Heterocyclic compounds containing sulfonamidnuyu group, the intermediate connection and antiangiogenic agent based on them

 

(57) Abstract:

The invention relates to sulfhemoglobinemia heterocyclic compound represented by formula (I), its pharmaceutically acceptable salts and their hydrates

where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims. The invention also relates to intermediate compounds of the formula (II)

to a method for producing compounds represented by formula IV, antitumor agent, to the agent, the vast metastasis of malignant tumors on the basis of the compounds of formula (I).

The technical result is to provide new compounds for the prevention and treatment of diabetic retinopathy, rheumatoid arthritis, hematomas, suppression of metastasis of a malignant tumor. 8 N. and 8 C.p. f-crystals, 2 PL.

The technical field

The present invention relates to sulfhemoglobinemia heterocyclic compound which is suitable as pharmaceutical compounds, and to its antiangiogenic action. In addition, it relates to an antitumor agent, the agent, the vast metastasis of malignant tumors, therapeutic agent diachenkoa agent for the treatment of bruises on the basis of antiangiogenic actions.

The level of technology

Was a close connection between the proliferation of malignant tumor and angiogenesis. So, when the malignant tumors is angiogenesis, cancer remains dormant. However, it was found that, when angiogenesis occurs, oxygen and nutrients from the blood delivered to the tumor, which contributes to the proliferation and metastasis of malignant tumors, leading to the deterioration of the clinical condition. Accordingly, it is expected that by inhibiting angiogenesis, it is possible to suppress the proliferation and metastasis of malignant tumors. Because the newly formed vessels built of endothelial cells and interstitial cells of the host, the target of antiangiogenic agent are not cells of a malignant tumor, and these normal cells of the host. Due to the fact that malignant tumors are not the direct target, you can expect efficiency in relation to a malignant tumor that does not respond to known anticancer agents, and, in addition, suppose that the probability tolerant of a malignant tumor that is large procne for tumors, and in vertebrates individuals he is limited by the formation of the endometrium, etc. involving the menstrual cycle. Accordingly, I believe that the adverse effect will be small in comparison with the known anticancer drugs. Recently, preclinical studies, it was experimentally proved that antiangiogenic agents are able to suppress and further to reduce the proliferation of malignant tumors in experimental animals with transplanted tumors that tolerant malignant tumor is not growing, and clinical trials have shown a correlation between angiogenesis and metastasis of many solid malignancies, such as breast cancer, prostate cancer, lung cancer and colorectal cancer.

In the tissues of malignant tumors constantly observed apoptosis and proliferation of tumor cells, and it is known that depending on the balance between them is observed progressive malignant tumor or dormant tumor. Antiangiogenic agent does not kill directly malignant tumors, and cuts off from their sources of supply takane, therefore, it is a drug, which, as you might expect, will show the excellent effect (increased life expectancy, the inhibition of the recurrence and the suppression of metastasis) in long-term treatment.

On preclinical stage there are antiangiogenic agents with different mechanisms of action, but because of their antitumor activity in preclinical stage is insufficient, their suitability for clinical stage is still questionable, and therefore there is an urgent need for antiangiogenic agents with reliable action.

It is also known that angiogenesis is involved in the development of retinopathy or retinitis. When a blood vessel sprouting in the retina, vision is impaired, and when the progression of the process comes blindness. Requires effective drugs for the treatment of this condition.

In the US 662798 described hydroxy - and ariloxipicolinamidei the quinoline and cinoxacin, but they belong to antiviral agents and differ from the present invention. In J. Sci.Ind.Res., sect B, 21 (1962) described 3-p-toluensulfonyl-8-hydroxyquinolin. However, there is no description relating to andany the sulfonamide, but they are herbicides and differ from the present invention. In JP-A 62-426 and 7-267936 described derivatives sulfadimethoxine with antitumor activity. However, there is no description related to the antiangiogenic action.

Accordingly, the present invention is to create a new sulfonamides heterocyclic compound that has excellent antiangiogenic effect and has a different structure from the structure of conventional antiangiogenic agent. Another objective of the present invention is to provide an intermediate product of the compounds and pharmaceutical compositions that contain the compound as an active ingredient.

Description of the invention

Were undertaken intensive research antiangiogenic agent. In the result, it was found that the new sulfonamides heterocyclic compound has excellent antiangiogenic action and exerts an excellent effect as a pharmaceutical drug. Thus was accomplished the present invention.

Specifically, the present invention relates to sulfhemoglobinemia heterocyclic the/P>

where a represents a hydrogen atom, halogen atom, hydroxyl group, C1-C4 alkyl group, or alkoxygroup, which may be substituted by halogen atom, cyano, -(CO)kNR2R3(where R2and R3the same or different and each means a hydrogen atom or a C1-C4 alkyl group which may be substituted by a halogen atom, and k is 0 or 1), C2-C4 alkenylphenol group or alkylamino group which may have a Deputy, or a phenyl group, or fenoxaprop, which may have a Deputy, selected from the following group A;

In represents an aryl group or monocyclic heteroaryl group which may have a Deputy, selected from the following group a, or

(where the ring Q is an aromatic ring which may have one or two nitrogen atom; ring M is an unsaturated C5-C12 monocyclic or polycyclic ring having a common double bond with a ring Q, and the ring may have 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom; ring Q, and the ring M may have a common nitrogen atom and the ring Q and the ring M may have a Deputy, selected from the following group a);

To prady means a hydrogen atom or a C1-C4 alkyl group, a m means an integer of 1 or 2);

T, W, X and Y are the same or different and each means =C(D) (where D represents a hydrogen atom, halogen atom, hydroxyl group, C1-C4 alkyl group, or alkoxygroup, which may be substituted by halogen atom, cyano, -(CO)nNR6R7(where R6and R7the same or different and each means a hydrogen atom or a C1-C4 alkyl group which may be substituted by a halogen atom, and n means 0 or 1), or C2-C4 alkenylphenol group or alkylamino group which may have a Deputy), or a nitrogen atom;

U and V are the same or different and each means =C(D) (where D has the values specified above), a nitrogen atom, -CH2-, an oxygen atom or-CO-;

Z represents a simple bond or-CO-NH-;

R1represents a hydrogen atom or a C1-C4 alkyl group, and

----- means simple or double bond.

Group A:

halogen atom, hydroxyl group, C1-C4 alkyl group or alkoxygroup, which may be substituted by halogen atom, cyano, -R8R9N(NH)p- (where R8and R9the same or different and each means a hydrogen atom or a C1-C4 alkyl group, katoom nitrogen, with which they are associated, with the formation of 5 - or 6-membered ring, which may include nitrogen atom, oxygen atom or sulfur atom and may have a Deputy), aminosulfonyl group which may be substituted by one or two C1-C4 alkyl groups, optionally substituted C1-C8 acyl group, C1-C4 alkyl-S(O)s-C1-C4 Allenova group (where s indicates an integer of 0, 1 or 2), phenylcarbonylamino, which may have a C1-C4 alkyl or Deputy, - (CO)qNR10R11(where R10and R11the same or different and each means a hydrogen atom or a C1-C4 alkyl group which may be substituted amino group which may be substituted by halogen atom or C1-C4 alkyl group, and q is 0 or 1), or an aryl or heteroaryl group, which may have a Deputy, provided that excluded the case when U represents an oxygen atom, V means-CO - or-CH2-; when V represents an oxygen atom, U represents-CO - or-CH2- and the following cases 1) where only one of T, U, V, W, X and Y represents a nitrogen atom and a and D both represent hydrogen atoms, 2) where T, U, V, W, X and Y all are nitrogen atoms, 3) where Y and W are nitrogen atoms; T, U, V and X are =C(D1)- (DG is y), and Z represents a simple bond, and a represents a hydrogen atom, methyl group, halogen atom, triptorelin group or a methoxy group, 4) where W represents a nitrogen atom; T, U, V, X and Y represent =C(D2)- (where D2means a hydrogen atom); and Z represent simple relationships; a represents a hydroxyl group and b is p-toluensulfonate, 5) where V and W are nitrogen atoms and 6) where T, V and W are nitrogen atoms.

The present invention relates to halogen-substituted quinoline compound represented by the following formula:

(where Y1and W1different and each means a nitrogen atom or =C(D3)- (where D3represents a hydrogen atom, halogen atom, hydroxyl group, C1-C4 alkyl group, or alkoxygroup, which may be substituted by halogen atom, cyano, or -(CO)nNR6R7(where R6and R7the same or different and each means a hydrogen atom or a C1-C4 alkyl group which may be substituted by a halogen atom, and n means 0 or 1)); E represents a halogen atom, cyano or C1-C4 alkyl group which may be substituted by a halogen atom; J represents an amino group which may have a protective group, or hydroximino group, C1-C4 alkyl group, or alkoxygroup, which may be substituted by halogen atom, cyano, or -(CO)tNR14R15(where R14and R15the same or different and each means a hydrogen atom or a C1-C4 alkyl group which may be substituted by a halogen atom, and t is 0 or 1); or optionally substituted C2-C4 alkenylphenol group or alkylamino group, provided that excluded the case where Y1represents a nitrogen atom; E represents a hydroxyl group; J represents an amino group and G1represents a hydrogen atom), which is an intermediate product of the compound represented by the above formula (I) or its salt.

In addition, the present invention relates to a method for producing a compound represented by the formula

(where E1represents a halogen atom; R16is carboxylato group; G2represents a hydrogen atom, halogen atom, hydroxyl group or C1-C4 alkyl group, or alkoxygroup, which may be substituted by halogen atom), which includes a step of recovery of the compounds represented by the formula

(where E1pretty group; G2represents a hydrogen atom, halogen atom, hydroxyl group or C1-C4 alkyl group, or alkoxygroup, which may be substituted by halogen atom), tin, zinc, or iron.

The compound represented by the above formula (IV) is a compound of the above formula (II) in which Y represents a nitrogen atom; W1is =CH-; E represents a halogen atom; J represents a carboxyl group having a protective group, and G1represents a hydrogen atom, halogen atom, hydroxyl group or C1-C4 alkyl group, or alkoxygroup, which may be substituted by a halogen atom.

The present invention relates to antiangiogenic agent, antitumor agent, the agent, the vast metastasis of malignant tumor, therapeutic agent for the treatment of diabetic retinopathy, a therapeutic agent for the treatment of rheumatoid arthritis or therapeutic agent for the treatment of bruises, comprising as an active ingredient sulfonamides heterocyclic compound represented by the above formula (I), its pharmaceutically acceptable salt or hydrate.

This is e is effective for prevention or treatment of a malignant tumor, metastasis of malignant tumors, diabetic retinopathy, rheumatoid arthritis or hematoma, by introducing the patient a pharmacologically effective amount sulfonamides heterocyclic compounds represented by the above formula (I), its pharmaceutically acceptable salt or hydrate.

The present invention relates to the use of sulfonamides heterocyclic compounds represented by the above formula (I), its pharmaceutically acceptable salt or hydrate for the production of antiangiogenic agent, antitumor agent, agent, suppressing the metastasis of malignant tumor, therapeutic agent for the treatment of diabetic retinopathy, a therapeutic agent for the treatment of rheumatoid arthritis or therapeutic agent for the treatment of bruises.

In the present invention, "aromatic ring which may have one or two nitrogen atom, in the ring Q is an aromatic hydrocarbon or 6-membered aromatic heterocycle comprising one or two nitrogen atom. Examples of these aromatic rings in the ring Q is a benzene, pyridine, pyrimidine, pyrazin, peridas the PEX heteroatoms, selected from nitrogen atom, oxygen atom and sulfur atom, as ring M, means unsaturated monocyclic or polycyclic ring, which has a common double bond with a ring Q, and includes aromatic hydrocarbon rings such as benzene and naphthalene; unsaturated hydrocarbon rings, such as cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cycloheptadiene and cyclooctadiene, and unsaturated heterocyclic rings, such as the tetrahydropyridine, pyrrole, furan, thiophene, oxazole, isoxazol, thiazole, isothiazol, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyrazin, pyridazine, triazine, indole, isoindole, quinoline, isoquinoline, indazole, naphthylidine, benzofuran, benzopyran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, pyrrolopyridine, pyridopyrimidines and imidazopyridine. The phrase "ring Q and the ring M can have one nitrogen atom" refers to the case where the nitrogen atom is in the position of condensation between the two rings, and these rings include, for example, indazolin, imidazo[1,2-a]pyridine, imidazo[1,5-a] pyridine and piraro[1,5-a]pyrimidine.

In the present invention, C1-C4 alkyl group, R1, R4and R5and C1-C4 alkyl group in C1-C4 alkyl is8, R9, R10, R11, R12, R13, R14, R15, G1, G2and the group include linear or branched alkyl group containing 1-4 carbon atoms, such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group and tert-bucilina group. The phrase "which may be substituted by a halogen atom, means that each of these alkyl groups may be substituted atom (atoms) halogen selected from fluorine atom, chlorine atom, bromine atom and iodine atom. These halogen-substituted alkyl groups include, for example, monitoramento group, monochloromethyl group, deformational group, triptorelin group, 1 - or 2-monitoramento group, 1 - or 2-monochloroethylene group, 1 - or 2-monobromodiphenyl group, 1,2-deperately group, 1,2-dichloroethylene group, 1,1,2,2,2-panafcortelone group and 3,3,3-triptorelin group. Of them, preferred are mooftormetilnoy group, deformational group, triptorelin group, 1 - or 2-nonoperational group, 1,2-deperately group and 1,1,2,2,2-panafcortelone group.

In the present invention, C1-Sanya or branched alkoxygroup, containing 1-4 carbon atoms, such as methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butylacrylate, isobutylacetate, second-butylacrylate and tert-butylacrylate. The phrase "which may be substituted by a halogen atom, means that each of these alkoxygroup may be replaced by atoms (atoms) halogen selected from fluorine atom, chlorine atom, bromine atom and iodine atom. These halogensubstituted alkoxygroup include, for example, monitortype, deformatsiyu, cryptometer, 1 - or 2-monitorexit, 1 - or 2-monochloroacetate, 1 - or 2-monobromoacetate, 1,2-dipterocarp, 1,1,2,2,2-pentafluoropropyl and 3,3,3-cryptocracy. Of them, preferred are monitortype, dipterocarp, tripterocarpa, 1 - or 2-monitorexit, 1,2-dipterocarp and 1,1,2,2,2-pentaceratops.

In the present invention, C2-C4 Alchemilla group or Alchemilla group a and D includes alkeneamine group or alkyline group containing 2-4 carbon atoms, such as vinyl group, allyl group, 2 - or 3-bucinellina group, 1,3-butadienyl group, etinilnoy group, 2-proponila groupsarmenia means and includes an aromatic hydrocarbon group, such as phenyl group and naftalina group. Heteroaryl group means and includes monocyclic and polycyclic rings, each of which contains one or more nitrogen atoms, oxygen atoms and sulfur atoms. These heteroaryl groups include, for example, pyrrolyl, imidazolidinyl group, pyrazolidine group, triazolyl group, follow group, thienyl group, oxazolidinyl group, isoxazolyl group, thiazolidine group, isothiazolinones group, thiadiazolyl group, pyridyloxy group, pyramidalnou group, perilou group, indolenine group, indolizinyl group, benzimidazolyl group, benzothiazolyl group, benzoxazolyl group, hyalinella group, athinodorou group, chinazolinei group and talinolol group.

The phrase "R8and R9can be combined with the nitrogen atom to which they are attached, with the formation of 5 - or 6-membered ring, which may include nitrogen atom, oxygen atom or sulfur atom in R8and R9in the present invention means that R8and R9together with the nitrogen atom to which they are attached, form a ring, such as pyrrolidinyl group, piperidinyl-C4 alkyl group aminosulfonyl group, which may be substituted by one or two C1-C4 alkyl groups, C1-C4 alkyl-S(O)s-C1-C4 Allenova group, C1-C4 alkyl - or phenylcarbonylamino, and mentioned phenyl group may have a Deputy, and C1-C4 alkyl group which may be substituted by C1-C4 alkyl group, in group a mean and include the same alkyl groups as above. Allenova group includes, for example, methylene group, ethylene group, propylene group and butylene group, and metilbutilovy group, 1 - or 2-methylethanol group, 1-, 2 - or 3-methylpropanoyl group and dimethylmethylene group.

C1-C8 alcoolica group means, for example, formyl group, acetyl group, propionyl group, butyryloxy group, isobutyryloxy group, valerino group, benzoyloxy group, etc.

The protective group in the "amino group which may have a protective group," J of the present invention is not specifically limited, as in organic synthesis it is usually used as aminosidine group. These protective groups include, but are not limited to, benzyloxycarbonyl group, tert-butoxycarbonyl group, formyl group, the group and trailing group. Protective group, a carboxyl group, which may have a protective group, and carboxyamide group in R16not specifically limited and may be any protective group, as in organic synthesis, they are usually used as carboxyamide groups. These protective groups include, but are not limited to, methyl group, ethyl group, through the group, isopropyl group, tert-boutelou group, methoxymethyl group, 2,2,2-trichlorethylene group, pivaloyloxymethyl group and benzyl group.

In the present invention Deputy in the phrase "which may have a Deputy" means and includes the above-mentioned halogen atoms, C1-C4 alkyl group or alkoxygroup, which can be substituted by halogen atom, hydroxyl group, hydroxy-C1-C4 alkyl group, amino group which may be substituted by one or two C1-C4 alkyl groups, C2-C4 alkeneamine group or alkyline group, cyano, C1-C8 acyl group, aminosulfonyl group which may be substituted by one or two C1-C4 alkyl groups, a carboxyl group, C1-C4 alkoxycarbonyl group and carbamoyl group, which may be of the view, represented by the above formula (I) can form salts with acids or bases. The present invention also includes salts of the compound (I). These salts with acids include, for example, salts of inorganic acids, such as hydrochlorate, Hydrobromic and sulfate, salts with organic acids such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonate acid and p-toluensulfonate acid. Examples of salts with base are inorganic salt such as sodium salt, potassium salt and calcium salt, and a salt with an organic base, such as triethylamine, arginine or lysine.

It goes without saying that the present invention includes all optical isomers when they exist, as well as the hydrates of these compounds. In addition, also included are compounds that exert an antiangiogenic effect, resulting from the metabolism of the compounds of the present invention, such as oxidation, recovery and hydrolysis in vivo. The present invention also includes compounds which as a result of metabolism such as oxidation, vosstanovlenieplastika can be obtained in different ways. Exemplary methods are as follows.

1) When Z represents a simple communication

where in formulas a, b, T, U, V, W, X and T have the same meanings defined above.

Specifically, these compounds can be obtained by the interaction of the sulfonic acid represented by the formula (V) or its reactive derivative with the compound represented by formula (VI).

These reactive derivatives of sulfonic acid (V) include, for example, commonly used reactive derivatives, such as sulphonylchloride, sulfanilamide and N-sulfanilimide. Are generally preferred sulphonylchloride. Solvents for use in the reaction are not specifically limited, but preferred are solvents that dissolve substances and are inert with respect to these substances. These solvents include pyridine, tetrahydrofuran, dioxane, benzene, diethyl ether, dichloromethane, dimethylformamide and mixtures of these solvents. When in the course of the reaction the acid, as in the case of use in the reaction of sulphonylchloride, the reaction is preferably carried out in the presence of K the other basic solvents. When using a neutral solvent, to the reaction system, you can add the carbonate of an alkali metal, an organic tertiary amine or other base material. Solvents that can be used in this case are not limited to the above. The reaction usually proceeds at room temperature, but the reaction system optionally cooling or heating. The reaction time can optionally be selected depending on the types of compounds and the reaction temperature, and it is usually from 10 minutes to 20 hours.

When the amino group or hydroxyl group of the obtained product is protected, you can get sulfonamidnuyu derivative (VII), having a free hydroxyl group, or amino group, subjecting the product to the action of acid, base, catalyst recovery, and other conventional procedures remove protection, in accordance with need.

2) When Z is-CO-NH-

where in the formula, L represents a chlorine atom or a bromine atom;

R17represents C1-C4 alkyl group or benzyl group;

A, b, T, U, V, W, X and T have the same meanings defined above.

The whole is lianmeng connection represented by formula (IX).

The reaction is usually carried out in water or miscible with water inert solvent such as tetrahydrofuran, and acetone, in the presence of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide and sodium hydride. The reaction is carried out at a temperature from 0 to 100°C, preferably from about 20 to 30°C.

Alternative target compound is obtained by the method in which a sulfonamide represented by the formula (IX), interacts and halogenfree represented by the formula (XIII), with carbamate represented by the formula (XII), and the obtained carbamate provide an opportunity to interact with the amine represented by the formula (XI).

The reaction between the sulfonamide represented by the formula (IX), and halogenfree represented by the formula (XIII) is carried out in an inert solvent, such as acetone, tetrahydrofuran and methyl ethyl ketone, in the presence of an acid binding agent such as potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide. The reaction temperature can vary from about 30°C to the boiling point of phlegmy. Subsequently carry out the reaction between carbamato the high boiling point, such as dioxane, toluene, diglyme, at temperatures ranging from about 50°C to the boiling point of phlegmy.

