyl-6-bromo-1,2 as a purple solid compound of Formula 14 15 mg (50%) of -dimethyl-5-piperazin-1-ylindole-4,7-dione was obtained.
    [194] 1 H-NMR (300 MHz, CDCl 3 ) δ3.92 (s, 3H), 3.57-3.59 (m, 4H), 3.09-3.11 (m, 4H), 2.57 (s, 3H), 2.38 (s, 3H )
    [195] Example 34 Preparation of 3-acetyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione (17)
    [196] 323 mg (0.86 mmol) of 3-acetyl-5,6-dibromo-1,2-dimethylindole-4,7-dione are dissolved in THF and 0.2 ml (3.0 equiv) of 2-methylaziridine is slowly added at room temperature. After addition, it was stirred for 1 hour. After completion of the reaction, the organic layer was distilled under reduced pressure with silica gel, separated and purified by column chromatography (ethyl acetate / hexane = 20/80) to give 3-acetyl-6-bromo-5- as a pale purple solid compound of Formula 17. 180 mg (60%) of (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione were obtained.
    [197] Melting point; 166-167 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ3.92 (s, 3H), 2.63 (s, 3H), 2.59-2.61 (m, 1H), 2.50-2.45 (m, 2H), 2.36 (s, 3H), 1.53 (d, J = 5.5 Hz, 3H) 13 C-NMR (75 MHz, CDCl 3 ) δ 198.3, 175.8, 171.7, 153.7, 140.7, 127.9 122.1, 120.8, 115.3, 38.0, 37.6, 32.5, 31.5, 17.9, 10.7
    [198] Example 35 Preparation of 3-acetyl-6- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione (34)
    [199] Dissolve 50 mg (0.17 mmol) of 3-acetyl-5-bromo-2-methylindole-4,7-dione in 5 ml of methanol, then slowly add 0.1 ml (6.0 equiv) of 2-methylaziridine, Reacted for 30 minutes. After completion of the reaction, the separation and purification step was carried out in the same manner as in Example 34, to give 3-acetyl-6- (2-methylaziridin-1-yl) -2-methylindole- of the orange compound of formula 34. 4,7-dione (30 mg, 65%) was obtained.
    [200] Melting point; 207-208 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ 5.30 (s, 1H), 2.71 (s, 3H) 2.61-2.56 (m, 1H), 2.51 (s, 3H), 2.48-2.45 (m, 2H), 1.52 (d, J = 5.3 Hz, 3H)
    [201] Example 36 Preparation of 3-Acetyl-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione (37)
    [202] 300 mg (1.38 mmol) of 3-acetyl-1,2-dimethylindole-4,7-dione are dissolved in THF and then 282 mg (1.5 equiv) of zinc chloride are added. After stirring for 5 minutes 0.29 ml (3.0 equiv) of 2-methylaziridine was added slowly and stirred for 2 hours. Then 0.29 ml (3.0 equivalents) of 2-methylaziridine was further added, and the reaction was terminated with water, extracted with ethyl acetate, and washed with water and brine. After washing, the organic layer was dried over sodium sulfate, distilled under reduced pressure, and purified by column chromatography (ethyl acetate / hexane = 40/60) to give 3-acetyl-5- (2-methylaziridine-) as an orange compound. 200 mg (53%) of 1-yl) -1,2-dimethylindole-4,7-dione were obtained.
    [203] 1 H-NMR (300 MHz, CDCl 3 ) δ 5.78 (s, 1H), 3.90 (s, 3H), 2.66 (s, 3H), 2.36 (s, 3H), 2.33-2.30 (m, 1H), 2.12-2.10 (m, 2H), 1.42 (d, J = 5.4 Hz, 3H)
    [204] Example 37 Preparation of 3-benzoyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindol-4,7-dione (41)
    [205] 30 mg (0.069 mmol) of 3-benzoyl-5,6-dibromo-1,2-dimethylindole-4,7-dione are dissolved in THF and 44 ul (6.0 equiv) of 2-methylaziridinyl at room temperature Was added slowly and stirred for 1 hour. After completion of the reaction, the organic layer was distilled under reduced pressure with silica gel and separated and purified by column chromatography (ethyl acetate / hexane = 20/80) to give a red violet 3-benzoyl-6-bromo-5- ( 25 mg (88%) of 2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione were obtained.
