MXPA00010243A - Sulfonamide-containing indole compounds - Google Patents

Abstract

Novel neovascularization inhibitors are constructed to provide antitumor agents which are superior in safety to conventional antitumor agents, are surely efficacious and can be administered over a prolonged period of time. Namely, indole compounds represented by general formula (I) or pharmacologically acceptable salts thereof or hydrates of the same wherein R1 represents hydrogen, etc.;R2 and R3 are the same or different and each represents hydrogen, etc.;R4 represents hydrogen or lower (C1-4) alkyl;and the ring A represents cyanophenyl, etc., provided that the following cases are excluded:the one where R1, R2 and R3 are all hydrogen atoms;the one where R2 and R3 are both hydrogen atoms;and the one where the ring A is an aminosulfonylphenyl group and R1 and R2 are both halogen atoms;and provided that when the ring A is a cyanophenyl, 2-amino-5-pyridyl or 2-halogeno-5-pyridyl group and R1 is a cyano group or a halogen atom, then at least one of R2 and R3 is not hydrogen.

Description

indole compounds containing sulfonamide Field of the Invention The present invention relates to an indo-dol compound containing sulfonamide and having an antiangiogenic effect thereof. More specifically, it is related to an antitumor agent, a suppressor of cancer metastasis, an agent • diabetic for diabetic retinopathy, a therapeutic agent for rheumatoid arthritis and a therapeutic agent for the hematoma based on an anticoagulant effect. Previous Technique It is clear that there is a close relationship between the proliferation of cancer and angiogenesis. Thus, when angiogenesis is not generated at the cancer site, the cancer remains in a latent tumor state. However, it has been seen that, when angiogenesis is generated, the oxygen and the blood's iirients are supplied to the tumor, so < They promote the proliferation and metastasis of cancer, leading to a clinically malignant state. Accordingly, it is expected that, by suppressing cancer angiogenesis, cancer proliferation and metastasis may be suppressed. Since the angiogenic vessels are composed of endothelial cells and interstitial cells of the host, the agent n = t? Oo The antiangiogenic agents are not the Caneeian cells but said normal host cells. Due to the fact that cancer cells are not a direct target, it can be expected that there is also efficacy for cancer that does not respond to known anticancer agents and, in addition, it is presumed that the possibility of cancer tolerance appears, which represents a large problem in cancer therapy, is scarce. In addition, angiogenesis is a phenomenon of tumors and, in mature individuals, it is limited to the tumor, endometrium, etc., accompanied by a mens-i-cycle. Consequently, it is believed that its effect adverse is pe- ___ É_É ___ I__I_____I compared to anticancer drugs known .G. Recently, it has been experimentally demonstrated in clinical trials that anti-angiogenic agents are able to suppress and further reduce cancer proliferation in models with cancer transplantation and that no tolerant cancer is generated and, in clinical trials, The correlation between angiogenesis and malignancy of many solid cancers has been demonstrated, such as breast cancer, prostate cancer, lung cancer and colon cancer. In cancerous tissues, there is continuous proliferation of cancer cells and it has been seen that, depending on the balance between them, a progressive cancer or a latent tumor appears as a result. An anticancer agent does not directly kill cancer cells, but interrupts the supply of nutrients, so that the balance is tilted towards apoptosis, which induces tumor latency or cancer reduction, so that 3? a drug that can be expected to exhibit an excellent effect (prolongation of life, inhibition of recurrence and suppression of metastasis) by long-term therapy. In a preclinical phase, there are anti-angiogenic agents with diverse mechanisms of action, but, as its antitumor effect in a preclinical phase is insufficient, its usefulness in the clinical phase is still doubtful and, therefore, there is a -nn demand for antiangiogenic agents. The effect of which is reliable. Re also knows that angiogenesis participates in retinopathy or retinitis. When the blood vessel proliferates (-M the retina, the vision gets worse and, as it progresses, blindness results.) There is no effective therapeutic drug for this currently and there is a demand for effective therapeutic drugs, WO 9301182 describes antitumor agents thanks to a Ms tjjM ^ Mm ^^ m ^ ^^ s? s ßß tyrosine kinase-specific inhibitory activity of the compounds having an indole backbone, but they are indolylmethylene-2-indolinone compounds and are different from those of the present invention. Similarly, WO 96 01G described an antitumor agent due to the specific inhibitory activity of tyrosine kinase of the compounds having an indole skeleton., but they are 2-indolinone-3-methylene compounds and are different from those of the present invention. LJ_ sulfonamide compounds having an indole structure are described in JP-A 7-165708 and JP-A 8-231505. However, the compounds specifically described in JP-A 7-165708 and have two substituents other than an aryl (ohtero-aryl) sulfonylamino group in an indole ring are limited and the combinations of those substituents are only six, ie, (1) 3-C1 and -Cl, (2) 3-C1 and -0CH3, (3) 3-C1 and -0H, (4) -C1 and 1-CH3, (5) 3-C1 and 4-CN and (6) 3-CN and 5-Br. No exis-1; combination of (a) 3-CN and 4-CH3, (b) 3-C1 and 5-Br, (c) 3-C1 and 4-Br and (d) 3-Br and 4-CH3. With respect to the compounds unsubstituted with 4-halogen, there is a description of 4-Br compounds, but their sulfonyl moiety is only one compound R-p-nitrophenol. In addition, the indole compounds described in JP-A 8-231505 are only compounds monosubstituted with 2-halogen or 3-cyano. In those publications open to the public, there is no description of an anti-angiogenic effect in aj. solute and there is also no description that suggests it. Description of the Invention An object of the present invention is to create a new anti-angiogenic agent and to provide an anti-tumor agent and show a high safety and a safe effect in comparison with conventional antitumor agents and that it can be administered over a long period of time. period. The present inventors have carried out an intensive study, and have insisted that the indole compound containing sulfone-mida represented by the following formula achieves the effect searched and have concluded the present invention. That is to say, that the present invention relates to an indole compound containing sulfonamide represented by the following formula (I), its pharmacologically acceptable salt or its hydrates.

In the formula, R 1 represents a hydrogen atom, a halogen atom or a cyano group; R2 and R3 are the same or different from each other and each represents a hydrogen atom, a C3-C4 lower alkyl group or a halogen atom; R4 represents hydrogen atom or a lower alkyl group C_-C4, and -_ ring A represents a cyanophenyl group, an amino-sulfomelnyl group, an aminopyridyl group, an aminopyrimidyl group, a halopyridyl group or a cyanothiophenyl group, always - before the case in which R1, R2 and R3 are all hydrogen atoms, in which R2 and R3 are both hydrogen atoms or in which ring A is an aminosulfonyl group and both R1 and R2 are atoms, are excluded of halogen. Also, when the A e. a cyanophenyl group, a 2-amino-5-pyridyl group. n group! -halo-5-pyridyl and R1 is a cyano group or a halogen atom, at least one of R2 and R3 must not be a hydrogen atom. The present invention relates to a method for the prevention or therapy of the disease against which the inhibition of angiogenesis at the tumor site, rheumatoid arthritis or diabetic retinopathy is effective pr -vention or therapy by administering a pharmacologically effective dose of the aforementioned indole compound, its pharmacologically salt or its hydrates to a patient.

- "--- * - The present invention is also related to the use-. ~ of the above mentioned indole, its pharmaceutically acceptable salt or its hydrates for the manufacture of a preventive or therapeutic agent for the disease against which an anti-angiogenic agent is effective for prevention or therapy. The present invention further relates to an anti-angiogenic agent, an anti-tumor agent, a therapeutic agent for pancreatic cancer, a therapeutic agent for colon cancer, a therapeutic agent for gastric cancer, a therapeutic agent for breast cancer, a therapeutic agent for prostate cancer, a therapeutic agent for lung cancer, a therapeutic agent for ovarian cancer, a suppressor of cancer metastasis, a therapeutic agent for diabetic retinopathy, a therapeutic agent for cancer Rheumatoid arthritis or a therapeutic agent for the hematoma, which consists of the indole compound, announces its pharmacologically acceptable salt or substances as an effective component, and is related to a method for the treatment, therapy and improvement through the use of Any of these pharmaceutical agents, in addition, was related to the use of the above compound for the manufacture of any of those pharmaceutical agents In the formula (I) above, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom in an iodine atom. A lower C 1 -C 4 alkyl means a straight or branched alkyl chain ij such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group, a isopropyl group, an isobutyl group and a tere-butyl group. The indole compound represented by the above formula ([) can form a salt with an acid or a base. The present invention also includes a salt of the indole (?) Compound. With examples of the salt with an acid a salt of a meo acid, lime as hydrochloride, hydrobromide or sulfate, and one of an organic acid such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid or p-tluensulfonic acid. Examples of the salt with a base are a lorganic salt such as a sodium salt, a potassium salt or an alkali salt, and that formed with an organic base, such as r-sheet, arginine or lysine. the hydrates of said compound and its pharmacologically acceptable salts are included, although the compounds of the present invention show a strong anti-angiogenic effect., also include compounds that are subject to metabolism, such as • iiclation, reduction, hydrolysis and conjugation in vivo. The present invention further includes the compounds that produce the compound of the present invention as a result of metabolism, such as by oxidation, reduction and hydrolysis in vivo. The compound of the present invention (I) can be manufactured by various methods and as representative among those the following can be cited. It can be manufactured by reaction of a sulphonic acid «Presented by the formula (II): (in the formula, the ring Aa represents a cyanophenyl group, -upo.-minosulfonyl, an aminopyridyl group, an aminiroxy group, a halopyridyl group or a cyanothiophenyl group) or a reactive derivative thereof with a compound represented by Formula (III): (III) (in the formula, Rla represents a hydrogen atom, a halogen atom or a cyano group and R 2a and R 3a are the same or different from each other and each represents a hydrogen atom, a C 1 -C 4 lower alkyl group or a carbon atom. halogen, provided that the case in which Rla, R2a and R3a are all omoc of hydrogen is excluded). Examples of the reactive derivative of sulfonic acid (II) are commonly used reactive derivatives, and very much, such as sulfonyl halide, sulfonyl acid anhydride and N-sulfonylimidazolide, and the particularly advantageous example is a sulfonyl halide. Although there is no particular limitation for the solvent used for the reaction, those which dissolve the par-no substances are preferred-they readily react with them. For example, pyridine, tetrahydrofuran, dioxane, benzene, and ethyl ether, dichloromethane, dimethylformamide, and a mixed solvent consisting of two or more selected from each other can be used. In addition, when an acid is released in the progress of the reaction, as in the case of the use of a sulfonyl halide in the reaction, it is preferred to carry out the reaction in the presence of an appropriate deacidifying agent and, what nto. the use of a basic solvent, such as pyridine, is particularly appropriate. When a neutral solvent is used, a basic substance, such as an alkali carbonate or an organic tertiary amine may be added. Of course, the solvent that can be used is not limited to those listed here. Normally, the present reaction proceeds at room temperature, but, if necessary, it can be cooled and heated. The reaction time is normally 10 minutes at a time and preferably selected depending on the type of starting compounds and the temperature of the reaction.