The amino compounds represented by formula (VI) or (XI) represent the initial substance for the sulfonamide or sulfonilmocevinnah heterocyclic compounds of the present invention and can be obtained by using combinations of conventional methods.

For example, quinoline and isoquinoline derivatives can be obtained in accordance with the following methods retrieve.

where in formulas A, E2, G2and R16have the same meanings defined above, and R18represents C1-C4 alkyl group or benzyl group.

where in formulas a and G2have the same meanings defined above.

where in the formula, R18has the same meaning as defined above, and R19represents C1-C4 alkyl group.

where in the formula, R18and E2have the same meaning as defined above; R20and R21each represents a hydrogen atom or a C1-C4 alkyl group; R22represents C1-C4 alkoxygroup, optional substituted the two C1-C4 alkyl groups, and E3represents a hydrogen atom, halogen atom, C1-C4 alkoxygroup, optionally substituted fenoxaprop or phenyl group, cyano or amino group which may be substituted by one or two C1-C4 alkyl groups.

When the compounds of the present invention are used as pharmaceutical drugs, they are administered to a patient orally or parenterally. The dose varies depending on the severity of symptoms, age, sex, weight and sensitivity of the patient, the route of administration of the drug, duration of injection, the interval between the introduction, characteristics, dosing and type of the obtained pharmaceutical preparation, the type of active ingredient and so on, it is not specifically limited. The dose is usually from 10 to 6000 mg, preferably from about 50 to 4000 mg, and more preferably from 100 to 3000 mg per day for an adult. The drug is administered to the patient from one to three times a day.

For the manufacture of solid preparations for oral administration fillers and, if necessary, other additives such as binding agents, disintegrating agents, lubricating agents, dyes and corrigentov add to base Noli, powders, capsules, etc. in accordance with the usual method.

These fillers include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide. Binding agents include, for example, polyvinyl alcohol, ethylcellulose, methylcellulose, Arabian gum, hydroxypropylcellulose and hypromellose. Lubricating agents include magnesium stearate, talc and silicon dioxide. Dyes include dyes approved for use in pharmaceutical drugs. The corrigentov include cocoa powder, menthol, aromatic powder, peppermint oil, borneol and powdered bark of the cinnamon tree. These tablets and granules can be coated with sugar, gelatin or other covering materials.

For the manufacture of drugs for injection using additives, such as agents, correcting pH (buffers). Basic feature add suspendresume agents, solubilizing agents, stabilizers, agents, giving isotonicity, and preservatives, and the resulting mixture is made preparations for intravenous injection, subcutaneous injection or intramuscular injection, in LASS="ptx2">These suspendresume agents include methylcellulose, Polysorbate 80, hydroxyethyl cellulose, Arabic gum, powdered tragakant, sodium carboxymethyl cellulose and monolaurin of polyoxyethylenesorbitan.

Solubilizing agents include polyoxyethylene, hydrogenated castor oil, Polysorbate 80, nicotinamide, monolaurin of polyoxyethylenesorbitan, macrogol and ethyl esters of fatty acids of castor oil.

Stabilizers include sodium sulfite and metasulfite sodium, and preservatives include, for example, methyl-para-hydroxybenzoate, ethyl-para-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.

The action of the compounds according to the present invention will be illustrated below in pharmacological experimental example.

Pharmacological experimental example.

Antiangiogenic action

The degree of inhibition of angiogenesis observed during the incubation of slices of rat aorta in the collagen was determined as antiangiogenic action. That is, the aorta taken from male rat line Sprague-Dawley (aged 10-12 weeks), washed with Hanks solution so that its surrounding adipose tissue was carefully removed. The aorta on, click 500 μl of neutralized collagen type I (Cell Matrix Type I-A; production company Nitta Gelatin) was poured into each cell and for curing gel was left to stand for approximately 20 minutes at room temperature on your desktop for aseptic manufacturing of medicines. After confirming the solidification of the gel was added 500 μl of medium MCDB 131 (production company Chlorella Kogyo), and then incubated in thermostat CO2(5% CO2) at 37°C. the next day the culture medium was replaced with 500 μl of medium MCDB 131 containing the test compound, and the incubation continued. After three days the medium was again replaced with 500 μl of medium MCDB 131 containing the test compound, and at the stage of the 7th day after the start of addition of the test compounds were counted under the microscope the number of capillaries formed around the aorta. The solution containing the test compound, produced according to the system of three-fold dilutions, in which 10 μg/ml was the highest concentration.

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

The degree of inhibition (%) = (s-T)x100,

With the number of capillaries, when the connection is not maintained "examples get", illustrating the receipt of the starting compounds for the compounds of the present invention, and the examples of typical representatives of the compounds of the present invention. However, the examples are not intended to limit the scope of the present invention.

Example a 1: 2-amino-5-bronchioles

After sufficient for 1 minute, stirring, 2-bromo-6-nitrobenzaldehyde (30,4 g), magnesium oxide (75 g) and dimethyl sulfoxide (11.3 ml) was added diethyl(cyanomethyl)phosphonate (25,8 ml) and the mixture was stirred for another 2 hours. After mixing, the mixture was left to stand over night. Then added ethyl acetate, and the mixture was stirred and then filtered. The filtrate was concentrated and the residue was purified column chromatography on silica gel (ethyl acetate) to obtain 32 g of 3-(2-bromo-6-nitrophenyl)-2-propenenitrile (E-isomer Z-isomer=3:1).

1H-NMR (CDCl3) (M. D.): 5,63 (d, J=16.5 Hz, E isomer 1H), of 5.81 (d, J=10,8 Hz, Z-isomer 1H), 7,42-7,52 (m, E-isomer 1H, Z isomer 2H), 7,56 (d, J=16.5 Hz, E isomer 1H), of 7.90-8,16 (m, E-2H isomer, Z-isomer 2N).

Then ethanol (250 ml), tin (60 g) and distilled water (150 ml) was added to 32 g of 3-(2-bromo-6-nitrophenyl)-2-propenenitrile (E-isomer Z-isomer=3:1), the resulting mixture Negril) and stirred at 90°C for 3 hours. After cooling to room temperature decantation of the liquid layer, and cooled to 0°C. the Obtained solid was filtered, diluted aqueous solution of ammonia and was extracted with ethyl acetate. The extract was concentrated and the residue was purified column chromatography on silica gel (ethyl acetate) to obtain 5.0 g specified in the connection header.

1H-NMR (CDCl3) (M. D.): 4,88 (2N, W), 6,79 (1H, d, J=9.3 Hz), 7,39 (1H, t, J=8,9 Hz), 7,51 (1H, d, J=8,9 Hz), to 7.61 (1H, d, J=8,9 Hz), of 8.27 (1H, d, J=9,3 Hz).

Example of getting a 2: 2-amino-5-chlorhydrin

Specified in the title compound was obtained from 2-chloro-6-nitrobenzaldehyde according to the similar method of the example of obtaining 1.

1H-NMR (CDCl3) (M. D.): the 5.25 (2H, W), to 6.80 (1H, d, J=9.7 Hz), 7,32 (1H, DD, J=7.5 Hz, 1.5 Hz), 7,46 (1H, t, J=7.5 Hz), EUR 7.57 (1H, m), 8,30 (1H, d, J=9.7 Hz).

An example of obtaining 3: 3 carbethoxy-4-hydroxy-8-bronchioles

A mixture of 50 g (0,291 mol) 2-bromoaniline and 63 g (0,291 mol) of diethylethoxymethylenemalonate was heated at 100°C under reduced pressure for 3 hours, then was heated at 200°C for another 12 hours. Upon completion of the reaction, the solid in the reaction mixture was washed with ethyl acetate, the crystals were filtered and dried to obtain the,2 Hz), 7,34 (1H, t, J=7,6 Hz), 8,03 (1H, DD, J=1.6 Hz and 7.6 Hz), 8,15 (1H, DD, J=1.6 Hz and 7.6 Hz), 8,43 (1H, s), to 11.56 (1H, s).

Example 4: 3-carbethoxy-8-bronchioles

A mixture of 2.5 g (8.4 mmol) of 3-carbethoxy-4-hydroxy-8-brainline and 10 ml of phosphorus oxychloride was heated at the boil under reflux for 1 hour. Upon completion of the reaction of phosphorus oxychloride was removed, the residue was purified with NH-silica gel to obtain 2.6 g of the chlorinated derivative. Then 500 mg (1.6 mmol) of chlorinated derivative was dissolved in 20 ml of dioxane was added 1 g of powdered zinc and 3 ml of acetic acid, then heated at 65°C for 30 minutes. To the reaction mixture were added ethyl acetate and then filtered through celite. The filtrate was washed with saturated salt solution, dried over magnesium sulfate and concentrated. To the residue was added 1 ml of acetic acid and the mixture was left to stand for 12 hours. Then acetic acid was removed, the residue was subjected to column chromatography on silica gel and was suirable eluent (ethyl acetate : n-hexane=1:7) to obtain 180 mg specified in the connection header.

1H-NMR (CDCl3) (M. D.): to 1.47 (3H, t, J=7.2 Hz), 4,50 (1H, q, J=7.2 Hz), to 7.50 (1H, d, J=7,6 Hz), to 7.93 (1H, DD, J=1.2 Hz and 7.6 Hz), 8,18 (1H, DD, J=1.2 Hz and 7.6 Hz), cent to 8.85 (1H, d, J=2 Hz), 9.5 NaOH solution (10 ml) was added 500 mg (1.8 mmol) 3 carbethoxy-8-brainline, then was stirred at room temperature for 3 hours. The ethanol was removed and the residue was neutralized 1 N. Hcl. The obtained solid was filtered, washed with water and dried to obtain 450 mg of the carboxylic acid. Then 450 mg (1.8 mmol) of carboxylic acid was added to 25 ml of tert-butanol was then added more of 0.58 ml (2.7 mmol) of DPPA and 0.37 ml (2.7 mmol) of triethylamine was heated at the boil under reflux for 12 hours. The reaction mixture was concentrated, the residue was subjected to column chromatography on silica gel and was suirable eluent (ethyl acetate : n-hexane=1:4) to obtain 352 mg amide derivative. Then 350 mg (1.1 mmol) of the amide derivative was added to a mixture of 4 ml of methanol and 2 ml of concentrated Hcl, then stirred at room temperature for 1 hour. The reaction mixture was podslushivaet the addition of an aqueous ammonia solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated to obtain 240 mg specified in the connection header.

1H-NMR (DMSO-d6) (M. D.): 5,88 (2H, s), 7,13 (1H, d, J=2,8 Hz), 7,24 (1H, DD, J=7,6 Hz and 8.4 Hz), to 7.59-the 7.65 (2H, m), 8,49 (1H, d, J=2,8 Hz).

An example of obtaining 6: 3-amino-8-eothinon

1H-NMR (DMSO-d3) (M. D.): to 5.85 (2H, s), 7,07 (1H, d, J=2,8 Hz), 7,10 (1H, DD, J=1.2 Hz and 7.6 Hz), a 7.62 (1H, DD, J=1.2 Hz and 7.6 Hz), of 7.90 (1H, DD, J=1.2 Hz and 7.6 Hz), to 8.45 (1H, d, J=2,8 Hz).

Example of getting a 7: 3-amino-8-cyanohydrin

Specified in the title compound was obtained from 2-cyanoaniline similar to the method of examples getting 3-5.

1H-NMR (DMSO-d6) (M. D.): 6,03 (2H, Shir.C), 7,22 (1H, d, J=2,8 Hz), of 7.48 (1H, DD, J=7,2 Hz and 8.4 Hz), to 7.84 (1H, DD, J=1.2 Hz, 8,4 Hz), 7,94 (1H, DD, J=1.2 Hz, 8,4 Hz), to 8.57 (1H, d, J=2,8 Hz).

An example of obtaining 8: 3-amino-8-(methylsulphonyl)quinoline

Specified in the title compound was obtained according to a similar method examples get 3-5.

1H-NMR (DMSO-d6) (M. D.): 6,00 (2H, s), 7,26 (1H, d, J=2.4 Hz), 7,53 (1H, t, J=7.2 Hz), to $ 7.91 (1H, DD, J=1.6 Hz, 7.2 Hz), of 7.96 (1H, DD, J=1.2 Hz, 8,4 Hz), 8,58 (1H, d, J=2,8 Hz).

Example of getting a 9: 3-amino-8-chlorhydrin

Specified in the title compound was obtained according to a similar method examples get 3-5.

1H-NMR (DMSO-d6) (M. D.): 5,90 (2H, s), 7,17 (1H, d, J=2,8 Hz), 7,33 (1H, t, J=7,6 Hz), 7,46 (1H, d, J=7,6 Hz), 7,58 (1H, d, J=7,6 Hz), charged 8.52 (1H, d, J=2,8 Hz).

Example 10: 3-amino-8-trifloromethyl

Specified in the title compound was obtained according to a similar method of Prim is,6 Hz), to $ 7.91 (1H, d, J=7,6 Hz), 8,55 (1H, d, J=2,8 Hz).

An example of obtaining 11: ethyl-8-chloro-4-vinylphenol-3-carboxylate

To a solution of 2.0 g (7.4 mmol) of ethyl-4,8-dichlorohydrin-3-carboxylate, obtained according to a similar method of example 4 in toluene (20 ml) was added tributyltinhydride (2.8 ml) and tetrakis(triphenylphosphine)palladium (171 mg), then stirred for 2 hours while boiling under reflux. The reaction mixture was filtered through celite and concentrated. Then the residue was purified column chromatography on silica gel to obtain 1.92 g specified in the connection header.

1H-NMR (DMSO-d6) (M. D.): of 1.36 (3H, t, J=7,6 Hz), 4,37 (2H, d, J=7,6 Hz), 5,52 (1H, d, J=18,0 Hz), to 5.58 (1H, d, J=16.4 Hz), 7,40 (1H, DD, J=16.4 Hz and 18.0 Hz), of 7.70 (1H, t, J=8.0 Hz), 8,11 (1H, d, J=8.0 Hz), of 8.25 (1H, d, J=8.0 Hz), 9,24 (1H, s).

Example 12: 3-amino-8-chloro-4-vinylphenol

Specified in the title compound was obtained from 4-vinyl-8-chlorhydrin-3-carboxylate by the same procedure of example receipt 5.

1H-NMR (DMSO-d6) (M. D.): 5,69 (1H, DD, J=1.6 Hz and 18.0 Hz), of 5.81 (2H, s), of 5.84 (1H, DD, J=1,6 Hz and 11.6 Hz), 6,91 (1H, DD, J=11,6 Hz and 18.0 Hz), 7,38 (1H, t, J=8.0 Hz), 7,52 (1H, DD, J=1.2 Hz, 8.0 Hz), the 7.85 (1H, DD, J=1.2 Hz, 8.0 Hz), at 8.60 (1H, s).

An example of obtaining 13: ethyl-7-amino-2-chlorhydrin-eremetical at 160°C for 1 hour. After cooling, the crystals were washed with methanol. To a solution of the crystals (3.0 g, 13 mmol) in chloroform (30 ml) was added phosphorus oxychloride (3.6 ml), then heated at the boil under reflux for 1 hour. After cooling, the reaction mixture was poured into ice water, podslushivaet 1 N. aqueous sodium hydroxide solution and the resulting crystals were filtered off. The crystals were washed with tetrahydrofuran and the filtrate evaporated to obtain 4,85 g specified in the connection header.

1H-NMR (DMSO-d6) (M. D.): of 1.31-1.42 (3H, m), 4,34-to 4.46 (2H, m), 6,92 (1H, d, J=2.4 Hz), 7,12 (1H, DD, J=2,4 Hz and 9.2 Hz), 7,40 (1H, s), 8,21 (1H, d, J=9,2 Hz).

Example of getting a 14: 2 benzylthio-4-methoxypyridazine

In dimethyl sulfoxide (30 ml) suspended 843 mg (21 mmol, 55% in oil) of sodium hydroxide was added 2.0 ml (16,7 mol) benzylmercaptan under ice cooling, and then stirred for 10 minutes. To the reaction mixture were added 2.5 g (17.6 mmol) of 4-methoxy-2-chloropyridazine, then stirred at room temperature overnight. To the reaction mixture was added aqueous saturated ammonium chloride, then extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated the connection.

1H-NMR (DMSO-d6) (M. D.): 3,98 (3H, s), 4,48 (2H, s), 7,12 (1H, d, J=8,8 Hz), 7,22-7,26 (1H, m), 7,29-7,37 (2H, m), 7,41-7,44 (2H, m), EUR 7.57 (1H, d, J=8,8 Hz).

An example of obtaining 15: 2-benzylthio-4-carboxamidine

To 25 mg (159 mmol) of 2-chlorisondamine acid was added thionyl chloride (120 ml), then was stirred for 3 hours at boiling under reflux. After cooling, the reaction mixture is evaporated to obtain a residue. A solution of the residue in tetrahydrofuran (200 ml) was poured into a mixed solution of saturated aqueous solution of ammonia (200 ml) and a solution of tetrahydrofuran (200 ml) under cooling with ice. After stirring for 15 minutes under ice cooling, the mixture is evaporated, the obtained crystals were filtered and washed with water to receive and 22.6 g of white crystals. To a solution 5,13 g (32 mmol) of the obtained white crystals in dimethylformamide (70 ml) was added to 4.2 ml (36 mmol) of benzyltoluene and 10 g (77 mmol) of potassium carbonate, and then was stirred for 3 hours at boiling under reflux. To the reaction mixture were added water and then extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated. Then the rest of acidulant connection.

1H-NMR (DMSO-d6) (M. D.): to 4.46 (2H, s), 7,22-7,33 (3H, m), 7,41 (2H, d, J=7,2 Hz), 7,49 (1H, DD, J=1,6 Hz, 5.2 Hz), to 7.67 (1H, s), 7,73 (1H, s), 8,21 (1H, s), 8,58 (1H, d, J=5,2 Hz).

Example 16: 7-amino-2-chloro-4-methylinosine

To 27 g (251 mmol) of m-phenylenediamine was added 32 g (251 mmol) of ethylacetoacetate, then stirred at 200°C for 1 hour. After cooling, the crystals were washed with hexane. To 9.5 g (54 mmol) of the crystals was added 15 ml of phosphorus oxychloride and then heated at the boil under reflux for 2 hours. After cooling, the reaction mixture was poured into ice water and was podslushivaet saturated aqueous ammonia. The obtained crystals were filtered and washed with water. The crystals were washed with methanol and the filtrate evaporated to obtain 4,85 g specified in the connection header.

1H-NMR (DMSO-d6) (M. D.): 3,18 (3H, s), 5,95 (2H, s), PC 6.82 (1H, d, J=2.4 Hz), 6,98 (1H, s), 7,01 (1H, DD, J=2,4 Hz and 8.8 Hz), 7,76 (1H, d, J=8,8 Hz).

An example of obtaining 17: 3,4-dihydroisoquinoline

To a solution of 26,67 g (0.2 mol) of 1,2,3,4-tetrahydroisoquinoline in methylene chloride (300 ml) was added N-bromosuccinimide (39,2 g) under ice cooling for 20 minutes. After stirring for 40 minutes to the reaction mixture were added 30% aqueous what slotow (200 ml) and the aqueous layer washed with methylene chloride. The aqueous layer was podslushivaet aqueous ammonia solution was extracted with methylene chloride. The extract was dried over magnesium sulfate and then evaporated. The obtained residue person to distil (about 16 mm RT.art., 120°C) obtaining a 21.5 g specified in the connection header in the form of oil.

1H-NMR (DMSO-d6) (M. D.): to 2.66 (2H, t, J=8 Hz), 3,62 (2H, dt, J=2 Hz, 8 Hz), 7,19-7,21 (1H, m), 7,29-7,33 (1H, m), 7,35-7,40 (1H, m), 8,31 (1H, t, J=2 Hz).

An example of obtaining 18: 7-nitroisoquinoline

To concentrated sulfuric acid (70 ml) was added 15 g of potassium nitrate was then added a solution of 18 g (0.14 mol) of 3,4-dihydroisoquinoline in concentrated sulfuric acid (70 ml) at -15°C for 20 minutes. After stirring at room temperature for 1 hour the mixture was heated at 60°C for 40 minutes. The reaction mixture was poured into ice water, and then gave her the basicity of an aqueous solution of ammonia and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated. To the residue was added decalin (100 ml), nitrobenzene (100 ml) and palladium black (2 g), then heated at 200°C in a stream of nitrogen overnight. The reaction mixture was washed with ethyl acetate and was extracted with 2 N. chlorite who I am. The obtained precipitation was filtered and washed with water to obtain 14.4 g specified in the connection header.

1H-NMR(CDCl3) (M. D.): 7,79 (1H, d, J=5.6 Hz), 8,00 (1H, d, J=9,2 Hz), 8,48 (1H, DD, J=2,4 Hz and 9.2 Hz), the rate of 8.75 (1H, d, J=5.6 Hz), 8,96 (1H, d, J=2 Hz), 9,48 (1H, s).