    [206] Melting point; 155-156 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ 7.84 (d, J = 7.2, 2H), 7.56 (d, J = 7.3, 1H), 7.42 (d, J = 7.6, 2H) , 3.96 (s, 3H), 2.50-2.45 (m, 1H), 2.37-2.33 (m, 2H), 2.26 (s, 3H), 1.38 (d, J = 5.5 Hz, 3H)
    [207] Example 38 Preparation of 3-Isopropanecarbonyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione (46)
    [208] 72 mg (0.18 mmol) of crude 3-isopropanecarbonyl-5,6-dibromo-1,2-dimethylindole-4,7-dione are dissolved in THF and 2-methylaziridine 76 at room temperature The procedure of Example 37 was repeated except that ul (6.0 equiv.) was added, to give a reddish violet 3-isopropanecarbonyl-6-bromo-5- (2-methylaziri compound of Formula 46. 30 mg (45%) of din-1-yl) -1,2-dimethylindole-4,7-dione was obtained.
    [209] Melting point; 104-105 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ3.91 (s, 3H), 3.52-3.43 (m, 1H), 2.61-2.56 (m, 1H), 2.49-2.42 (m, 2H ), 2.26 (s, 3H), 1.51 (d, 5.4 Hz, 3H), 1.13 (d, J = 6.9 Hz, 6H)
    [210] Example 39 Preparation of 3-Isopropanecarbonyl-6-bromo-5- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione (47)
    [211] 50 mg (0.13 mmol) of crude 3-isopropanecarbonyl-5,6-dibromo-2-methylindole-4,7-dione were dissolved in THF and 55 ul 2-6.0 of 2-methylaziridine at room temperature The same procedure as in Example 37 was carried out except for the addition of 3 equivalents) of purple 3-isopropanecarbonyl-6-bromo-5- (2-methylaziridine-1- 31) (66%) of il) -2-methylindole-4,7-dione was obtained.
    [212] Melting point; 214-215 ° C., 1 H-NMR (300 MHz, CDCl 3 ) δ 3.75-3.63 (m, 1H), 2.68-2.61 (m, 1H), 2.55-2.53 (m, 2H), 2.48 (s, 3H) , 1.54 (d, J = 5.3 Hz, 3H), 1.14 (d, J = 6.8 Hz, 6H)
    [213] Example 40 Preparation of 3-cyclopropanecarbonyl-6-bromo-5- (2-methylaziridin-1-yl)-1,2-dimethylindole-4,7-dione (48)
    [214] 40 mg (0.1 mmol) of 3-cyclopropanecarbonyl-5,6-dibromo-1,2-dimethylindole-4,7-dione are dissolved in THF and 42 ul (6.0 equiv. Of 2-methylaziridine at room temperature In the same manner as in Example 37, except for the addition of), purple 3-cyclopropanecarbonyl-6-bromo-5- (2-methylaziridine-1- 20 mg (53%) of 1) 2-dimethylindole-4,7-dione was obtained.
    [215] 1 H-NMR (300 MHz, CDCl 3 ) δ 3.92 (s, 3H), 2.63-2.57 (m, 1H), 2.52-2.47 (m, 1H), 2.49-2.51 (m, 1H), 2.33 (s, 3H), 1.52 (d, J = 5.3 Hz, 3H), 1.26-1.21 (m, 2H), 1.07-1.01 (m, 2H)
    [216] Example 41 Preparation of 3-cyclopropanecarbonyl-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione (49)
    [217] 35 mg (0.144 mmol) of 3-cyclopropanecarbonyl-5,6-dihydro-1,2-dimethylindole-4,7-dione were dissolved in THF and 50 mg (2.5 equiv) of zinc chloride were added. After stirring for 5 minutes, 61 ul (6.0 equiv) of 2-methylaziridine was added slowly at room temperature and then stirred for 1 hour. After completion of the reaction, the organic layer was distilled under reduced pressure with silica gel and separated and purified by column chromatography (ethyl acetate / hexane = 25/75) to give 3-cyclopropanecarbonyl-5- (2-) as a compound of Chemical Formula 49. Methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione 8 mg (19%) was obtained.
