Sulfonamides connection indole

 

The invention relates to new indole derivative of the formula Iwhere R1- H, halogen, CN; R2and R3the same or different is H, C1-C4alkyl, halogen; R4- H, C1-C4alkyl; And means cyanoaniline, aminosulphonylphenyl, aminopyridine, aminopyrimidine, halogenopyrimidines or cianciarulo group, provided that if all R1, R2and R3- N, when both R2and R3- N or when ring A - aminosulphonylphenyl group and both R1and R2the halogen atoms is excluded; and, in addition, when the ring a represents cyanophenyl group, 2-amino-5-pyridyloxy group or 2-halogen-5-pyridyloxy group, and R1represents a cyano or halogen group, at least one of R2and R3must not be a hydrogen atom. The compounds I are antiangiogenic effect and can be used as anticancer agents, especially against malignant tumors of the pancreas, colon, stomach, mammary gland, tumors of the prostate, lung, ovarian and other 15 C. and 12 C.p. f-crystals, 6 PL.

The invention against the s refers to the antitumor agent, the suppressor of metastasis of a malignant tumor, a medicinal remedy for diabetic retinopathy, drug against rheumatoid arthritis and medicinal remedy for bruises, based on antiangiogenic effect.

It was found that there is a close relationship between the proliferation of malignant tumor and angiogenesis. Thus, when angiogenesis does not occur in the hearth of a malignant tumor, malignant tumor remains in a state of dormant tumors. However, it was found that, with the development of angiogenesis oxygen and nutrients from the blood come to the tumor tissue, which contributes to the proliferation and metastasis of malignant tumors, which leads to clinically malignant state. Accordingly, it can be expected that with the suppression of angiogenesis in malignant tumors can be suppressed proliferation and metastasis of malignant tumors. Since angiogenic vessels consist of endothelial cells and interstitial cells of the host, the target of antiangiogenic drugs are not malignant cells, such as normal cells of the host. Because malignant cells are not directly Mish is m antitumor means, and, in addition, it is assumed that the probability of formation of a tolerant malignant tumor that is a big problem in therapy of malignant tumors, small. In addition, angiogenesis is a tumor-specific phenomenon, and in adults is limited by the formation of endometrial and other processes that accompany the menstrual cycle. Accordingly, undesired effect is presumably small in comparison with the known antitumor agents. Recently, it was experimentally proved in clinical trials that antiangiogenic means capable of supressive continue to reduce the proliferation of malignant tumors in models with transplanted tumor and prevent formation of tolerant malignant tumors, and clinical trials show a correlation between angiogenesis and malignancy for many malignant tumors, such as malignant tumor of the breast, cancer of the prostate, cancer of the lung and malignant tumor of the colon.

In the tissues of malignant tumors continuously processes of apoptosis and proliferation of malignant cells, and it is known that for the Antiangiogenic tool does not directly destroy cancer cells, and stops the flow of nutrients, thus shifting this balance towards apoptosis, which causes swelling in the state of rest or reduce the malignant tumor, it is a tool that may show great effect (life extension, inhibition of relapse and suppression of metastasis) with long-term therapy.

On preclinical stage there are antiangiogenic means with different mechanisms of action, but because of their anti-tumor effects in pre-clinical stage was found to be inadequate, its acceptance on the clinical stage is still questionable, and therefore there is a great demand for antiangiogenic drugs with reliable effect.

It is also known that angiogenesis is involved in the development of retinopathy and retinitis. With the proliferation of blood vessels in the retina is blurred vision and if progression occurs blindness. Currently there are no effective drugs against this disease, and there is a demand for effective medicines.

WO 9301182 relates to antitumor tools with specific tyrosinekinase inhibitory activity of the compounds of the available the present invention. Similarly, WO 964016 relates to antitumor tools with specific tyrosinekinase inhibitory activity of compounds with indole skeleton, but they are 2-indoline-3-methylene compounds and non-compounds of the present invention. JP-A 7-165708 and JP-A 8-231505 refer to sulfonamidnuyu compounds containing the indole structure. However, the compounds specifically disclosed in JP-A 7-165708 and containing indole ring two Deputy, other than aryl (heteroaryl) sulfonylamino limited and have only six combinations of data substituents, i.e., (1) 3-CL 4-CL; (2) 3-CL and 4-och3; (3) 3-CL and 4-one; (4) 3-CL and 4-CH3; (5) 3-CL 4-CN; and (6) 3-CN 5-Br. Combinations (a) 3-CN and 4-CH3; (b) 3-Cl 5-Br; (C) 3-CL 4-Br; and (d) 3-Br and 4-CH3not available. About 4-halogencontaining compounds, there is a description for 4-VG-substituted compounds, but their sulfonylurea component represents only the p-nitrophenolate connection. In addition, the indole compounds disclosed in JP-A 8-231505 represent only 3-halogen - or 3-cyanomelana connection. In the data laid out publications not include a description of the antiangiogenic effect, and does not contain his predictions.

Order n is about drug with high safety and reliable effect compared with conventional anticancer drugs, which it would be possible to take a long time.

The authors of the present invention conducted intensive research showed that sulfonamides connection indole represented by the following formula, reaches the goal, and thus made the present invention. That is, the present invention relates to sulfhemoglobinemia connection indole represented by the following formula (I), its pharmaceutically acceptable salts or its hydrates.

In this formula, R1represents a hydrogen atom, halogen atom or cyano; R2and R3are the same or different, and each represents a hydrogen atom, a C1-C4lower alkyl group or halogen atom; R4represents a hydrogen atom or a C1-C4lower alkyl group; and ring a represents cyanophenyl group, aminosulphonylphenyl group, aminopyridine group, aminopyrimidine group, halogenopyrimidines group or cyanocobalamine group, provided that when R1and R2and R3represent hydrogen atoms, when both R2and R3are subjectable a halogen atoms, excluded. In addition, when the ring a is cyanophenyl group, 2-amino-5-pyridyloxy group or 2-halogen-5-pyridyloxy group, and R1represents a cyano or halogen group and at least one of R2and R3must not be a hydrogen atom.

The present invention relates to a method for prevention or treatment of diseases in which inhibition of angiogenesis in the tumor, rheumatoid arthritis, and diabetic retinopathy is effective for prevention or treatment by introducing a pharmacologically effective dose of the above compounds indole, its pharmaceutically acceptable salt or hydrate the patient.

In addition, the present invention relates to the use of the above compounds indole, its pharmaceutically acceptable salts or its hydrates, for the manufacture of a prophylactic or medicines against diseases in which an antiangiogenic drug is effective for prevention or treatment.

In addition, the present invention relates to the antiangiogenic agent, antitumor agent, therapeutic agent against malignant tumors of the pancreas, those who political tool against malignant tumors of the breast, therapeutic agent against malignant tumors of the prostate, therapeutic agent against lung cancer, a therapeutic agent against malignant ovarian tumor, suppressor of metastasis of a malignant tumor, therapeutic agent against diabetic retinopathy, therapeutic remedy for rheumatoid arthritis and therapeutic tool against bruising, which contains as an effective ingredient the above-mentioned compound indole, their pharmaceutically acceptable salt or its hydrate. The invention relates to a method for prevention, treatment and improvement of the application of any of these pharmaceutical drugs. In addition, the invention relates to the use of the above compounds to obtain any of these pharmaceutical drugs.

In the above formula (I), the halogen atom means a fluorine atom, chlorine atom, bromine atom or iodine atom. C1-C4the lower alkyl group means a linear or branched alkyl group such as methyl group, ethyl group, n-sawn group, n-bucilina group, isopropyl group, isobutylene group and tert-bucilina group.

Connection indole, before which includes a salt of the compound indole (I). Examples of salts formed with an acid is a salt of an inorganic acid such as hydrochloride, hydrobromide or sulfate, and salt of organic acid such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonate acid or p-toluensulfonate acid. Examples of salts formed with the base are inorganic salts such as sodium salt, potassium salt or calcium salt and a salt of organic bases such as triethylamine, arginine or lysine.

Needless to say, that includes all the hydrates of such compounds and pharmaceutically acceptable salts. Although the compounds of the present invention have a strong antiangiogenic effect, also included compound subjected to metabolism in vivo, such as oxidation, reduction, hydrolysis and conjugation. The present invention also includes compounds, which are metabolized in vivo, such as oxidation, recovery and hydrolysis, the obtained compound of the present invention.

The compound of the present invention (I) can be obtained in various ways, and representative of them will be src="https://img.russianpatents.com/img_data/62/621331.gif">(in the formula, ring AA is cyanophenyl group, aminosulphonylphenyl group, aminopyridine group, aminopyrimidine group, halogenopyrimidines group or cyanocobalamine group) or its reactive derivative, with a compound represented by the formula (III)(in the formula, R1arepresents a hydrogen atom, halogen atom or cyano; and R2aand R3aare the same or different and each represents a hydrogen atom, a C1-C4lower alkyl group or halogen atom, provided that excluded the cases where all R1a, R2aand R3arepresent hydrogen atoms or when both R2aand R3arepresent hydrogen atoms).