An example of obtaining 19: 4-bromo-7-nitroisoquinoline

To 1.6 g (9,19 mmol) 7-nitroquinoline was added 1.2 ml of aqueous Hydrobromic acid and 3 ml of bromine, and then was heated at 180°C for 5.5 hours. The reaction mixture was extracted with ethyl acetate, the extract was washed successively with an aqueous solution of sodium hydroxide, aqueous sodium thiosulfate solution and saturated salt solution, dried over magnesium sulfate and concentrated. Then the obtained residue was purified column chromatography on silica gel (elution hexane : ethyl acetate=1:4) to obtain 500 mg specified in the connection header.

1H-NMR(CDCl3) (M. D.): at 8.36 (1H, d, J=9,2 Hz), 8,58 (1H, d, J=2,4 Hz and 9.2 Hz), 8,93 (1H, s), 8,96 (1H, d, J=3.2 Hz), 9,38 (1H, s).

An example of obtaining 20: 7-amino-4-bromoisoquinoline

In 1 ml of ethanol, 2 ml of tetrahydrofuran and 1 ml of water was dissolved 66 mg (0.26 mmol) of 7-nitro-4-bromoisoquinoline and added 70 mg of iron powder and 140 mg of ammonium chloride, then was heated at 50°With what formom. The organic layer was dried over magnesium sulfate and concentrated. Then the obtained residue was led from isopropyl ether to obtain 33 mg specified in the connection header.

1H-NMR (DSMO-d6) (M. D.): 5,98 (2H, s), 6,97 (1H, d, J=2.4 Hz), 7,31 (1H, DD, J=2,4 Hz and 8.8 Hz), of 8.28 (1H, s) 8,89 (1H, s).

An example of obtaining 21: 6-(4-toluensulfonyl)isoquinoline

In pyridine (30 ml) was dissolved 6-aminoisoquinoline (3,348 g, Synthesis, 733 (1975)) was added 4-toluensulfonate (5,13 g), then stirred at room temperature overnight. Added water and then extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was recrystallized from ethanol to obtain specified in the connection header (5,958 g, 85%) as crystals pale yellow color.

1H-NMR (DMSO-d6) (M. D.): 2,28 (3H, s), 7,32 (2H, d, J=8,2 Hz), 7,40 (1H, DD, J=1,6 Hz and 9.2 Hz), 7,55 (1H, Shir.C) to 7.67 (1H, d, J=5.6 Hz), 7,74 (2H, d, J=8,2 Hz), of 7.97 (1H, d, J=9,2 Hz), at 8.36 (1H, d, J=5.6 Hz), 9,10 (1H, s).

Example of getting a 22: 1-chloro-6-(4-toluensulfonyl)isoquinoline

In chloroform (100 ml) was dissolved 3.0 g of 6-(4-toluensulfonyl)isoquinoline (example obtain 21) and was added m night. The solvent is evaporated, the obtained crystals were washed with diethyl ether, filtered and dried to obtain crystals of pale yellow color. The obtained crystals suspended in chloroform (83 ml) was added phosphorus oxychloride (19 ml) and then heated at the boil under reflux for 5 hours. After cooling, the solvent evaporated and the residue was podslushivaet aqueous sodium bicarbonate in a water bath, then was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified on a column of silica gel to obtain crude crystals specified in the connection header (1,630 g, 49,40%). The crude crystals are recrystallized from ethanol to obtain specified in the title compounds as colorless crystals.

1H-NMR (DMSO-d6) (M. D.): to 2.29 (3H, s), 7,34 (2H, d, J=8.0 Hz), 7,52 (1H, DD, J=2.0 Hz, 9.0 Hz), the 7.65 (1H, d, J=2.0 Hz), 7,76 (1H, d, J=5.6 Hz), to 7.77 (2H, d, J=8.0 Hz), 8,14 (1H, d, J=9.0 Hz), 8,16 (1H, d, J=5.6 Hz).

An example of retrieving 23: 6-amino-1-chloroisoquinoline

In sulfuric acid (30 ml) was dissolved 3,323 g of 1-chloro-6-(4-toluensulfonyl)isoquinoline (example getting 22), then stirred at room is droxia sodium and then potassium carbonate and was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated to obtain specified in the connection header (1,37 g, 76,81%) in the form of crystals of yellowish-brown color.

1H-NMR (DMSO-d6) (M. D.): 6,23 (2H, Shir.C) 6,76 (1H, s), to 7.09 (1H, d, J=9.6 Hz), 7,37 (1H, d, J=6.4 Hz), 7,89 (1H, d, J=9.6 Hz), of 7.90 (1H, d, J=6,4 Hz).

An example of obtaining 24: 2-chloro-1,6-naphthylidine

In phosphorus oxychloride (19 ml) was dissolved 1.0 g of 1, 6-naphthiridine-2-it (J. Org. Chem., 4744 (1990)), then was heated at boiling under reflux at 120°C for 2 hours. After cooling, the solvent evaporated, the residue was podslushivaet water and potassium carbonate, and then the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated to obtain specified in the connection header (0,658 g, 58,45%) as orange crystals.

1H-NMR (CDCl3) (M. D.): at 7.55 (1H, d, J=8,8 Hz), 7,86 (1H, d, J=6.0 Hz), of 8.28 (1H, DD, J=8,8 Hz), 8,80 (1H, d, J=6.0 Hz), 9,29 (1H, s).

An example of obtaining 25: 2-amino-1,6-naphthylidine

In a sealed tube, 2-chloro-1,6-naphthylidine (0,628 g, an example of obtaining 24) and aqueous ammonia (40 ml) was heated at 130&asystem salt solution, was dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified on a column of silica gel with obtaining specified in the connection header (0,497 g, 89,73%) in the form of crystals of pale yellow color.

1H-NMR (DMSO-d6) (M. D.): for 6.81 (1H, d, J=8,8 Hz), 7,24 (1H, d, J=5.8 Hz), of 7.97 (1H, d, J=8,8 Hz), a 8.34 (1H, d, J=5.8 Hz), 8,80 (1H, s).

An example of obtaining 26: N-(3-nitratomethyl)phthalimide

In tetrahydrofuran (225 ml) was dissolved 15 g of 3-nitroacetanilide alcohol, then added triphenylphosphine (26 g) and phthalimide (13,9 g). Then the mixture was cooled with ice and then was added dropwise diethylazodicarboxylate (15,5 ml). After stirring at room temperature for 1 hour the resulting crystals were filtered off, washed with diethyl ether and dried to obtain N-(3-nitratomethyl)phthalimide in the form of colorless crystals.

1H-NMR (CDCl3) (M. D.): of 3.12 (2H, t, J=7.4 Hz), 3,98 (2H, t, J=7.4 Hz), 7,47 (1H, DD, J=8.0 Hz, 8.0 Hz), 7,60 (1H, d, J=8.0 Hz), 7,72 (2H, m), 7,83 (2H, m), of 8.09 (1H, d, J=8.0 Hz), to 8.12 (1H, s).

Example obtain 27: 3-nitroacetanilide

In ethanol (150 ml) was added N-(3-nitratomethyl)phthalimide received in the sample receiving 26. To the mixture was added hydrazine (5.7 ml), then was heated at boiling is whether to precipitate crystals. The crystals were filtered and washed with chilled ethanol. The solvent is then evaporated to obtain specified in the connection header (5,559 g, 99%) as a yellow oil.

1H-NMR (CDCl3) (M. D.): 2,87 (2H, t, J=6.8 Hz), totaling 3.04 (2H, t, J=6.8 Hz), of 7.48 (1H, DD, J=7,6 Hz and 8.4 Hz), 7,55 (1H, DDD, J=1.2 Hz, 1.6 Hz and 7.6 Hz), 8,08 (2H, m).

An example of retrieving 28: N-acetyl-N-(3-nitratomethyl)Amin

In pyridine (33 ml) was dissolved 5,559 g 3-nitroacetanilide (example receiving 27), then was added dropwise acetylchloride (2.5 ml) under cooling with ice. After stirring at room temperature for 0.5 hours, the mixture was again cooled with ice. Added water and then extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated to obtain specified in the connection header (6,323 g, 91%) as a yellow oil.

1H-NMR (CDCl3) (M. D.): 1,97 (3H, s), 2,95 (2H, t, J=7.0 Hz), 3,55 (2H, dt, J=6.0 Hz, 7.0 Hz), the ceiling of 5.60 (1H, Shir.C), 7,49 (1H, DD, J=7,2 Hz, 8.0 Hz), 7,55 (1H, d, J=7,2 Hz), 8,07 (1H, s) to 8.12 (1H, d, J=8.0 Hz).

An example of obtaining 29: N-acetyl-N-(3-aminoethoxyethanol)Amin

In ethanol (40 ml) was added 2.1 g of N-acetyl-N-(3-nitratomethyl)amine (example receiving 28), seriatim refrigerator for 1.5 hours. The solid material was filtered, washed with ethanol and a portion of the filtrate is evaporated. The residue was extracted with ethyl acetate, washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated to obtain specified in the connection header (1,723 g, 96%) as a yellow oil.

1H-NMR (CDCl3) (M. D.): 1,94 (3H, s), of 2.72 (2H, t, J=6.8 Hz), 3,50 (2H, dt, J=6.0 Hz, 6.8 Hz), 6,53 (1H, s), to 6.57 (1H, d, J=8.0 Hz), 6,59 (1H, d, J=7,2 Hz), 7,10 (1H, DD, J=7,2 Hz, 8.0 Hz).

Example 30: N-acetyl-N-(3-ethoxycarbonylmethoxy)Amin

In pyridine (5 ml) was dissolved 1.7 g of N-acetyl-N-(3-aminoethoxyethanol)amine (example receiving 29), then was added dropwise ethylchloride (1,4 ml) under cooling with ice. After stirring at room temperature for 1 hour the mixture was again cooled with ice. Added water, then was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated to obtain specified in the connection header (2,358 g, 97%) as a yellow oil.

1H-NMR (CDCl3) (M. D.): of 1.29 (3H, t, J=7.2 Hz), of 1.93 (3H, s), was 2.76 (2H, t, J=7.0 Hz), 3,47 (2H, dt, J=6.0 Hz, 7.0 Hz), 4,20 (2H, q, J=7.2 Hz), to 5.57 (1H, Shir.C) 6,86 (1H, d, J=7,2 Hz), 7,21 (1H, DD, J=7,2 Olin

Using 1.0 g of N-acetyl-N-(3-ethoxycarbonylmethoxy)amine (example 30) was carrying out the cyclization reaction according to the method described in Heterocycles 31(2), 341 (1990). After the specified reaction, the reaction mixture was poured on ice, the mixture was podslushivaet potassium carbonate and was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated to obtain specified in the connection header in the form of a brown oil.

1H-NMR (CDCl3) (M. D.): to 1.19 (3H, t, J=7.2 Hz), of 2.23 (3H, s), 2,60 (1H, t, J=7.4 Hz), 3,55 (2H, t, J=7.4 Hz), of 4.13 (2H, q, J=7.2 Hz), 7,31 (1H, d, J=6.8 Hz), 7,32 (1H, s), 7,34 (1H, d, J=6,8 Hz).

An example of obtaining 32: 6 ethoxycarbonyl-1-methylisoquinoline

At 6-ethoxycarbonyl-1-methyl-3,4-dihydroisoquinoline was added p-cYmen (100 ml) and palladium on coal (0.9 g), then heated under stirring at 195°C in nitrogen atmosphere for 1 hour. After filtering off the catalyst, the reaction mixture was washed with ethanol and a portion of the filtrate is evaporated. The residue was extracted with 1 N. hydrochloric acid, then was podslushivaet potassium carbonate and was extracted with ethyl acetate. The extract was washed with a saturated solution from which inania (0,629 g, 69%, stage 2) in the form of crystals of pale yellow color.

1H-NMR(CDCl3) (M. D.): of 1.30 (3H, t, J=7.2 Hz), 2,89 (3H, s), 4.26 deaths (1H, q, J=7.2 Hz), 7,40 (1H, d, J=5.8 Hz), 7,56 (1H, DD, J=1,6 Hz and 8.8 Hz), to 7.99 (1H, d, J=8,8 Hz), with 8.05 (1H, d, J=1.6 Hz), 8,30 (1H, d, J=5.6 Hz), of 8.37 (1H, s).

An example of obtaining 33: 6-amino-1-methylisoquinoline

In ethanol (20 ml) suspended 0,629 g 6 ethoxycarbonyl-1-methylisoquinoline (example obtain 32) and 8 N. aqueous sodium hydroxide solution (6.8 ml), then heated at the boil under reflux for 1.5 hours. After cooling to room temperature was added a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated to obtain specified in the connection header (0,311 g, 72%) as crystals pale yellow color.

1H-NMR (CDCl3) (M. D.): 2,81 (3H, s), 4,24 (2H, Shir.C) 6,60 (1H, d, J=2.0 Hz), 6,91 (1H, DDD, J=1,6 Hz, 2.0 Hz and 8.8 Hz), 7,18 (1H, d, J=5.6 Hz), to 7.84 (1H, d, J=8,8 Hz), 8,16 (1H, DD, J=1.6 Hz, 5.6 Hz).

An example of retrieving 34: N-tert-butoxycarbonyl-3-nitroacetanilide

In tetrahydrofuran (130 ml) was dissolved 4,559 g 3-nitroacetanilide (example receiving 27) and added to tritium oritel evaporated, to the residue was added a saturated salt solution and then was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated to obtain specified in the connection header (8,789 g, including impurities) in the form of a yellow oil. The specified product was used in subsequent reactions without further purification.

1H-NMR (CDCl3) (M. D.): 1,53 (N, C) of 2.92 (2H, t, J=7,6 Hz), 3,42 (2H, dt, J=6,4 Hz, 6.8 Hz), 4,58 (1H, Shir.C) of 7.48 (1H, DD, J=7,2 Hz, 8.0 Hz), 7,54 (1H, d, J=8.0 Hz), 8,07 (1H, s), 8,10 (1H, d, J=7,2 Hz).

An example of obtaining 35: 3-(2-tert-butoxycarbonylamino)aniline

Using N-tert-butoxycarbonyl-3-nitroacetanilide (8,789 g, including impurities, the sample receiving 34) specified in the header connection (5,521 g, 76%) was obtained as yellow oil by the same method of example obtaining 17.

1H-NMR (CDCl3) (M. D.): 1,44 (N, C) 2,70 (3H, t, J=7.4 Hz), to 3.36 (2H, Shir.kV) of 4.54 (1H, Shir.C) is 6.54 (1H, s), to 6.57 (1H, d, J=8.0 Hz), 6,60 (1H, d, J=7,2 Hz), 8,10 (1H, DD, J=7,2 Hz, 8.0 Hz).

An example of retrieving 36: 3-(2-tert-butoxycarbonylamino)ethoxycarbonylmethyl

Using 3-(2-tert-butoxycarbonylamino)aniline (5,521 g, an example of obtaining 35) specified in the Specified product was used in subsequent reactions without further purification.

1H-NMR (CDCl3) (M. D.): is 1.31 (3H, t, J=7.2 Hz), 1,43 (N, C) 2,77 (2H, t, J=7.4 Hz), to 3.67 (2H, Shir.kV), 4,22 (2H, q, J=7.4 Hz), 4,55 (1H, Shir.C) of 6.52 (1H, Shir.C) 6,89 (1H, m), 7,24 (1H, m).

An example of retrieving 37: hydrochloride 3-ethoxycarbonylmethylene

In ethanol (15 ml) was dissolved 14,96 g 3-(2-tert-butoxycarbonylamino)ethoxycarbonylmethyl (example receive 36). Under ice cooling was added hydrochloric acid (15 ml), then stirred at room temperature for 20 minutes. Again was added hydrochloric acid (12 ml) and ethanol (15 ml) and then stirred at room temperature for 20 minutes. Then again, was added hydrochloric acid (20 ml) and ethanol (30 ml) and then stirred at room temperature for 30 minutes. The solvent is evaporated (azeotropic distillation with toluene) to obtain specified in the connection header (11,99 g) in the form of crystals of pale yellow color.

1H-NMR (DMSO6) (M. D.): 1,22 (3H, t, J=7.2 Hz), 2,82 (2H, m), 2,95 (2H, m), 4,10 (2H, q, J=7.2 Hz), 6,86 (1H, d, J=7,6 Hz), 7,20 (1H, DD, J=7,6 Hz and 8.4 Hz), 7,31 (1H, d, J=8,4 Hz), was 7.36 (1H, s), with 8.05 (2H, s), being 9.61 (1H, s).

An example of retrieving 38: 6-amino-ethyl-1,2, 3, 4-tetrahydroisoquinoline

Specified in the header ull., 42(8), 1676 (1994), except that used hydrochloride 3-ethoxycarbonylmethylene (4.7 g) obtained in example receiving 37.

1H-NMR (CDCl3) (M. D.): of 1.29 (3H, t, J=7.2 Hz), 2,68 (1H, Shir.C), and 2.83 (3H, m), of 3.73 (2H, m), 4,20 (1H, q, J=7.2 Hz), 6,77 (1H, s) 6,94 (1H, d, J=8,4 Hz), 7,07 (1H, d, J=8,4 Hz), 7,18 (1H, Shir.C).

An example of retrieving 39: 6-ethoxycarbonylmethylene

To 10 g of 6-amino-ethyl-1,2,3,4-tetrahydroisoquinoline (example getting 38) was added p-cYmen (100 ml) and palladium on coal (0.9 g) was then heated with stirring to 195°C in nitrogen atmosphere for 1 hour. After filtering off the catalyst and washing with ethanol, the filtrate is evaporated. The obtained crystals were washed with diethyl ether and dried. The solvent is evaporated to obtain specified in the connection header (6,51 g, 66%) as crystals pale yellow color.

1H-NMR (CDCl3) (M. D.): of 1.36 (3H, t, J=7.2 Hz), 3,74 (1H, m), the 4.29 (2H, q, J=7.2 Hz), 6,70 (1H, d, J=2.0 Hz), 7,46 (1H, DD, J=2.0 Hz, 8,8 Hz), 7,58 (1H, d, J=6.0 Hz), of 7.90 (1H, d, J=8,8 Hz), of 8.04 (1H, Shir.C) 8,46 (1H, d, J=6.0 Hz), 9,13 (1H, s).

An example of obtaining 40: N-oxide 6-ethoxycarbonylmethylene

Specified in the title compound (293 g) was obtained as crystals pale yellow color similar methdilazine 39).

1H-NMR (DMSO-d6) (M. D.): a 1.25 (3H, t, J=7.2 Hz), 4.26 deaths (2H, q, J=7.2 Hz), to 7.61 (1H, DD, J=2.0 Hz, 8,8 Hz), 7,79 (1H, d, J=8,8 Hz), 7,81 (1H, d, J=7,2 Hz), of 8.04 (1H, DD, J=2.0 Hz, 7.2 Hz), 8,79 (1H, s), 8,46 (1H, d, J=6.0 Hz), 9,13 (1H, s).

An example of retrieving 41: 1-chloro-6-ethoxycarbonylmethyl

Specified in the title compound (173 mg, 60%, stage 2) was obtained in the form of crystals pale yellow color similar to the method of example obtaining 22, except that he used the N-oxide 6-ethoxycarbonylmethylene (250 mg).

1H-NMR (CDCl3) (M. D.): of 1.34 (3H, t, J=7.2 Hz), the 4.29 (2H, q, J=7.2 Hz), was 7.36 (1H, Shir.C) to 7.50 (1H, d, J=5.6 Hz), 7,52 (1H, DD, J=2,4 Hz and 9.2 Hz), 8,11 (1H, m), 8,19 (1H, d, J=5.6 Hz), by 8.22 (1H, d, J=9,2 Hz).

An example of retrieving 42: 1-methoxy-6-methoxycarbonylaminophenyl

In dimethyl sulfoxide (45 ml) was dissolved, and 2.27 g of 1-chloro-6-ethoxycarbonylmethylene (example obtain 41). To the mixture was added a 28% solution of sodium methoxide (8,7 ml), then was heated with stirring to 110°C for 1.5 hours. After cooling to room temperature was added a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated with n the Cl3) (M. D.): 3,74 (3H, s), a 4.03 (3H, s), 7,05 (1H, d, J=5.8 Hz), 7,41 (1H, DD, J=2.0 Hz, 9,2 Hz), 7,86 (1H, d, J=5.8 Hz), of 7.90 (1H, Shir.C) of 8.06 (1H, d, J=9,2 Hz), 8,08 (1H, s).

An example of retrieving 43: 6-amino-1-methoxyethanol

Specified in the title compound (1.04 g, 99%) was obtained as crystals light brown color similar to the method of example obtaining 41, except that used 1-methoxy-6-methoxycarbonylaminophenyl (1.75 g, an example of obtaining 42) and methanol as a solvent.

1H-NMR (CDCl3) (M. D.): 4,07 (3H, s) 4,07 (2H, Shir.C) is 6.78 (1H, d, J=2.2 Hz), to 6.88 (1H, DD, J=2.2 Hz, 8,8 Hz), to 6.95 (1H, d, J=6.0 Hz), to 7.84 (1H, d, J=6.0 Hz), 8,03 (1H, d, J=8,8 Hz).