    [218] 1 H-NMR (300 MHz, CDCl 3 ) δ 5.78 (s, 1H), 3.93 (s, 3H), 2.62-2.53 (m, 1H), 2.33 (s, 3H), 2.30-2.25 (m, 1H ), 2.13-2.08 (m, 2H), 1.42 (d, J = 5.5 Hz, 3H), 1.25-1.22 (m, 2H), 1.07-1.02 (m, 2H)
    [219] Example 42 Preparation of 3-benzoyl-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione (50)
    [220] 50 mg (0.18 mmol) of 3-benzoyl-5,6-dihydro-1,2-dimethylindole-4,7-dione were dissolved in THF and 120 mg (5.0 equiv) of zinc chloride were added. After stirring for 5 minutes, 76 ul (6.0 equiv) of 2-methylaziridine was added slowly at room temperature and then stirred for 1 hour. After completion of the reaction, separation and purification of the reactants were carried out in the same manner as in Example 41, where the red 3-benzoyl-5- (2-methylaziridin-1-yl) -1,2 compound of Formula 50 was used. 15 mg (25%) of dimethylindole-4,7-dione was obtained.
    [221] 1 H-NMR (300 MHz, CDCl 3 ) δ 7.86 (d, J = 7.0, 2H), 7.55 (d, J = 7.3, 1H), 7.42 (d, J = 7.5, 2H), 5.77 (s, 1H), 3.95 (s, 3H), 2.25 (s, 3H), 2.22-2.19 (m, 1H), 2.05-1.99 (m, 2H), 1.26 (d, J = 5.5 Hz, 3H)
    [222] Example 43 Preparation of 3-cyclohexanecarbonyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione (52)
    [223] 40 mg (0.09 mmol) of 3-cyclohexanecarbonyl-5,6-dibromo-1,2-dimethylindole-4,7-dione are dissolved in THF and 38 ul (6.0 equiv. Of 2-methylaziridine at room temperature ) Was added slowly and stirred for 1 hour. After completion of the reaction, separation and purification of the reactants were carried out in the same manner as in Example 41, to give a red-purple 3-cyclohexanecarbonyl-6-bromo-5- (2-methylaziridine- compound of formula 52. 22.5 mg (60%) of 1-yl) -1,2-dimethylindole-4,7-dione was obtained.
    [224] 1 H-NMR (300 MHz, CDCl 3 ) δ 3.90 (s, 3H), 3.21-3.14 (m, 1H), 2.61-2.56 (m, 1H), 2.49-2.44 (m, 2H), 2.26 (s , 3H), 1.92-1.19 (m, 10H), 1.51 (d, J = 5.5 Hz, 3H)
    [225] Example 44 Preparation of 3-Isopropanecarbonyl-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione (53)
    [226] 30 mg (0.12 mmol) of 3-isopropanecarbonyl-5,6-dihydro-1,2-dimethylindole-4,7-dione were dissolved in THF and 83 mg (5.0 equiv) of zinc chloride were added. After stirring for 5 minutes, 0.05 ml (6.0 equiv) of 2-methylaziridine was added slowly at room temperature, followed by stirring for 1 hour. After completion of the reaction, separation and purification of the reactants were carried out in the same manner as in Example 41, to give red 3-isopropanecarbonyl-5- (2-methylaziridin-1-yl)-which is a compound of formula 53. 14 mg (39%) of 1,2-dimethylindole-4,7-dione was obtained.