When an amino group is protected in the resulting product, a conventional method of protection, such as treatment with an acid, working with an alkali and catalytic reduction, as necessary, whereby it is possible to obtain a mdol compound (I) having a free ammo group. will now illustrate methods for manufacturing the < starting materials (II), their reactive derivatives and (III) used in the present invention. The starting compound (II) and the reactive derivative of p mcli 'in both known compounds and new compounds. In the case of the new compounds, these may be fabpcacos by applying the synthetic method already described for the known compounds or by combination from them. For example, a new sulfonyl chloride can be manufactured by a method which applies the synthetic methods mentioned in 5 Chem. Ver., 90, 841 (1957); J. Med. Chem., 6, 307 (1963); J. Chem Soc (c), 1968, 1265; Chem. Lett., 1992, 1483; J. Am. I-m Soc. 59, 1837 (1937); J. Med. Chem., 22_, 1376 (1980); . ii. Chem. Soc., 70, 375 (1948); J. Am. Chem.? Oc. , 7j3, 2171 (1956) etc. When Rla and R 3a are hydrogen atoms and R 2a is an i • halogen atom in the starting compound (III), it can be manufactured by a synthetic method. When Ra and R3a are the same or different from each other and each represents a hydrogen atom, a lower alkyl group C_-C4 or a halogen atom, the case in which both are hydrogen atoms - Rla s a cyano group, can be manufactured as follows: rjrmu_a_ reaction 1 _____? __ «___ Í__l__g ___-_ In the formulas, Rla, R2a and R3a have the same meanings as defined above.

Reaction formulas 2 In the formulas, Rla, Ra and Ra have the same meanings as defined above and "DPPA" means diphenyl- "forylazide. When Rla is a halogen atom, it can be manufactured in such a way that formula (a) or formula ( g) in the aforementioned reaction formulas (1) and (2) are halogenated by a conventional means and the nitro group is reduced or a protecting group is removed from an ammo group When the compound of the present invention is used as medication, is administered orally or parenterally.; osis varies depending on the degree of symptoms, age, sex, body weight and the difference in sensitivity of the patient, the method of administration, the l ^ »á ____ á ____ Í _____ l? period for administration, of the range of administration of the property of the pharmaceutical preparation, of the ti-; of preparation, of the type of effective components, etc. and it is not particularly limited. In the case of intravenous administration, it is 1-2,000 mg, preferably 1-1500 mg and, more preferably, 5-1,000 mg, while, in the case of oral administration, it is usually 10- 6,000 mg, preferably about 50-4,000 mg and, more preferably, 100-3,000 mg per day for adults and Is it usually administered once a day or dividing in has-? i three times a day. When preparing a solid preparation for oral administration, fillers and, if necessary, binders, disintegrating agents, lubricants, coloring agents, correctors, etc. are added. to the main component, then submitting to a common method for making tablets, coated tablets, granules, fine granules, powders, capsules, etc. Examples of lactose filler, corn starch, sa-? irosa, glucose, sorbitol, crystalline cellulose and silicon dioxide; Examples of binders are polyvinyl alcohol, ethylcellulose, methylcellulose, gum arabic, hydroxypropylcellulose and hydroxypropylmethylcellulose; Examples of lubricant are magnesium stearate, talc and silica; Examples of coloring agent are those which are allowed to be added to pharmaceutical products, and are examples of cocoa flavoring agent in Ivo menthol, aromatics, peppermint oil, borneol and cinnamon and powder. Of course, it is not a problem to coat said tablets and granules with a layer of sugar, a layer of gelatin or others, if necessary. In preparing the injection, a pH adjusting agent, a buffer, a suspending agent, a solubilizer, a stabilizer, an inizing agent, a preservative, etc. are added, if necessary, to the main component, subjecting a method to conflation. conventional to prepare injections for intravenous, subcutaneous or intramuscular administration. At that time, it can be converted into a lyophilized product by a common method, if necessary. Examples of the suspending agent methylcellulose, poly- ,. jrbato 80, hydroxyethylcellulose, gum arabic, tragacanth powder, sodium carboxymethylcellulose and polyoxyethylene sorbitan monolaurate. Examples of the solubilizing agent are polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotine-mida, polyoxyethylene sorbitan monolaurate, macrogol and fatty acid ethyl ester of castor oil. Examples of the stabilizer are sodium sulfite and sodium inetasulfite. Examples of the preservative are methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol. The effect of the compounds of the present invention will be shown by means of the following pharmacological experimental examples. Experimental pharmacological example 1. Antiangiogenic effect The degree of inhibition of angiogenesis ob- was defined. -warved when pieces of rat aorta were incubated in collagen as an anti-angiogenic effect. That is, the aorta was cut from male rats of the Sprague-Da ley strain (10-12 weeks of age) with Hanks solution, in such a way that the surrounding fatty tissues were carefully eliminated. The aorta was cut to prepare pieces of 2 mm square and they were allowed to rest in a 24-well plate holding the endothelial cells up. 500 μl of neutralized Type I collagen (Cell Ma-trix Type I-A, manufactured by Nitta Gelatin) was then poured into the well house and allowed to stand at room temperature for about 20 minutes on a clean table to solidify the goal. After confirming that the gel had solidified, 500 μl of MCDB 131 medium (manufactured by Chlore) was added. lia Kogyo), followed by incubation in a C02 incubator (5% C02) at 37 ° C. The next day, the culture medium was exchanged with 500 μl of MCDB 131 medium containing the test compound and continued to incubate. After three days, the medium was exchanged again with 500 μl of MCDB 131 medium containing the test compound and, in the <stageOn the 7th day from the start of the addition of the test compound, the number of capillaries formed around the aorta was counted under the microscope. The solution containing the test compound was prepared in a triple dilution system, in which 10 μg / ml was the highest concentration. The inhibition ratio was calculated from the following formula and the 50% inhibitory concentration (IC 50) was determined for each test compound. Reason for inhibition (%) = (C-T) / CxlOO C: Number of capillaries when no compound was added. T: Number of capillaries when a compound was added. Table 1 Experimental pharmacological effect 2. Inhibitory effect of endothelial cell growth Endothelial cells derived from the human umbilical vein (HUVEC, manufactured by Sanko Junyaku), incubated in an EGM medium (manufactured by Sanko Junyaku) containing 100 units of penicillin were adjusted and 100 μg / ml streptomycin at 0.8-lxlO4 cells / ml and placed every 100 μl separately on a 96-well plate. After incubation in a C02 incubator (5% C02) at 37 ° C overnight. 100 μl of EGM medium containing diluted test compound was added as a triple dilution, followed by incubation for three days. Cell numbers were measured at that time by the MTT method. That is, 50 μl of phosphate buffer containing 0.33% of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) was added and continued for 3-4 hours. hours. Then, after removing the. culture supernatant, 100 μl of dimethyl sulfoxide ("DMSO") was added to dissolve a formazan that formed in the cells and the absorbance was measured at a wavelength of 540 nm by the use of a plate reader ( manufactured by Corona Denki). The inhibition ratio was calculated from the following formula and the inhibitory concentration of 50% "Iso" was determined for each compound: Inhibition ratio (%) = (CT) / Cxl00 C: Absorbance when not added compound T: Absorbance when a compound was added.