An example of retrieving 44: N-PROPYNYL(3-nitratomethyl)Amin

Specified in the header connection (3,070 g, 77%, including impurities) was obtained in the form of a yellow oil by the same method of example obtaining 28, except that used a 3-nitroacetanilide (3.0 g, an example of obtaining 27) and propionate (2.5 ml).

1H-NMR (CDCl3) (M. D.): to 1.14 (3H, t, J=7,6 Hz), 2,19 (2H, q, J=7,6 Hz), 2,96 (2H, t, J=6.8 Hz), of 3.56 (2H, dt, J=6,4 Hz, 6.8 Hz), 7,49 (1H, DD, J=7,6 Hz, 8.0 Hz), 7,55 (1H, d, J=7,6 Hz), 8,07 (1H, s), 8,10 (1H, d, J=8.0 Hz).

An example of retrieving 45: N-PROPYNYL(3-aminoethoxyethanol)Amin

Carried is,070 g, an example of retrieving 44). The resulting residue was purified on a column of silica gel with obtaining specified in the connection header (0,857 g, 32%) as oil pale yellow color.

1H-NMR (CDCl3) (M. D.): of 1.12 (3H, t, J=7,6 Hz), 2,19 (2H, q, J=7,6 Hz), a 2.71 (2H, t, J=6.8 Hz), 3,49 (2H, dt, J=6.0 Hz, 6.8 Hz), to 5.56 (1H, Shir.C) of 6.52 (1H, s), 6,56 (1H, d, J=7,6 Hz), to 7.09 (1H, DD, J=7,6 Hz and 7.6 Hz).

An example of retrieving 46: N-PROPYNYL(3-ethoxycarbonylmethoxy)Amin

Carried out a reaction similar to that described in example 30, using N-PROPYNYL(3-aminoethoxyethanol)amine (0,857 g, an example of obtaining 44). The resulting residue was purified on a column of silica gel with obtaining specified in the connection header (0,747 g, 61%) as oil is light yellow in color.

1H-NMR (CDCl3) (M. D.): of 1.12 (3H, t, J=7,6 Hz) of 1.30 (3H, t, J=7,0 Hz) of 2.16 (2H, q, J=7,6 Hz), 2,78 (2H, t, J=6.8 Hz), 3,50 (2H, dt, J=6.0 Hz, 6.8 Hz), is 4.21 (2H, q, J=7.0 Hz), to 6.67 (1H, Shir.C) 6,87 (1H, d, J=6.8 Hz), 7,00 (1H, Shir.C), 7,22 (1H, DD, J=6,8 Hz and 8.4 Hz), 7,26 (1H, d, J=8,4 Hz), 7,28 (1H, s).

An example of retrieving 47: 6 ethoxycarbonyl-1-utilizacion

Repeated methods of examples obtain 31 and 32, except that he used the N-PROPYNYL-(3-ethoxycarbonylmethoxy)Amin (0,747 g, an example of obtaining 46) to obtain 6-ethoxylate connection (0,516 g, 75% in stage 2) in the form of a yellow oil.

Data for the intermediate product and specified in the title compound were as follows.

6 Ethoxycarbonyl-1-ethyl-3,4-dihydroxyethylene

1H-NMR (CDCl3) (M. D.): to 1.21 (3H, t, J=7,6 Hz) of 1.30 (3H, t, J=7,0 Hz) to 2.66 (2H, t, J=7.4 Hz), is 2.74 (2H, q, J=7,6 Hz) to 3.64 (2H, t, J=7.4 Hz), to 4.23 (2H, q, J=7.0 Hz), 7,32 (1H, d, J=8,4 Hz), 7,37 (1H, s), the 7.43 (1H, d, J=8,4 Hz), 7,79 (1H, s).

6 Ethoxycarbonyl-1-utilizacion

1H-NMR (CDCl3) (M. D.): to 1.32 (3H, t, J=7.0 Hz), of 1.41 (3H, t, J=7,6 Hz), with 3.27 (2H, q, J=7,6 Hz), 4,27 (1H, q, J=7.0 Hz), 7,40 (1H, d, J=6.0 Hz), 7,52 (1H, DD, J=2.0 Hz, 8,8 Hz), 7,89 (1H, s), 8,02 (1H, d, J=2.0 Hz), of 8.25 (1H, d, J=8,8 Hz), a 8.34 (1H, d, J=6.0 Hz).

Example obtain 48: 6-amino-1-utilizacion

Specified in the header connection (0,320 g, 88%) was obtained as crystals pale yellow color similar to the method of example obtaining 33, except that used 6-ethoxycarbonyl-1-utilizacion (0,516 g, an example of obtaining 47).

1H-NMR (CDCl3) (M. D.): is 1.31 (3H, t, J=7.2 Hz), 3,21 (2H, q, J=7.2 Hz), 4,20 (2H, Shir.C) PC 6.82 (1H, d, J=2.4 Hz), to 6.95 (1H, DD, J=2,4 Hz and 8.8 Hz), 7,21 (1H, d, J=6.0 Hz), 7,94 (1H, d, J=8,8 Hz), 8,24 (1H, d, J=6.0 Hz).

Example of getting a 49: 1-methoxy-4-(3-nitrophenyl)propane-1-ene

Chloride methoxymetopon is (10.2 g). At that moment, when the reaction mixture turns red, portions of the pipette solution was added 3-nitroacetophenone (10 g) in tetrahydrofuran (100 ml). After stirring at room temperature for 2.5 hours under ice cooling was added a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate, the extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting residue was purified on a column of silica gel with obtaining specified in the connection header (8,010 g) as a yellow oil.

An example of obtaining 50: 2-(3-nitrophenyl)propanal

1-methoxy-4-(3-nitrophenyl)propane-1-ENU (8,010 g) was added 2 N. hydrochloric acid (150 ml), then was heated with stirring at 80°C for 4 hours. Then added hydrochloric acid (5 ml) and was heated at the boil under reflux for 2.5 hours. After cooling, the reaction mixture was neutralized with an aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated to obtain specified in the header is connected to the Ola (100 ml) was dissolved 7,531 g of 2-(3-nitrophenyl)propanal. Under ice cooling was added borohydride sodium (1.9 g), then stirred at room temperature for 1 hour. To the mixture was added a saturated salt solution and was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting residue was purified on a column of silica gel with obtaining specified in the connection header (6,275 g, 57,19%, 3 phase) in the form of a brown oil.

1H-NMR (CDCl3) (M. D.): of 1.34 (3H, d, J=6,8 Hz) and 1.51 (1H, Shir.C) to 3.09 (1H, TCEs, J=6.8 Hz, 6.8 Hz), of 3.78 (2H, d, J=6.8 Hz), to 7.50 (1H, DD, J=7,6 Hz and 8.4 Hz), 7,60 (1H, DDD, J=1.2 Hz, 1.6 Hz and 7.6 Hz), 8,10 (1H, DDD, J=1.2 Hz, 2.4 Hz, 8,4 Hz), 8,13 (1H, DD, J=1.6 Hz, 2.4 Hz).

An example of retrieving 52: 2-(3-nitrophenyl)Propylamine

Specified in the title compound was obtained as yellow oil in accordance with the techniques described in the examples of the preparation 26 and 27, except that used 2-(3-nitrophenyl)propan-1-ol (1,908 g, an example of obtaining 51).

Example of getting 53: 1-tert-butoxycarbonylamino-2-(3-nitrophenyl)propane

Carried out the reaction in the same manner as in the example of a 35 using 2-(3-nitrophenyl)Propylamine obtained in example receiving 52. On the e butter yellow color.

1H-NMR (CDCl3) (M. D.): 1,31 (3H, d, J=6.8 Hz), 1,40 (N, C) 3,10 (1H, m), 3,26 (1H, m), 3,88 (1H, m), 7,49 (1H, DD, J=7,6 Hz and 8.4 Hz), 7,56 (1H, d, J=7,6 Hz), 8,08 (1H, s), 8,10 (1H, d, J=8,4 Hz).

An example of retrieving 54: 2-(3-AMINOPHENYL)-1-tert-butoxycarbonylamino

Specified in the header connection (0,320 g, 88%) was obtained as yellow oil by the same method of example receiving 29, except that used the above 1-tert-butoxycarbonylamino-2-(3-nitrophenyl)propane (2,626 g).

Example of getting a 55: 1-tert-butoxycarbonylamino-2-(3-ethoxycarbonylphenyl)propane

Carried out a reaction similar to that described in example 30 using the above 2-(3-AMINOPHENYL)-1-tert-butoxycarbonylamino. The resulting residue was purified on a column of silica gel with obtaining specified in the connection header (2,960 g, 77,56%, 3 phase) in the form of a brown oil.

1H-NMR (CDCl3) (M. D.): a 1.25 (3H, d, J=7,6 Hz) is 1.31 (3H, t, J=7.2 Hz), 1,41 (N, C) 2,90 (1H, m), 3,18 (1H, DDD, J=4,2 Hz and 7.6 Hz and 9.2 Hz), 3,39 (1H, m), 4,42 (2H, q, J=7,6 Hz), of 4.45 (1H, Shir.C) 6,87 (1H, Shir.C) 6,94 (1H, m), 7,22 (3H, m).

An example of receiving 56: 6 ethoxycarbonyl-4-methyl-1,2,3,4-tetrahydroisoquinoline

Specified in the header shennymi in the examples get 38 and 39, except that used 1-tert-butoxycarbonylamino-2-(3-ethoxycarbonylphenyl)propane (2,960 g, an example of obtaining 55).

An example of retrieving 57: 6 ethoxycarbonyl-4-methylisoquinoline

Specified in the header connection (2,061 g, crude) was obtained in the form of crystals pale yellow in accordance with the reaction described in example getting 40, except that used the above 6 ethoxycarbonyl-4-methyl-1,2,3,4-tetrahydroisoquinoline (2,967 g, crude).

1H-NMR (CDCl3) (M. D.): of 1.36 (3H, t, J=7.2 Hz), at 2.59 (3H, s), 4,30 (2H, q, J=7.2 Hz), 7,12 (1H, d, J=2.0 Hz), 7,49 (1H, DD, J=2.0 Hz, 8,8 Hz), to $ 7.91 (1H, d, J=8,8 Hz) to 8.12 (1H, s), 8,32 (1H, s), of 9.00 (1H, s).

An example of retrieving 58: 6-amino-4-methylisoquinoline

Obtained above 6 ethoxycarbonyl-4-methylisoquinoline (2,061 g, crude) was subjected to a reaction in accordance with the procedure described in example 30. The obtained crystals were washed with diethyl ether and dried to obtain specified in the connection header (0,403 g, 27,75% in stage 4) in the form of crystals of pale yellow color.

1H-NMR (CDCl3) (M. D.): 2,48 (3H, s), 4,18 (2H, Shir.C) to 6.95 (1H, d, J=2.0 Hz), 7,00 (1H, DD, J=2.0 Hz, 8,8 Hz), 7,76 (1H, d, J=8,8 Hz), 8,19 (1H, s), 8,86 (1H, s).

An example is whether in the form of a yellow oil in accordance with the methods described in the examples get 52-55, except that used a 3-nitropropiophenone (10 g).

1H-NMR (CDCl3) (M. D.): 0,86 (3H, t, J=7.4 Hz), and 1.63 (1H, m), of 1.85 (1H, m), 3,24 (1H, m), 3,83 (2H, m) to 7.50 (1H, DD, J=7,2 Hz, 8.0 Hz), EUR 7.57 (1H, d, J=8.0 Hz), 8,10 (1H, s), 8,13 (1H, d, J=7,2 Hz).

Example of getting 60: 2-(3-nitrophenyl)butylamine

Specified in the header connection (5,247 g) was obtained as yellow oil in accordance with the techniques described in the examples of the preparation 26 and 27, except that used 2-(3-nitrophenyl)butane-1-ol (5,456 g, an example of obtaining 59).

An example of retrieving 61: 1-tert-butoxycarbonylamino-2-(3-nitrophenyl)butane

Then the above 2-(3-nitrophenyl)butylamine (5,247 g) were subjected to reaction in accordance with methods described in the example of a 27. The resulting residue was purified on a column of silica gel with obtaining specified in the connection header (7,679 g) in the form of oil pale yellow color.

1H-NMR (CDCl3) (M. D.): or 0.83 (3H, t, J=7.4 Hz), 1.39 in (N, C), and 1.63 (1H, m) to 1.79 (1H, m), 2,84 (1H, m), 3,21 (1H, m), 3,52 (1H, m), 4,42 (1H, Shir.C), 7,49 (1H, d, J=7,6 Hz), 7,52 (1H, DD, J=6,8 Hz and 7.6 Hz), of 8.04 (1H, s), 8,10 (1H, d, J=6,8 Hz).

An example of retrieving 62: 2-(3-AMINOPHENYL)-1-tert-butoxycarbonylamino

Specified in the header is the first example of receiving 29, except that used 1-tert-butoxycarbonylamino-2-(3-nitrophenyl)butane (7,679 g).

An example of retrieving 63: 1-tert-butoxycarbonylamino-2-(3-ethoxycarbonylphenyl)Bhutan

The above compound was then subjected to the reaction in accordance with the procedure described in example 30 to obtain specified in the connection header (8,230 g, crude) as a solid orange color.

1H-NMR (CDCl3) (M. D.): 0,81 (3H, t, J=7.4 Hz), is 1.31 (3H, t, J=7.2 Hz), 1,40 (N, C) of 1.55 (1H, m), by 1.68 (1H, m), 2.63 in (1H, m), 3,14 (1H, DDD, J=4,8 Hz, 8,8 Hz to 13.6 Hz), 3,52 (1H, m), 4,22 (2H, q, J=7.2 Hz), to 4.38 (1H, Shir.C) 6,63 (1H, Shir.C) 6,87 (1H, m), 7.23 percent (3H, m).

Example of getting 64: 6 ethoxycarbonyl-4-ethyl-1,2,3,4-tetrahydroisoquinoline

Specified in the title compound was obtained as brown oil in accordance with the techniques described in the examples get 38 and 39, except that used 1-tert-butoxycarbonylamino-2-(3-ethoxycarbonylphenyl)butane (8,230 g, crude, is an example of retrieving 63).

Example getting 65: 6 ethoxycarbonyl-4-utilizacion

Obtained above 6 ethoxycarbonyl-4-ethyl-1,2,3,4-tetrahydroisoquinoline (3.0 g) was subjected to reaction according to met the new ether and dried to obtain specified in the title compound as orange crystals.

1H-NMR (DMSO-d6) (M. D.): of 1.27 (3H, t, J=7.2 Hz), of 1.28 (3H, t, J=7.2 Hz), 2.91 in (2H, q, J=7.2 Hz), 4,18 (2H, q, J=7.2 Hz), to 7.64 (1H, d, J=8,8 Hz), 8,00 (1H, d, J=8,8 Hz), of 8.25 (1H, s), of 8.27 (1H, s), 8,98 (1H, s), 10,12 (1H, s).

An example of retrieving 66: 6-amino-4-utilizacion

Obtained above 6 ethoxycarbonyl-4-utilizacion were subjected to reaction in accordance with the procedure described in example 30. The resulting residue was purified on a column of NH-silica gel, the crude crystals were washed with diethyl ether and dried to obtain specified in the connection header (0,637 g) as orange crystals.

1H-NMR (CDCl3) (M. D.): to 1.35 (3H, t, J=7,6 Hz), of 2.92 (2H, q, J=7,6 Hz), 4,17 (2H, Shir.C) of 6.99 (1H, d, J=8,4 Hz), 7,00 (1H, s), to 7.77 (1H, d, J=8,4 Hz), 8,21 (1H, s), 8,86 (1H, s).

An example of retrieving 67: diethylether(3-nitrobenzyl)malonate

In ethanol (45 ml) dissolved sodium (0.7 g) was added diethylmalonate (5,26 ml) and 3-nitrobenzanthrone (5 g), then heated at the boil under reflux for 2 hours. The reaction mixture was cooled with ice, was added a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and races who

1H-NMR (CDCl3) (M. D.): 1,27 (6N, t, J=7.2 Hz), of 1.37 (3H, s), 3,32 (2H, s), is 4.21 (4H, q, J=7.2 Hz), 7,44 (1H, d, J=7,6 Hz), of 7.48 (1H, DD, J=7,6 Hz and 7.6 Hz), 8,03 (1H, s), 8,11 (1H, d, J=7,6 Hz).

Example of getting 68: ethyl-1-methyl-2-(3-nitrophenyl)propionate

In dimethyl sulfoxide (30 ml) was dissolved the above diethylether(3-nitrobenzyl)malonate (9,724 g), was added water (0.54 ml) and lithium chloride (2,54 g) and then heated at the boil under reflux at 190°C for 3.5 hours. After cooling to room temperature, added water, then was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated to obtain specified in the connection header (5,071 g, 73,35% in stage 2) in the form of a brown oil.

1H-NMR (CDCl3) (M. D.): of 1.20 (3H, t, J=7.2 Hz), to 1.21 (3H, d, J=7,2 Hz), and 2.79 (2H, m), 3,10 (1H, m), 4,10 (2H, q, J=7.2 Hz), was 7.45 (1H, DD, J=7,6 Hz, 8.0 Hz), 7,52 (1H, d, J=7,6 Hz), of 8.06 (1H, s), 8,08 (1H, d, J=8.0 Hz).

Example of getting 69: 1-methyl-2-(3-nitrophenyl)propionic acid

In ethanol (50 ml) was dissolved 5,071 g ethyl-1-methyl-2-(3-nitrophenyl)propionate (example getting 68), was added 5 N. aqueous sodium hydroxide solution (43 ml) and then heated at boiling with reverse holodilnie water layer. The organic layer was extracted with a saturated solution of salt. The aqueous layers were combined, acidified with diluted hydrochloric acid and then was extracted with diethyl ether. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting residue was purified on a column of silica gel with obtaining specified in the connection header (2,918 g, 65,27%) in the form of oil red.

1H-NMR (CDCl3) (M. D.): 1,24 (3H, d, J=6.0 Hz), and 2.83 (2H, s), and 3.16 (1H, m), 7,47 (1H, DD, J=7,2 Hz, 8.0 Hz), 7,54 (1H, d, J=7,2 Hz), 8,08 (1H, s), 8,10 (1H, d, J=8.0 Hz). Example of getting 70: N-BOC-1-methyl-2-(3-nitrophenyl)ethylamine

In tert-butanol (36 ml) was dissolved 2,918 g of 1-methyl-2-(3-nitrophenyl)propionic acid (example getting 69), was added triethylamine (4.09 to ml) and diphenylphosphoryl and then heated at the boil under reflux for 2.5 hours. After cooling, the solvent is evaporated. To the residue was added a saturated solution of sodium bicarbonate and then extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting residue was purified on a column of silica gel with obtaining specified in the title is=6,8 Hz), 2,82 (1H, m), of 2.92 (1H, m), of 3.94 (1H, Shir.C), 7,47 (1H, DD, J=7,2 Hz, 8.0 Hz), 7,54 (1H, d, J=7,2 Hz), with 8.05 (1H, s), of 8.09 (1H, d, J=8.0 Hz).

Example of getting 71: N-Boc-2-(3-AMINOPHENYL)-1-methylethylamine

N-BOC-1-methyl-2-(3-nitrophenyl)ethylamine (2,117 g, an example of obtaining 70) were subjected to reaction in accordance with the procedure described in example receiving 29. After extracting the resulting residue was purified on a column of silica gel with obtaining specified in the connection header (0,976 g, 51,63%) as a yellow oil.

Example of getting 72: N-BOC-1-methyl-2-(3-ethoxycarbonylphenyl)ethylamine

Specified in the header connection (1,173 g, crude) was obtained as yellow oil in accordance with the procedure described in example 30, except that he used the N-Boc-2-(3-AMINOPHENYL)-1-methylethylamine (0,976 g). The obtained product was used in subsequent reactions without further purification.

1H-NMR (CDCl3) (M. D.): 1,09 (3H, d, J=6.4 Hz), is 1.31 (3H, t, J=7.2 Hz), 1,43 (N, C), 2,62 (1H, DD, J=6,8 Hz to 13.2 Hz), 2,82 (1H, m), 3,88 (1H, m), 4,22 (2H, q, J=7.2 Hz), to 4.38 (1H, m), 6,56 (1H, m), 6.89 in (1H, d, J=6.8 Hz), 7,18 (1H, s), 7,22 (1H, DD, J=6,8 Hz, 8.0 Hz), 7.23 percent (1H, d, J=8.0 Hz).

Example of getting 73: hydrochloride of 2-(3-ethoxycarbonylphenyl)-1-methylethylamine

In etnologico acid (5 ml) and then stirred at room temperature for 1.5 hours. Then again, was added hydrochloric acid (2.5 ml) and stirred at room temperature for 2 hours. The solvent is evaporated to obtain specified in the connection header (1,148 g, crude) as a yellow oil. The obtained compound was used in subsequent reactions without further purification.

