Derivatives dioxide benzothiazine, the pharmaceutical composition is based on them having inhibitory receptor endothelin activity, and a method of inhibiting endothelin receptor

 

(57) Abstract:

Describes the new derivatives dioxide benzothiazine General formula 1, where R2means a group of formula 2, or alkyl with 1 to 7 carbon atoms, each of Raand Rcmeans from one to five substituents, and Rbmeans from one to four substituents, independently from each other selected from the group comprising hydrogen, chlorine, methylenedioxy, Ethylenedioxy, groups, OR, and OCH2OR, where R denotes hydrogen, alkyl with 1 to 6 carbon atoms or phenyl, Rdmean group CO2R, SO3R, CONRR1where R has the above significance, and R1has the meaning given for the radical R, n means an integer from zero to two, --- means simple or double bond; X is (CH2)nor S(O)nwhere n has the above meaning, or their pharmaceutically acceptable salts accession acid or base. Also disclosed are pharmaceutical compositions on the basis of the presented compounds having activity of inhibiting endothelin, and how inhibition of the endothelin receptor. The invention expands the Arsenal of heterocyclic compounds, suitable as active substances, pharmaceutical the ical compounds with valuable biological properties, in particular derived dioxide benzothiazine, the pharmaceutical compositions based on them having inhibitory receptor endothelin activity, and to a method of inhibiting receptor endothelin.

It is known to use as an inhibitor of endothelin receptor derived cyclopentene with precondensation heteroaromatic ring (see U.S. patent N 5389620, class A 61 K 31/435, C 07 D 221/04, 14.02.1995 year).

The objective of the invention is to expand the Arsenal of heterocyclic compounds suitable as an active substance in the pharmaceutical composition having inhibitory receptor endothelin activity.

The problem is solved proposed derivative dioxide benzothiazine General formula (I)

< / BR>
where R2means or alkyl with 1 to 7 carbon atoms, each of Raand Rwithmeans from one to five substituents, and Rbmeans from one to four substituents, independently from each other selected from the group comprising hydrogen, chlorine, methylenedioxy, Ethylenedioxy, groups, OR, and OCH2OR, where R denotes hydrogen, alkyl with 1-6 carbon atoms or phenyl,

Rdmean group CO2R, SO3R, CONRR1where R is in the La to two;

- - - means simple or double bond; and

X represents (CH2)nor S(O)nwhere n has the above meaning, or their pharmaceutically acceptable salts accession acid or base.

In the first group of preferred derivatives dioxide benzothiazine the above formula (I) include compounds in which

R2means or alkyl with 1-5 carbon atoms,

each of Raand Rcmeans from one to five substituents, a Rbmeans from one to four substituents, independently from each other selected from the group comprising hydrogen, chlorine, methylenedioxy, Ethylenedioxy,

Rd means carboxyl;

n means an integer from zero to one;

- - - indicates a double bond; and

X represents (CH2)nor sulfonyl.

The second group preferred derivatives dioxide benzothiazine the above formula (I) include compounds in which

R2means or alkyl with 1-5 carbon atoms,

each of Raand Rcmeans from one to five substituents, independently from each other selected from the group including hydrogen and chlorine;

Rbmeans from one to four mandated is also, independently from each other, can mean up to two substituents from the group comprising methylendioxy and Ethylenedioxy;

n means an integer of zero or one;

- - - indicates a double bond; and

X represents (CH2)nor sulfur.

Particularly preferred derivatives dioxide benzothiazine the above formula (I) are selected from the group including

4-benzo[1,3] dioxol-5-yl-2-methyl-1,1-dioxo-1,2-dihydro-16benzo-[e] [1,2]-thiazin-3-carboxylic acid;

4-benzo[1,3] dioxol-5-yl-2-benzo[1,3] dioxol-5-yl-methyl-1,1 - dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

4-benzo[1,3] dioxol-5-yl-2-benzyl-1,1-dioxo-1,2-dihydro-16benzo-[e] [1,2]-thiazin-3-carboxylic acid;

4-benzo[1,3] dioxol-5-yl-2-(4-methoxybenzyl)-1,1-dioxo-1,2 - dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

4-benzo[1,3] dioxol-5-yl-1,1-dioxo-2-(3,4,5 - trimethoxybenzyl)-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

4-benzo[1,3] dioxol-5-yl-2-(2-carboxymethoxy-4 - methoxybenzyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3 - carboxylic acid;

4-benzo[1,3] dioxol-5-yl-2-(6-chlorobenzo[1,3] dioxol-5-yl - methyl)-1,1-dioxo-1,2-dihydro-16-benzo[e]][1,2]enous is -16-benzo[e][1,2]thiazin-3 - carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-4-(3,4-acid) 1,1 - dioxo-1,2-dihydro-16-benzo[e](1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-1,1-dioxo-4-(3,4,5 - trimethoxyphenyl)-1,2-dihydro-16-benzo[e][1,2]thiazin-3 - carboxylic acid;

N-(4-benzo[1,3] dioxol-5-yl-2-benzo[1,3] dioxol-5-yl-methyl - 1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carbonyl)- benzosulfimide;

4-benzo[1,3] dioxol-5-yl-2-benzo[1,3] dioxol-5-yl-methyl-6 - methoxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

2,4-bis-benzo[1,3] dioxol-5-yl-6,7-dimethoxy-1,1-dioxo-1,2 - dihydro-16-benzo-[e][1,2]thiazin-3-carboxylic acid;

4-benzo[1,3] dioxol-5-yl-2-(2-Chlorobenzyl)-1,1-dioxo-1,2 - dihydro-16-benzo-[e][1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-4-(benzo[1,3] dioxol-5-yl)-7 - methoxy-1,1-dioxo-1,2-dihydro-16-benzo[e](1,2]thiazin-3 - carboxylic acid;

and

2-benzo[1,3] dioxol-5-yl-methyl-4-(2,3 - dihydrobenzo[1,4]dioxin-6-yl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid.