Table 2 Pharmacological Experimental Example 3. Inhibitory Effect of Mouse B16 Melanoma Proliferation Mouse B16 melanoma cells incubated in Dulbecco's modified Eagle's medium (DMEM, manufactured by Nissui Seiyaku) containing 10% fetal bovine serum were adjusted, 100 units / ml of penicillin and 100 μg / ml of streptomycin at 2 × 10 4 cells / ml and placed each 100 μl of these separately in a 96-well plate. After carrying out an incubation in a CO 2 incubator (5% CO 2) at 37 ° C overnight, 100 μl of the above culture, which contained a test compound diluted in the triple dilution series, was then added, followed by incubation for 3 i ..as v the cell numbers were measured at that time by means of an MTT method. Incidentally, a treatment with a 0.33% MTT solution was carried out for 1-2 hours. The inhibition ratio was calculated from the following formula and the 50% inhibitory concentration (IC 50) was determined for each compound. _3__fi ___ W ____ HÍ _____ £ __? __ Reason of inhibition (%) = (C-T) / CxlOO C: Absorbance when compound was not added. T: Absorbance when a compound was added.

Table 3 It is evident from Experimental Pharmacological Example 1 that the compounds of the present invention exhibit a clear antiangiogenic t-fect. It is evident from the pharmacological Experimental Examples 2 and 3 that the inhibitory effect of the proliferation of the compounds of the present invention on B16 melanoma cells was 5 to 100 times weaker than that exerted on endothelial cells and , consequently, they act specifically on the endothelial cells of the blood vessel. In the meantime, an evaluation of the anti-tumor effect was carried out according to the method of Koyanagi et al. (Cancer Res.,,, 702-1706, 1994), using a KP-1 cell line derived from human pancreatic cancer and an HCT 116 cell line derived from human colon cancer. The aforementioned human cancer cells (5 × 10 6 cells) were transplanted subcutaneously to nude mice (KSN) from 6 to 7 weeks of age and, ^ m¡ ^ ._of the stage in which a size of approximately 100 mm3 was reached, administration of the compound of the present invention was initiated. In the experiments, ten mice were used for a group to which no drug was administered, while, in a group administered drug, five mice were used per dose. A dose of 50 mg / kg, 100 mg / kg or 200 mg / kg orally was continuously administered twice >The results were 37%, 30% and 11%, and the tumor size was compared on day 22 of des-I ', from the beginning of administration to the group to which no drug had been administered. respectively, in the KP-1 cell line derived from human pancreatic cancer and 0.2%, 0.3% and 0.0%, respectively, in the HCT 116 cell line derived from human colon cancer in the case of a group to which the compound of Example 1 was administered for example, Thus, the compound of Example 1 showed a significant antitumor effect.From the above results, the compound of the present invention can be expected to exhibit an excellent effect in view of the of efficacy and safety compared to known antibacterial antitumour agents, which are directed directly to cancer cells.As noted in the above Experimental Examples, the compounds of the present invention have an "anti-angiogenic effect". ys They are useful as antitumor agents for pancreatic cancer, colon cancer, stomach cancer, breast cancer, prostate cancer, lung cancer and ovarian cancer and also as therapeutic agents for diabetic retinopathy, rheumatoid arthritis and the hematoma. EXAMPLES Next, production examples will be illustrated to show the manufacture of the starting compounds for the compounds of the present invention and examples for the compounds of the present invention, although it goes without saying that the present invention is not limited thereto. production mole 1. Ethyl pyruvate N- (5-methyl-2-nitrophenyl) hydrazone To a mixed solution of 160 ml of water and 170 ml of concentrated hydrochloric acid was added 75.0 g (493 mmol) of 5-methyl -2-nitroaniline, followed by stirring. An aqueous solution (80 ml) of 36.0 g (517 mmol) of sodium nitrite was added dropwise at -20 ° C. The reaction solution was added to a solution which was prepared by dissolving ethyl 2- cylacetoacetate in 100 ml of ethanol, followed by the addition of 200 ml of a 12N aqueous solution of potassium hydroxide at -20 ° C, with stirring, during 30 minutes. After stirring the reaction at the same temperature for 30 minutes, 100 ml of concentrated hydrochloric acid was added and the resulting precipitates were collected by filtration, washed with water and dried in vacuo overnight. A mixed solution of diethyl ether and hexane was added and the resulting crystals were collected by filtration to obtain 130 g of the title compound. 1 H-RM (DMSO-d 6) d (ppm): 1.29 (3 H, t, J = 7.2 Hz), 2.16 (3 H, s), 2.40 (3 H, s), 4.25 ( 2H, c, J = 7.2Hz), 6.91 (1H, dd, J = 8.8, 2.0Hz), 7.63 (1H, s), 8.07 (1H, d, J = 8 , 8Hz), 10.69 (1H, s). Production Example 2. Ethyl 4-Methyl-7-nitro-lH-indole-2-carboxylate 250 ml of a suspension of 25.0 g (94.2 mmol) of the tax of Production Example 1 in xylene were added 100 g of polyphosphoric acid, followed by heating to re-flow for 3 hours. They were added to the reaction solution SO my water and 300 ml of ethyl acetate cooling with ice. The resulting insoluble matters were filtered, followed by washing with 1.5 liters of ethyl acetate, and the resulting filtrate was extracted with ethyl acetate. He washed successively The organic layer was washed with a saturated solution of sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated to dryness. A mixed solution of tert-butyl methyl ether and hexane was added to the resulting residue and the resulting crystals were collected by filtration for r 11. g of the title compound. LH-NMR (DMSO-de) d (ppm): 1.35 (3H, t, J = 7.2Hz), 2.65 (3H, s), 4.38 (2H, c, J = 7.2Hz) ), 7.16 (1H, d, J = 8.4Hz), 7.51 (1H, s), 8.19 (1H, d, J = 8.4Hz), 11.29 (1H, broad s) . Production Example 3. 4-Methyl-7-nitro-lH-indole-2-carboxylic acid To 150 ml of a solution of 11.0 g (44.3 mmol) of the com pound of Production Example 2 in tetrahydrofuran 150 ml of an aqueous IN solution of sodium hydroxide were followed, followed by heating with stirring at 80 ° C for 30 minutes. The reaction solution was concentrated, 40 ml of 5N hydrochloric acid was added to the resulting residue under cooling with ice to adjust to pH 1, and the resulting precipitates were filtered and washed with water. The precipitates were dissolved in 300 ml of tetrahydrofuran and "i" ethyl acetate was extracted. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to dryness to obtain 9.60 g of the title compound. 1 H-NMR (DMSO-d 6) d (ppm): 2.62 (3 H, s), 7.13 (1 H, d, J-8.0 Hz), 7.42 (1 H, s), 8.15 ( 1H, d, J = 8.0 Hz), 11.00 (1H s broad). Production Example 4. 4-Methyl-7-nitro-lH-indole They were dissolved in 60 ml of 1,3-dimethyl-2-imidazolidinone "58 g (43.5 mmol) of the compound of Production Example 3, They added 1.04 g (4.35 mmol) of basic copper carbonate and the mixture was heated with stirring at 180 ° C for 4 hours, 120 ml of ethyl acetate were added to the reaction mixture under ice cooling. The resulting insoluble matters were filtered and the resulting filtrate was extracted with acetone. ethyl acetate. The organic layer was washed with water and brine successively and dried over magnesium sulfate. After concentrating, the resulting residue was purified by silica gel column chromatography, to obtain 87 g of the title compound. XH-NMR (DMSO-d6) d (ppm): 2, 59 (3H, s), 6.74 (1H, s), - "3 (1H,, J = 8.4Hz), 7.48 (1H, s), 8.00 (1H, d, J = 8.4Hz), 11, 86 (1H, broad s) Production example 5. 3-Formyl-4-methyl-7-nitro-lH-indole To 12 ml (154 mmol) of dimethylformamide was added 1.5 ml. (16.1 mmol) of phosphorus oxychloride at 0 ° C in a nitrogen atmosphere, followed by stirring at room temperature at the same temperature for 20.5 hours A solution (20 ml) of 2.0 g was added ( 11.4 mmol) of the compound of Production Example 4 in dimethylformamide at 0 ° C, followed by heating at 90 ° C for 21 hours with stirring, 100 ml of an aqueous solution of sodium hydroxide IN was added to the reaction solution. cooling with ice, followed by extraction with ethyl acetate.The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated to dryness.To the resulting residue was added a mixed solution of tert-butyl methyl ether and hexane and the crystals were collected resulting by filtration, to obtain 2.23 g of the title compound. ^ -NMR (DMSO-d6) d (ppm): 2.90 (3H, s), 7.21 (1H, d, J = 8.4Hz), 8.11 (1H, d, J = 8.4Hz), 8.39 (1H, s), 10.01 (1H, s), 12, 71 (1H, broad s). Production example 6. 3-Cyano-4-methyl-7-nitro-lH-indole 2.21 g (10.8 mmol) of the compound of Production Example 5 were dissolved in 100 ml of dimethylformamide, followed by . of addition of 900 mg (13.0 mmol) of hydroxylamine hydrochloride and 1.05 ml (13.0 mmol) of pyridine. After heating at 60 ° C with stirring for 40 minutes, 53.9 mmol of 1,1 '-carbonyldiimidazole (53.9 mmol) was added to the suspension. reaction reaction cooling with ice. After heating for a further 30 minutes with stirring, 3.0 ml (21.5 mmol) of triethylamine was added to the reaction solution, followed by heating to the same temperature for 1 h plus 5 with stirring. 50 ml of ice water were added to the reaction mixture under cooling with ice, followed by extraction with ethyl acetate.The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated to dryness. The resulting residue was a mixed solution of tert-butyl methyl ether and hexane, and the resulting crystals were collected by filtration to obtain 1.95 g of the title compound. ^ H-RM (DMS0-d6) d (ppm) : 2.78 (3H, s), 7.22 (1H, d, J ^ 8.0Hz), 8.14 (1H, d, J = 8.0Hz), 8.41 (1H, s), 12 76 (1H, broad S 15) Production example 7. 7-Bromo-4-methyl-1H-indole To 300 ml of a solution of 65.0 g (301 mmol) of 2-JIT. lnitrobenzene in tetrahydrofuran was added 1 liter of a 1.0M solution of vinylmagnesium bromide (1 mol) 20 in tetrahydrofuran at -60 ° C in a nitrogen atmosphere, with stirring, for 1 hour. A saturated aqueous solution of ammonium chloride and ethyl acetate was added to the mixed reaction solution and the resulting insoluble matters were filtered. The resulting filtrate was dried over magnesium sulfate, concentrated and the residue was then purified by chromatography on a silica gel column to obtain J5.5 g of the title compound. .1H-NMR (DMSO-d6) d (ppm): 2.42 (3H, s), 6.55 (1H, s), 6.73 (1H, d, J = 7.6Hz), 7.16 (1H, d, J = 7.6Hz), 7.35 (1H, s), 30 11.24 (1H, broad s) Production example 8. 4-Methyl-lH-indole-7-carbohydrate acid xylitol To a solution (200 ml) of 35.5 g (169 mmol) of the compound of Example 7 in tetrahydrofuran was prepared. added a 1.6M solution (350 ml) of butyllithium (384 mmol) in hexane under a nitrogen atmosphere at -78 ° C and with stirring. After stirring for 40 minutes with ice cooling, carbon dioxide was introduced into the reaction solution at -50 ° C and stirred as is for 15 minutes. Water was added to the reaction mixture at the same temperature, the solvent was evaporated and the resulting precipitates were collected by filtration and washed with water. The precipitates were dissolved in 300 ml of tetrahydrofuran, dried over magnesium sulfate and then concentrated to dryness to obtain 25.9 g of the title compound. ^ H-RM (DMS0-d6) d (ppm): 2.51 (3H, s), 6.53 (1H, s), 6.88 (1H, d, J = 7.6Hz), 7.31 (1H, s), 7.62 (1H, d, J = 7.6Hz), 10.99 (1H, broad s), 12.79 (1H, broad s). Production Example 9. 7- (N-tert-Butoxycarbonyl) amino-4-methyl-1H-indole In 7.0 mL of toluene, 7.0 g (40.0 mmol) of the compound of Production Example 8 were suspended, added then 22 ml (160 mmol) of triethiamine and 11.2 ml (52 mmol) of i. tenylphosphorylazide under a nitrogen atmosphere and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 8 ml (84 mmol) of tert-butanol, the mixture was heated with stirring at 100 ° C for 2.5 hours and then the reaction solution was concentrated. The resulting residue was dissolved in ethyl acetate, washed with 0.1 N hydrochloric acid, water and brine successively, dried over magnesium sulfate and concentrated in vacuo. A mixed solution of diethyl ether and hexane was added to the resulting residue and the resulting crystals were collected by filtration, to obtain 7.87 g of the title compound.