1H-NMR (CDCl3) (M. D.): of 1.03 (3H, d, J=6,8 Hz) to 1.22 (3H, t, J=7.2 Hz), to 2.55 (1H, m), 2,95 (1H, m), 3,32 (1H, m), 4,10 (2H, q, J=7.2 Hz), at 6.84 (1H, d, J=7,2 Hz), 7,21 (1H, DD, J=7.2 Hz, 7.2 Hz), 7,29 (1H, d, J=7,2 Hz), 7,35 (1H, s), 8,00 (1H, Shir.C) a 9.60 (1H, s).

Example of getting 74: 6 ethoxycarbonyl-3-methyl-1,2,3,4-tetrahydroisoquinoline

Specified in the header connection (0,441 g) was obtained by reaction using the methods described in Chem.Pharm.Bull., 42(8), 1676 (1994), using the hydrochloride of 2-(3-ethoxycarbonylphenyl)-1-methylethylamine (1,148 g, example of getting 73) and purification of the product on a column of NH-silica gel.

1H-NMR (CDCl3) (M. D.): 1,24 (3H, d, J=6.4 Hz), of 1.30 (3H, t, J=7.2 Hz), 2,48 (1H, DD, J=10.0 Hz, and 16.4 Hz), a 2.75 (1H, DD, J=3,6 Hz, and 16.4 Hz), 3,01 (1H, m), a 4.03 (2H, Shir.kV), is 4.21 (2H, q, J=7.2 Hz), of 6.66 (1H, s), to 6.95 (1H, d, J=8,4 Hz), to 7.09 (1H, d, J=8,4 Hz), 7,14 (1H, s).

Example of getting 75: 6 ethoxycarbonyl-3-methylisoquinoline

Specified in the header connection (0,356 g) who received more than 6-ethoxycarbonyl-3-methyl-1,2,3,4-tetrahydroisoquinoline (0,441 g).

1H-NMR (CDCl3) (M. D.): of 1.34 (3H, t, J=7.2 Hz), to 2.67 (3H, s), 4,28 (2H, q, J=7.2 Hz), was 7.08 (1H, Shir.C), 7,39 (1H, DD, J=2.0 Hz, 8,8 Hz), 7,40 (1H, s), a 7.85 (1H, d, J=8,8 Hz), 7,94 (1H, s), 9,05 (1H, s).

Example of getting 76: 6-amino-3-methylisoquinoline

Obtained above 6 ethoxycarbonyl-3-methylisoquinoline (0,356 g) were subjected to reaction in accordance with the procedure described in example obtain 33, to obtain crude crystals (of 0.182 g). The crystals were washed with diethyl ether and dried to obtain specified in the title compound (93 mg) as crystals pale yellow color.

1H-NMR (CDCl3) (M. D.): 2,63 (3H, s), 4,14 (2H, Shir.C) 6,77 (1H, d, J=2.0 Hz), 6,93 (1H, DD, J=2.0 Hz, 8,8 Hz), 7,18 (1H, s), 7,72 (1H, d, J=8,8 Hz).

Example 1: N-(8-bronchioles-3-yl)-3-pyridinesulfonamide

In pyridine (5 ml) was dissolved 3-amino-8-bromohydrin (example obtaining 5) was added 3-pyridinesulfonamide (254 ml), then stirred at room temperature for 30 minutes. Upon completion of the reaction, the reaction mixture was poured in a saturated salt solution and was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The obtained crude crystals were washed with ethyl acetate and the IPA with obtaining specified in the header coedine,22 (1H, m) 8,71 (1H, d, J=2.4 Hz), 8,78 (1H, DD, J=1.6 Hz, 4.8 Hz), 8,98 (1H, d, J=2.4 Hz), 11,23 (1H, Shir.C).

Example 2: N-(5-bronchioles-2-yl)-5-methyl-3-pyridinesulfonamide

Specified in the title compound was obtained from 2-amino-5-brainline (example obtain 1) and 5-methyl-3-pyridinesulfonamide in accordance with the procedure described in example 1.

1H-NMR (DMSO-d6) (M. D.): is 2.37 (3H, s), 7,58-7,72 (4H, m), 8,11 (1H, Shir.C) of 8.37 (1H, d, J=9.6 Hz), 8,59 (1H, d, J=1.2 Hz), 8,86 (1H, Shir.C).

Example 3: 6-amino-N-(8-bronchioles-3-yl)-3-pyridinesulfonamide

Specified in the title compound was obtained from 3-amino-8-brainline (example obtaining 5) and 6-amino-3-pyridinesulfonamide in accordance with the procedure described in example 1.

1H-NMR (DMSO-d6) (M. D.): 6,40 (1H, t, J=8,8 Hz), 6,93 (2H, Shir.C), 7,44 (1H, t, J=8.0 Hz), the 7.65 (1H, DD, J=2,4 Hz and 8.8 Hz), of 7.96-to 7.99 (2H, m), 8,01 (1H, d, J=2.4 Hz), 8,31 (1H, d, J=2.4 Hz), to 8.70 (1H, d, J=2.4 Hz), of 10.73 (1H, Shir.C).

Example 4: N-(8-bronchioles-3-yl)-4-cyanobenzenesulfonyl

Specified in the title compound was obtained from 3-amino-8-brainline (example obtaining 5) and 4-cyanobenzenesulfonyl in accordance with the procedure described in example 1.

1H-NMR (DMSO-d6) (M. D.): 7,46 (1H, t, J=8.0 Hz), of 7.96-8,07 (7H, m), to 8.70 (1H, d, J=2.4 Hz), 11,27 (1H, the unity was obtained from 3-amino-8-brainline (example obtaining 5) and 6-chloro-3-pyridinesulfonamide in accordance with the methodology described in example 1.

1H-NMR (DMSO-d6) (M. D.): 7,47 (1H, t, J=8.0 Hz), 7,71 (1H, d, J=8,4 Hz), 7,99-8,03 (2H, m), 8,10 (1H, d, J=2.4 Hz), to 8.20 (1H, DD, J=8,4 Hz), 8,71 (1H, d, J=2.4 Hz), 8,83 (1H, d, J=2.4 Hz), of 10.73 (1H, Shir.C).

Example 6: N-(8-bronchioles-3-yl)-4-(N-ethylsulfonyl)benzosulfimide

Specified in the title compound was obtained from 3-amino-8-brainline (example obtaining 5) and 4-(N-ethylsulfonyl)benzosulfimide in accordance with the procedure described in example 1.

1H-NMR (DMSO-d6) (M. D.): of 0.82 (3H, t, J=7.2 Hz), 2,69 was 2.76 (2H, m), 7,45 (1H, t, J=8,4 Hz), of 7.75 (1H, t, J=5.6 Hz), of 7.90-8,04 (7H, m), to 8.70 (1H, d, J=2,8 Hz), 11,18 (1H, Shir.C).

Example 7: N-(8-bronchioles-3-yl)-5-cyano-2-pyridinesulfonamide

Specified in the title compound was obtained from 3-amino-8-brainline (example obtaining 5) and 5-cyano-3-pyridinesulfonamide in accordance with the procedure described in example 1.

1H-NMR (DMSO-d6) (M. D.): 7,46 (1H, t, J=8.0 Hz), 7,95 (1H, d, J=8.0 Hz), 8,01 (1H, d, J=8.0 Hz), 8,11 (1H, d, J=2.4 Hz), 8,21 (1H, d, J=8,4 Hz), to 8.57 (1H, DD, J=2.0 Hz, 8,4 Hz), 8,79 (1H, d, J=2.4 Hz), 9,14 (1H, d, J=2.0 Hz), 11,49 (1H, Shir. C).

Example 8: N-(8-cyanohydrin-3-yl)-3-pyridinesulfonamide

Specified in the title compound was obtained from 3-amino-8-cyanohydrin (example receiving 7) and 3-pyridinol DD, J=4.8 Hz, 8.0 Hz), of 7.70 (1H, t, J=8.0 Hz), 8,21-of 8.25 (3H, m), with 8.33 (1H, d, J=8.0 Hz), 8,77-8,79 (2H, m), 9,01 (1H, d, J=2,8 Hz), 11,34 (1H, Shir.C).

Example 9: N-(8-cyanohydrin-3-yl)-4-cyanobenzenesulfonyl

Specified in the title compound was obtained from 3-amino-8-cyanohydrin (example receiving 7) and 4-cyanobenzenesulfonyl in accordance with the procedure described in example 1.

1H-NMR (DMSO-d6) (M. D.): 7,71 (1H, t, J=8.0 Hz), of 7.96-8,07 (4H, m), 8,18 (1H, d, J=2,8 Hz), 8,24 (1H, d, J=8.0 Hz), 8,31 (1H, d, J=8.0 Hz), 8,78 (1H, d, J=2,8 Hz), 11,37 (1H, Shir. C).

Example 10: N-(5-bronchioles-2-yl)-3-pyridinesulfonamide

Specified in the title compound was obtained from 2-amino-5-brainline (example obtain 1) and 3-pyridinesulfonamide in accordance with the procedure described in example 1.

1H-NMR (DMSO-d6) (M. D.): EUR 7.57-to 7.61 (3H, m), 7,70-7,72 (2H, m), of 8.28 (1H, W), scored 8.38 (1H, d, J=9.6 Hz), the rate of 8.75 (1H, DD, J=1.2 Hz, 4.8 Hz), 9,07 (1H, Shir.).

Example 11: N-(8-bronchioles-3-yl)-5-endosulfane

Specified in the title compound was obtained from 3-amino-8-brainline (example obtaining 5) and 5-indiancontrolled in accordance with the procedure described in example 1.

1H-NMR (DMSO-d6) (M. D.): 1,92 is 2.01 (2H, m), 2,81-of 2.86 (4H, m), 7,34 (1H, d, J=8.0 Hz), 7,44 (1H, t, J=8.0 Hz), 7,60 (1H, DD, J=1.6 Hz, 8.0 Hz), of 7.70 (1H inolin-3-yl)-N-acetyl-5-indolinecarboxylic

Specified in the title compound was obtained from 3-amino-8-ichinomiya (example obtaining 6) and N-acetyl-6-indolinecarboxylic in accordance with the procedure described in example 1.

1H-NMR (DMSO-d6) (M. D.): 2,11 (3H, s), 3,11 (2H, t, J=8,4 Hz) 4,06 (2H, t, J=8,4 Hz), 7,28 (1H, t, J=8.0 Hz), 7,65-to 7.68 (2H, m), 7,93-of 7.96 (2H, m), with 8.05 (1H, d, J=9,2 Hz), by 8.22 (1H, DD, J=1.2 Hz and 7.6 Hz), 8,64 (1H, d, J=2.4 Hz), 10,87 (1H, Shir.C).

Example 13: N-(8-bronchioles-3-yl)-3-chinaincorporated

Specified in the title compound was obtained from 3-amino-8-brainline (example obtaining 5) and 3-chinaincorporated in accordance with the procedure described in example 1.

1H-NMR (DMSO-d6) (M. D.): 7,38 (1H, t, J=8.0 Hz), 7,70-7,74 (1H, m), of 7.90-of 8.00 (3H, m), 8,07 (1H, d, J=8.0 Hz), 8,13 (1H, d, J=2.4 Hz), 8,19 (1H, DD, J=0.8 Hz, and 8.4 Hz), the rate of 8.75 (1H, d, J=2.4 Hz), 9,00-9,01 (1H, m), 9,19 (1H, d, J=2.4 Hz), to 11.31 (1H, Shir.C).

Example 14: N-(8-bronchioles-3-yl)-N*-acetyl-1,2,3,4-tetrahydroquinolin-6-sulfonamide

Specified in the title compound was obtained from 3-amino-8-brainline (example obtaining 5) and N-acetyl-1,2,3,4-tetrahydroquinolin-6-sulphonylchloride in accordance with the procedure described in example 1.

1H-NMR (CDCl3) (M. D.): 1,86 is 2.01 (2H, m), 2,77 (2H, t, J=6.4 Hz), 3,65 is 3.76 (1H, m).

Example 15: N-(8-eothinon-3-yl)-4-skinny 6) and 4-ethynodiolthinyl in accordance with the methodology described in example 1.

1H-NMR (DMSO-d6) (M. D.): 7,26 (1H, t, J=8.0 Hz), 7,82-7,86 (1H, m), 7,93-of 7.95 (2H, m), 7,98 (1H, d, J=2.4 Hz), 8,02-of 8.06 (1H, m), 8,19 (1H, DD, J=1.2 Hz and 7.6 Hz), of 8.27 (1H, d, J=8,4 Hz), 8,59 (1H, d, J=2.4 Hz), 8,67 (1H, d, J=8,4 Hz), 9,12 (1H, s) 9,52 (1H, s), 11,57 (1H, Shir.C).

Example 16: 4-cyano-N-(8-eothinon-3-yl)benzosulfimide

Specified in the title compound was obtained from 3-amino-8-ichinomiya (example obtaining 6) and 4-cyanobenzenesulfonyl in accordance with the procedure described in example 1.

1H-NMR (DMSO-d6) (M. D.): 7,31 (1H, t, J=8.0 Hz), of 7.96-8,04 (6N, m), compared to 8.26 (1H, DD, J=1.2 Hz, 7.2 Hz), 8,65 (1H, d, J=2,8 Hz), 11,24 (1H, Shir.C).

Example 17: N-(8-eothinon-3-yl)-3-pyridinesulfonamide

Specified in the title compound was obtained from 3-amino-8-ichinomiya (example obtaining 6) and 3-pyridinesulfonamide in accordance with the procedure described in example 1.

1H-NMR (DMSO-d6) (M. D.): 7,31 (1H, t, J=8.0 Hz), EUR 7.57-of 7.60 (1H, m), to 7.99 (1H, d, J=1.2 Hz, 8,4 Hz), of 8.04 (1H, d, J=2,8 Hz), 8,18-8,21 (1H, m), compared to 8.26 (1H, DD, J=1.2 Hz, 7.2 Hz), 8,66 (1H, d, J=2,8 Hz), 8,77 (1H, DD, J=1,6 Hz, 4.8 Hz), 8,98 (1H, d, J=2,8 Hz), 11,20 (1H, Shir.C).

Example 18: N-(5-bronchioles-2-yl)-4-cyanobenzenesulfonyl

Specified in the title compound was obtained from 2-amino-5-brainline (example obtain 1) and 4-cyanobenzoyl): EUR 7.57-7,73 (4H, m), 8,00-8,08 (4H, m), scored 8.38 (1H, d, J=8,8 Hz).

Example 19: N-(8-bronchioles-3-yl)-6-ethyl-3-pyridinesulfonamide

Pyridine (0.5 ml) and a solution of 6-ethyl-3-pyridinesulfonamide (30 ml) in methylene chloride (0.5 ml) was added to 3-amino-8-brainline (18 mg, example of obtaining 5) when 0°C. After stirring at room temperature for 30 minutes was added water and the mixture was extracted with ethyl acetate. The extract was purified preparative TLC (hexane : ethyl acetate=1:1) to obtain the specified title compound (20 mg).

1H-NMR (CDCl3) (M. D.): a 1.25 (3H, t, J=7.5 Hz), 2,70 (2H, q, J=7.5 Hz), 7,34-7,98 (5H, m), 8,19 (1H, d, J=3.3 Hz), 8,54 (1H, s), 8,83 (1H, d, J=3.3 Hz).

Example 20: 4-chloro-N-(5-chlorhydrin-2-yl)benzosulfimide

Pyridine (1 ml) and 4-chlorobenzenesulfonamide (255 mg) was added to 2-amino-5-chlorhydrin (119 mg, example of obtaining 2) at room temperature. After stirring at room temperature for 3 days was added water and the mixture was extracted with ethyl acetate. An ethyl acetate layer was dried over magnesium sulfate and concentrated. Then the obtained solid was washed with methanol to obtain specified in the title compound (20 mg).

1H-NMR (CDCl3) (M. D.): of 6.96 (1H, d, J=9.7 Hz), 7,34 (1H, d, J=8,4 Hz), 7,42-of 7.48 (3H, m),MFA

Specified in the title compound was obtained from 3-amino-8-chlorhydrin (example obtain 9) and 6-ethyl-3-pyridinesulfonamide in accordance with the procedure described in example 1.

1H-NMR (CDCl3) (M. D.): of 1.28 (3H, t, J=8,3 Hz), of 2.86 (2H, q, J=8,3 Hz), 7,24 (1H, d, J=8.0 Hz), 7,49 (1H, t, J=8.0 Hz), 7,73 (1H, d, J=8.0 Hz), 7,78 (1H, d, J=8.0 Hz), 7,95 (2H, DD, J=8.0 Hz, 2.1 Hz), 8,18 (1H, d, J=2.5 Hz), 8,67 (1H, d, J=2.5 Hz), 8,93 (1H, d, J=2.1 Hz).

Example 22: N-(5-chlorhydrin-2-yl)-6-ethyl-3-pyridinesulfonamide

Specified in the title compound was obtained from 2-amino-5-chlorhydrin (example obtaining 2) and 6-ethyl-3-pyridinesulfonamide in accordance with the procedure described in example 1.

1H-NMR (CDCl3) (M. D.): to 1.32 (3H, t, J=8,3 Hz), 2,89 (2H, q, J=8,3 Hz), 6,97 (1H, d, J=9.4 Hz), 7,29 (1H, t, J=8.0 Hz), 7,35 (1H, d, J=8.0 Hz), 7,44 (1H, d, J=8.0 Hz), 7,56 (1H, t, J=8.0 Hz), 8,18 (1H, DD, J=8.0 Hz, 2.6 Hz), 8,30 (1H, d, J=9.4 Hz), 9,10 (1H, d, J=2,6 Hz).

Example 23: N-(8-chlorhydrin-3-yl)benzosulfimide

Specified in the title compound was obtained from 3-amino-8-chlorhydrin (example obtain 9) and benzosulfimide in accordance with the procedure described in example 1.

1H-NMR (CDCl3) (M. D.): 7,30-of 7.48 (6N, m), to 7.84 (2H, d, J=7,4 Hz), 8,11 (1H, d, J=3.1 Hz), 8,66 (1H, d, J=3.1 Hz).

Example 24: 4-cyano-N-(5-chlorhydrin-2-yl)teaching 2) and 4-cyanobenzenesulfonyl in accordance with the methodology described in example 1.

1H-NMR (CDCl3) (M. D.): of 6.96 (1H, d, J=9.5 Hz), 7,35 (1H, d, J=8.7 Hz), was 7.45 (1H, d, J=8.7 Hz), EUR 7.57 (1H, t, J=8.7 Hz), 7,78 (2H, d, J=8,9 Hz), 8,10 (2H, d, J=8,9 Hz), with 8.33 (1H, d, J=9.5 Hz).

Example 25: N-(5-chlorhydrin-2-yl)-4-methylbenzenesulfonamide

Specified in the title compound was obtained from 2-amino-5-chlorhydrin (example obtaining 2) and 4-toluensulfonate in accordance with the procedure described in example 1.

1H-NMR (CDCl3) (M. D.): to 2.41 (3H, s), 6,98 (1H, d, J=9.3 Hz), 7,28 (2H, d, J=8,2 Hz), 7,35 (1H, d, J=7.9 Hz), 7,41 (1H, d, J=7.9 Hz), 7,53 (1H, t, J=7.9 Hz), 7,88 (2H, d, J=8,2 Hz), compared to 8.26 (1H, d, J=9,3 Hz).

Example 26: N-(5-chlorhydrin-2-yl)-4-sulfamoylanthranilic

Specified in the title compound was obtained from 2-amino-5-chlorhydrin (example obtaining 2) and 4-sulfamoylanthranilic in accordance with the procedure described in example 1.

1H-NMR (CDCl3) (M. D.): 7,42-7,49 (3H, m), 7,58 (1H, t, J=8.0 Hz), 8,00-to 8.12 (4H, m), 8,39 (1H, d, J=9,3 Hz).

Example 27: N-(5-bronchioles-2-yl)-4-(N-ethylsulfonyl)benzosulfimide

Specified in the title compound was obtained from 2-amino-5-chlorhydrin (example obtaining 2) and 4-(N-ethylsulfonyl) benzosulfimide in accordance with the procedure described in example 1.

, the d, J=7,6 Hz, 1.3 Hz), of 7.96 (2H, d, J=8.7 Hz), 8,10 (2H, d, J=8.7 Hz), 8,31 (1H, d, J=9.5 Hz).

Example 28: 3-cyano-N-(8-chlorhydrin-3-yl)benzosulfimide

Specified in the title compound was obtained from 3-amino-8-chlorhydrin (example obtain 9) and 3-cyanobenzenesulfonyl in accordance with the procedure described in example 1.

1H-NMR (CDCl3) (M. D.): 7,52 (1H, t, J=7.9 Hz), to 7.59 (1H, t, J=7.9 Hz), 7,72-7,86 (3H, m), of 8.00 (1H, d, J=7.9 Hz), 8,13 (1H, d, J=3.2 Hz), 8,16 (1H, s) 8,64 (1H, d, J=3.2 Hz).

Example 29: N-(8-chlorhydrin-3-yl)-3-methylbenzenesulfonamide

Specified in the title compound was obtained from 3-amino-8-chlorhydrin (example obtain 9) and 3-toluensulfonate in accordance with the procedure described in example 1.