    [227] 1 H-NMR (300 MHz, CDCl 3 ) δ 5.30 (s, 1H), 3.90 (s, 3H), 3.59-3.61 (m, 1H), 2.27 (s, 3H), 2.18-2.20 (m, 1H ), 2.09-2.11 (m, 2H), 1.42 (d, J = 5.7 Hz, 3H), 1.13 (d, J = 7.0 Hz, 3H)
    [228] On the other hand, the compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
    [229] Preparation Example 1 Tablet (Direct Pressurization)
    [230] After sifting 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to prepare a tablet.
    [231] Preparation Example 2 Tablet (Wet Assembly)
    [232] After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed to make tablets.
    [233] Preparation Example 3 Powder and Capsule
    [234] After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Filled in 5 gelatin capsules.
    [235] <Example 4> Injection
    [236] Injectables were prepared by containing 100 mg as the active ingredient, 180 mg of mannitol, 26 mg of Na2HPO4.12H2O and 2974 mg of distilled water.
    [237] The indolequinone derivatives prepared in the above examples were tested as follows to evaluate their usefulness as anticancer agents.
    [238] Experimental Example 1 Anticancer Activity Investigation
    [239] In order to investigate the anticancer activity of the indolequinone derivatives of the present invention, human cancer cells were treated with SALB (SRB method, Skehan, et al., Proc. Am. Assoc. Cancer Res., 30: 612, 1989) . It was performed together.
    [240] Cancer cell lines are lung cancer cell lines (A549), melanoma cell lines (LOX-IMVI and G 361), colon cancer cell lines (HCT-15 and SW 620), prostate cancer cell lines (PC-3), breast cancer cell lines (MCF 7) and breast cancer-adria Mycin-resistant cancer cell lines (MCF / ADR) were used.
    [241] Step 1: Cell Culture
    [242] The cell line was used RPMI1640 culture medium containing calf serum of 10% and was incubated at a constant 37 ℃ in a 5% carbon dioxide thermostat.
    [243] Step 2: Determination of Cytotoxicity
    [244] Cytotoxicity was measured according to the method of NCI. The loading concentration of the cell line varied with the growth rate of the cell line. Each cell line was loaded from day 0 and then time zero plate (Tz plate) was made until the day of drug treatment and counted as zero at the time of calculation. The drug was diluted to a concentration of 30.0, 10.0, 3.0, 1.0, 0.3 and treated so that the final concentration of the solvent was 0.1%. After 48 hours, the drug-treated plate was fixed by adding 50 ul / well of 50% TCA (Trichloroacetic acid). The fixed plate was left at 4 ° C. for 60 minutes and then washed 4 to 5 times with tap water. The washed plates were dried and then 100 ul / well of 0.4% Sulforhodamine B (SRB) was added. After standing for about 30 minutes, washed with 0.1% acetic acid to remove the unbound dye. After drying, 100 ul / well of 10 mM Tris Base (pH 10.5) was added to dissolve the dyeing reagent, and the absorbance was measured at 540 nm. The absorbance measured was calculated as a percentage of the solvent treated group.
    [245] Step 3: Preparation of Sample
    [246] Samples prepared using DMSO (Dimethylsulfoxide) were diluted to 30, 10, 3, 1, 0.3 mg / ml. Culture cell line (culture media: RPMI 1640 + 5% FBS) was diluted 100-fold using stock solution. The results are shown in Table 2 below.