^ -NMR (DMS0-d6) d (ppm): 1.48 (9H, s), 2.38 (3H, s), (,, 37-6.44 (1H, m), 6.68 (1H, d, J = 8.4Hz), 7.22-7.31 (2H, m), 8.86 (1H, broad s), 10.73 (1H, broad s). Production example 10. 7- (N-tert-Butoxycarbonyl) amino-3- formyl-4-methyl-lH-indole To 400 ml (5.2 mol) of dimethylformamide was added 40 ml (429 mmol) of phosphorus oxychloride (0 ° C) under a nitrogen atmosphere, followed by stirring at the same temperature for 25 min. At 0 ° C, 74.0 g (300 mmol) of the compound of Production Example 9 was added, followed by stirring at room temperature for 1.5 h. 250 ml of a 5N aqueous solution of sodium hydroxide were added to the reaction mixture under cooling with ice to adjust to pH 8. 3-Trahydrofuran, ethyl acetate and water were added to separate the organic layer, followed by washing with water. and brine successively. After drying over magnesium sulfate, the solvent was evaporated. A mixed solution of diethyl ether and hexane was added to the resulting residue and the crystal-1 'was collected. resulting by filtration to obtain 53.7 g of the title compound. ^ -RMN (DMS0-d6) d (ppm): 1.50 (9H, s), 2.71 (3H, s), 6.90 (1H, d, J = 7.6Hz), 7.32- 7.41 (1H, m), 8.21 (1H, d, J = 1, 6Hz), 8.99 (1H, broad s), 9.93 (1H, s), 11.88 (1H, s) large) . Production Example 11. 7- (N-tert-Butoxycarbonyl) amino-3-riano-4-methyl-1H-indole in 50 ml of dimethylformamide was dissolved 4.43 g (16.2 mmol) of the compound of Example Production 10, followed by the addition of 1.35 g (19.4 mmol) of hydroxylamine hydrochloride and 1.6 ml (19.8 mmol) of pyridine. After heating with stirring at 60 ° C for 45 min, 1,1'-carbonyldiimidazole (80.8 mmol) was added to the reaction solution under ice-cooling. After heating with stirring at 60 ° C. for another 30 min, 4.5 ml (32.3 mmol) of i-ethylamine was added to the reaction solution, followed by heating with stirring at the same temperature for another 30 min. . Water was added to the reaction mixture under cooling with ice, followed by extraction with ethyl acetate. He washed The mixture was then treated with water and brine successively, dried over magnesium sulphate and then concentrated to obtain 4.27 g of the title compound. '? -RM (DMS0-d6) d (ppm): 1.49 (9H, s), 2.60 (3H, s), 6.89 (1H, d, J = 8.0Hz), 7.34 -7.42 (1H, m), 8.20 (1H, d, J = 2.8Hz), 9.04 (1H, broad s), 11.80 (1H, broad s). Production Example 12. 7-Amino-3-cyano-4-methyl-1H-in-dol in a mixed solution of 100 ml of tetrahydrofuran and III L of methanol were suspended 12.6 g (62.6 mmol) of the compound of Production Example 6 and hydrogenated at a pressure of 3 atmospheres and at room temperature in the presence of 430 mg (1.87 mmol) of platinum oxide. The filtrate was filtered, then concentrated to dryness, a mixed solution of tert-butyl methyl ether and hexane was added to the residue and the crystals were collected by filtration to obtain 10.7 g of the title compound. In 400 ml of dichloromethane, L'i, 5 g (186 mmol) of the compound of Production Example 11 were added and 210 ml (2.76 mmol) of trifluoroacetic acid were added at 0 ° C in an atmosphere of nitrogen, followed by stirring at room temperature for 40 minutes. To the reaction solution was added a 5N aqueous solution of sodium hydroxide at -20 ° C to adjust to pH 7. The solvent was removed and the residue was extracted with ethyl acetate. The organic layer was washed with water and brine successively, dried. > on magnesium sulfate and concentrated to dryness. A mixed solution of diethyl ether and hexane was added to the resulting residue and the crystals were collected by filtration to obtain 24.5 g of the title compound. 'H-NMR (DMS0-d6) d (ppm): 2.47 (3H, s), 5.07 (2H, s), 6.34 (1H, d, J = 7.6Hz), 6.64 (1H, d, J = 7.6Hz), 8.10 (1H, s), 11, 70 (1H, broad s). Production agent 13. 3-cyanobenzenesulfonyl chloride, a mixed solution of 200 ml of water and 250 ml of concentrated l-Hydrochloric acid, 25.0 g (212 mmol) of 3- cyanoaniline, followed by agitation. An aqueous solution (80 ml) of 15.5 g (223 mmol) of sodium nitrite was added dropwise at -10 ° C. The reaction solution was added to acetic acid saturated with sulfur dioxide (prepared by saturating sulfur dioxide in 250 ml of acetic acid, followed by the addition of 2.1 g of cuprous chloride) under ice cooling and with stirring. After 1 hour, the reaction solution was poured. ion in 500 ml of ice water and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water and brine successively and dried over magnesium sulfate. The solvent was evaporated, a mixed solution of diethyl ether and hexane was added to the residue and the crystals were collected by filtration to obtain 16.0 g of the title compound. \ H-NMR (DMS0-d6) d (ppm): 7.55 (1H, t, J = 8.0Hz), 7.78 (1H, dd, J = 8.0, 1.2Hz), 7.86-7.92 (2H, m). Production Example 14. 4-Sulfamoylbenzenesulfonyl Chloride To a mixed solution of 80 ml of water and 50 ml of concentrated hydrochloric acid was added 25.0 g (145 mmol) of 4-aminobenzenesulfonamide, followed by stirring. An aqueous solution (20 mL) of 10.5 g (152 mmol) of sodium nitrite was added dropwise at a temperature of -13 ° C to -10 ° C for 15 mm. After 10 min, the reaction solution was added to a mixed solution saturated with sulfur dioxide (prepared by saturating sulfur dioxide in a mixed solution of 150 ml of acetic acid and 12.5 ml of concentrated hydrochloric acid, followed by addition of 3.7 g of cuprous chloride) at -30 ° C with stirring. After 1 h, 500 ml of ice water was added to the reaction solution and the resulting precipitates were collected by filtration. The precipitates were dissolved in a mixed solution of 450 ml of toluene and 150 ml of ethyl acetate. After filtering the resulting insoluble matters, the filtrate was extracted with ethyl acetate. HE washed the organic layer with a saturated solution of bicarbonate-t or sodium and brine successively and dried over magnesium sulfate. The solvent was evaporated, 100 ml of toluene was added to the resulting residue and the crystals were collected by filtration to obtain 20.9 g of the title compound.