Examples of the reactive derivative of sulfonic acid (II) are usually well utilized reactive derivatives, such as sulfonylmethane, sulfonic acid anhydride and N-sulfanilimide and particularly suitable example is sulfonylmethane. Although not imposed special restrictions on the nature of the solvent used in the reaction, preferred are those which dissolve the prophetic is ensol, ethyl ether, dichloromethane, dimethylformamide and mixed solvent consisting of two or more selected from them. In addition, when the release of acid during the reaction, as in the case of use in the reaction of sulphonylchloride, it is preferable to conduct the reaction in the presence of a suitable removing the acid substances, and therefore particularly suitable is the use of a basic solvent such as pyridine. When using a neutral solvent can be added to the base material such as a carbonate of an alkali metal or an organic tertiary amine. Of course, the solvent which can be used, not limited to these examples here. Typically this reaction is carried out at room temperature, but if necessary can be carried out by cooling or heating. The reaction time is usually from 10 minutes to 20 hours, and optionally selected depending on the nature of the compounds and the reaction temperature.

When the amino group in the resulting product is protected, if necessary, may be conducted by a conventional method of removing the protective group, such as acid treatment, alkali treatment and catalytic reduction, resulting in the possibility of the ways of obtaining the source of the compounds (II), their reactive derivatives and (III) used in this invention.

The original compound (II) and its reactive derivative include known compounds, and new connections. In the case of new connections, they can be obtained by the use of already published method for the synthesis of known compounds or its combination. For example, the new sulphonylchloride can be obtained by using method, using methods of synthesis specified in Chem. Ber. , 90, 841 (1957); J. Med. Chem., 6, 307 (1963); J. Chem. Soc. (c), 1968, 1265; Chem. Lett., 1992, 1483; J. Am. Chem. Soc., 59, 1837 (1937); J. Med. Chem. , 23, 1376 (1980); J. Am. Chem. Soc., 70, 375 (1948); J. Am. Chem. Soc., 78, 2171 (1956) and others.

When R1aand R3arepresent hydrogen atoms, and R2ais a halogen atom in the initial compound (III) can be obtained by a known method of synthesis. When R2aand R3aare the same or different, and each represents a hydrogen atom, a C1-C4lower alkyl group or a halogen atom (case when both are hydrogen atoms is excluded) and R1arepresents a cyano, can be obtained as follows (see the reaction scheme at the end of the description).

When R1arepresents a halogen atom, a connection morgenrot in the usual way and restore the nitrogroup or remove the protective group of amino group.

When the compound of the present invention is used as a medicine, it can be administered as oral and parenteral. The dose varies depending on the severity of symptoma, age, sex, body weight and individual sensitivity of the patient, method of administration, the period of introduction, interval of administration, the pharmaceutical properties of the drug, type of drug, type of effective ingredient and other things and is not particularly limited. In the case of intravenous dose of 1-2000 mg, preferably 1-500 mg, and more preferably 5-1000 mg, although in the case of oral administration, it is usually 10-6000 mg, preferably of about 50-4000 mg and more preferably 100-3000 mg per day for adults and is normally administered once daily or divided into three times a day.

When preparing a solid preparation for oral administration, the main ingredient is added a filler and, if necessary, binder, dezintegriruetsja substance, grease, dye, corrigent and so on with subsequent processing in the usual way to obtain tablets, tablets in the shell, granules, fine granules, powders, capsules and other things.

Examples of the filler are l the binder are polyvinyl alcohol, ethylcellulose, methylcellulose, Arabian gum, hydroxypropylcellulose and hypromellose; examples of lubricants are magnesium stearate, talc and silica; examples of the dye are substances that are acceptable for addition to pharmaceuticals; and examples of flavoring agents include cocoa powder, menthol, aromatic oils, peppermint oil, borneol and cinnamon powder. Of course, if you want, it is not a problem to cover accordingly these tablets and granules by the sugar-coated, gelatin shell or other.

In the preparation of injections, if necessary, to the main ingredient add substance that regulates pH, buffer, suspendisse substance, solubilizer, stabilizer, isotonic agent, preservative and the like to further processing in accordance with a conventional method to obtain injections for intravenous, subcutaneous and intramuscular injection. At the same time, if necessary, it may be converted in accordance with the conventional method of freeze-dried product.

Examples of suspending agents are methylcellulose, Polysorbate 80, hydroxyethylcellulose, Aravis is the reamers of the solubilizer are polyoxyethylenesorbitan castor oil, Polysorbate 80, nicotinamide, polyoxyethylenesorbitan, macrogol and ethyl ester of fatty acids of castor oil.

Examples of the stabilizer include sodium sulfite and metasulfite sodium. Examples of preservatives are methyl parahydroxybenzoate, metilparagidroksibenzoat, sorbic acid, phenol, cresol and chlorocresol.

The action of the compounds according to the present invention will be illustrated by the following pharmacological experimental examples.

Pharmacological experimental example 1.

Antiangiogenic effect.

The degree of inhibition of angiogenesis, which was observed after incubation of the parts of the aorta in rats with collagen was determined as antiangiogenic effect. Thus, the aorta isolated from the body of the male rat line Sprague-Dawley (aged 10-12 weeks), washed with Hanks solution so that the surrounding fat tissue were carefully removed.

The aorta was cut to obtain parts area of 2 mm and was left in a 24-hole tablet endothelial cells to the outside. Then brought to 500 μl of neutralized collagen type I (Cell Matrix Type I-A; production Nitta Gelatin) into each well and left at room temperature for about 20 minutes in the kelp to solidification of the CO2-incubator (5% CO2) at 37oC. the next day the culture medium was replaced with 500 μl of medium MCDB 131 containing the test compound, and continued incubation. After three days the medium was again replaced with 500 μl of medium MCDB 131 containing the test compounds at the stage of the 7th day from the start of addition of the test compounds were calculated number of capillaries formed around the aorta, under the microscope. The solution containing the tested compounds were obtained in three of the distribution system where the highest concentration was 10 µg/ml.

The degree of inhibition was calculated by the following formula and determine the 50% inhibition concentration (IC50for each of the tested compounds (see table.1).

The degree of inhibition (%) = (s - T)/S100: the number of capillaries in the absence of the compound, T: the number of capillaries when adding the connection.

Pharmacological experimental example 2.

The effect of inhibition of growth endothelially cells.

Endothelial cells from umbilical vein human (HUVEC; production Sanko Junyaku), incubated in the medium EGM (production Sanko Junyaku) containing 100 units of penicillin and 100 μg/ml streptomycin, and drove up to 0.8-1

The degree of inhibition was calculated by the following formula and determine the 50% inhibition concentration (IC50for each connection (see tab.2).

The degree of inhibition (%) = (s - T)/S100,
From: the absorption in the absence of a connection,
T: absorption while adding the connection.

Pharmacological experimental example 3.

The effect of inhibition of proliferation of mouse melanoma B16
Cells of mouse melanoma B16, incubated in modified medium Dulbecco-Eagle (DMED; production is bodily to 2104cells/ml and 100 μl was separately placed in a 96-well plate. After the incubation was performed in CO2incubator (5% CO2) at 37oC for one night, then added 100 μl of the above culture containing the test compound, dissolved in three series, followed by incubation for three days and measured the number of cells at that time using the MTT method. In addition, the processing 0,33% solution of MTT in 1-2 hours.

The degree of inhibition was calculated by the following formula and determine the 50% inhibition concentration (IC50for each connection (see tab.3).

The degree of inhibition (%) = (s - T)/S100,
From: the absorption in the absence of a connection,
T: absorption while adding the connection.

Of pharmacological experimental example 1, it is clear that the compounds of the present invention are clear antiangiogenic action. Of pharmacological experimental examples 2 and 3 it is clear that the effect of inhibition of cell proliferation by compounds of the present invention of B16 melanoma cells was 5-100 times weaker than endothelial cells, and that they specifically affect endothelial cells in blood suck the 702-1706, 1994), using the cell line KR-1, originating from malignant tumor of the pancreas of a person, and cell line HCT 116, originating from malignant tumors of the colon of a person. The above malignization human cells (5106cells) subcutaneously transplanted bare mice (KSN) 6-7 weeks of age and began introducing the compound of the present invention from the stage, when they have reached a size of approximately 100 mm3. In our experiments we used a group of ten mice that were not injected a drug, and in the group that was administered the drug for each dose used five mice. Continuously, twice a day was administered a dose of 50 mg/kg 100 mg/kg or 200 mg/kg per os and compared the size of the tumor on the 22nd day from the start of injection with the group, which did not enter the drug. The result was 37%, 30% and 11%, respectively, in cell lines KR-1, originating from malignant tumor of the pancreas of a person, and 0.2%, 0.3% and 0.0 percent, respectively, in the cell line HCT 116, originating from malignant tumors of the colon of a person, in the case of a group, which for example has introduced the compound of example 1. Thus, the compound of example 1 showed semestinya invention has an excellent effect from the point of view of efficacy and safety in comparison with the known bactericidal drugs, which directly affect malignization cells.