    [247] Compound cell lineFormula 1Formula 2Formula 3Formula 4Formula 5Formula 6Formula 7 Lung Cancer (A549)2.25111.312.8158.0180.8432.0516.785 Melanoma (LOX-IMVI)0.6991.8361.0372.5090.7621.0864.037 Colon Cancer (HCT 15)0.3101.5550.6391.528<0.30.8611.972 Colon Cancer (SW620)0.2841.8590.7312.6350.2891.2652.901 Breast Cancer (MCF7)<0.30.7210.6741.2050.3971.3513.621 Breast Cancer-Adriamycin Resistance (MCF7 / ADR)0.2562.2180.9062.389<0.30.6031.861 Prostate Cancer (PC-3)0.8272.6951.2443.0760.7560.6412.843 Average GI 50 <0.7043.1711.1493.051<0.5211.1233.431
    [248] Compound cell lineFormula 8Formula 9Formula 10Formula 11Formula 12Adriamycin Lung Cancer (A549)6.7507.83710.7527.80> 300.352 Melanoma (LOX-IMVI)4.4412.8694.55814.65> 300.200 Colon Cancer (HCT 15)3.1073.1792.69914.28> 300.601 Colon Cancer (SW620)3.3941.7501.059> 30> 300.263 Breast Cancer (MCF7)6.0153.5153.58417.01> 300.132 Breast Cancer-Adriamycin Resistance (MCF7 / ADR)2.5161.2261.54517.2521.76> 3 Prostate Cancer (PC-3)2.3331.6904.12320.8027.320.489 Average GI 50 4.0793.1524.045> 20.26> 28.44> 0.720
    [249] Compound cell lineFormula 13Formula 14Formula 15Formula 16Formula 17Formula 18Formula 19 Lung Cancer (A549)7.7051.0518.5909.4701.0127.0053.743 Melanoma (LOX-IMVI)2.9712.0707.6556.7900.7643.6151.815 Melanoma (G361)1.3740.2715.5683.5090.3433.4691.165 Colon Cancer (HCT 15)1.3410.81510.777.2420.5123.9061.628 Colon Cancer (SW620)1.2820.43112.507.9750.3743.4401.242 Prostate Cancer (PC-3)2.2041.3126.7878.4440.7684.7951.886 Average GI 50 2.8130.9928.6457.2690.6294.3721.868
    [250] Compound cell lineFormula 20Formula 21Formula 22Formula 23Formula 24Formula 25Formula 26 Lung Cancer (A549)> 3016.366.1834.65813.556.1774.180 Melanoma (LOX-IMVI)27.3215.0320.383.8399.6314.0653.385 Melanoma (G361)> 304.3837.2151.4164.5281.6641.395 Colon Cancer (HCT 15)> 307.746> 303.433> 301.7432.811 Colon Cancer (SW620)> 308.16310.542.06110.502.5662.614 Prostate Cancer (PC-3)> 3014.17> 302.67625.373.3242.393 Average GI 50 > 29.5511.05> 17.393.014> 15.604.8852.398
    [251] Compound cell lineFormula 27Formula 28Formula 29Formula 30Formula 31Formula 32Formula 33 Lung Cancer (A549)> 3015.298.9513.963> 303.93710.07 Melanoma (LOX-IMVI)> 3014.479.7772.904> 303.4963.289 Melanoma (G361)> 306.2083.4571.36516.481.1062.867 Colon Cancer (HCT 15)> 3018.157.7653.361> 301.8995.781 Colon Cancer (SW620)> 3012.414.6931.603> 301.1153.087 Prostate Cancer (PC-3)> 3013.837.1502.966> 302.7572.869 Average GI 50 > 3013.326.9662.694> 27.752.3854.661
    [252] Compound cell lineFormula 34Formula 35Formula 36Formula 37Formula 38Formula 39Formula 40Adriamycin Lung Cancer (A549)1.66515.007.2182.0797.71622.09> 300.364 Melanoma (LOX-IMVI)0.9703.8343.2861.4943.815> 30> 300.349 Melanoma (G361)0.6573.1772.4811.1561.8195.36212.450.176 Colon Cancer (HCT 15)0.9824.0723.2571.2584.59025.11> 301.071 Colon Cancer (SW620)0.7145.1373.0360.8143.47718.1325.150.273 Prostate Cancer (PC-3)0.5634.7025.1902.1983.374> 30> 300.341 Average GI 50 0.9257.6274.0781.5004.132> 21.78> 26.270.429
    [253] Compound cell lineFormula 41Formula 42Formula 43Formula 44Formula 45Formula 46Formula 47 Lung Cancer (A549)1.1883.5533.7271.27624.051.3711.567 Melanoma (LOX-IMVI)0.7071.2581.55010.5612.530.4610.630 Colon Cancer (HCT 15)0.8961.1371.8972.86723.900.6960.847 Colon Cancer (SW620)0.6210.9631.6225.51410.100.4030.821 Prostate Cancer (PC-3)0.6962.2113.02922.21> 300.8340.948 Breast Cancer (MCF7)0.5570.7450.8613.33911.320.5590.392 Average GI 50 0.7781.6452.1147.628> 18.650.7210.868