NMR (DMSO-ds) d (ppm): 7.65-7.69 (2H, m), 7.71-7.78 (4H,). Production example 15. 5-Bromo-3-chloro-7-nitro-lH-in-dol To a solution of 12.00 g (49.8 mmol) of 5-bromo-7-nitro-lH-indole in 140 ml of tetrahydrofuran were added 1.4 ml of dimethylformamide and 6.98 g (52.3 mmol). of N-chlorosuccinimide, followed by stirring at room temperature overnight. A 10% aqueous solution of sodium was added, followed by extraction with ethyl acetate. The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated seriously to obtain 14.84 g of the title compound. \ H-NMR (DMSO-d.) D (ppm): 7.79 (1H, s), 8.15 (1H, s), 8.23 (1H, s), 12.32 (1H, broad s ). Production Example 16. 7-amino-5-bromo-3- < • Gold -1H- Indole a solution (250 ml) of 14.84 g (53.9 mmol) of the compound of Production Example 15 in methanol, 70 ml of concentrated hydrochloric acid and 31.97 g ( 269 mmol) of tin powder, followed by stirring at room temperature for 80 minutes. After adding a 5N aqueous solution of sodium hydroxide under cooling with ice to adjust to pH 10, the resulting precipitates were filtered and the filtrate was washed with ethyl acetate.The .ca layer was washed with a saturated bicarbonate solution. Sodium and brine were successively dried over magnesium sulfate and concentrated, The resulting residue was then purified by silica gel column chromatography to obtain 14.35 g of 7-amino-5-bromo-3-chloro lH-indole, dissolved in acetate ethyl acetate and a mixed solution (17 ml) of 4N hydrogen chloride and ethyl acetate was added. The resulting precipitates were collected by filtration and washed with hexane to obtain, 23 g of the title compound. H-NMR (DMSO-d6) d (ppm): 5.11 (3H, broad s), 6.64 (1H, s), 6.93 (1H, s), 7.50 (1H, d, J = 2.0Hz), 11.38 (1H, broad s). Production example 17. Ethyl pyruvate 2- (4-methyl-2-roienyl) hydrazone In 110 ml of water, 30.00 g (0.197 mol) of 4-methyl-2-n-troaniline were suspended, followed by adding 66 ml of concentrated hydrochloric acid, added an aqueous solution (35 ml) of 16.33 g (0.237 mol) of sodium nitrite dropwise at 10 ° C or less, followed by stirring for 40 minutes with ice cooling To prepare a salt solution of (thiazonium) In a mixed solution of 150 ml of methanol and 300 ml of water, 28.43 g (0.197 mol) of ethyl 2-methylacetoacetate were dissolved, followed by the addition of 120 ml of a aqueous solution of 53.36 g (0.808 mol) of potassium hydroxide under ice cooling.