As described above in the experimental examples, the compounds of the present invention have excellent antiangiogenic effect and are useful as anticancer agents against malignant pancreatic tumor, a malignant tumor of the colon, stomach cancer, malignant breast tumors, malignant tumors of the prostate, lung cancer and malignant ovarian tumors and in the quality of medicines for diabetic retinopathy, rheumatoid arthritis, and bruises.

Examples
Hereinafter will be illustrated by examples receipt showing the manufacture of the starting compounds for the compounds of the present invention, and examples of compounds of the present invention, although of course that this invention is not limited to this only.

Example of getting 1. Etherpiraat-N-(5-methyl-2-nitrophenyl)hydrazone
To a mixed solution of 160 ml of water and 170 ml of concentrated chloride-hydrogen acid was added 75,0 g (493 mmol) 5-methyl-2-nitroaniline, followed by stirring. An aqueous solution of 80 ml 36,0 g (517 mmol) NITR the creation ethyl-2-acetate in 100 ml of ethanol, then add 200 ml 12 N. aqueous solution of potassium hydroxide at -20oWith stirring for 30 minutes. After stirring the mixture at the same temperature for 30 minutes was added 100 ml of concentrated chloride-hydrogen acid and the resulting precipitates were collected by filtration, washed with water and dried in vacuum over night. There was added a mixed solution of diethyl ether and hexane, and the obtained crystals were collected by filtration to obtain 130 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); of 1.29 (3H, t, J=7.2 Hz), of 2.16 (3H, s), is 2.40 (3H, s), 4,25 (2H, q, J=7.2 Hz), 6,91 (1H, DD, J=8,8, 2.0 Hz), 7,63 (1H, s), 8,07 (1H, d, J=8,8 Hz), 10,69 (1H, s).

Example of getting a 2. Ethyl-4-methyl-7-nitro-1H-indole-2-carboxylate
To 250 ml of a suspension of 25.0 g (a 94.2 mmol) of the compound from example a 1 in xylene was added 100 g of polyphosphoric acid, followed by heating under reflux for 3 hours. To the reaction solution was added 80 ml of water and 300 ml of ethyl acetate while cooling with ice. The obtained insoluble substance was filtered followed by washing with 1.5 liters of ethyl acetate, and the obtained filtrate was extracted with ethyl acetate. The organic phase placentas is Agnes and concentrated to dryness. To the obtained residue was added a mixed solution of tert-butyl methyl ether and hexane, and the obtained crystals were collected by filtration to obtain 11.1 g of the compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); to 1.35 (3H, t, J=7.2 Hz), 2,65 (3H, s), to 4.38 (2H, q, J=7.2 Hz), 7,16 (1H, d, J=8,4 Hz), 7,51 (1H, s), 8,19 (1H, d, J=8,4 Hz), of 11.29 (1H, user.C).

Example of getting a 3. 4-Methyl-7-nitro-1H-indole-2-carboxylic acid
To 150 ml of a solution of 11.0 g (44,3 mmol) of the compound from example getting 2 in tetrahydrofuran was added 150 ml of 1 N. aqueous sodium hydroxide solution followed by heating under stirring at 80oC for 30 minutes. The reaction solution was concentrated, to the residue under ice cooling was added 40 ml of 5 N. chloride-hydrogen acid to reach pH 1 and the resulting precipitates were filtered and washed with water. The precipitates were dissolved in 300 ml of tetrahydrofuran and extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over magnesium sulfate and concentrated to dryness to obtain 9.60 g of the compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); 2,62 (3H, s), 7,13 (1H, d, J=8.0 Hz), 7,42 (1H, s), 8,15 (1H, d, J=8.0 Hz), the 9,58 g (of 43.5 mmol) of the compound from example get 3, there was added 1.04 g (4.35 mmol) of basic copper carbonate and the mixture was heated with stirring to 180oC for 4 hours. To the reaction solution were added 120 ml of ethyl acetate under ice cooling, the obtained insoluble substance was filtered and the obtained filtrate was extracted with ethyl acetate. The organic phase is then washed with water and saturated saline and dried over magnesium sulfate. After concentration, the obtained residue was purified through column chromatography with silica gel with getting to 4.87 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); at 2.59 (3H, s), 6,74 (1H, s), 7,03 (1H, d, J= 8,4 Hz), of 7.48 (1H, s), of 8.00 (1H, d, J=8,4 Hz), up 11,86 (1H, user.C).

Example of getting a 5. 3-Formyl-4-methyl-7-nitro-1H-indole
To 12 ml (154 mmol) of dimethylformamide was added 1.5 ml (16,1 mmol) of phosphorus oxychloride at 0oIn nitrogen atmosphere, followed by stirring at room temperature in a nitrogen atmosphere in the course of 20.5 hours. Solution (20 ml) 2.0 g to (11.4 mmol) of the compound from example 4 in dimethylformamide was added at 0oC, followed by heating to 90oC for 21 hours under stirring. To the reaction solution was added 100 ml of 1 N. water raw then washed with water and saturated saline solution, was dried over magnesium sulfate and concentrated to dryness. To the obtained residue was added a mixed solution of tert-butyl methyl ether and hexane, and the obtained crystals were collected by filtration receipt of 2.23 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); 2,90 (3H, s), 7,21 (1H, d, J=8,4 Hz), 8,11 (1H, d, J=8,4 Hz), 8,39 (1H, s), of 10.01 (1H, s), 12,71 (1H, user.C).

Example of getting a 6. 3-cyano-4-methyl-7-nitro-1H-indole
In 100 ml of dimethylformamide was dissolved of 2.21 g (10,8 mmol) of the compound from example get 5 and then adding back 900 mg (13,0 mmol) hydroxylaminopurine and 1.05 ml (13,0 mmol) of pyridine. After heating to 60oWith stirring for 40 minutes to the reaction solution was added 53,9 mmol of 1,1'-carbonyldiimidazole or 53.9 mmol) under cooling with ice. After heating at 60oC for further 30 minutes under stirring to the reaction solution was added 3.0 ml (21.5 mmol) of triethylamine, followed by heating at the same temperature additionally for 1 hour under stirring. To the reaction mixture were added 50 ml of ice water with ice cooling, followed by extraction with ethyl acetate. The organic phase is then washed with water and the weave was added a mixed solution of tert-butyl methyl ether and hexane, and the obtained crystals were collected by filtration to obtain 1,95 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); 2,78 (3H, s), 7,22 (1H, d, J=8.0 Hz), 8,14 (1H, d, J=8.0 Hz), to 8.41 (1H, s), of 12.76 (1H, user.C).

Example of getting a 7. 7-Bromo-4-methyl-1H-indol
To 300 ml of a solution of 65.0 g (301 mmol) of 2-bromo-5-methylnitrobenzene in tetrahydrofuran was added 1 liter of 1.0 M solution of vinylboronic magnesium (1 mol) in tetrahydrofuran at -60oC in nitrogen atmosphere with stirring for 1 hour. To the reaction mixed solution was added a saturated aqueous solution of ammonium chloride and ethyl acetate, and the resulting insoluble matter was filtered. The obtained filtrate was dried over magnesium sulfate, concentrated, and then the obtained residue was purified by chromatography on a column of silica gel to obtain 35.5 g of the compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); to 2.42 (3H, s), 6,55 (1H, s), of 6.73 (1H, d, J= 7,6 Hz), 7,16 (1H, d, J=7,6 Hz), 7,35 (1H, s), 11,24 (1H, user.C).

Example of getting 8. 4-Methyl-1H-indole-7-carboxylic acid
To a solution (200 ml) 35.5 g (169 mmol) of the compound from example get 7 in tetrahydrofuran was added a 1.6 M solution (350 ml) and utility (384 mmol) in hexane, at which the reaction solution was injected carbon dioxide at -50oC and was stirred for 15 minutes. To the reaction mixture was added water at the same temperature, the solvent evaporated and the resulting precipitate was collected by filtration and washed with water. The precipitate was dissolved in 300 ml of tetrahydrofuran, dried over magnesium sulfate and then concentrated to dryness obtaining of 25.9 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); of 2.51 (3H, s), 6,53 (1H, s), to 6.88 (1H, d, J= 7,6 Hz), 7,31 (1H, s), a 7.62 (1H, d, J=7,6 Hz), 10,99 (1H, user.C) 12,79 (1H, user.C).