1H-NMR (CDCl3) (M. D.): 2,35 (3H, s), 7,16-7,79 (7H, m), of 8.09 (1H, d, J=2.7 Hz), 8,65 (1H, d, J=2.7 Hz).

Example 30: N-(8-chlorhydrin-3-yl)-3-sulfamoylanthranilic

Specified in the title compound was obtained from 3-amino-8-chlorhydrin (example obtain 9) and 3-sulfamoylanthranilic in accordance with the procedure described in example 1.

1H-NMR (CDCl3) (M. D.): 7,46 (1H, t, J=7,6 Hz), 7,53 (1H, t, J=7,6 Hz), 7,58 for 7.78 (2H, m), of 8.00 (1H, d, J=7,6 Hz), of 8.04 (1H, d, J=7,6 Hz) to 8.14 (1H, d, J=2,8 Hz), of 8.47 (1H, s), 8,59 (1H, d, J=2,8 Hz).

Example 31:iMER 1 except what used 1,02 g (5.2 mmol) of 7-amino-2-chloro-4-methylinosine (example 16) and 0.9 g (5.2 mmol) of 3-pyridinesulfonamide. To 102 mg (0.29 mmol) of white crystals was added methanol (4 ml), tetrahydrofuran (4 ml) and 10% palladium on coal (5 mg) and then stirred in an atmosphere of hydrogen for 6 hours. The reaction mixture was filtered through celite and then evaporated.

The residue was washed with ethyl acetate to obtain 65 mg specified in the connection header.

1H-NMR (DMSO-d6) (M. D.): 2,82 (3H, s), of 7.64-7,66 (2H, m), 7,73 (1H, d, J=5,2 Hz), 8,03 (1H, s), 8.30 to-8,35 (2H, m), 8,82 (1H, DD, J=1.2 Hz, 4.8 Hz), of 9.00 (1H, d, J=5,2 Hz), 9,11 (1H, d, J=2.0 Hz).

Example 32: N-(8-methylinosine-3-yl)-4-cyanobenzenesulfonyl

White crystals (358 mg) was obtained similarly to the method of example 1, except that used 305 mg (1,58 mmol) 7-amino-2-chloro-4-methylinosine (example 16) and of 0.48 g (2.4 mmol) of 4-cyanobenzenesulfonyl. White crystals (140 mg, 0.38 mmol) was added acetic acid (6 ml), water (2 ml) and zinc (122 mg), then stirred at 60°C for 15 minutes. The reaction mixture was filtered through celite, and then was added a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed of NASA is and silica gel to obtain 82 mg specified in the connection header.

1H-NMR (DMSO-d6) (M. D.): 2,60 (3H, s), 7,26 (1H, DD, J=1.2 Hz, 4.4 Hz), 7,41 (1H, DD, J=2,4 Hz and 8.8 Hz), to 7.64 (1H, d, J=2.4 Hz), 7,97-of 8.06 (1H, m), 7,98 (1H, d, J=8,4 Hz), of 8.04 (1H, d, J=8,4 Hz), 8,66 (1H, d, J=4.4 Hz), 11,06 (1H, Shir.C).

Example 33: N-(6-chloro-8-cyanohydrin-3-yl)-3-pyridinesulfonamide

White crystals (764 mg) was obtained similarly to the method of example 1, except that used 3.0 g (13 mmol) of ethyl-7-amino-2-chlorhydrin-4-carboxylate (example getting 13) and 2.3 g (13 mmol) of 3-pyridinesulfonamide. To a solution of 108 mg (0.28 mmol) of the obtained crystals in ethanol (6 ml) was added 1 n sodium hydroxide (0.5 ml) and then stirred overnight. To the reaction mixture were added 1 N. hydrochloric acid and then was extracted twice with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated to obtain a residue. To a solution of the residue in tetrahydrofuran (10 ml) under ice cooling was added oxalicacid (0.04 ml) and one drop of dimethylformamide, and then stirred at room temperature for 30 minutes. After 30 minutes, was added saturated aqueous ammonia (5 ml), then stirred for another 10 minutes. To the reaction mixture were added a saturated solution of salt and then the extras is and. To a solution of the residue in tetrahydrofuran (6 ml) under ice cooling was added pyridine (0.06 ml) and the anhydride triperoxonane acid (0.05 ml), then stirred at room temperature for 30 minutes. To the reaction mixture were added a saturated salt solution and then was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel to obtain 37 mg specified in the connection header.

1H-NMR (DMSO-d6) (M. D.): 7,62-7,66 (1H, m), 7.68 per-7,72 (2H, m), 8,08 (1H, d, J=8,8 Hz), 8,23 (1H, s), compared to 8.26-8,29 (1H, m), 8,81 (1H, DD, J=1.6 Hz, 4.8 Hz), 9,04 (1H, d, J=2,4 Hz).

Example 34: N-(8-chlorhydrin-3-yl)-4-cyanobenzenesulfonyl

Specified in the title compound (58 mg) was obtained in accordance with the procedure described in example 1, except that used 38 mg (0.21 mmol) of 3-amino-8-chlorhydrin (example obtain 9) and 43 mg (0.21 mmol) of 4-cyanobenzenesulfonyl.

1H-NMR (DMSO-d6) (M. D.): at 7.55 (1H, t, J=7,6 Hz), to 7.84 (1H, d, J=7,6 Hz), 7,95 (1H, t, J=7,6 Hz), to 7.99 (2H, d, J=8,8 Hz), of 8.04 (2H, d, J=8,8 Hz), of 8.09 (1H, d, J=2,8 Hz), 8,73 (1H, d, J=2,8 Hz), is 11.39 (1H, s).

Example 35: N-(8-chlorhydrin-3-yl)-4-(N-ethylsulfonyl)benzosulfimide

Specified in the title compound (36 mg) Palacino-8-chlorhydrin (example obtain 9) and 52 mg (0,19 mmol) of 4-(N-ethylsulfonyl)benzosulfimide.

1H-NMR (DMSO-d6) (M. D.): 0,84 (3H, t, J=7.2 Hz), 2,78-a 2.71 (2H, m), 7,54 (1H, t, J=7,6 Hz), to 7.77 (1H, t, J=6.0 Hz), 7,83 (1H, t, J=7,6 Hz), 7,92-of 7.95 (1H, m), to 7.93 (2H, d, J=8,8 Hz), 8,03 (2H, d, J=8,8 Hz), 8,07 (1H, d, J=2.4 Hz), 8,73 (1H, d, J=2.4 Hz), 11,20 (1H, s).

Example 36: N-(8-chlorhydrin-3-yl)-3-pyridinesulfonamide

Specified in the title compound (29 mg) was obtained in accordance with the procedure described in example 1, except that used 33 mg (0,19 mmol) 3-amino-8-chlorhydrin (example obtain 9) and 33 mg (0,19 mmol) 3-pyridinesulfonamide.

1H-NMR (DMSO-d6) (M. D.): rate of 7.54 (1H, t, J=7,6 Hz), 7,60 (1H, DD, J=4,8 Hz and 7.6 Hz), 7,81 (1H, d, J=7,6 Hz), 7,94 (1H, d, J=7,6 Hz), of 8.09 (1H, d, J=2,8 Hz), 8,19 compared to 8.26 (1H, m), 8,72 (1H, d, J=2,8 Hz), 8,77 (1H, DD, J=1,6 Hz, 4.8 Hz), of 9.00 (1H, d, J=2,8 Hz), 11,46 (1H, s).

Example 37: N-(8-chlorhydrin-3-yl)-5-ethylsulfonyl-2-pyridinesulfonamide

Specified in the title compound (10 mg) was obtained in accordance with the procedure described in example 1, except that used 30 mg (0,17 mmol) 3-amino-8-chlorhydrin (example obtain 9) and 95 mg (0.34 mmol) of 5-ethylsulfonyl-2-chlorosulfonylphenyl.

1H-NMR (DMSO-d6) (M. D.): to 0.88 (3H, t, J=7,6 Hz), 2,79-of 2.86 (2H, m), 7,55 (1H, t, J=7,6 Hz), the 7.85 (1H, t, J=7,6 Hz), 7,94 (1H, d, J=7,6 Hz), 8,00 (1H, t, J=6.4 Hz), 8,16 (1H, d, J=2,8 Hz), of 8.27 (1H, d, J=8.0 Hz), is)-4-cyanobenzenesulfonyl

Specified in the title compound (59 mg) was obtained in accordance with the procedure described in example 1, except that used 35 mg (0,17 mmol) 3-amino-8-triptoreline (example 10) and 37 mg (0.18 mmol) 4-cyanobenzenesulfonyl.

1H-NMR (DMSO-d6) (M. D.): 7,71 (1H, t, J=7,6 Hz), 8,03-8,09 (5H, m), 8,19 (1H, d, J=2.4 Hz), 8,30 (1H, d, J=7,6 Hz), 8,78 (1H, d, J=2.4 Hz), 11,72 (1H, s).

Example 39: N-(8-trifloromethyl-3-yl)-4-(N-ethylsulfonyl)benzosulfimide

Specified in the title compound (60 mg) was obtained in accordance with the procedure described in example 1, except that used 35 mg (0,17 mmol) 3-amino-8-triptoreline (example 10) and 56 mg (0.20 mmol) 4-(N-ethylsulfonyl)benzosulfimide.

1H-NMR (DMSO-d6) (M. D.): or 0.83 (3H, t, J=7.2 Hz), 2.71 to 2,78 (2H, m), of 7.69 (1H, t, J=8.0 Hz), 7,76 (1H, t, J=5.6 Hz), to 7.93 (1H, d, J=8,8 Hz), 8,04-8,07 (3H, m), 8,13 (1H, d, J=2,8 Hz), of 8.25 (1H, d, J=8.0 Hz), the rate of 8.75 (1H, d, J=2,8 Hz), to 11.28 (1H, s).

Example 40: N-(8-trifloromethyl-3-yl)-3-pyridinesulfonamide

Specified in the title compound (71 mg) was obtained in accordance with the procedure described in example 1, except that used 45 mg (0.21 mmol) of 3-amino-8-triptoreline (example of 16 Hz), of 8.06 (1H, d, J=7,6 Hz), to 8.20 (1H, d, J=2,8 Hz), 8,23-8,24 (1H, m), 8,30 (1H, d, J=7,6 Hz), 8,76 (1H, d, J=2,8 Hz), 8,79 (1H, DD, J=1.6 Hz, 4.8 Hz), 9,03 (1H, d, J=2.0 Hz), 11,64 (1H, s).

Example 41: N-(8-chlorhydrin-3-yl)-1,2,3,4-tetrahydro-6-naphthalenesulfonic

Specified in the title compound (46 mg) was obtained in accordance with the procedure described in example 1, except that used 33 mg (0,19 mmol) 3-amino-8-chlorhydrin (example obtain 9) and 73 mg (0.22 mmol) of 6-chlorosulfonyl-1,2,3,4-tetrahydronaphthalene.

1H-NMR (DMSO-d6) (M. D.): 1,68 (4H, W), a 2.71 (4H, W), then 7.20 (1H, t, J=8,4 Hz), 7,52 (1H, t, J=7,6 Hz), 7,53 (1H, DD, J=2.0 Hz, 8,4 Hz), 7,58 (1H, d, J=2.0 Hz), 7,80 (1H, d, J=7,6 Hz), to 7.93 (1H, d, J=7,6 Hz), of 8.06 (1H, d, J=2.4 Hz), 8,73 (1H, d, J=2.4 Hz), 10,94 (1H, s).

Example 42: N-(8-chlorhydrin-3-yl)-2,3-dihydro-5-benzofuranol

Specified in the title compound (57 mg) was obtained in accordance with the procedure described in example 1, except that used 30 mg (0,17 mmol) 3-amino-8-chlorhydrin (example obtain 9) and 44 mg (0.20 mmol) of 5-chlorosulfonyl-2,3-dihydrobenzofuran.

1H-NMR (DMSO-d6) (M. D.): 3,19 (2H, t, J=8,8 Hz), 4,58 (2H, t, J=8,8 Hz) 6,86 (1H, d, J=8,8 Hz), 7.23 percent (1H, t, J=7,6 Hz), a 7.62 (1H, DD, J=1,6 Hz and 8.8 Hz), 7,72 (1H, d, J=1.6 Hz), 7,80 (1H, d, J=7,6 Hz), 7,92 (1H, d, J=7,6 Hz), 8,03 (1H, d, J=2.4 Hz), 8,73 (1H, d, J=2.4 Hz), 10,85 (1H, the compound (15 mg) was obtained in accordance with the methodology described in example 1, except that used 30 mg (0.15 mmol) 3-amino-4-vinyl-8-chlorhydrin (example 12) and 36 mg (0.18 mmol) 4-cyanobenzenesulfonyl.

1H-NMR (DMSO-d6) (M. D.): from 5.29 (1H, d, J=17.6 Hz), 5,59 (1H, d, J=11,6 Hz), to 6.75 (1H, DD, J=11,6 Hz, 17.6 Hz), to 7.59 (1H, t, J=8.0 Hz), 7,80 (1H, DD, J=8,8 Hz), of 7.96 (1H, d, J=8.0 Hz), 8,00-of 8.04 (3H, m), a total of 8.74 (1H, s), of 10.58 (1H, s).

Example 44: N-(8-trifloromethyl-3-yl)-5-(N-acetylindole)sulfonamide

Specified in the title compound (186 mg) was obtained in accordance with the procedure described in example 1, except that used 109 mg (0.51 mmol) of 3-amino-8-triptoreline (example 10) and 200 mg (0.77 mmol) of 5-chlorosulfonyl-N-acetylindole.

1H-NMR (DMSO-d6) (M. D.): a 2.13 (3H, s), 3,14 (2H, t, J=8.0 Hz), 4.09 to (2H, t, J=8,8 Hz), to 7.67 (1H, t, J=8,4 Hz), 7,69-7,73 (2H, m), 8,01 (1H, d, J=7,2 Hz), 8.07-a of 8.09 (2H, m), 8,24 (1H, d, J=8,4 Hz), 8,73 (1H, d, J=2,8 Hz), 10,98 (1H, s).

Example 45: N-(8-bronchioles-3-yl)-2-methylthio-5-pyridinesulfonamide

White crystals (197 mg, 0,556 mmol) was obtained similarly to the method of example 1, except that used 100 mg high (0.56 mmol) 3-amino-8-brainline (example obtaining 5) and 142 mg (0.67 mmol) of 2-chloro-5-pyridinesulfonamide. To the crystals (60 mg, 0,17 mmol) was added, the temperature for 3 hours. To the reaction mixture were added a saturated salt solution, then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The obtained residue was purified by chromatography on silica gel to obtain 62 mg specified in the connection header.

1H-NMR (DMSO-d6) (M. D.): to 3.33 (3H, s), 7,47 (1H, d, J=8,8 Hz), 7,55 (1H, t, J=8.0 Hz), to 7.84 (1H, d, J=6.8 Hz), of 7.97 (1H, d, J=8,8 Hz), 7,98 (1H, d, J=8,8 Hz), 8,13 (1H, d, J=2.0 Hz), a total of 8.74 (1H, d, J=2.4 Hz), 8,82 (1H, d, J=2.0 Hz), 11,16 (1H, s).

Example 46: N-(8-bronchioles-3-yl)-4-(2-methylsulfonylamino)benzosulfimide

Specified in the title compound (55 mg) was obtained in accordance with the procedure described in example 1, except that used 30 mg (0.13 mmol) of 3-amino-8-brainline (example obtaining 5) and 57 mg (0.20 mmol) 4-(2-methylsulfonylamino)benzosulfimide.

1H-NMR (DMSO-d6) (M. D.): 2,92 (3H, s), 3.00 and was 3.05 (2H, m), 3,37-3,44 (2H, m), 7,46 (1H, t, J=7,6 Hz), of 7.48 (2H, d, J=8.0 Hz), 7,80 (2H, d, J=8.0 Hz), of 7.96 (1H, d, J=7,6 Hz), to 7.99 (1H, d, J=7,6 Hz), of 8.04 (1H, d, J=2.4 Hz), 8,71 (1H, d, J=2.4 Hz), 11,02 (1H, s).

Example 47: N-(8-bronchioles-3-yl)-4-oxa-7-benzothiazolesulfonamide

Specified in the title compound (99 mg) was obtained in accordance with the procedure described in example 1, except sensationalise.

1H-NMR (DMSO-d6) (M. D.): 3,18 (2H, t, J=8,4 Hz), 4,39 (2H, t, J=8,4 Hz), 6,92 (1H, d, J=8,8 Hz), 7,42 (1H, DD, J=2,4 Hz and 8.8 Hz), 7,46 (1H, t, J=7,6 Hz), to 7.59 (1H, d, J=2.4 Hz), to 7.99 (1H, d, J=7,6 Hz), 8,02 (1H, d, J=7,6 Hz), with 8.05 (1H, W), 8,71 (1H, d, J=2.4 Hz), 10,92 (1H, s).

Example 48: N-(8-bronchioles-3-yl)-4-(2-acetamide)benzosulfimide

Specified in the title compound (56 mg) was obtained in accordance with the procedure described in example 1, except that used 30 mg (0.13 mmol) of 3-amino-8-brainline (example obtaining 5) and 201 mg (0.77 mmol) of N-(4-chlorosulfonylisocyanate)ndimethylacetamide.

1H-NMR (DMSO-d6) (M. D.): a 2.71 (2H, t, J=7.2 Hz), 3.25 to 3,20 (2H, m), 7,37 (2H, d, J=8,4 Hz), 7,46 (1H, t, J=8.0 Hz), 7,78 (2H, d, J=8,4 Hz), 7,86 (1H, W), of 7.97 (1H, d, J=8.0 Hz), 8,00 (1H, d, J=8.0 Hz), of 8.04 (1H, d, J=2,8 Hz), 8,72 (1H, d, J=2,8 Hz), 10,99 (1H, s).

Example 49: N-(8-bronchioles-3-yl)-1,2,3,4-tetrahydro-N-acetyl-7-ethynodiolthinyl

White crystals (180 mg) was obtained similarly to the method of example 1, except that used 145 mg (of 0.65 mmol) 3-amino-8-brainline (example obtaining 5) and 277 mg (0.85 mmol) of 1,2,3,4-tetrahydro-2-(TRIFLUOROACETYL)isoquinoline-7-sulphonylchloride. To the crystals was added ethanol (20 ml) and 1 N. aqueous sodium hydroxide solution (0.5 ml), then stirred at room temp is listed with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated. To the obtained residue were added pyridine (0.5 ml) and acetic anhydride (0,014 ml), then stirred at room temperature for 1 hour. Was added a saturated salt solution and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel to obtain 113 mg specified in the connection header.

1H-NMR (DMSO-d6) (M. D.): 1,19 of 1.28 (2H, m), is 2.05 (3H, s), 2,97 (1H, t, J=6.4 Hz), 3,03 (1H, t, J=6,4 Hz in), 3.75 (1H, t, J=6.4 Hz), to 4.73 (1H, s), 7,37 (1H, t, J=8,8 Hz), 7,53-7,58 (1H, m), 7,75-7,87 (2H, m), to $ 7.91 (1H, d, J=8.0 Hz), 8,19-of 8.27 (2H, m), 8,76-8,78 (1H, m).

Example 50: N-(8-bronchioles-3-yl)-1,1-dioxide-6-benzothiazolesulfonamide

White crystals were obtained similarly to the method of example 1, except that used 71 mg (0.32 mmol) of 3-amino-8-brainline (example obtaining 5) and 119 mg (0.48 mmol) of 6-chlorosulfonylisocyanate. To the crystals was added chloroform (10 ml) and meta-chloroperbenzoic acid (145 mg) under ice cooling, and then stirred at room temperature for 1 hour. Was added a saturated aqueous solution of sodium thiosulfate and the mixture extrage who has centriole. The residue was purified by chromatography on silica gel to obtain 113 mg specified in the connection header.

1H-NMR (DMSO-d6) (M. D.): and 2.26-to 2.29 (2H, m), 3,05 (2H, t, J=6.0 Hz), 3,53 of 3.56 (2H, m), of 7.48 (1H, t, J=7,6 Hz), 7,86-of 7.90 (2H, m), of 7.96-of 8.04 (3H, m), 8,10 (1H, d, J=2.4 Hz), the rate of 8.75 (1H, d, J=2.4 Hz), 11,24 (1H, s).

Example 51: N-(8-bronchioles-3-yl)-4-(3-methylsulfinylpropyl)benzosulfimide

Specified in the title compound (62 mg) was obtained in accordance with the procedure described in example 1, except that used 33 mg (0.14 mmol) of 3-amino-8-brainline (example obtaining 5) and 66 mg (0.22 mmol) of 4-(3-methylsulfinylpropyl)benzosulfimide.