The diazonium salt prepared previously dropwise at the same temperature and stirred by cooling with ice for 20 minutes. After adding concentrated hydrochloric acid to The resulting precipitates were collected at pH 1. After being washed with water and dried under vacuum over phosphorus pentaoxide to obtain 46.42 g of the title compound, LR-NMR (DMSO-d6) d. (ppm): 1.40 (3H, t, J = 7.2Hz), 2.23 (; H, G), 2.36 (3H, s), 4.35 (2H, c, J = 7, 2Hz), 7.44 (1H, dd, J = 8.8, 1.6Hz), 7.93 (1H, d, J = 8.8Hz), 8.00 (1H, s), 10.87 ( 1H, broad) Production Example 18. Ethyl 5-methyl-7-nitro-lH-indole-2-car-b-ixylate To a solution (320 ml) of 15.92 g (60.0 mmol) of the com- From Example 17 of production in xylene, polyphosphoric acid was added, followed by heating with stirring overnight. Water and ethyl acetate were added, the resulting insoluble matters were filtered and the organic layer was separated. The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated. The resulting residue was then purified by silica gel column chromatography to obtain 7.32 g of the title compound. X H-NMR (DMSO-d 6) d (ppm): 1.34 (3 H, t, J = 7.0 Hz), 2.47". i), 4.36 (2H, c, J = 7.0Hz), 7.35 (1H, s), 7.99 (1H, s), 8.11 (1H, s), 11.25 (1 H, broad s) Production Example 19. 5-Methyl-7-nitro-lH-indole To a solution (80 ml) of 7.86 g (31.7 mmol) of the compound of Production Example 18 In tetrahydrofuran, 150 ml of an aqueous IN sodium hydroxide solution were added under ice-cooling, followed by stirring at a temperature of 3.5 hours, while cooling with ice, 2N hydroic acid was added to adjust to pH 1, followed by extraction with ethyl acetate The organic layer was washed with water and brine successively, dried over magnesium sulfate and then concentrated to dryness to obtain 7.13 g of 5-methyl-7-nitro-1H-indole 2-carboxylic acid The resulting compound was dissolved in 160 ml of 1,3-dimethyl-2-imidazolidinone, followed by addition of 716 mg (3.24 mmol) of basic carbonate of stirring at 185 ° C. for 2 h, the solution was poured into water, insoluble matters were filtered The resulting filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated. The resulting residue was then purified by silica gel column chromatography to obtain 4.50 g of the title compound. 'H-NMR (DMSO-d6) d (ppm): 2.46 (3H, s), 6.62 (1H, d, J = 2.8Hz), 7.47 (1H, d, J = 2.8Hz), 7.87 (1H, s), 7.92 (lH, s), 11, 77 (1H, broad s). Production example 20. 3-Bromo-5-methyl-7-nitro-lH-in-dol To a solution (70 ml) of 4.50 g (25.5 mmol) of the Compound of Production Example 19 in tetrahydrofuran was 0 7 ml of dimethylformamide and 4.78 g (26%). 9 mmol) of N-bromosuccinimide was added, followed by stirring at room temperature for 70 min.A 10% aqueous solution of sodium thiosulfate was added, followed by extraction with ethyl acetate.The organic layer was washed with water and brine successively, it was dried over magnesium sulfate and then concentrated to dryness to obtain 6.53 g of the title compound: j'I-NMR (DMSO-d6) d (ppm): 2.50 (3H,, s), 7, 67 (1H,,, /, 73 (1H, s), 8.02 (1H, s), 12.10 (1H, broad s), Production example 21. 7-Amino-3-bromo-5-methyl -lH-in-dol In a mixed solution of 150 ml of methanol and 75 ml of water, 6.76 g (26.5 mmol) of the compound of Production Example 20 were suspended and then 11.34 g (212 mmol) of ammonium chloride were added and 5.92 g (106 mmol) of iron powder. After stirring at 80 ° C for 1 hour, the resulting insoluble materials were filtered. An added solution of sodium bicarbonate was added to the filtrate to adjust to pH 8, followed by extraction with ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate, water and brine successively, dried over magnesium sulfate and concentrated. The resulting residue was then purified by silica gel column chromatography to obtain 3.30 g of the title compound. pH-NMR (DMS0-d6) d (ppm): 2.24 (3H, s), 5.08 (2H, s am-pyl), 6.20 (1H, s), 6.41 (1H, s) ), 7.35 (1H, s), 10.86 (1H, broad s). Production Example 22. 6-Amino-3-pyridine- chloride, ulphonyl A 123.8 g (1.06 mol) of chlorosulfonic acid was added to .00 g (0.106 mol) of 2-aminopyridine were added portionwise with ice cooling. Thionyl chloride (50.56 g, 0 425 mol), followed by heating under reflux for 2.5 hours and then stirring at 150 ° C. for 7 hours.The reaction solution was seen in ice water, neutralized by adding sodium bicarbonate and extracted with acetate. The organic layer was washed with a saturated solution of sodium bicarbonate, water and brine successively, dried over magnesium sulfate and then concentrated to dryness.The resulting residue was suspended in ethyl ether and the filtrate was filtered off. insoluble matters The filtrate was concentrated to dryness and the resulting residue was recrystallized from ethyl ether-hexane to obtain 6.58 g of the title compound Example of production 23. 4, 7-Dibromo-1H-indole From 62 , 0 g (0.224 mol) of 2,5-iylmononitrobenzene, 27.2 g of the title compound were obtained in the same manner as in Production Example 1 of JPA 7-165708.2H-NMR (DMS0-d6) d (ppm): 6.52 (1H, d, J = 3.2Hz), 7.18 (1H, d, J = 8.0Hz), 7.26 (1H, d, J = 8.0) Hz), 7.53 (1H, d, J = 3.2Hz), 11.75 (1H, broad s). Production Example 24. 7-Amino-4-bromo-lH-Ndol Hydrochloride V A solution (300 ml) of 27.2 g (98.9 mmol) of the compound of Production Example 23 in tetrahydrofuran was added dropwise drop 186 ml (116.3 mmol) of a solution 6M of n-butyl-lithium in hexane in a nitrogen atmosphere at -78 ° C, followed by stirring for 1 hour under ice cooling. After cooling again to -78 ° C, 28 ml (0.13 mmol) of diphenylphosphorylazide was added dropwise and stirred 1 i mix at -78 ° C for 1 hour and then at -40 ° C for 1 i. go to. After adding 150 g of a 3. 4M solution of sodium hydride and bis (2-methoxyethoxy) aluminum in toluene at -40 ° C, it was stirred at room temperature for 1 hour. Water was added (120 ml), the resulting soluble solids were collected and the filtrate was extracted with ethyl ether. The organic layer was washed with a saturated solution of sodium bicarbonate and brine successively and dried over magnesium sulfate. After concentrating, the resulting residue was dissolved in ethyl ether, 50 ml of a mixed solution of 4N hydrochloric acid and ethyl acetate were added and the resulting precipitates were collected by filtration to obtain 14.5 g of the title compound. (i NMR (DMSO d_) d (ppm): 6.41-6.43 (1H, m), 6.80 (1H, d, J-8.0.0Hz), 7.16 (1H, d, J = 8.0Hz), 7.54 (1H, t, J = 2.8Hz), 11.57 (1H, broad s). Production Example 25. 7-Bromo-4-chloro-lH-? Ndol The title compound was obtained in the same manner as in Production Example 23. XH-NMR (DMSO-d.) D (ppm): , 60-6.61 (1H, m), 7.04 (1H, d, rP, lHz), 7.32 (1H, d, J = 8, lHz), 7.53 (1H, t, J = 2.7Hz), 11.74 broad). Production Example 26. 7-Am? No-4-chloro-lH-0-indole hydrochloride The title compound was obtained in the same manner as in Production Example 24. ^ -RMN (DMSO-ds) d (ppm) : 6.54-6.55 (1H, m), 7.05 (1H, d, J = 8, lHz), 7.11 (1H, d, J = 8, lHz), 7.60 (1H, t, J = 2.7 Hz), 11.82 r 'IH, s broad) i ° m of production 27 5 -Bromo 2-t? ofenocarboxialdehyde To a solution (80 ml) of 10.0 g (41, 3 mmol) of 5-dibromothiophene in tetrahydrofuran was added dropwise 27.0 ml (43.4 mmol) of a 1.6M solution of n-butyllithium in 0 hexane or a nitrogen atmosphere at a temperature of - 78 ° C, followed by stirring at the same temperature for 10 min. Then 3.5 ml (45.5 mmol) of dimethylformamide was added. At the same temperature, followed by stirring for 20 minutes, added water, followed by extraction with ethyl acetate. ethyl. The organic layer was washed with a 0.1 N aqueous solution of hydrochloric acid, water and brine successively and dried over magnesium sulfate. It was concentrated to dryness to obtain > r 6.4 g of the title compound. 1 H-NMR (DMSO-d.) D (ppm): 7.49 (1 H, d, J = 4.0 Hz), 7.87 (1 H, d, J = 3.9 Hz), 9.81 (1 H, s). Production example 28. 5-Bromo-2-thiophenecarbonitrile / _ a solution of 82 g (43.1 mmol) of the compound of Production Example 27 in 40 ml of dimethylformamide were added, 3.3 g (51.7 mmol) of hydroxylamine hydrochloride and 4.1 g (51.7 mmol) of pyridine were added. , followed by stirring at tempe- - •: -. Ambient for 30 minutes. Then 34.9 g (215.5 mmol / l, 1'-carbonyldiimidazole were added under ice cooling, followed by stirring at room temperature for 1 hour.) Ice water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous INOH solution of hydrochloric acid, water and brine successively and dried over magnesium sulfate.After concentrating, the resulting residue was purified by column chromatography. silica gel to obtain 6.7 g of the title compound.2H-NMR (DMSO-d.) d (ppm): 7.45 (1H, d, J = 4.0Hz), 7.84 (1H, d, J = 4 0Hz). Production method 29. 5-Benzylthio-2-thiophenecarbonyl trile In 10 ml of dimethyl sulfoxide, 585 mg (13.4 mmol, 55% oily) of sodium hydride were suspended and 1- e eq. 1.4 was added; (11.2 mmol) of benzylmercaptan cooling with _i-: eq? After stirring for 10 minutes, then 2.1 i (11.2 mmol) of the compound of Production Example 14 were added, followed by stirring at room temperature for 1 hour, water was added to the reaction solution, followed by Extraction with ethyl acetate The organic layer was washed with water and brine successively and dried over magnesium sulfate, After concentration, the resulting residue was purified. by column chromatography on silica gel to obtain 1.51 [j] of the title compound. 1 H-NMR (DMSO-d 6) d (ppm): 4.26 (2H, s), 7.18 (1H, d, J = 4.0Hz), 7.27-7.30 (5H, m), 7.83 (1H, d, J = 4.0Hz). Production example 30. 4-Bromo-lH-indolecarboxylic acid from 51 g of the compound of the production example - obtained 34 g of the title compound of the same moiety as in Production Example 8. '-H-RM (CDC13) d (ppm): 6.51-6.52 (1H, m), 7.35 (1H, d, J = 8.0Hz), 7.48 (1H, t, J = 2.8Hz), 7.66 (1H, d, J = 8Hz), 11.4 (1H, broad s), 13.2 (1H, broad s). Production Example 31. 7- (N-tert-Butoxycarbonyl) amino-4-bromo-lH-indole - from 34 g of the compound of the Production Example - obtained 32 g of the title compound in the same manner as in Production Example 9. 'H-NMR (CDCl 3) d (ppm): 1.51 (9H, s), 6.38-6.39 (1H, m), 7.13 (1H, d, J = 8.0Hz), 7.44-7.46 (2H, m), 9.11 (1H, broad s), 11.2 (1H, broad s) . Production Example 32. 7- (N-tert-Butoxycarbonyl) amino-4-bromo-3-chloro-1H-indole or the title compound was treated with N-orosuccinimide in a solution of the compound of Production Example Jl in tetrahydrofuran / dimethylformamide. 1 H-NMR (CDCl 3) d (ppm): 1.50 (9H, s), 7.19 (1H, d, J = 8.4Hz), 7.45 (1H, d, J = 8.4Hz), 7.62 (1H, d, J = 2.8Hz), 9.08 (1H, broad s), 11.41 (1H, broad s). Production Example 33. 7-Amino-4-bromo-3-chloro-1H-indole hydrochloride - dissolved the compound (10.87 g, 31.5 mmol) of Example 1-32, proc. 32 in 120 ml. of methanol and 20 ml of concentrated hydrochloric acid were added, followed by stirring 60 ° C for 40 minutes. After completion of the reaction, 1 -? Im? Nó the solvent and the resulting residue was subjected to a - ^ azeotropic tiiation three times with ethanol. The resulting residue was washed with ether to obtain 8.5 g of the title compound X H NMR (CDCl 3) d (ppm): 6.67 (1 H, d, J = 8.0 Hz), 7.13 (1 H, a J = 8.0Hz) 7.65 81H, d, J = 2.8Hz), 11.74 (1H, broad s). Production Example 34. 2-amino-5-p? Nm? D? - nasulfonyl chloride and 21 ml (0.316 mol) of chlorosulfonic acid aa hei.da and 3 g (0.032 mol) were added in portions (stirring) 9.2 ml (0.126 mol) of thionyl chloride were further added, followed by stirring at 150 ° C for 70 hours. The reaction solution was cooled to room temperature and poured into water and the mixture was extracted with water. ethyl acetate The extract was dried over sodium sulfate and concentrated to dryness to obtain 1.7 g of the title compound? H NMR (CDCl 3) d (ppm) -5.97 (2H, broad), 8.83 ( 2H, s).