Example of getting a 9. 7-(N-tert-Butoxycarbonyl)amino-4-methyl-1H-indol
In 80 ml of toluene added 7.0 g (40.0 mmol) of the compound from example get 8, then there was added 22 ml (160 mmol) and 11.2 ml (52 mmol) diphenylphosphinite in nitrogen atmosphere and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added 8 ml (84 mmol) of tert-butanol, the mixture was heated under stirring at 100oC for 2.5 hours and then the reaction solution was concentrated. The obtained residue was dissolved in ethyl acetate, sequentially washed with 0.1 G. of chloride-hydrogen acid, water and saturated saline solution, dried over magnesium sulfate and concentrated to visually was collected by filtration to obtain 7,87 g connection specified in the header.

1H-NMR (DMSO-d6)(M. D.); 1,48 (N, C) of 2.38 (3H, s), 6,37-6,44 (1H, m), of 6.68 (1H, d, J=8,4 Hz), 7,22-7,31 (2H, m), 8,86 (1H, user.C) of 10.73 (1H, user.C).

Example 10. 7-(N-tert-Butoxycarbonyl)amino-3-formyl-4-methyl-1H-indol
To 400 ml (5.2 mol) of dimethylformamide was added 40 ml (429 mmol) of phosphorus oxychloride at 0oIn nitrogen atmosphere, followed by stirring at the same temperature for 25 minutes. At 0oSince there was added 74,0 g (300 mmol) of the compound from example receiving 9, followed by stirring at room temperature for 1.5 hours. To the reaction mixture was added 250 ml of 5 N. of an aqueous solution of sodium hydroxide under ice cooling to adjust the value of pH 8. For separation of the organic phase there was added tetrahydrofuran, ethyl acetate and water followed by washing with water and brine successively. After drying of magnesium sulfate the solvent evaporated. To the obtained residue was added a mixed solution of diethyl ether and hexane, and the obtained crystals were collected by filtration to obtain of 53.7 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); 1,50 (N, C), a 2.71 (3H, s), make 6.90 (1H, d, J= 7,6 Hz), 7,32-7,41 the-3-cyano-4-methyl-1H-indol
In 50 ml of dimethylformamide was dissolved 4,43 g (16.2 mmol) of the compound from example 10 and then adding there 1.35 g (to 19.4 mmol) gidroxinimesoulid and 1.6 ml (to 19.8 mmol) of pyridine. After heating under stirring at 60oC for 45 minutes, to the reaction solution was added 1,1-carbonyldiimidazole (80,8 mmol) under cooling with ice. After heating under stirring at 60oC for further 30 minutes to the reaction solution was added to 4.5 ml (32,3 mmol) of triethylamine, followed by heating under stirring at the same temperature for 30 minutes. To the reaction mixture under ice cooling was added water, followed by extraction with ethyl acetate. The organic phase is then washed with water and brine, dried over magnesium sulfate and then concentrated to obtain 4,27 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); 1,49 (N, C) 2,60 (3H, s), 6.89 in (1H, d, J= 8.0 Hz), 7,34-7,42 (1H, m), to 8.20 (1H, d, J=2,8 Hz), 9,04 (1H, user.C) 11,80 (1H, user.C).

Example 12. 7-Amino-3-cyano-4-methyl-1H-indol
In the mixed solution of 100 ml of tetrahydrofuran and 100 ml of methanol added to 12.6 g (and 62.6 mmol) of the compound from example get 6, and proved mmol) of platinum oxide. After filtration, the filtrate was concentrated to dryness, the residue was added a mixed solution of tert-butyl methyl ether and hexane and collecting the crystals by filtration to obtain 10.7 g of the compound indicated in the title. In 400 ml of dichloromethane was dissolved and 50.5 g (186 mmol) of the compound from example receiving 11 and there was added 210 ml (was 2.76 mmol) triperoxonane acid at 0oIn nitrogen atmosphere, followed by stirring at room temperature for 40 minutes. To the reaction solution was added 5 N. aqueous sodium hydroxide solution at -20oWith up to pH 7. The solvent was removed, and the residue was extracted with ethyl acetate. The organic phase is then washed with water and brine, dried over magnesium sulfate and concentrated to dryness. To the obtained residue was added a mixed solution of diethyl ether and hexane, and the crystals were collected by filtration to obtain 24.5 g of the compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); 2,47 (3H, s), 5,07 (2H, s), 6,34 (1H, d, J= 7,6 Hz), only 6.64 (1H, d, J=7,6 Hz), 8,10 (1H, s), 11,70 (1H, user.C).

Example of receipt 13. 3-Cyanobenzenesulfonyl
To a mixed solution of 200 ml of water and 250 ml of concentrated x is PR (80 ml) 15.5 g (223 mmol) of sodium nitrite was added dropwise there at -10oC. the Reaction solution was added acetic acid saturated with sulfur dioxide (obtained by dissolving sulfur dioxide in 250 ml of acetic acid followed by the addition of 2.1 g of monovalent copper chloride) under cooling with ice and stirring. After 1 hour the reaction solution was introduced into 500 ml of ice water and was extracted with diethyl ether. The extract was sequentially washed with saturated aqueous sodium bicarbonate solution, water and brine and dried over magnesium sulfate. The solvent is evaporated, to the residue was added a mixed solution of diethyl ether and hexane, and the crystals were collected by filtration to obtain 16.0 g of the compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); at 7.55 (1H, t, J=8.0 Hz), 7,78 (1H, DD, J=8,0, 1.2 Hz), 7,86-a 7.92 (2H, m).

Example of getting a 14. 4-Sulfamoylanthranilic
To a mixed solution of 80 ml of water and 50 ml of concentrated chloride-hydrogen acid was added to 25.0 g (145 mmol) of 4-aminobenzenesulfonamide, followed by stirring. An aqueous solution (20 ml) and 10.5 g (152 mmol) of sodium nitrite was added dropwise at a temperature from -13oWith -10oC for 15 minutes. After 10 minutes the reaction solution was added to the mixed Renai acid and 12.5 ml of concentrated chloride-hydrogen acid followed by the addition of 3.7 g of monovalent copper chloride) at -30oWith under stirring. After 1 hour the reaction solution was added ice water (500 ml) and the resulting precipitate was collected by filtration. The precipitate was dissolved in a mixed solution of 450 ml of toluene and 150 ml of ethyl acetate. After the insoluble matter was filtered, the filtrate was extracted with ethyl acetate. The organic phase is then washed with a saturated solution of sodium bicarbonate and brine and dried over magnesium sulfate. The solvent is evaporated, to the residue was added 100 ml of toluene, and the crystals were collected by filtration to obtain of 20.9 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); the 7.65 of 7.69 (2H, m), 7,71 for 7.78 (4H, m).

Example of receipt 15. 5-Bromo-3-chloro-7-nitro-1H-indole
To a solution of 12.00 g (49,8 mmol) 5-bromo-7-nitro-1H-indole in 140 ml of tetrahydrofuran was added to 1.4 ml of dimethylformamide and 6,98 g (52,3 mmol) N-chlorosuccinimide, followed by stirring at room temperature over night. There was added 10% aqueous sodium thiosulfate solution, followed by extraction with ethyl acetate. The organic phase is then washed with water and brine, dried over magnesium sulfate and concentrated to dryness with under.); 7,79 (1H, s), 8,15 (1H, s) 8,23 (1H, s), 12,32 (1H, user.C).

Example of 16. 7-Amino-5-bromo-3-chloro-1H-indolepropionic
To a solution (250 ml) 14,84 g (53,9 mmol) of the compound from example receive 15 in methanol was added 70 ml of concentrated chloride-hydrogen acid and 31,97 g (269 mmol) of powdered tin, followed by stirring at room temperature for 80 minutes. After there was added 5 N. aqueous sodium hydroxide solution while cooling with ice to bring to pH 10, the resulting precipitate was filtered and the filtrate was extracted with ethyl acetate. The organic phase is then washed with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. Then the obtained residue was purified by chromatography on a column of silica gel with getting 14,35 g 7-amino-5-bromo-3-chloro-1H-indole. It was dissolved in ethyl acetate, and there was added a mixed solution (17 ml) and 4 n hydrogen chloride and ethyl acetate. The resulting precipitate was collected by filtration and washed with hexane to obtain 13,23 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); 5,11 (3H, user.C), only 6.64 (1H, s), 6,93 (1H, s) to 7.50 (1H, d, J=2.0 Hz), 11,38 (1H, user.C).