    [254] Compound cell lineFormula 48Formula 49Formula 50Formula 51Formula 52Formula 53Adriamycin Lung Cancer (A549)1.3291.7881.1794.8890.9881.1920.135 Melanoma (LOX-IMVI)0.3860.8660.8774.5090.7330.7970.089 Colon Cancer (HCT 15)0.6411.1301.0186.1330.9281.9840.967 Colon Cancer (SW620)0.4290.8690.7804.1700.7461.3610.204 Prostate Cancer (PC-3)0.7081.2050.9704.0880.6041.2490.310 Breast Cancer (MCF7)0.4601.1630.8544.7800.5701.0260.046 Average GI 50 0.6591.1700.9464.7620.7621.3880.292
    [255] As shown in the above table, the indolequinone derivative of the present invention showed the effect of inhibiting the growth of most cancer cell lines, and the precursor of the compound and the indolequinone derivative of the present invention in which the primary amine was introduced at position C5 Except for the 4,7-dimethoxy indoquinone derivatives, the indolequinone derivatives of the invention exhibited good anticancer activity with an average GI 50 of 5 ug / ml or less.
    [256] In particular, the compounds of Formulas 1, 5, and 17 of the present invention showed excellent anticancer activity of 1 ug / ml or less.
    [257] Experimental Example 2 Oral Acute Toxicity in Mice
    [258] In order to clinically utilize the compounds of the present invention, acute toxicity was investigated in the following manner.
    [259] Six-week-old SPF ICR mice were divided into five mice per group, 3-acetyl-6-bromo-5- (2-methylaziridin-1-yl) -2-, a compound of Formula 1 of the present invention. Methylindole-4,7-dione was suspended in 0.5% methylcellulose solution and administered orally at a dose of 0.5 g / kg / 15 mL. After administration, the mortality, general symptoms, and weight changes of the animals were observed and necropsied by the naked eye.
    [260] As a result, the compound of Formula 1 of the present invention was not observed in animals, such as general symptoms, weight changes and autopsy findings. In addition, mice showed no significant toxicity change up to 500 mg / kg, and the minimum lethal dose (LD 10 ) of oral administration was determined to be a relatively low toxicity substance of 500 mg / kg or more.
    [261] As described above, the indolequinone derivative represented by Formula 1 according to the present invention introduces various substituents into indolequinone into the mother nucleus, and in particular, by introducing a halogen element into C5 or C6, the indolequinone derivative is a lung cancer cell line. It would be useful as a cancer disease dentifrice by showing more selective, less toxic and side effects anti-cancer activity against melanoma cell lines, colon cancer cell lines, prostate cancer cell lines, breast cancer and breast cancer-adriamycin resistant cancer cell lines.
    权利要求:
    Claims (8)
    [1" claim-type="Currently amended] Indolequinone derivatives represented by the following formula (1) and pharmaceutically acceptable salts thereof.
    Formula 1

    (Wherein R 1 is hydrogen or an alkyl group of C 1 to C 3 ;
    R 2 is Wherein R a is C 1 to C 4 straight or branched alkyl, or aryl; Cyclo C 3 to C 6 carbonyl or 1-hydroxy C 1 to C 3 alkyl group;
    R 3 and R 4 are each independently hydrogen, C 1 -C 6 straight or branched alkyl amino, cyclo C 3 -C 6 alkyl amino, piperidinyl, 2-methylaziridinyl, N-phenylamino, N- (4-halophenyl) amino or halogen.