Example 1 3 Cyano-N- (3-c? Ano-4-met? L-lH-? Ndol-7-? L) benzenesulfonamide ( The compound (2.00 g, 11.7 mmol) of Production Example 12 was dissolved in 60 ml of tetrahydrofuran and 4.0 ml (49.5 mmol) of pipdma and 2.60 g (12.9 g) were added. mmol) of the compound of Production Example 13. After stirring at room temperature for 16 h, 2N hydrochloric acid was added to adjust to pH 1-2 and the mixture was extracted with ethyl acetate. The oranic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated. The resulting residue was then purified by chromatography. column chromatography on silica gel to obtain 3.90 g of the title compound. 'f. :: 20-221 ° C (recrystallized with ethanol / n-hexane). '-H-NMR (DMSO-d.) D (ppm): 2.55 (3H, s), 6.50 (1H, d, J = 8.0Hz), 6.77 (1H, d, J = 8.0Hz), 7.71 (1H, t, J = 8.0Hz), 7.90 (LH, d, J = 8.0Hz), 8.05-8.13 (2H, m), 8, 16 (1H, s), 10.11 (1H, broad s), 12.01 (1H, broad s). Example 2. 6-Chloro-N- (3-cyano-4-methyl-lH-indol-7-yl) -3-pyridinesulfonamide The compound (700 mg, 4.09 mmol) of Production Example 12 was dissolved in 20 ml of tetrahydrofuran and then 1.3 ml (16.1 mmol) of pyridine and 950 mg (4.48 mmol) were added. 6-Chloro-3-pyridinesulfonyl. After stirring at room temperature for 2 hours, 1N hydrochloric acid was added to adjust to pH 1-2 and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated. The resulting residue was then purified by silica gel column chromatography to obtain 1.16 g of the title compound. 1 f. 2 '2-263 ° C (recrystallized with ethanol / hexane). H-NMR (DMS0-d6) d (ppm): 2.57 (3H, s), 6.55 (1H, d, J = 7.6Hz), b 82 (1H, d, J = 7.6Hz) , 7.69 (1H, d, J = 8.4Hz), 8.01 (1H, dd, J = 8.4, 2.4Hz), 8.17 (1H, d, J = 2.8Hz), 8.60 (1H, d,? H2.4Hz), 10.21 (1H, broad s), 12.03 (1H, broad s). Example 3. N- (3-Bromo-5-methyl-lH-indol-7-yl) -4-sulfamoyl-benzenesulfonamide The compound (200 mg, 0.89 mmol) from Production Example 22 was dissolved in 6 ml of tetrahydrofuran and then 0.3 ml (3.71 mmol) of pyridine and 300 mg (1.17 mmol) 1 were added. of Production Example 14. After stirring at room temperature for 48 h, IN hydrochloric acid was added to adjust the pH to 1-2 and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then washed successively, dried over magnesium sulfate and concentrated. A mixed solution of diethyl ether and hexane was then added to the resulting residue and the crystals were collected by filtration to obtain 387 mg of the compound "L '" tule.Pf: 196-197 ° C (recrystallized with ethanol / n-hexane). XH-NMR (DMS0-d6) d (ppm): 2.24 (3H, s), 6.60 (1H, s), 6.98 (1H, s), 7.44 (1H, s), 7.55 (2H, broad s), 7.85-7.95 84H, m), 10.13 (1H, broad s), 11.01 (1H, broad s).

Example !_. 6-Amino-N- (5-bromo-3-chloro-lH-indol-7-yl) -3-pyridmasuironamide The compound (1.00 g, 3.55 mmol) of the Ejem-pjlo of Production 16 was suspended in 25 ml of tetrahydrofuran and then 0.86 ml (10.6 mmol) of pyridine and 718 mg (3.73 g.) Were added. mmol) of the compound of Production Example 8 was cooled with ice. After stirring at room temperature for 3 p., Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated. The resulting residue was then purified by silica gel column chromatography to obtain 1.27 g of the title compound. P.f. : It began to color around 237 ° C and decomposed at 240-242 ° C (recrystallized with ethanol-water).

? -NRM (DMSO-d6) d (ppm): 6.37 (1H, d, J = 8.8Hz), 6.94 (H, broad S), 6.97 (1H, s), 7, 36 (1H, s), 7.54-7.57 (2H, m), 8.16 (1H, d, J = 2.8Hz), 9.94 (1H, broad s), 11.17 (1H , s broad). hydrochloride: 1 H-NMR (DMSO-d 6) d (ppm): 6.59 (1 H, d, J = 9.2 Hz), 7.00 (1 H, s), 7.40 (1 H, s), 7, 56 (1H, d, J = 2.4Hz), 7.70 (1H, dd, J = 9.2, 2.0Hz), 8.20 (1H, d, J = 2.0Hz), 10.20 (1H, broad s), 11.37 (1H, broad s).

N- (3-Bromo-5-methyl-1-lH-ndol-7-l) -3-cyanobenzene. i ontiuda A solution (6 ml) of 260 mg (1.16 mmol) of the compound of Production Example 21 in tetrahydrofuran was added 0.19 ml (2.35 mmol) of pipdin and 280 mg (1.39 mmol). of 3-c-anobenzenesulfonyl chloride was cooled with ice and the mixture was stirred at room temperature overnight. 0.2N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, dried over magnesium sulfate and the resulting residue was chromatographed on a column of silica gel to obtain 360 mg of the title compound P. decomposed close to 148 ° C and decomposed rapidly at 163-164 ° C (recrystallized with ethanol-n hexane). 'H NMR (DMSO d6) d (ppm) 2.25 (3H, s), 6.54 (1H, s), 7 01 (1H, s), 7.42 (1H, d, J = 2.8Hz ), 7.71 (1H, t, J = 7.6Hz),? T_,, J = 7.6Hz), 8.07-8.11 82H, m), 10.09 (1H, broad s), 11.04 (1H, broad s). Example 6 N- (4-Bromo-lH-? Ndol-7-? L) -4-c-anobenzenesulfonamide _ É _____________ The title compound (686 mg) was obtained by treating 700 mg (2.8 mmol) of the compound of Production Example 24 and i > 85 mg (3.4 mmol) of 4-cyanobenzenesulfonyl chloride in the same manner as in Example 1. P.f. : 214-216 ° C. 'H-NMR (DMS0-d6) d (ppm): 6.35 (1H, d, J = 2.6Hz), 6.53 (LH, d, J- = 8.0Hz), 7.04 (1H , d, J = 8.0Hz), 7.41 (1H, t,, r = 2.8Hz), 7.85 (2H, d, J = 8.0Hz), 8.00 3 (2H, d, J = 8.0 Hz), 1.24 (LH, broad s), 11.19 (1 H, broad s). Example 7. 6-Amino-N- (4-chloro-lH-indol-7-yl) -3-pyridine-culfonamide The title compound (961 mg) was obtained by treating 1330 mg (6.4 mmol) of the compound of Production Example 2 and 1,000 mg (4.9 mmol) of the compound of Production Example 12 in the same manner as in Example 1. Pf. : 204-206 ° C. 1 H-NMR (DMS0-d 6) d (ppm): 6.38 (1H, d, J = 9.0Hz), 6.43 (.H, c, J = 2.2Hz), 6.77 (1H, d, J = 7.7 Hz), 6.86 (2H, broad s), 7.42 (1H, t, J = 2.6Hz), 7.56 (1H, dd, J = 2, 6, 9, 0Hz), 8.14 (1H, d, J = 2.6Hz), 9.70 (1H, broad s), 11.07 (1H, broad s). Example 8. 6-Amino-N- (3-bromo-4-chloro-lH-indol-7-yl) -3-Ridinesulfonamide and its hydrochloride To a solution (10 mL) of 650 mg (2.0 mmol) of the compound of Example 7 in tetrahydrofuran was added 1 mL of dimethylformamide and 359 mg (2.0 mmol) of N-bromosuccinimide, followed by stirring at room temperature during the night. A 0.2N aqueous solution of hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous solution of sodium thiosulfate, water and brine successively, dried over magnesium sulfate and concentrated. The resulting residue was then purified by silica gel column chromatography to obtain 662 mg of the title compound. XH-NMR (DMSO-d.) D (ppm): 6.38 (1H, d, J = 8.8Hz), 6.76 (1H, d, J = 8.4Hz), 6.88 (2H, s broad), 6.97 (1H, d, J = 8.4Hz), 7 52-7.56 (2H, m), 8.12 (1H, d, J = 2.4Hz), 9.68 ( 1H, s amp-pl), 11.44 (1H, broad s). In 3 ml of acetone, 660 mg of the resulting title compound were dissolved, 0.62 ml of 4N hydrochloric acid in ethyl acetate was added and the resulting precipitates were collected by filtration to obtain 590 mg of a hydrochloride of the title compound. P.f. : It began to decompose gradually around the '267 ° C. ? -NMR (DMSO-d6) d (ppm): 6.65 (1H, d, J = 9.2 Hz), 6.78 (1H, d, J = 8, lHz), 6.98 (1H, d) , J = 8.2Hz), 7.57 (1H, d, .1 = 2, 6Hz), 7.73 (1H, dd, J = 2.0, 9.0Hz), 8.15 (1H, d , J = 2.4Hz), .00 (1H, broad s), 11.67 (1H, broad s).

Use 9 ^ N- (3-Bromo-5-methyl-lH-indol-7-yl) -5-cyano-2-thiophenesulfonamide It was introduced into a solution of 1.3 g (5.6 mmol) of the compound of Production Example 29 in 15 ml of concentrated hydrochloric acid (15 ml) of gaseous chlorine under ice-cooling. After stirring for 30 minutes, the reaction solution was added to ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and salted successively, dried over magnesium sulfate and concentrated. The resulting residue was added to a solution of 1.2 g (5.35 mmol) of the compound of Production Example 22 in 6 ml of pyridine, followed by stirring at room temperature overnight. Water was added, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous IN solution of hydrochloric acid, water and brine successively, dried over magnesium sulfate and concentrated. The residue was then quenched by column chromatography on silica gel to obtain 1227 mg of the title compound. P.f .: 166-169 ° C (decomposition). 1 H-NMR (DMSO-d.) D (ppm): 2.30 (3H, s), 6.65 (1H, s), 7.07 (1H, s), 7.44 (1H, s), 7.54 (1H, d, J = 4.0Hz), 7.94 (1H, d, J = 4.0Hz), 10.47 (1H, broad s), 11.04 (1H, broad s).