Use the 2-nitroaniline and then adding back the same 66 ml of concentrated chloride-hydrogen acid. An aqueous solution (35 ml) 16,33 g (0,231 mol) of sodium nitrite was added dropwise there at 10oC or lower, followed by stirring for 40 minutes while cooling with ice to obtain a solution of diazonium salts. In the mixed solution of 150 ml of ethanol and 300 ml of water was dissolved 28,43 g (0,197 mol) ethyl-2-methylacetoacetate and then adding back the same 120 ml of an aqueous solution 53,36 g (0,808 mol) of potassium hydroxide while cooling with ice. Then there was added dropwise the previously prepared solution of diazonium salts at the same temperature and was stirred under ice cooling for 20 minutes. After you add it as a concentrated chloride-hydrogen acid to reach pH 1, the resulting precipitate was collected by filtration, washed with water and dried in vacuum over phosphorous pentoxide to obtain 46,42 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); of 1.40 (3H, t, J=7.2 Hz), of 2.23 (3H, s), a 2.36 (3H, s), 4,35 (2H, q, J=7.2 Hz), 7,44 (1H, DD, J=8,8, 1,6 Hz), to 7.93 (1H, d, J=8,8 Hz), 8,00 (1H, s), 10,87 (1H, user.C).

Example obtain 18. Ethyl-5-methyl-7-nitro-1H-indole-2-carboxylate
To a solution (320 ml) 15,92 g (60,0 mmol) of the compound from example getting 17 in xylene was added polyphosphoric acid with subsequent substance was filtered and the organic phase was separated. The organic phase is then washed with water and brine, dried over magnesium sulfate and concentrated. Then the obtained residue was purified by chromatography on a column of silica gel with getting to 7.32 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); of 1.34 (3H, t, J=7.0 Hz), 2,47 (3H, s), 4,36 (2H, q, J= 7.0 Hz), 7,35 (1H, s), to 7.99 (1H, s), 8,11 (1H, s), 11,25 (1H, user.C).

Example obtain 19. 5-Methyl-7-nitro-1H-indole
To a solution (80 ml) 7,86 g (and 31.7 mmol) of the compound from example get 18 in tetrahydrofuran was added 150 ml of 1 N. aqueous solution of sodium hydroxide under ice cooling, followed by stirring at room temperature for 3.5 hours. Under ice cooling was added there 2 N. chloride-hydrogen acid to reach pH 1, followed by extraction with ethyl acetate. The organic phase is then washed with water and brine, dried over magnesium sulfate and then concentrated to dryness to obtain 7,13 g 5-methyl-7-nitro-1H-indole-2-carboxylic acid. The compound obtained was dissolved in 160 ml of 1,3-dimethyl-2-imidazolidinone then adding 716 mg (3,24 mmol) of basic copper carbonate and stirring at 185oWith t the obtained filtrate was extracted with ethyl acetate. The organic phase is then washed with water and brine, dried over magnesium sulfate and concentrated. Then the obtained residue was purified by chromatography on a column of silica gel with getting 4,50 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); the 2.46 (3H, s), 6,62 (1H, d, J=2,8 Hz), 7,47 (1H, d, J=2,8 Hz), 7,87 (1H, s), 7,92 (1H, s), 11,77 (1H, user.C).

An example of obtaining 20. 3-Bromo-5-methyl-7-nitro-1H-indole
To a solution (70 ml) 4,50 g (25.5 mmol) of the compound from example getting 19 in tetrahydrofuran was added 0.7 ml of dimethylformamide and 4,78 g (26.9 mmol) of N-bromosuccinimide, followed by stirring at room temperature for 70 minutes. There was added 10% aqueous sodium thiosulfate solution, followed by extraction with ethyl acetate. The organic phase is then washed with water and brine, dried over magnesium sulfate and then concentrated to dryness to obtain 6,53 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); of 2.50 (3H, s), to 7.67 (1H, s), 7,73 (1H, s), 8,02 (1H, s), 12,10 (1H, user.C).

Example of getting a 21. 7-Amino-3-bromo-5-methyl-1H-indol
In the mixed solution of 150 ml of methanol and 75 ml of water suspended 6,76 g (26,5 is l) of iron powder. After stirring at 80oC within 1 hour of insoluble substances were filtered off. To the filtrate was added a saturated solution of sodium bicarbonate to bring to pH 8, followed by extraction with ethyl acetate. The organic phase is then washed with a saturated solution of sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated. Then the obtained residue was purified by chromatography on a column of silica gel with getting 3,30 g of compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); of 2.24 (3H, s) 5,08 (2H, user.C) of 6.20 (1H, s) 6,41 (1H, s), 7,35 (1H, s), 10,86 (1H, user.C).

Example of getting a 22. 6-Amino-3-pyridinesulfonamide
To 123,8 g (1.06 mol) of chlorosulfonic acid was added portions of 10.00 g (0,106 mol) of 2-aminopyridine with ice cooling. There was added thionyl chloride (50,56 g 0,425 mol) followed by heating under reflux for 2.5 hours and further stirring at 150oWith over 7 hours. The reaction solution was introduced into ice water, neutralized by the addition there of sodium bicarbonate solution and was extracted with ethyl acetate. The organic phase is then washed nasushiobara before drying. The resulting residue is suspended in ethyl ether and the insoluble substance was filtered. The filtrate was concentrated to dryness and the obtained residue was recrystallized from a mixture of ethyl ether-hexane to obtain a return of 6.58 g of compound indicated in the heading.

An example of retrieving 23. 4,7-Dibromo-1H-indole
From 62,0 g (0,224 mol) of 2,5-dibromantratsena got to 27.2 g of compound indicated in the title, in the same way as described in example obtaining 1 of JP-A 7-165708.

1H-NMR (DMSO-d6)(M. D.); of 6.52 (1H, d, J=3.2 Hz), 7,18 (1H, d, J=8.0 Hz), 7,26 (1H, d, J=8.0 Hz), 7,53 (1H, d, J=3.2 Hz), 11,75 (1H, user.C).

Example of getting 24. 7-Amino-4-bromo-1H-indolepropionic
To a solution (300 ml) of 27.2 g (the 98.9 mmol) of the compound from example get 23 in tetrahydrofuran was added dropwise 186 ml (116,3 mmol) of 1.6 M solution of n-utility in hexane in a nitrogen atmosphere at -78oC, followed by stirring for 1 hour under ice cooling. After re-cooling to -78oSince there was added dropwise 28 ml (0.13 mmol) diphenylphosphinite and the mixture was stirred at -78oC for 1 hour and then at -40oC for 1 hour. After adding back the same at -40oWith 150 g of 3.4 M solution of bis (2-methoxyethoxy)aluminum hydride is obtained insoluble substance was collected by filtration and the filtrate was extracted with ethyl ether. The organic phase is then washed with a saturated solution of sodium bicarbonate and brine and dried over magnesium sulfate. After it was concentrated, the obtained residue was dissolved in ethyl ether, there was added 50 ml of a mixed solution of 4 N. chloride-hydrogen acid and ethyl acetate, and the resulting precipitate was collected by filtration to obtain 14.5 g of the compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); 6,41-to 6.43 (1H, m), to 6.80 (1H, d, J=8.0 Hz), 7,16 (1H, d, J=8.0 Hz), 7,54 (1H, t, J=2,8 Hz), 11,57 (1H, user.C).

An example of obtaining 25. 7-Bromo-4-chloro-1H-indole
The connection specified in the header of the received manner similar to that described in example receiving 23.

1H-NMR (DMSO-d6)(M. D.); 6,60-of 6.61 (1H, m),? 7.04 baby mortality (1H, d, J=8.1 Hz), 7,2 (1H, d, J=8.1 Hz), 7,53 (1H, t, J=2.7 Hz), 11,74 (1H, user.C).

Example of receipt 26. 7-Amino-4-chloro-1H-indolepropionic
The connection specified in the header of the received manner similar to that described in example completion of 24.

1H-NMR (DMSO-d6)(M. D.); 6,54-6,55 (1H, m), 7,05 (1H, d, J=8.1 Hz), 7,11 (1H, d, J=8.1 Hz), 7,60 (1H, t, J=2.7 Hz), 11,82 (1H, user.C).

Example of getting 27. 5-Bromo-2-thiophenecarboxaldehyde
To a solution (80 ml) 10.0 g (a 41.3 mmol) 5-dibromothiazole at -78oC, followed by stirring at the same temperature for 10 minutes. Then add it as 3.5 ml (to 45.5 mmol) of dimethylformamide at the same temperature, followed by stirring for 20 minutes. There was added water, followed by extraction with ethyl acetate. The organic phase is successively washed with 0.1 N. aqueous solution of chloride-hydrogen acid, water and brine and dried over magnesium sulfate. Were concentrated to dryness to obtain 6.4 g of the compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); 7,49 (1H, d, J=4.0 Hz), 7,87 (1H, d, J=3,9 Hz), 9,81 (1H, s).