    [2" claim-type="Currently amended] The compound of claim 1 , wherein R 1 is hydrogen, methyl, ethyl group or acetyl group; R 2 is an acetyl, isopropanecarbonyl, benzoyl, cyclopropanecarbonyl, cyclohexanecarbonyl, 1-hydroxyethyl group; R 3 and R 4 are each independently hydrogen, methylamino, dimethylamino, propylamino, cyclopropylamino, cyclohexylamino, 2-methylaziridinyl, N-phenylamino, piperidinyl, N- (4- Chlorophenyl) amino or a bromine atom.
    [3" claim-type="Currently amended] The method of claim 1, wherein the indole quinone derivative is
    3-acetyl-6-bromo-5- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione;
    3-acetyl-6-bromo-5- (2-methylaziridin-1-yl) -1-ethyl-2-methylindole-4,7-dione;
    3-acetyl-5- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione;
    3-acetyl-5- (2-methylaziridin-1-yl) -1-ethyl-2-methylindole-4,7-dione;
    3-acetyl-6-bromo-1,2-dimethyl-5-piperazin-1-ylindole-4,7-dione;
    3-acetyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione;
    3-acetyl-6- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione;
    3-acetyl-5- (2-methylaziridin-1-yl) -1,2-dimethylindol-4,7-dione;
    3-benzoyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione;
    3-isopropanecarbonyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindol-4,7-dione;
    3-isopropanecarbonyl-6-bromo-5- (2-methylaziridin-1-yl) -2-methylindole-4,7-dione;
    3-cyclopropanecarbonyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindol-4,7-dione;
    3-cyclopropanecarbonyl-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione;
    3-benzoyl-5- (2-methylaziridin-1-yl) -1,2-dimethylindol-4,7-dione;
    3-cyclohexanecarbonyl-6-bromo-5- (2-methylaziridin-1-yl) -1,2-dimethylindol-4,7-dione; And
    Indoquinone derivatives, characterized in that 3-isopropanecarbonyl-5- (2-methylaziridin-1-yl) -1,2-dimethylindole-4,7-dione.
    [4" claim-type="Currently amended] 1) introducing a carbonyl group (R 2 ) at the C 3 position of 2-methyl-4,7-dimethoxyindole;
    2) protecting (R 1 ) nitrogen of 2-methyl-4,7-dimethoxyindole having the carbonyl group introduced therein;
    3) oxidizing and deacetylating the 2-methyl-4,7-dimethoxyindole; And
    4) A method for preparing indole quinone, characterized in that the step of introducing a substituent to the C5 and C6 of the deacetylated indole quinone derivative using a competitive reaction.
    Scheme 1

    (Wherein R 1 , R 2 , R 3 and R 4 are as mentioned in claim 1 above)
    [5" claim-type="Currently amended] 5. The process according to claim 4, wherein in step 1 R 2 is selected from the group consisting of acetyl chloride, isopropylcarbonyl chloride, benzoyl chloride, cyclopropylcarbonyl chloride and cyclohexylcarbonyl chloride.
    [6" claim-type="Currently amended] The method according to claim 4, wherein step 4 introduces halogen into C5 or C6 as in Scheme 2 below.
    Scheme 2

    (Wherein R 1 and R 2 are as mentioned in claim 1 above)
    [7" claim-type="Currently amended] 5. The method of claim 4, wherein step 4 introduces a substituent to C5 or C6 as in Scheme 3 below. 6.
    Scheme 3

    (Wherein R 1 and R 2 are as mentioned in claim 1 above)
    [8" claim-type="Currently amended] An anticancer and antitumor agent comprising the indolquinone derivative of claim 1 as an active ingredient.
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    同族专利:
    公开号 | 公开日
    KR100525706B1|2005-11-03|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2002-11-20|Application filed by 주식회사 켐온
    2002-11-20|Priority to KR10-2002-0072164A
    2004-05-27|Publication of KR20040043773A
    2005-11-03|Application granted
    2005-11-03|Publication of KR100525706B1
    优先权:
    申请号 | 申请日 | 专利标题
    KR10-2002-0072164A|KR100525706B1|2002-11-20|2002-11-20|An indolequinone derivative having anticancer activity and a process for the preparation thereof|
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