Example 10 2 -Amino-N- (4-bromo-3-chloro-l-indol-7-yl) -5 -pipmidmasulf onamide To 5 ml of a solution of 712 mg (2.52 mmol) of the compound of Production Example 33 in pyridine were added 1 q (2.65 mmol) of the compound of Production Example 34 and the mixture was stirred for 15 hours . Water was added to the reaction solution and then extracted with a mixed solution of ethyl acetate and tetrahydrofuran (10: 1). The organic layer was dried over magnesium sulfate and then concentrated and purified by chromatography on silica gel, to obtain 950 mg of the title compound. P.f. 285-289 ° C. LH-NMR (DMSO-d6) d (ppm): 6.75 (1H, d, J = 8.0Hz), 7.19 (1H, d, J = 8.0Hz), 7.59 (1H, d , J = 3.0Hz), 7.65 (2H, s), 8.37 (2H, s), 9.82 (1H, s), 11.43 (1H.s).

Claims (4)

Claims 1. An indole compound represented by the following formula 'I), its pharmacologically acceptable salt or its hydrates. In the formula, R1 represents a hydrogen atom, an i'.l.oqeno atom or a cyano group; R2 and R3 are the same or different i-utre si and each represents a hydrogen atom, a lower alkyl group Ci-C4 or a halogen atom; R 4 represents a hydrogen atom or a C 1 -C 4 lower alkyl group, and ring A represents a cyanophenyl group, an aminosulfonylphenyl group, an aminopyridyl group, an aminopyrimidyl group, a halopyridyl group or a cyanothiophenyl group, always to exclude the case where R1, R2 and R3 are all .moy of hydrogen, wherein R2 and R3 are both hydrogen atoms or wherein ring A is an aminosulfonyl group and R1 and R2 are both halogen atoms. Further, when ring A is a cyanophenyl group, a 2-amino-5-pyridyl group or a 2-halo-5-pyridyl group and R 1 is a cyano group or a halogen atom, at least one of R 2 and R 3 is not It must be a hydrogen atom. The indole compound claimed in Claim 1, its pharmacologically acceptable salt or its hydrates, wherein two of R1, R2 and R3 are not hydrogen atoms. 3. The indole compound claimed in the claim 1 or 2, its pharmacologically acceptable salt or its hydrates, where ring A is a cyanophenyl group or an amino group sulfonylphenyl. 4. The indole compound claimed in Claim 1 or 2, its pharmacologically acceptable salt or its hydrates, wherein ring A is a 2-amino-5-pyridyl group. . The indole compound claimed in Claim 1 or 2, its pharmacologically acceptable salt or its hydrates, wherein ring A is a 2-amino-5-pyrimidyl group. i. The indole compound claimed in Claim 1 or 2, its pharmacologically acceptable salt or its hydrates, wherein ring A is a 2-halo-5-pyridyl group. /. The indole compound claimed in the claim 1 or 2, its pharmacologically acceptable salt or its hydrates, where ring A is a cyanothiophenyl group. : The indole compound claimed in Claim 1 or 2, its pharmacologically acceptable salt or its hydrates, wherein ring A is a cyanophenyl group. The indole compound claimed in Claim 1, selected from the following compounds, its pharmacologically acceptable salt or its hydrates: 1) 3-Cyano-N- (3-cyano-4-methyl-1H-indol-7-yl) ) -benzenesulfonamide, 2) 6-chloro-N- (3-cyano-4-methyl-lH-indol-7-yl) -3-pyridinesulfonamide. 3) N- (3-bromo-5-methyl-lH-indol-7-yl) -4-sulfa-nioylbenzenesulfonamide, 4) 6-amino-N- (5-bromo-3-chloro-lH-indol-7) -yl) -3-pyridinesulfonamide, 5) N- (3-bromo-5-methyl-lH-indol-7-yl) -3-cyano-

1. encenosulfonamide, 6) N- (4-bromo-lH-indol-7-yl) -4-cyanobenzenesulfonamide, 7) 6-amino-N- (4-chloro-lH-indol-7-yl) -3-pyridine-sulfonamide, 8) 6-amino-N- (3-bromo-4-chloro-lH-indol-7) -yl) -3-pyridinesulfonamide, 9) N- (3-bromo-5-methyl-lH-indol-7-yl) -5-cyano-2-thiophenesulfonamide and 10) 2-amino-N- (4-bromo) -3-chloro-lH-indol-7-yl) -5-pyrimidinesulfonamide. 10. The indole compound claimed in Claim 1, selected from the following compounds, its pharmacologically acceptable salt or its hydrates: 1) 3-Cyano-N- (3-cyano-4-methyl-lH-indol-7-yl) -benzenesulfonamide, 2) 6-chloro-N- (3-cyano-4-methyl-lH-indol-7-yl) -3-ridmasulfonamide. 3) N- (3-bromo-5-methyl-lH-indol-7-yl) -4-sulfa-moylbenzenesulfonamide, 4) 6-amino-N- (5-bromo-3-chloro-lH-indol-7 -yl) -3-pyridinesulfonamide, 5) N- (3-bromo-5-methyl-lH-indol-7-yl) -3-cyano-benzenesulfonamide, 6) 6-amino-N- (3-bromo-4) -chloro-lH-indol-7-yl) -3- pdinasulfonamide, 7) N- (3-bromo-5-methyl-lH-indol-7-yl) -5-cyano-2-thiophenesulfonamide and 8) 2- amino-N- (4-bromo-3-chloro-lH-indol-7-yl) -5-pyrimidinesulfonamide. 11. An anti-angiogenic agent that includes the indole compound claimed in any of Claims 1 to the pharmacologically acceptable salt or its hydrates as an effective component. .

2 . A use of the indole compound claimed in Claim 1 to 10, its pharmacological salt, or its metabolites, or its hydrates for the manufacture of a preventive or therapeutic agent for diseases against diseases. which an anti-angiogenic agent is effective for the prevention and treatment thereof 1

3. An antitumor agent that includes the indole compound claimed in any of Claims 1 to 10, its immunologically acceptable il or its hydrates as an effective component. A therapeutic agent for pancreatic cancer, which includes the indole compound claimed in any one of Claims 1 to 10, its pharmacologically acceptable salt or its hydrates as an effective component. '' A therapeutic agent for colon cancer, which i. The indole compound claimed in any of Claims 1 to 10, its pharmacologically acceptable salt or its hydrates as an effective component, is included. Therapeutic agent for stomach cancer, including the indole compound claimed in any of Claims 1 to 10, its pharmacologically acceptable salt or its hydrates as an effective component. 17. A therapeutic agent for breast cancer, which includes the indole compound claimed in any of the Claims 1 to 10, its pharmacologically acceptable salt or its hydrates as an effective component. 18. A therapeutic agent for prostate cancer, which includes the indole compound claimed in any of Claims 1 to 10, its pharmacologically acceptable salt or its hydrates as an effective component. 19. A therapeutic agent for lung cancer, which includes the indole compound claimed in any of Claims 1 to 10, its pharmacologically acceptable salt or its hydrates as an effective component. 0 A therapeutic agent for ovarian cancer, which includes the indole compound claimed in any of Claims 1 to 10, its pharmacologically acceptable salt or its hydrates as an effective component. .1. A suppressor of cancer metastasis, which includes the indole compound claimed in any of Claims 1 to 10, its pharmacologically acceptable salt or its hydrates as an effective component. 22. A therapeutic agent for diabetic retinopathy, which includes the indole compound claimed in any of .s i. 1 to 10, its pharmacologically acceptable salt or its hydrates as an effective component. 3. A therapeutic agent for rheumatoid arthritis, including the indole compound claimed in any of Claims 1 to 10, its pharmacologically acceptable salt or its hydrates as an effective component. A therapeutic agent for the hematoma, including, - 1 indole compound claimed in any of Claims 1 to 10, its pharmacologically acceptable salt or its hydrates as an effective component. J. A method for preventing or treating a disease against which the inhibitory effect of angiogenesis at the site of a tumor, rheumatoid arthritis or diabetic retinopathy for the prevention or treatment thereof is effective, by administering a pharmacologically effective dose of the indole compound claimed in any of Claims 1 to 10, its pharmaceutically acceptable salt or its hydrates to a patient. 26. Use of the indole compound as claimed in any of Claims 1 to 10, its pharmacologically acceptable salt or its hydrates for the manufacture of an antitumor agent, a therapeutic agent for pancreatic cancer, a therapeutic agent for cancer of colon, a therapeutic agent for stomach cancer, a therapeutic lens for breast cancer, a therapeutic agent for prostate cancer, a therapeutic agent for lung cancer, a therapeutic agent for ovarian cancer, a suppressor of cancer metastasis, a therapeutic agent for diabetic retinopathy, a therapeutic agent for rheumatoid arthritis or a therapeutic agent for the hematoma. .7. The method claimed in Claim 25, wherein the disease is a tumor, pancreatic cancer, colon cancer, stomach cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cancer metastasis, diabetic retinopathy , rheumatoid arthritis or hematoma.