Example of getting 28. 5-Bromo-2-thiophenecarbonitrile
To a solution of 8.2 g (to 43.1 mmol) of the compound from example getting 27 in 40 ml of dimethylformamide was added to 3.3 g (of 51.7 mmol) hydroxylaminopurine and 4.1 g (of 51.7 mmol) of pyridine, followed by stirring at room temperature for 30 minutes. Then he added there is 34.9 g (215,5 mmol) of 1,1'-carbonyldiimidazole under ice cooling, followed by stirring at room temperature for 1 hour. To the reaction solution was added ice-cold water followed by extraction with ethyl acetate. The organic phase is then washed OLE spent concentrating, the obtained residue was purified by chromatography on a column of silica gel to obtain 6.7 g of the compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); was 7.45 (1H, d, J=4.0 Hz), to 7.84 (1H, d, J=4.0 Hz).

Example get 29. 5-Benzylthio-2-thiophenecarbonitrile
In 10 ml of dimethyl sulfoxide suspended 585 mg (13,4 mmol; 55% in oil) of sodium hydride, and then added back the same 1.4 g in (11.2 mmol) of benzylmercaptan under ice cooling, followed by stirring for 10 minutes. Then there was added 2.1 g in (11.2 mmol) of the compound from example get to 14, followed by stirring at room temperature for 1 hour. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic phase is then washed with water and brine and dried over magnesium sulfate. After you have performed this concentration, the obtained residue was purified by chromatography on a column of silica gel to obtain 1.51 g of the compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); 4.26 deaths (2H, s), 7,18 (1H, d, J=4.0 Hz), 7,27-7,30 (5H, m), 7,83 (1H, d, J=4.0 Hz).

Example 30. 4-Bromo-1H-indolocarbazole acid
51 g of compound from example getting 231H-NMR (DMSO-d6)(M. D.); 6,51-of 6.52 (1H, m), 7,35 (1H, d, J=8.0 Hz), of 7.48 (1H, t, J=2,8 Hz), 7,66 (1H, d, J=8 Hz), and 11.4 (1H, user.C) to 13.2 (1H, user.C).

Example of getting 31. 7-(N-tert-Butoxycarbonyl)amino-4-bromo-1H-indole
34 g of the compound from example 30 was obtained 32 g of compound indicated in the heading, by a method similar to that described in example receipt 9.

1H-NMR (DMSO-d6)(M. D.); 1,51 (N, C), 6,38-to 6.39 (1H, m), 7,13 (1H, d, J=8.0 Hz), 7,44-7,46 (2H, m), 9,11 (1H, user.C), and 11.2 (1H, user.C).

Example get 32. 7-(N-tert-Butoxycarbonyl)amino-4-bromo-3-chloro-1H-indole
The connection specified in the header, was obtained by treatment of N-chlorosuccinimide solution of the compound from example getting 31 in a mixture of tetrahydrofuran/dimethylformamide.

1H-NMR (DMSO-d6)(M. D.); 1,50 (N, C), 7,19 (1H, d, J=8,4 Hz), was 7.45 (1H, d, J= 8,4 Hz), a 7.62 (1H, d, J=2,8 Hz), the remaining 9.08 (1H, user.C) 11,41 (1H, user.C).

An example of obtaining 33. 7-Amino-4-bromo-3-chloro-1H-indolepropionic
Connection (10,87 g of 31.5 mmol) following the example of obtaining 32 was dissolved in 120 ml of methanol, was added 20 ml of concentrated chloride-hydrogen acid, followed by stirring at 60oC for 40 minutes. After completion of reaction solvent was removed and the obtained onium 8.5 g connection specified in the header.

1H-NMR (DMSO-d6)(M. D.); to 6.67 (1H, d, J=8.0 Hz), 7,13 (1H, d, J=8.0 Hz), the 7.65 (1H, d, J=2,8 Hz), 11,74 (1H, user.C).

An example of retrieving 34. 2-Amino-5-pyrimidinemethanol
In water with ice cooled 21 ml (0,316 mol) of chlorosulfonic acid was added up to the same portions 3 g (to 0.032 mol) with stirring. Next was added there to 9.2 ml (0,126 mol) of thionyl chloride, followed by stirring at 150oWith over 70 hours. The reaction solution was returned to room temperature and added water and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated to dryness to obtain 1.7 g of the compound indicated in the heading.

1H-NMR (DMSO-d6)(M. D.); 5,97 (2H, usher.), 8,83 (2N,C).

Example 1. 3-Cyano-N-(3-cyano-4-methyl-1H-indol-7-yl)benzosulfimide

The compound (2.00 g, 11.7 mmol) from example 12 was dissolved in 60 ml of tetrahydrofuran, and then added there 4,0 ml (a 49.5 mmol) of pyridine and 2,60 g (12.9 mmol) of the compound from example receiving 13. After stirring at room temperature for 16 hours, there was added 2 N. chloride-hydrogen acid to bring up the values by Rohr, was dried over magnesium sulfate and concentrated. Then the obtained residue was purified by chromatography on a column of silica gel with getting 3,90 g of compound indicated in the title. Melting point: 220-221oC (recrystallization from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.); to 2.55 (3H, s), of 6.50 (1H, d, J=8.0 Hz), 6,77 (1H, d, J=8.0 Hz), 7,71 (1H, t, J=8.0 Hz), of 7.90 (1H, d, J=8.0 Hz), 8,05-8,13 (2H, m), 8,16 (1H, s), 10,11 (1H, user.C) 12,01 (1H, user.C).

Example 2. 6-Chloro-N-(3-cyano-4-methyl-1H-indol-7-yl)-3-pyridinesulfonamide

The compound (700 mg, 4.09 to mmol) from example 12 was dissolved in 20 ml of tetrahydrofuran, and then added back the same 1.3 ml (16,1 mmol) of pyridine and 950 mg (4,48 mmol) 6-chloro-3-pyridinesulfonamide. After stirring at room temperature for 2 hours there was added 1 N. chloride-hydrogen acid to reach pH 1-2 and the mixture was extracted with ethyl acetate. The organic phase is then washed with water and brine, dried over magnesium sulfate and concentrated. Then the obtained residue was purified by chromatography on a column of silica gel with receipt of 1.16 g of compound indicated in the heading.

Melting point: 262-2630days); to 2.57 (3H, s), 6,55 (1H, d, J=7,6 Hz), PC 6.82 (1H, d, J= 7,6 Hz), 7,69 (1H, d, J=8,4 Hz), 8,01 (1H, DD, J=8,4, 2.4 Hz), 8,17 (1H, d, J=2,8 Hz), at 8.60 (1H, d, J=2.4 Hz), of 10.21 (1H, user.C) a 12.03 (1H, user.C).

Example 3. N-(3-Bromo-5-methyl-1H-indol-7-yl)-4-sulfamoylanthranilic

The compound (200 mg, 0.89 mmol) according to example getting 22 was dissolved in 6 ml of tetrahydrofuran, and then added there, 0.3 ml (3,71 mmol) of pyridine and 300 mg (1,17 mmol) of the compound from example get 14. After stirring at room temperature for 48 hours, was added 1 N. chloride-hydrogen acid to reach pH 1-2 and the mixture was extracted with ethyl acetate. The organic phase is then washed with water and brine, dried over magnesium sulfate and concentrated. Then, a mixed solution of diethyl ether and hexane were added to the obtained residue, and the crystals were collected by filtration to obtain 387 mg of the connection specified in the header.

Melting point: 196-197oC (recrystallization from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.); of 2.24 (3H, s), 6,60 (1H, s), 6,98 (1H, s), 7,44 (1H, s), 7,55 (2H, user.C) a 7.85-of 7.95 (4H, m), 10,13 (1H, user.C) br11.01 (1H, user.C).

Example 4. 6-Amino-N-(5-bromo-3-chloro-1H-indol-7-yl)-3-pyridinesulfonamide is tetrahydrofuran, and then he added there 0,86 ml (10.6 mmol) of pyridine and 718 mg (3.73 mmol) of the compound from example get 8 while cooling with ice. After stirring at room temperature for 3 hours was added up to the same water and the mixture was extracted with ethyl acetate. The organic phase is then washed with water and brine, dried over magnesium sulfate and concentrated. Then the obtained residue was purified by chromatography on a column of silica gel to obtain 1.27 g of the compound indicated in the title. Melting point: start painting around 237oWith decomposition at 240-242oC (recrystallization from a mixture of ethanol/water).

1H-NMR (DMSO-d6)(M. D.); 6,37 (1H, d, J=8,8 Hz) 6,94 (2H, user.C), 6,97 (1H, s), of 7.36 (1H, s), 7,54-EUR 7.57 (2H, m), 8,16 (1H, d, J=2,8 Hz), 9,94 (1H, user.C), 11,17 (1H, user.C).