1H-NMR (DMSO-d6) (M. D.): 1,90-to 1.98 (2H, m), of 2.72 (2H, t, J=8.0 Hz), with 2.93 (3H, s), 3,06 (2H, t, J=8.0 Hz), 7,42 (2H, d, J=8.0 Hz), 7,46 (1H, d, J=7,6 Hz), of 7.97 (2H, d, J=7,6 Hz), 8,00 (1H, d, J=7,6 Hz), with 8.05 (1H, d, J=2.4 Hz), 8,72 (1H, d, J=2.4 Hz), br11.01 (1H, s).

Example 52: N-(8-bronchioles-3-yl)-4-forbindelsesfaneblad

Specified in the title compound (50 mg) was obtained in accordance with the procedure described in example 1, except that used 33 mg (0.14 mmol) of 3-amino-8-brainline (example obtaining 5) and 39 mg (0.20 mmol) 4-forbindelsesfaneblad.

1H-NMR (DMSO-d6) (M. D.): 7,40 (1H, t, J=8,8 Hz), 7,47 (1H, t, J=7,6 Hz), 7,89-7, N-(8-bronchioles-3-yl)-4-methoxy-2-pyridinesulfonamide

Under ice cooling gaseous chlorine was barbotirovany through a solution of 2-benzylthio-5-methoxypyridazine (0,86 g, 3.7 mmol, example of getting 14) in concentrated hydrochloric acid (8 ml), then was stirred for 1 hour. Then to the reaction mixture were added ice water and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated salt solution, dried over magnesium sulfate and concentrated to obtain residue 700 mg (2.1 mmol). Specified in the title compound (93 mg) was obtained in accordance with the procedure described in example 1, except that used 180 mg (0.54 mmol) obtained above residue and 60 mg (0.27 mmol) of 3-amino-8-brainline (example obtaining 5).

1H-NMR (DMSO-d6) (M. D.): 4,07 (3H, s), 7,44 (1H, d, J=9,2 Hz), 7,47 (1H, t, J=7,6 Hz), of 7.96 (1H, t, J=7,6 Hz), 8,02 (1H, t, J=7,6 Hz), 8,13 (1H, d, J=2.4 Hz), 8,17 (1H, d, J=9,2 Hz), 8,82 (1H, d, J=2.4 Hz), 11,54 (1H, s).

Example 54: N-(8-bronchioles-3-yl)benzosulfimide

Specified in the title compound (49 mg) was obtained in accordance with the procedure described in example 1, except that used 30 mg (0.13 mmol) of 3-amino-8-brainline (example obtaining 5) and 35 mg (0.20 mmol) of benzosulfimide.

Example 55: N-(8-bronchioles-3-yl)-4-carboxamid-2-pyridinesulfonamide

Under ice cooling gaseous chlorine was barbotirovany through a solution of 2-benzylthio-4-carboxamidine (1.1 g, 4.3 mmol, example of getting 15) in concentrated hydrochloric acid (16 ml), then was stirred for 1 hour. Then to the reaction mixture were added ice water and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated salt solution, dried over magnesium sulfate and concentrated. Specified in the title compound (37 mg) was obtained in accordance with the procedure described in example 1, except that used 140 mg (0.40 mmol) obtained above residue and 45 mg (0.20 mmol) of 3-amino-8-brainline.

1H-NMR (DMSO-d6) (M. D.): 7,46 (1H, d, J=8.0 Hz), 7,94-of 7.96 (2H, m), 8,00-8,02 (2H, m) to 8.12 (1H, d, J=2.4 Hz), 8,44 (1H, W), 8,49 (1H, W), 8,83 cent to 8.85 (2H, m), 11,35 (1H, s).

Example 56: N-(8-bronchioles-3-yl)-3-methoxybenzenesulfonamide

Specified in the title compound (70 mg) was obtained in accordance with the procedure described in example 1, except that used 40 mg (0.18 mmol) 3-amino-8-brainline (example obtaining 5) and 56 mg (0 to 8.0 Hz), 7,34-7,40 (2H, m), 7,45 (1H, t, J=7,6 Hz), 7,47 (1H, t, J=7,6 Hz), to 7.99 (2H, t, J=7,6 Hz), 8,07 (1H, d, J=2.4 Hz), 8,72 (2H, m), 11,35 (1H, d, J=2,4 Hz).

Example 57: N-(8-bronchioles-3-yl)-3-hydroxybenzenesulfonate

Specified in the title compound (73 mg) was obtained in accordance with the procedure described in example 1, except that used 45 mg (0.20 mmol) of 3-amino-8-brainline (example obtaining 5) and 117 mg (0.61 mmol) of 3-hydroxybenzenesulfonate.

1H-NMR (DMSO-d6) (M. D.): 6,97 (1H, d, J=8.0 Hz), 7,18 (1H, W), of 7.25 (1H, d, J=8.0 Hz), 7,34 (1H, t, J=8.0 Hz), 7,47 (1H, t, J=8.0 Hz), of 7.97 (1H, d, J=8.0 Hz), 8,01 (1H, d, J=8.0 Hz), of 8.04 (1H, d, J=2.4 Hz), 8,73 (1H, d, J=2.4 Hz), 10,15 (1H, s), 10,96 (1H, s).

Example 58 N-(4-bronchioles-7-yl)-4-chlorobenzenesulfonamide

In 1.5 ml of pyridine was dissolved 20 mg (0.09 mmol) of 7-amino-4-bromoisoquinoline (example receive 20), was added 23 mg of 4-chlorobenzenesulfonamide, then stirred at room temperature overnight. To the reaction mixture were added water and then extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. Then the obtained residue was purified by thin-layer chromatography on silica gel to obtain 13 mg specified in the connection header. Melting point: the substance is gradually decomposed in the beginning of the m), to 7.99 (1H, d, J=9,2 Hz), at 8.60 (1H, s).

Example 59: N-(4-bromoisoquinoline-7-yl)-6-chloro-3-pyridinesulfonamide

Specified in the title compound was obtained from 7-amino-4-bromoisoquinoline (example receive 20) and 6-chloro-3-pyridinesulfonamide similarly to the method of example 57.

1H-NMR (DMSO-d6) (M. D.): 7,66 (1H, DD, J=2,4 Hz and 9.2 Hz), of 7.70 (1H, d, J=8,4 Hz), 7,89 (1H, d, J=2.4 Hz), 8,02 (1H, d, J=9,2 Hz), to 8.20 (1H, DD, J=2,4 Hz and 8.4 Hz), 8,64 (1H, s), 8,84 (1H, d, J=2.4 Hz), 9,26 (1H, s).

Example 60: 2-(4-chlorobenzenesulfonyl)-1,6-naphthylidine

In dichloromethane (6.0 ml) was dissolved 200 mg of 2-amino-1,6-naphthiridine (example receive 25) was added triethylamine (0,20 ml) and 4-chlorobenzenesulfonamide (0.31 g), then stirred at 40°C for 1.5 hours. Was added a saturated aqueous solution of sodium bicarbonate and then extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified on a column of silica gel with obtaining specified in the title compound (84 mg, 21,44%) in the form of crystals of pale yellow color.

1H-NMR (CDCl3) (M. D.): 7,10 (1H, d, J=9,2 Hz), 7,37 (1H, d, J=5.4 Hz), 7,46 (2H, d, J=8,8 Hz), to 7.93 (2H, d, J=8,8 Hz), to 8.94 (1H, d, J=9,2 Hz), 8,66 (1H, d, J=5.4 Hz), of 8.92 (1H, Shir. C).

An example is Ted methodology described in example 1, except that used 6-amino-1-chloroisoquinoline (an example of retrieving 23) and 4-cyanobenzenesulfonyl.

1H-NMR (DMSO-d6) (M. D.): 7,52 (1H, DD, J=2.0 Hz, 8,8 Hz), to 7.68 (1H, d, J=2.0 Hz), 7,79 (1H, d, J=5.6 Hz), 8,03 (4H, m), 8,18 (1H, d, J=5.6 Hz), 8,21 (1H, d, J=8,8 Hz), 11,36 (1H, s).

Example 62: 1-chloro-6-(4-chlorobenzenesulfonyl)isoquinoline

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-chloroisoquinoline (an example of retrieving 23) and 4-chlorobenzenesulfonamide.

1H-NMR (CDCl3) (M. D.): 7,33 (1H, Shir.C), 7,39 (1H, DD, J=2.0 Hz, 8,8 Hz), 7,44 (2H, d, J=8,8 Hz) to 7.50 (1H, d, J=5.6 Hz), 7,58 (1H, d, J=2.0 Hz), 7,81 (2H, d, J=8,8 Hz), 8,24 (1H, d, J=5.6 Hz), of 8.25 (1H, d, J=8,8 Hz).

FAB-MS: 353.

Example 63: 1-chloro-6-(4-(pyrrolidin-1-ylsulphonyl)benzosulfimide)isoquinoline

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-chloroisoquinoline (an example of retrieving 23) and 4-(pyrrolidin-1-ylsulphonyl)benzosulphochloride.

1H-NMR (CDCl3) (M. D.): 1,71 (4H, m), 3,20 (4H, t, J=7.0 Hz), 7,46 (1H, d, J=5.4 Hz), 7,49 (1H, DD, J=2.0 Hz, 9,2 Hz), to 7.61 (1H, d, J=2.0 Hz), 7,87 (2H, d, J=8,8 sulfonylamino)isoquinoline

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-chloroisoquinoline (an example of retrieving 23) and 4-(N-ethylsulfonyl)benzosulphochloride.

1H-NMR (DMSO-d6) (M. D.): 0,81 (3H, t, J=7.2 Hz), 2,73 (2H, m), 7,53 (1H, d, J=9,2 Hz), to 7.67 (1H, s), of 7.75 (1H, d, J=6.0 Hz), 7,78 (1H, d, J=6.0 Hz), 7,92 (2H, d, J=8.0 Hz).

Example 65: 1-methoxy-6-(pyridine-3-ylsulphonyl)isoquinoline

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-methoxyethanol (example receiving 43) and 3-pyridinesulfonamide.

1H-NMR (DMSO-d6) (M. D.): 4.09 to (3H, s), to 7.09 (1H, d, J=6.0 Hz), 7,25 (1H, DD, J=2.0 Hz, 8,8 Hz), 7,37 (1H, DD, J=8.0 Hz, 8,8 Hz), of 7.48 (1H, d, J=2.0 Hz), of 7.96 (1H, d, J=6.0 Hz), 8,07 (1H, DDD, J=1,6 Hz, 2.0 Hz, 8.0 Hz), to 8.14 (1H, d, J=8,8 Hz), a total of 8.74 (1H, DD, J=1,6 Hz and 8.8 Hz), the remaining 9.08 (1H, d, J=2.0 Hz).

ESI-MS: 316,0.

Example 66: 6-(4-cyanobenzenesulfonyl)-1-methoxyethanol

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-methoxyethanol (example receiving 43) and 4-cyanobenzenesulfonyl.

1, =7,6 Hz), 8,03 (1H, d, J=8,8 Hz).

Example 67: 6-(4-carbamoylmethyl)-1-methoxyethanol

Specified in the title compound was obtained in accordance with the method described in Synthesis, 949 (1989), except that used 6-(4-cyanobenzenesulfonyl)-1-methoxyethanol (example 65).

1H-NMR (DMSO-d6) (M. D.): 3,96 (3H, s), 7,24 (1H, d, J=6.4 Hz), 7,33 (1H, d, J=9,2 Hz), 7,51 (1H, s), 7,55 (1H, Shir.C) 7,88 (1H, d, J=6.4 Hz), 7,89 (2H, d, J=8.0 Hz), to 7.93 (2H, d, J=8.0 Hz), 8,01 (1H, d, J=9,2 Hz), of 8.06 (1H, Shir.C) 10,95 (1H, s).

FAB-MS: 358.

Example 68: 6-(4-(N-ethylsulfonyl)benzosulfimide)-1-methoxyethanol

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-methoxyethanol (example receiving 43) and 4-(N-ethylsulfonyl)benzosulphochloride.

1H-NMR (DMSO-d6) (M. D.): 0,81 (3H, t, J=6.8 Hz), 2,71 (2H, m), of 3.96 (3H, s), 7.23 percent (1H, d, J=6.4 Hz), 7,32 (1H, d, J=8,8 Hz), of 7.48 (1H, s), 7,73 (1H, Shir.C), 7,89 (2H, d, J=8.0 Hz), of 7.90 (1H, d, J=6.4 Hz), 8,01 (3H, m), 11,03 (1H, Shir.C).

ESI MS: 422,0.

Example 69: 6-(2-aminopyridine-5-ylsulphonyl)-1-methoxyethanol

Specified in the title compound was obtained in accordance with the procedure described in example 1 for chloride.

1H-NMR (DMSO-d6) (M. D.): 3,96 (3H, s), to 6.39 (1H, d, J=8,8 Hz), 6.89 in (2N, C), 7,25 (1H, d, J=4, 2 Hz), 7,32 (1H, d, J=9,2 Hz), 7,47 (1H, s), to 7.64 (1H, d, J=9,2 Hz), 7,89 (1H, d, J=4, 2 Hz), 8,01 (1H, d, J=8,8 Hz), 8,31 (1H, s), 10,95 (1H, s).

ESI MS: 331,0.

Example 70: 1-methoxy-6-(4-methylbenzoyl vanillin)isoquinoline

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-methoxyethanol (example receiving 43) and 4 - toluensulfonate.

1H-NMR (DMSO-d6) (M. D.): 2,28 (3H, s), of 3.96 (3H, s), 7,22 (1H, d, J=6.0 Hz), 7,32 (3H, m), of 7.48 (1H, s), 7,71 (2H, d, J=8,4 Hz), 7,88 (1H, d, J=6.0 Hz), 8,00 (1H, d, J=9,2 Hz), 10,79 (1H, s).

ESI MS: 329,0.

Example 71: 6-(4-acetamidobenzenesulfonyl)-1-methoxyethanol

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-methoxyethanol (example receiving 43) and 4-acetamidobenzenesulfonyl.

1H-NMR (DMSO-d6) (M. D.): a 2.01 (3H, s), of 3.96 (3H, s), 7.23 percent (1H, d, J=6.0 Hz), 7,32 (1H, d, J=9,2 Hz), 7,47 (1H, s), to 7.67 (1H, d, J=8,8 Hz), 7,76 (2H, d, J=8,8 Hz), 7,88 (1H, d, J=6.0 Hz), 8,00 (1H, d, J=9,2 Hz), 10,26 (1H, s), is 10.75 (1H, s).

ESI MS: 372,1.

Example 72: 6-(4-methanesulfonyl ogino the method of example 1, except that used 6-amino-1-methoxyethanol (example receiving 43), and 4-nitrobenzenesulfonamide restored by the similar method of example getting 170. The compound obtained was dissolved in pyridine under ice cooling was added methanesulfonamide and then left under stirring for 4 hours. Was added a saturated salt solution and then was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified on a column of silica gel and the obtained crystals are recrystallized from ethanol to obtain specified in the connection header.

1H-NMR (DMSO-d6) (M. D.): a 3.06 (3H, s), of 3.97 (3H, s), from 7.24 (3H, m), 7,33 (1H, d, J=9.0 Hz), 7,49 (1H, s), 7,79 (2H, d, J=8,8 Hz), 7,89 (1H, d, J=6.0 Hz), 8,01 (1H, d, J=9.0 Hz), accounted for 10.39 (1H, s) 10,80 (1H, s).

ESI MS: 372,1.

Example 73: 6-(2-chloropyridin-5-ylsulphonyl)-1-methoxyethanol

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-methoxyethanol (example receiving 43) and 6-chloro-3-pyridinesulfonamide.

1H-NMR (DMSO-d6) (M. D.): and 3.31 (3H, s), 3,99 (1N which, C).

ESI MS: 350,1.

Example 74: 1-methoxy-6-(3-methylbenzenesulfonyl)isoquinoline

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-methoxyethanol (example receiving 43) and 3-toluensulfonate.

1H-NMR (DMSO-d6) (M. D.): 2,31 (3H, s), of 3.96 (3H, s), 7,22 (1H, d, J=6.0 Hz), 7,32 (1H, DD, J=2.0 Hz, 8,8 Hz), 7,39 (2H, m), 7,47 (1H, d, J=2.0 Hz), a 7.62 (1H, m), to 7.67 (1H, s), 7,87 (1H, d, J=6.0 Hz), 8,00 (1H, d, J=8,8 Hz), 10,84 (1H, s).

Example 75: 6-benzylmethylamine-1-methoxyethanol

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-methoxyethanol (example receiving 43) and benzolsulfonate.

1H-NMR (DCl3) (M. D.): 4,13 (3H, s), 4,42 (2H, s), 6,69 (1H, Shir.C) 7,13 (2H, m), 7,22 (2H, m), 7,30-7,37 (3H, m) to 7.50 (1H, d, J=2.4 Hz), to 7.99 (1H, d, J=6.0 Hz), to 8.20 (1H, d, J=8,8 Hz).

Example 76: 6-(3-cyanobenzenesulfonyl)-1-methoxyethanol

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-methoxyethanol (example receiving 43) and 3-cyanobenzenesulfonyl), of 7.75 (1H, DD, J=8.0 Hz, 8.0 Hz), to $ 7.91 (1H, d, J=6.0 Hz), of 8.04 (1H, d, J=8,8 Hz), of 8.09 (2H, m), 9,29 (1H, m) 11,05 (1H, s).

Example 77: 1-methoxy-6-(4-thiazol-2-eventulally) isoquinoline

The compound (40 mg) obtained in accordance with the procedure described in example 1, except that used 6-amino-1-methoxyethanol (example receiving 43) and 4-iodobenzonitrile, as well as 2-tri-n-butylstannane (136 mg), tetrakis(triphenylphosphine)palladium(0) (11 mg) was heated at boiling under reflux in toluene in a nitrogen atmosphere for 1 hour. The solvent is evaporated, the residue was purified on a column of silica gel. The obtained crystals are recrystallized from methanol to obtain specified in the title compound (20 mg).

1H-NMR (CDCl3) (M. D.): 4,08 (3H, s) 6,94 (1H, Shir.C) to 7.09 (1H, d, J=6.0 Hz), 7.23 percent (1H, DD, J=2.0 Hz, 8,8 Hz), 7,41 (1H, d, J=3.6 Hz), was 7.45 (1H, d, J=2.0 Hz), 7,89 (2H, d, J=8,4 Hz), of 7.90 (1H, d, J=8.6 Hz), 7,95 (1H, d, J=6.0 Hz), 7,82 (2H, d, J=8,4 Hz), 8,13 (1H, d, J=8,8 Hz).

Example 78: 6-(4-chlorobenzenesulfonyl)-1-methoxyethanol

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-methoxyethanol (example receiving 43) and 4-chlorobenzenesulfonyl is Hz), 7,63 (2H, d, J=8,8 Hz), the 7.85 (1H, d, J=8,8 Hz), 7,92 (1H, d, J=5.6 Hz), of 8.06 (1H, d, J=8,8 Hz), 10,97 (1H, s).

Example 79: 6-(4-chlorobenzenesulfonyl)-1-methylisoquinoline

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-methylisoquinoline (example obtain 33) and 4-chlorobenzenesulfonamide.

1H-NMR (DMSO-d6) (M. D.): was 2.76 (3H, s), 7,56 (1H, d, J=6.0 Hz), 7,52 (2H, m), 7,60 (2H, d, J=8,8 Hz), 7,82 (2H, d, J=8,8 Hz), 8,08 (1H, d, J=9,2 Hz), to 8.20 (1H, d, J=6.0 Hz).

ESI-MS: 333,0.

Example 80: 6-(4-chlorobenzenesulfonyl)-1-utilizacion

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-1-utilizacion (example obtain 48) and 4-chlorobenzenesulfonamide.

1H-NMR (DMSO-d6) (M. D.): of 1.39 (3H, t, J=7,6 Hz) at 3.25 (2H, q, J=7,6 Hz), 7,35 (1H, DD, J=2,4 Hz and 9.2 Hz), 7,38 (1H, d, J=5.6 Hz), 7,41 (2H, d, J=8,8 Hz), 7,53 (1H, d, J=2.4 Hz), 7,81 (2H, d, J=8,8 Hz), with 8.05 (1H, d, J=9,2 Hz), of 8.37 (1H, d, J=5.6 Hz).

ESI-MS: 347,0.

Example 81: 6-(4-chlorobenzenesulfonyl)-4-utilizacion

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that the NMR (DMSO-d6) (M. D.): of 1.18 (3H, t, J=7.2 Hz), 2,85 (1H, q, J=7.2 Hz), 7,38 (1H, d, J=8,8 Hz), 7,60 (1H, s), a 7.62 (2H, d, J=8.0 Hz), 7,82 (2H, d, J=8.0 Hz), 8,00 (1H, d, J=8,8 Hz), compared to 8.26 (1H, s), 8,99 (1H, s).

Example 82: 6-(4-chlorobenzenesulfonyl)-4-methylisoquinoline

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-4-methylisoquinoline (example receiving 58) and 4-chlorobenzenesulfonamide.

1H-NMR (DMSO-d6) (M. D.): 2,43 (3H, s), 7,41 (1H, d, J=8,8 Hz), 7,56 (1H, s), a 7.62 (2H, d, J=8,8 Hz), the 7.85 (2H, d, J=8,8 Hz), to 7.99 (1H, d, J=8,8 Hz), compared to 8.26 (1H, s), 8,98 (1H, s), 11,09 (1H, Shir.C).