Hydrochloride:1H-NMR (DMSO-d6)(M. D.); 6,59 (1H, d, J=9,2 Hz), 7,00 (1H, s), 7,40 (1H, s), 7,56 (1H, d, J=2.4 Hz), of 7.70 (1H, DD, J=9,2, 2.0 Hz), to 8.20 (1H, d, J=2.0 Hz), and 10.20 (1H, user.C) 11,37 (1H, user.C).

Example 5. N-(3-Bromo-5-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonyl

To a solution (6 ml) 260 mg (1,16 mmol) of the compound from example getting 21 in tetrahydrofuran was added to 0.19 ml (2,35 mmol) pyridi is mperature during the night. There was added to 0.2 N. chloride-hydrogen acid, and the mixture was extracted with ethyl acetate. The organic phase is then washed with water and brine, dried over magnesium sulfate and concentrated. Then the obtained residue was purified by chromatography on a column of silica gel to obtain 360 mg of the connection specified in the header.

Melting point: the beginning of decomposition of about 148oAnd rapid decomposition when 163-164oC (recrystallization from a mixture of ethanol/n-hexane)
1H-NMR (DMSO-d6)(M. D.); of 2.25 (3H, s), is 6.54 (1H, s), 7,01 (1H, s), 7,42 (1H, d, J= 2,8 Hz), 7,71 (1H, t, J=7,6 Hz), to 7.93 (1H, d, J=7,6 Hz), 8.07-a 8,11 (2H, m), of 10.09 (1H, user.C) 11,04 (1H, user.C).

Example 6. N-(4-Bromo-1H-indol-7-yl)-4-cyanobenzenesulfonyl

The connection specified in the header (686 mg) was obtained by processing 700 mg (2.8 mmol) of the compound from example obtain 24 and 685 mg (3.4 mmol) of 4-cyanobenzenesulfonyl manner similar to that described in example 1, melting point: 214-216oC.

1H-NMR (DMSO-d6)(M. D.); 6,35 (1H, d, J=2.6 Hz), 6,53 (1H, d, J=8.0 Hz),? 7.04 baby mortality (1H, d, J=8.0 Hz), 7,41 (1H, t, J=2,8 Hz), the 7.85 (2H, d, J=8.0 Hz), 8,00 (2H, d, J=8.0 Hz), 10,24 (1H, user.C), 11,19 (1H, user.C).

Example 7. 6-Amino-N-(4-chloro-1H-) was obtained by processing 1330 mg (6.4 mmol) of the compound from example getting 22 and 1000 mg (4.9 mmol) of the compound from example 12 way similar to that described in example 1. Melting point: 204-206oC.

1H-NMR (DMSO-d6)(M. D.); 6,38 (1H, d, J=9.0 Hz), to 6.43 (1H, t, J=2.2 Hz), 6,77 (1H, d, J=7,7 Hz) 6,86 (2H, user.C), 7,42 (1H, t, J=2,6 Hz), 7,56 (1H, DD, J= 2,6, 9.0 Hz), 8,14 (1H, d, J=2.6 Hz), to 9.70 (1H, user.C) 11,07 (1H, user.C).

Example 8. 6-Amino-N-(3-bromo-4-chloro-1H-indol-7-yl)-3-piperidinemethanol and its hydrochloride

To a solution (10 ml) 650 mg (2.0 mmol) of the compound from 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 over night. There was added to 0.2 N. aqueous solution of chloride-hydrogen acid, followed by extraction with ethyl acetate. The organic phase is then washed with an aqueous solution of sodium thiosulfate, water and brine, dried over magnesium sulfate and concentrated. Then the obtained residue was purified by chromatography on a column of silica gel with getting 662 mg of the connection specified in the header.

1H-NMR (DMSO-d6)(M. D.); 6,38 (1H, d, J=8,8 Hz), 6,76 (1H, d, J=8,4 Hz), to 6.88 (2H, user.C), 6,97 (1H, d, J=8,4 Hz), 7,52-7,56 (2H, m) to 8.12 (1H, d, J=2.4 Hz), 9,68 (1H, user.C) 11,44 (1H, user.C).

In 3 ml of acetone restwood in ethyl acetate and the resulting precipitate was collected by filtration to obtain 590 mg of the hydrochloride compounds specified in the header.

Melting point: the beginning of the gradual decomposition of about 267oC.

1H-NMR (DMSO-d6)(M. D.); of 6.65 (1H, d, J=9,2 Hz), 6,78 (1H, d, J=8.1 Hz), 6,98 (1H, d, J=8,2 Hz), EUR 7.57 (1H, d, J=2.6 Hz), 7,73 (1H, DD, J=2.0 a, 9,0 Hz), 8,15 (1H, d, J=2.4 Hz), 10,00 (1H, user.C) 11,67 (1H, user.C).

Example 9. N-(3-Bromo-5-methyl-1H-indol-7-yl)-5-cyano-2-thiophenesulfonyl

In a solution of 1.3 g (5.6 mmol) of the compound from example get 29 in 15 ml of concentrated chloride-hydrogen acid (15 ml) was introduced chlorine gas while cooling with ice. After stirring for 30 minutes the reaction solution was added to the mixture with ice water, followed by extraction with ethyl acetate. The organic phase is then washed with water and brine, dried over magnesium sulfate and concentrated. The obtained residue was added to a solution of 1.2 g (to 5.35 mmol) of the compound from example getting 22 in 6 ml of pyridine, followed by stirring at room temperature over night. There was added water, followed by extraction with ethyl acetate. The organic phase is successively washed with 1 N. aqueous solution of chloride-hydrogen acid, water and brine, dried over magnesium sulfate and continine, specified in the header.

Melting point: 166-169oC (decomposition).

1H-NMR (DMSO-d6)(M. D.); 2,30 (3H, s), of 6.65 (1H, s), 7,07 (1H, s), 7,44 (1H, s), 7,54 (1H, d, J=4.0 Hz), 7,94 (1H, d, J=4.0 Hz), of 10.47 (1H, user.C) 11,04 (1H, user.C).

Example 10. 2-amino-N-(4-bromo-3-chloro-1H-indol-7-yl)-5-pyrimidinemethanol

To 5 ml of a solution of 712 mg (2,52 mmol) of the compound from example get 33 in pyridine was added 513 mg (approximately 2.65 mmol) of the compound from example obtain 34 and the mixture was stirred for 15 hours. To the reaction solution was added water, and then carried out the extraction of a mixed solution of ethyl acetate and tetrahydrofuran (10:1). The organic phase was dried over magnesium sulfate, and then concentrated and purified by chromatography on a column of silica gel to obtain 950 mg of the connection specified in the header.

Melting point: 285-289oC.

1H-NMR (DMSO-d6)(M. D.); by 6.75 (1H, d, J=8.0 Hz), 7,19 (1H, d, J=8.0 Hz), to 7.59 (1H, d, J=3.0 Hz), the 7.65 (2H, s) of 8.37 (2H, s), 9,82 (1H, s) 11,43 (1H, s).

1) Antiproliferative activity against melanoma B16 mice (in vitro)
Experimental method table.4
Cm. pharmacological experimental example 3.

Inhibitory activity of the is, while the potency of the compound of example 1 of this application (example 1) is 10 μg/ml In comparison with example 51 cytotoxicity (antiproliferative activity) compound of example 1 against tumor cells is one-sixth of that figure for the connection in example 51. At the same time, as shown in table pharmacological experimental example 1 in the description of the present invention, the inhibitory activity (IC50) of the compound of example 1 in a model of angiogenesis in vitro is 0.8 µg/ml and is 125 times greater than cytotoxicity. Therefore suggest that therapeutic effect of the compound of example 1 on the tumor cells (in vivo), described below, is the result of antiangiogenic action, and the compound of example 1, as was expected, has fewer side effects in comparison with the compound from example 51.



2) Inhibiting activity in a model of angiogenesis in mice (in vivo)
Experimental method
Inhibitory activity of compounds was evaluated by the method of the dorsal air SAC (Funahashi et al., Oncol.Res. 11, 319-329, 1999). Ring Millipore (from the company Millipore) was condensed 0.22 μm membrane filter (HAWPO: Millipore), produces x 107 cells), suspendirovanie in collagen gel Type I (type I-A: Nitta Gelatin), were injected with the camera and hermetically closed. Then the cells containing tumor cells, or not containing, implanted in the dorsal air pouch, educated female mice C57BL/6N at the age of 6-8 weeks by injection of 10 ml of air through the needle 25. Approximately 6 hours after implantation oral injected connection once a day for 4 days. On day 4 after the start of the experiment the mice were injected via tail vein labeled51SG erythrocytes mouse. After 1 hour under anesthesia cut part of the skin around the camera. After freezing accurately separated only by the fabric, which is in contact with the camera. Labeled cells were counted usingcounter, then a defined volume of blood. The amount of angiogenesis was determined by subtracting the volume of the blood chamber with or without tumor cells. In this experiment used 8 mice for the control group, 5 mice were used for the test compound at each dose, PL.5.