Example 83: 6-(4-chlorobenzenesulfonyl)-3-methylisoquinoline

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-amino-3-methylisoquinoline (example getting 76) and 4-chlorobenzenesulfonamide.

1H-NMR (DMSO-d6) (M. D.): 2,53 (3H, s), 7,30 (1H, d, J=8,8 Hz), 7,45 (1H, s) to 7.50 (1H, s), a 7.62 (2H, d, J=8,4 Hz), to 7.84 (2H, d, J=8,4 Hz), to 7.93 (1H, d, J=8,8 Hz), 9,03 (1H, s).

Example 84: 6-(4-chlorobenzenesulfonyl)-1-cyanoethylene

Specified in the title compound was obtained in accordance with the procedure described in example 1, except that used 6-AMI is Denia ice was added m-chloroperbenzoic acid (0.9 g), then was stirred at room temperature overnight. The solvent is evaporated, the obtained crystals were washed with diethyl ether, filtered and dried to obtain N-oxide 6-(4-chlorobenzenesulfonyl)isoquinoline (1,072 g). In acetonitrile (1.5 ml) was dissolved 50 mg of the obtained compound. To the mixture was added trimethylsilane (0,08 ml) and triethylamine (0.04 ml), then heated at the boil under reflux for 3.5 hours. After evaporation of the solvent the residue was purified on a column of silica gel with obtaining specified in the title compound (23 mg, 64%) as yellow crystals.

1H-NMR (DMSO-d6) (M. D.): 7,66 (2H, d, J=8,8 Hz), to 7.67 (1H, DD, J=2.0 Hz, 9,2 Hz), 7,80 (1H, d, J=2.0 Hz), to 7.93 (2H, d, J=8,8 Hz), 8,17 (1H, d, J=9,2 Hz), 8,18 (1H, d, J=5.6 Hz), 8,59 (1H, d, J=5.6 Hz).

ESI-MS: 344,1.

Example 85: 1-carbarnoyl-6-(4-chlorobenzenesulfonyl)isoquinoline

The crystals obtained in accordance with the method described in Synthesis, 949 (1989), except that used 6-(4-chlorobenzenesulfonyl)-1-cyanoethylene (30 mg, example 83), washed with diethyl ether to obtain specified in the title compound (26 mg, 82%) as colorless crystals.

1H-NMR (CDCl3) (M. D.): of 6.25 (1H, Shir.C) to 7.35 (2H, d, J 2 Hz), 9,76 (1H, Shir.C).

Example 86: 6-(4-chlorobenzenesulfonyl)-1-methylaminoethanol

A mixture of 1-chloro-6-(4-chlorobenzenesulfonyl)isoquinoline (50 mg, example 61) and 40% solution of methylamine in methanol (5.0 ml) was heated in a sealed tube at 130°C for 18 hours. After cooling, was added saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified on a column of silica gel with obtaining specified in the title compound (28 mg, 52%) as a solid pale yellow color.

1H-NMR (CDCl3) (M. D.): 3,14 (3H, s), with 5.22 (1H, Shir.C) 6,89 (1H, d, J=6.0 Hz), 7,19 (H, DD, J=2,4 Hz and 9.2 Hz), 7,31 (1H, d, J=2.4 Hz), 7,40 (2H, d, J=8,8 Hz), to 7.64 (1H, d, J=9,2 Hz), 7,73 (2H, d, J=8,8 Hz), 7,98 (1H, d, J=6.0 Hz).

Example 87: 1-amino-6-(4-chlorobenzenesulfonyl)isoquinoline

The crystals obtained in accordance with the methodology described in YAKUGAKU ZASSHI (Journal of the Pharmaceutical Society of Japan), 84, 35 (1964), except that used the N-oxide 6-(4-chlorobenzenesulfonyl)isoquinoline (50 mg, an intermediate compound in example 83), washed with diethyl ether and dried to obtain specified in the.): 7,76 (1H, d, J=6.0 Hz), 6,93 (2H, Shir.C) to 7.15 (1H, DD, J=2.0 Hz, 8,8 Hz), 7,27 (1H, d, J=2.0 Hz), to 7.59 (2H, d, J=8,8 Hz), 7,63 (1H, d, J=6.0 Hz), 7,80 (2H, d, J=8,8 Hz), 9,05 (1H, d, J=6.0 Hz).

ESI-MS: 334,1.

Example 88: 6-(4-chlorobenzenesulfonyl)-1-dimethylaminoethanol

In dimethyl sulfoxide (1 ml) was dissolved 60 mg of 1-chloro-6-(4-chlorobenzenesulfonyl)isoquinoline (example 61). To the mixture was added a 50% solution of dimethylamine in methanol (0.04 ml), then was heated at 80°C under stirring for 10 hours. After cooling, was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified preparative TLC and utverjdali from isopropyl ether to obtain specified in the title compound (17 mg).

1H-NMR (DMSO-d6) (M. D.): 2,96 (6N, (C), 7,12 (1H, d, J=6.0 Hz), 7,27 (1H, DD, J=2.0 Hz, 9,2 Hz), was 7.45 (1H, d, J=2.0 Hz), to 7.64 (2H, d, J=8,8 Hz), the 7.85 (2H, d, J=8,8 Hz), to 7.93 (1H, d, J=6.0 Hz), 8,01 (1H, d, J=9,2 Hz), 10,91 (1H, Shir.C).

Example 89: 6-(4-chlorobenzenesulfonyl)-1-hydroxyisoquinoline

In acetic anhydride (0.75 ml) was dissolved 50 mg of N-oxide-6-(4-chlorobenzenesulfonyl)isoquinoline (intermediate compound in example (83), then was heated at 80°C under stirring in those is sodium and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was dissolved in ethanol (2.0 ml) and water (0.5 ml), then heated at the boil under reflux for 0.5 hours. After evaporation of the solvent the residue was purified on a column of silica gel with obtaining specified in the title compound (20 mg) as a solid pale red color.

1H-NMR (CDCl3) (M. D.): to 6.58 (1H, d, J=7,2 Hz), 7,22 (1H, d, J=7,2 Hz), 7,31 (1H, DD, J=2.0 Hz, 8,4 Hz), 7,54 (1H, d, J=2.0 Hz), 7,56 (2H, d, J=8,8 Hz), 8,01 (2H, d, J=8,8 Hz), 8,53 (1H, d, J=8,4 Hz), 10,36 (1H, Shir.C).

ESI-MS: 335,1.

Example 90: 6-(4-chlorobenzenesulfonyl)-1-ethoxyethanol

In dimethyl sulfoxide (1 ml) was dissolved 57 mg of 1-chloro-6-(4-chlorobenzenesulfonyl)isoquinoline (example 61). To the mixture was added ethanol (0.1 ml) and 60% sodium hydride (14 mg), and then was heated at 80°C under stirring for 9 hours. After cooling, was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent evaporated. Then the residue was purified preparative TLC and utverjdali from isopropyl ether to obtain specified in the connection header (21 9,2 Hz), to 7.50 (1H, d, J=2.0 Hz), 7,63 (2H, d, J=8,8 Hz), of 7.90 (1H, d, J=6.0 Hz), of 8.04 (1H, d, J=9,2 Hz), 10,94 (1H, Shir.C).

Example 91 N-(5-vinylpyridin-2-yl)-3-pyridinesulfonamide

A solution of 2-amino-5-brainline (510 mg, example a 1), vinyltrimethylsilane (0,94 ml), toluene (4 ml), tetrakis(triphenylphosphine)palladium(0) (20 mg) and 2,6-di-tert-butyl-p-cresol (about 0.1 mg) was stirred at 120°C for 4 hours. After cooling to room temperature was added water and the mixture was extracted with ethyl acetate. An ethyl acetate layer was dried over magnesium sulfate and concentrated. Then the obtained solid was washed with hexane to obtain 282 mg of a solid product containing vinyl derivative. The solid was dissolved in 2 ml of pyridine was added 412 mg of 3-pyridinesulfonamide, then stirred at room temperature overnight. Added water and the mixture was extracted with ethyl acetate. An ethyl acetate layer was dried over magnesium sulfate and concentrated. Then the obtained solid was washed with methanol to obtain specified in the title compound (235 mg).

1H-NMR (CDCl3) (M. D.): 5,59 (1H, DD, J=10,8 Hz, 1.5 Hz), of 5.82 (1H, DD, J=16.9 and Hz, 1.5 Hz), to 6.95 (1H, d, J=10.3 Hz), 7,20 (1H, DD, J=10,8 Hz and 16.9 Hz), was 7.36 (1H, d, J=8.5 Hz), the 7.43 (1H, m) to 7.50 (1H, d, J=8.5 Hz), a 7.62 (1H,sulfonamid

To a solution of 7-amino-4-triptorelin (200 mg, 0.87 mmol) and 4-dimethylaminopyridine (1 mg) in pyridine (3 ml) was added 4-chlorobenzenesulfonamide (203 mg, 0.96 mmol), then stirred at 70°C for 50 minutes. To the reaction mixture were added 2 N. hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. The obtained residue was led from a mixture of ethyl acetate-diisopropyl ether to obtain 253 mg specified in the connection header in the form of a solid pale yellow color.

1H-NMR (DMSO-d6) (M. D.): 6,87 (1H, s), 7,12 (1H, d, J=2,4), 7,17 (1H, DD, J=2,6 Hz and 8.4 Hz), 7,60 (1H, d, J=8,4 Hz), to 7.67 (2H, d, J=6.8 Hz), 7,87 (2H, d, J=6.8 Hz), of 11.29 (1H, s).

1. Sulfonamides heterocyclic compound represented by formula (I), its pharmaceutically acceptable salt or hydrate

where a represents a hydrogen atom, halogen atom, hydro is the Rupp, (CO) kNR2R3(where R2and R3the same or different and each means a hydrogen atom or a C1-C4 alkyl group, and k = 0 or 1) or C2-C4 alkenylphenol group;

In represents an aryl group or pyridyloxy or pyridazinyl group which may have a Deputy, selected from the following group a, or

where the ring Q is an aromatic ring which may have one or two nitrogen atom;

ring M is an unsaturated C5-C12 monocyclic ring having a common double bond with a ring Q, and the ring may contain 1 or 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom; ring M may have a Deputy, selected from the following group A;

It represents a simple bond or -(CR4R5)m- (where R4and R5each means a hydrogen atom, a m = 1 or 2);

T, W, X and Y are the same or different and each means =C(D) (where D represents a hydrogen atom, halogen atom, C1-C4 alkyl group or a C2-C4 alkenylphenol group) or a nitrogen atom;

U and V are the same or different and each means =C(D) (where D has the values defined above), a nitrogen atom, an oxygen atom or-CO-;

Z Pravasi;

group a halogen atom, hydroxyl group, C1-C4 alkyl group or alkoxygroup, cyano, -R8R9N(NH)p- (where R8and R9the same or different and each means a hydrogen atom or a C1-C4 alkyl group; p = 0 and R8and R9can be combined with the nitrogen atom to which they relate, with the formation of 5-membered rings), aminosulfonyl group which may be substituted by one or two C1-C4 alkyl groups, C1-C8 acyl group, C1-C4 alkyl-S(O)s-C1-C4 Allenova group (where s = 2), -(CO)qNR10R11(where R10and R11each means a hydrogen atom, and q = 0 or 1) or 1,3-thiazolidine group,

provided that the excluded cases, when U represents an oxygen atom, V means-CO - or-CH2-; when V represents an oxygen atom, U represents-CO - or-CH2-; and the following cases: 1) where only one of T, U, V, W, X and Y represents a nitrogen atom and a and D both represent hydrogen atoms; 2) where T, U, V, W, X and Y all are nitrogen atoms; 3) where Y and W are nitrogen atoms; T, U, V and X are =C(D1)- (where D1means a hydrogen atom, methyl group, halogen atom, triptorelin group or a methoxy group); 4) where W represents a nitrogen atom; T, U, a hydroxyl group, and B represents p-toluensulfonyl group; 5) where V and W are nitrogen atoms; 6) where T, V and W are nitrogen atoms; 7) X and Y represent C(CH3), Z represents a simple bond, R1 represents a hydrogen atom, represents a simple bond, is 4-were, W represents a nitrogen atom, V, U and T represent-CH= and a represents a hydrogen atom; 8) X represents-C(och3)=, Y represents a nitrogen atom, Z represents a simple bond, R1 represents a hydrogen atom, represents a simple bond, is 4-were, W is-C(CONH2)=, V, U and T represent-CH= and a represents a hydrogen atom.

2. Sulfonamides heterocyclic compound under item 1, its pharmaceutically acceptable salt or hydrate, in which U and V are =C(D) (where D has the values defined above) or a nitrogen atom.

3. Sulfonamides heterocyclic compound under item 1 or 2, its pharmaceutically acceptable salt or hydrate, in which Z represents a simple link.

4. Sulfonamides heterocyclic compound according to any one of paragraphs.1-3, its pharmaceutically acceptable salt or hydrate, in which at least one of T, U, V, W, X and Y represents a nitrogen atom.

5. Sulfonamides heterocyclic halogen atom, C1-C4 alkyl or alkoxygroup, which can be locked by a halogen atom, cyano, -(CO)kNR2R3(where R2and R3the same or different and each means a hydrogen atom or a C1-C4 alkyl group which may be substituted by a halogen atom, and k = 0 or 1) or C2-C4 alkenylphenol group.

6. Sulfonamides heterocyclic compound according to any one of paragraphs.1-5, its pharmaceutically acceptable salt or hydrate, in which only one of T, U, V, W, X and Y represents a nitrogen atom.

7. Sulfonamides heterocyclic compound according to any one of paragraphs.1-6, its pharmaceutically acceptable salt or hydrate, in which only one of T, W and Y represents a nitrogen atom.

8. Substituted with halogen quinoline compound represented by the formula

where Y1and W1different and each means a nitrogen atom or =C(D3)- (where D3represents a hydrogen atom or hydroxyl group);

E represents a halogen atom, cyano or C1-C4 alkyl group which may be substituted by a halogen atom;

J represents an amino group which may have a protective group;

G1represents a hydrogen atom,

em hydroxyl group; J represents the amino group and G1represents a hydrogen atom.

9. The method of obtaining the compound represented by the formula

where E1represents a halogen atom;

R16is carboxylato group;

G2represents a hydrogen atom, halogen atom, hydroxyl group or C1-C4 alkyl group, or alkoxygroup, which may be substituted by a halogen atom,

which includes a step of recovery of the compounds represented by the formula

where E1represents a halogen atom;

E2represents a chlorine atom or a bromine atom;

R16is carboxylato group;

G2represents a hydrogen atom, halogen atom, hydroxyl group or C1-C4 alkyl group, or alkoxygroup, which may be substituted by a halogen atom,

tin, zinc, or iron.

10. The antitumor agent comprising as an active ingredient sulfonamides heterocyclic compound according to any one of paragraphs.1-7, its pharmaceutically acceptable salt or hydrate.

11. The agent for suppressing the metastasis zlokacestvennoe according to any one of paragraphs.1-7, its pharmaceutically acceptable salt or hydrate.

12. Therapeutic agent for the treatment of conditions in which antiangiogenic action is effective, comprising as an active ingredient sulfonamides heterocyclic compound according to any one of paragraphs.1-7, its pharmaceutically acceptable salt or hydrate.

13. The antitumor agent according to p. 10, comprising as an active ingredient sulfonamides heterocyclic compound 4-cyano-N-(8-eothinon-3-yl)-benzosulfimide, its pharmaceutically acceptable salt or hydrate.

14. The agent for suppressing the metastasis of malignant tumor, comprising as an active ingredient sulfonamides heterocyclic compound 4-cyano-N-(8-eothinon-3-yl)-benzosulfimide, its pharmaceutically acceptable salt or hydrate.

15. A method of preventing or treating diseases in which an antiangiogenic effect is effective for prevention or treatment, which includes an introduction to the patient a pharmacologically effective amount sulfonamides heterocyclic compounds according to any one of paragraphs.1-7, its pharmaceutically acceptable salt or ESCI acceptable salt or hydrate for the production of antiangiogenic agent, antitumor agent, agent, suppressing the metastasis of malignant tumor, therapeutic agent for the treatment of conditions in which antiangiogenic action is effective.



 

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The invention relates to the derivatives of imidazopyridine formula

or its pharmaceutically acceptable salts, where R1- H, CH3or CH2OH; R2- CH3CH2CH3; R3- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl, halogen; R4- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or halogen; R5- H or halogen; R6, R7are the same or different and mean H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or C1-C6alkoxy-substituted C1-C6alkyl; X represents NH or O, which inhibit exogenously or endogenously stimulated secretion of gastric acid and therefore can be used for the prevention and treatment of gastrointestinal inflammatory diseases

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The invention relates to 7-chloro-4-hydroxy-2(2-chloro-4-were)-1,2,5,10-tetrahydropyridine[4,5-b]quinoline-1,10-dione, its pharmaceutically acceptable salts, methods for treating pain, when administered pain relieving effective amount of this compound, and pharmaceutical compositions containing this compound

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

The invention relates to compounds of General formula I:

where n is 1, 2 or 3; R1and R2independently selected from hydrogen and alkyl; R3represents alkyl; R4-R7independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, alkoxy, aryloxy, alkylthio, aaltio, alkylsulfonyl, alkylsulfonyl, arysulfatase, arylsulfonyl, amino, monoalkylamines, dialkylamino, nitro, cyano, carboxaldehyde, alkylcarboxylic, arylcarbamoyl, aminocarbonyl, monoalkylammonium, dialkylaminoalkyl, alkoxycarbonyl, aminocarbonyl, monoalkylammonium, dialkylaminoalkyl, monoalkylammonium, dialkylaminomethyl, or R5and R6together form a carbocyclic or heterocyclic ring, its pharmaceutically acceptable salts and prodrugs and a method of treatment and pharmaceutical compositions having the properties of agonist 5-HT2

The invention relates to new and nitrate salts of compounds of formulas (I) to(VI), which can be used in medicine for the treatment of bone disorders such as abnormalities in bone and joints
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The invention relates to compounds of formula (I)

in which f represents phenylenebis radical, a represents the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; R11represents a hydrogen atom, an unbranched or branched alkyl radical having from 1 to 6 carbon atoms, or the radical

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where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

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Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to new derivatives of amine of the formula (I), where R1is karbamoilnuyu group (which may have one or two Deputydescribed later), thiocarbamoyl group (which may have one or two Deputydescribed later), sulfonyloxy group (which has one Deputydescribed next) or carbonyl group (which has one Deputydescribed below); R2represents a hydrogen atom; R3represents C1-C10alkyl group; W1, W2and W3each represents a single bond or C1-C8alkylenes group; X represents an oxygen atom or a sulfur atom; Y represents an oxygen atom; Q represents a sulfur atom; Z represents = CH-group or a nitrogen atom; Ar represents a benzene or naphthalene ring; L represents 1 to 2 substituents in Ar ring and each Deputy represents a hydrogen atom, a C1-C6alkyl group; Deputyrepresents (i) C1-C10alkyl group, (ii)3-Сu/chr/947.gif" ALIGN="ABSMIDDLE">described later), and so on; Deputyrepresents (i) C1-C6alkyl group, (ii) C1-C6halogenating group, (iii) C1-C6CNS group, (iv) halogen atom, (v) hydroxyl group, (vi) cyano, (vii) a nitro-group, (viii) alkylenedioxy; or its pharmaceutically acceptable salts or esters

The invention relates to new derivatives of benzopyran formula (I)

where R1and R2each independently represent a hydrogen atom, a C1-6-alkyl group, where this alkyl group may be optionally substituted by a halogen atom, a C1-6-alkoxygroup or a hydroxyl group; R3represents a hydroxyl group or a C1-6-alkylcarboxylic; R4represents a hydrogen atom, or R3and R4together form a bond, m is an integer from 0 to 4, n represents an integer from 0 to 4, Y is absent or represents CR11R12where R11and R12each independently represents a hydrogen atom or a C1-6is an alkyl group, R5represents an aryl group or heteroaryl group, such as thienyl, pyridyl or indolyl, where this aryl group may be optionally substituted(R10), where R10represents a halogen atom, a hydroxyl group, a C1-6-alkyl group, where this alkyl group may be optionally substituted by atom galactography, di-C1-6-alkylamino, C1-6-alkoxycarbonyl group, carboxyl group, q is an integer from 1 to 3, and each R10may be the same or different when q is 2 or 3, R6represents a hydrogen atom or a C1-6is an alkyl group, R10represents a hydrogen atom or a C1-6is an alkyl group, X is absent or represents C=O or SO2; R8represents a hydrogen atom, a C1-6-alkyl group, where this alkyl group may be optionally substituted by a halogen atom, or WITH3-6-cycloalkyl group, and R9represents a halogen atom, a nitro-group, or cyano; or their pharmaceutically acceptable salts, as well as a drug on the basis of these compounds with anti-arrhythmic activity
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