Inhibitory effect on angiogenesis induced by tumor cells (in vivo) - see table.5.

At the dose of 100 mg/kg of the compound from example 51 angiogenesis Engibarov indicated, what this dose is toxic. Thus, the compound from example 51 showed only a minor effect at the maximum tolerated dose (100 mg/kg).

Whereas the compound of example 1 in which one hydrogen atom in position 4 (R2) indole ring of the compound from example 51 substituted methyl group, inhibited angiogenesis up to 53.1% at the dose of 50 mg/kg, to 57.2% at the dose of 100 mg/kg to 49.6% at the dose of 200 mg/kg and up to 12.7% at the dose of 400 mg/kg, respectively.

When comparing the compound from example 51 and connection example 1, the first of these compounds shows a weak inhibitory effect on angiogenesis, whereas the compound of example 1 shows a remarkable inhibitory effect on angiogenesis.

3) anti-tumor effect on xenograft models mouse (in vivo)
Experimental method
The antitumor effect was determined in accordance with the method Koyanagi et al. (cancer Res., 54, 1702-1706, 1994). Tumor cells NST derived from colon cancer cells human (5 x 106 cells) subcutaneously implanted "Nude" mice (KSN) aged 6 to 7 weeks. After 1 week of oral injected compounds suspended in 0.5% methylcellulose, twice a day for 5 days a week for 2 weeks. In this day counted the number of mice no tumors.

therapeutic effect of the test compounds on tumor cells of human colon ST, subcutaneously implanted mice
Bespokely coefficient on day 12 (two times a day, 5 days/week for 2 weeks).

therapeutic effect of the compounds of example 1 and the compound from example 51 in relation to tumor human colon HCT 116 (in vivo), PL.6.

In mice treated with compound from example 51, 4 of 5 treated mice died at a dose of 100 mg/kg for 12 days, and did not observe any no tumors mouse at a dose of 50 mg/kg whereas in mice treated with compound of example 1, there were no side effects, and therapeutic efficacy was definitely confirmed. This means that the compound of example 1 is significantly improved for use.

From the above test results it should be noted that the compound of example 1 of this application is unexpectedly superior connection example 51 EP 0673937 in light of the observed in vivo in the absence of side-effects, antiangiogenic action and antitumor action.


Claims

1. �/img_data/62/621346.gif">
where R1is a hydrogen atom, halogen atom or cyano;
R2and R3are the same or otlichnymi, and each represents a hydrogen atom, a C1-C4alkyl group or a halogen atom;
R4represents a hydrogen atom or a C1-C4alkyl group;
ring And represents cyanophenyl group, aminosulphonylphenyl group, aminopyridine group, aminopyrimidine group, halogenopyrimidines group or cyanocobalamine group,
provided that if all R1, R2and R3represent hydrogen atoms, when both R and R3represent hydrogen atoms or when ring a represents aminosulphonylphenyl group and both R1and R2represent halogen atoms is excluded; and, in addition, when the ring a is cyanophenyl group, 2-amino-5-pyridyloxy group or 2-halogen-5-pyridyloxy group, and R1represents a cyano or halogen group, at least one of R2and R3must not be a hydrogen atom.

2. The connection of indole under item 1, its pharmacologically acceptable salt or hydrates, where two of R1, R2and R

4. The connection of indole under item 1 or 2, its pharmacologically acceptable salt or hydrates, where the ring a represents a 2-amino-5-pyridyloxy group.

5. The connection of indole under item 1 or 2, its pharmacologically acceptable salt or hydrates, where the ring a represents a 2-amino-5-pyramidalnou group.

6. The connection of indole under item 1 or 2, its pharmacologically acceptable salt or hydrates, where ring a is a 2-halogen-5-pyridyloxy group.

7. The connection of indole under item 1 or 2, its pharmacologically acceptable salt or hydrates, where the ring And represents cyanothiophene group.

8. The connection of indole under item 1 or 2, its pharmacologically acceptable salt or hydrates, where the ring And represents cyanophenyl group.

9. The connection of indole under item 1, selected from the following compounds, its pharmacologically acceptable salt or hydrates:
1) 3-cyano-N-(3-cyano-4-methyl-1H-indol-7-yl)benzosulfimide,
2) 6-chloro-N-(3-cyano-4-methyl-1H-indol-7-yl)-3-pyridinesulfonamide,
3) N-(3-bromo-5-methyl-1H-indol-7-yl)-4-sulfamoylanthranilic,
4) 6-amino-N-(5-bromo-3-chloro-1H-indol-7-yl)-3-pyridinesulfonamide,
7) 6-amino-M-(4-chloro-1H-indol-7-yl)-3-pyridinesulfonamide,
8) 6-amino-N-(3-bromo-4-chloro-1H-indol-7-yl)-3-pyridinesulfonamide
9) N-(3-bromo-5-methyl-1H-indol-7-yl)-5-cyano-2-thiophenesulfonyl and
10) 2-amino-N-(4-bromo-3-chloro-1H-indol-7-yl)-5-pyrimidinemethanol.

10. The connection of indole under item 1, selected from the following compounds, its pharmacologically acceptable salt or hydrates:
1) 3-cyano-N-(3-cyano-4-methyl-1H-indol-7-yl)benzosulfimide,
2) 6-chloro-N-(3-cyano-4-methyl-1H-indol-7-yl)-3-pyridinesulfonamide,
3) N-(3-bromo-5-methyl-1H-indol-7-yl)-4-sulfamoylanthranilic,
4) 6-amino-N-(5-bromo-3-chloro-1H-indol-7-yl)-3-pyridinesulfonamide
5) N-(3-bromo-5-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonyl,
6) 6-amino-N-(3-bromo-4-chloro-1H-indol-7-yl)-3-pyridinesulfonamide
7) N-(3-bromo-5-methyl-1H-indol-7-yl)-5-cyano-2-thiophenesulfonyl and
8) 2-amino-N-(4-bromo-3-chloro-1H-indol-7-yl)-5-pyrimidinemethanol.

11. Antiangiogenic agent, containing as an effective ingredient the compound indole according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrates.

12. Connection indole according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrates as an active ingredient of a prophylactic or antiangiogenic drug Preah according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrates.

14. Remedy against malignant tumors of the pancreas, containing as an effective ingredient the compound indole according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrates.

15. Remedy against malignant tumors of the colon containing as an effective ingredient the compound indole according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrates.

16. Remedy against malignant tumors of the stomach, containing as an effective ingredient the compound indole according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrates.

17. Remedy against malignant tumors of the mammary gland containing as an effective ingredient the compound indole according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrates.

18. Remedy against malignant tumors of the prostate gland, containing as an effective ingredient the compound indole according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrates.

19. The drug against slocate is, the th pharmacologically acceptable salt or hydrates.

20. Remedy against malignant tumors of the ovary, containing as an effective ingredient the compound indole according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrates.

21. Suppressor of metastasis of a malignant tumor containing as an effective ingredient the compound indole according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrates.

22. Drug against diabetic retinopathy, containing as an effective ingredient the compound indole according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrates.

23. Drug against rheumatoid arthritis, containing as an effective ingredient the compound indole according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrates.

24. Drug against bruising, which contains as an effective ingredient the compound indole according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrates.

25. A method of preventing or treating a disease against which a prophylactically or therapeutically effective inhibition angioprotective dose of indole compounds according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrate the patient.

26. Connection indole according to any one of paragraphs.1-10, its pharmacologically acceptable salt or hydrate as an active ingredient of anti-cancer drugs, medicines against malignant tumors of the pancreas, medicines against malignant tumors of the colon, medicines against malignant tumors of the stomach, drugs against malignant tumors of the breast, medicines against malignant tumors of the prostate, drugs against malignant tumors of the lung, drugs against malignant ovarian tumor, suppressor of metastasis of a malignant tumor, drugs against diabetic retinopathy, drug against rheumatoid arthritis or drugs against bruising.

27. The method according to p. 25, wherein the disease is a tumor, a pancreatic tumor, a malignant tumor of the colon, cancer of the stomach, cancer of the lung, malignant the atom.

 

Same patents:

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Arylalkylamine // 2201923
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< / BR>
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-converting enzyme)" target="_blank">

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< / BR>
where W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, with

< / BR>
is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is a phenyl which allows an alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts

Arylalkylamine // 2201923
The invention relates to arylalkylamines formula I, where B - A, OA, NH2, CF3, aromatic heterocycle selected from pyridine, pyrazine and pyrimidine; Q is absent or denotes alkylene with 1-6 carbon atoms; R1and R2independently from each other represent OR5where R5- Or cycloalkyl with 3-7 carbon atoms; And the alkyl with 1-10 carbon atoms, and their physiologically acceptable salts

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