4-(benzo[1,3] dioxol-5-yl-sulfanyl)-2-methyl-1,1-dioxo-1,2 - dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl -) - Rev. BR> 4-(benzo[1,3] dioxol-5-yl-sulfanyl)-2-(4-methoxybenzyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,]thiazin-3-carboxylic acid;

4-(benzo[1,3] dioxol-5-yl-sulfanyl)-2-(carboxymethoxy-4 - methoxybenzyl)-1,1-dioxo-1,2-dihydro - 16-benzo[e][1,2]thiazin-3 - carboxylic acid;

4-(benzo[1,3] dioxol-5-yl-sulfanyl)-2-(7 - methoxybenzo[1,3]dioxol-5-yl-methyl)-1,1-dioxo-1,2-dihydro - 16-benzo[e][1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-4-(3,4-dimethoxyphenylacetone)-1,1 - dioxo-1,2-dihydro-16- benzo[e][1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-4-(3-methoxybenzenesulfonyl)- 1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-4-(benzo[1,3] dioxol-5-yl - sulfanyl)-6,7-dimethoxy-1,1-dioxo-1,2-dihydro-16- benzo[e]][1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-4-(benzo[1,3] dioxol-5-yl - sulfanyl)-6-methoxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

4-(benzo[1,3] dioxol-5-yl-sulfanyl)-2-(2-Chlorobenzyl)-1,1 - dioxo-1,2-dihydro-16-benzo[e]][1,2]thiazin-3-carboxylic acid;

2-(2-benzo[1,3] dioxol-5-yl-methyl)-4-(benzo[1,3] dioxol-5-yl - sulfanyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3 - Carbo is)-1,2-dihydro - 16- benzo[e][1,2]thiazin-3-carboxylic acid.

Pharmaceutically acceptable salts of accession of the acid compounds of formula (I) include salts derived from nontoxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, Hydrobromic acid, iodomethane acid, hydrofluoric acid, phosphoric acid and the like, as well as salts derived from nontoxic organic acids, such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate acid, arcangioli acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Thus, such salts include the sulfate, persulfate, bisulfate, the sulfite, bisulfite, nitrate, phosphate, monohydratefast, dihydrophosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, triptorelin, propionate, kaprilat, isobutyrate, oxalate, malonate, succinate, suberate, sebacina, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, bansilalpet, toluensulfonate, phenyl acetate, citrate, lactate, tartrate, methanesulfonate and the like. Also discusses salts of amino acids such as arg Science, 66,1-19 (1977)).

Salt accession acid of the above basic compounds receive the usual way by bringing into contact of the compound in free base form with a sufficient amount of the desired acid.

Pharmaceutically acceptable salts joining the Foundation of the get with metals or amines, such as alkali or alkaline earth metals or organic amines. Examples used as the metal cations are sodium, potassium, magnesium, calcium and the like.

Examples of suitable amines are N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, dicyclohexylamine, Ethylenediamine, N-methylglucamine, and procaine (see , for example, Berge S. M., and others, "Pharmaceutical salts", Journal of Pharmaceutical Science, 66,1-19 (1977)).

Salt joining the Foundation of the above-mentioned acidic compounds receive the usual way by introducing the contact connection in the form of the free acid with a sufficient amount of the desired base.

Some of the compounds according to the present invention may exist in resolutiony forms, as well as in solvated forms, including hydrated forms. Usually solvated forms, vlur CLASS="ptx2">

Some of the compounds according to the present invention contain one or more chiral centers and each center can have the R configuration or s of the Present invention includes all enantiomeric and epimeria forms, and their respective diastereomeric mixture.

The second object of the invention is a pharmaceutical composition having activity of inhibiting endothelin receptor containing as active substances derived dioxide benzothiazine the above formula (I) or its pharmaceutically acceptable salt accession acid or base in therapeutically effective amounts, as well as pharmaceutically acceptable carrier.

The proposed pharmaceutical composition, which may be any standard drug, get known in the pharmaceutical industry.

Examples of possible drugs

Tablets

10 mg of the active substance, for example, example 24

50 mg lactose

35 mg of corn starch

5 mg of magnesium stearate.

The ingredients are mixed to obtain a mixture, which is well-known techniques translate into tablets weighing 100 mg.

Solution

10 mg is g saccharin

10 mg red dye

20 mg cherry flavor

100 ml of distilled water.

The ingredients are thoroughly mixed and filled them to capacity, which is sterile closed.

The third object of the invention is a method of inhibiting endothelin receptor by the introduction of the patient-derived dioxide benzothiazine the above formula (I) in a therapeutically effective amount in the form of a single dose.

The tests show that the compounds according to the invention are antagonistic towards endothelin activity. So, the compounds were investigated for their ability to inhibit the binding of [125]-ET-1([125] -endothelin-1) when tested with the receptor. A series of compounds was also tested for antagonistic activity by inhibiting stimulated by endothelin-1 release of arachidonic acid and stimulated with endothelin-1 vasoconstriction. Were used the following test methods (Doherty A. M. and others, "the purpose of the C-terminal peptide antagonists of endothelin: correlation of activity with the structure of ET-1[16-21, D-His16]", Bioorganic and Medicinal Chemistry Letters, 3, 497-502 (1993)).

Test linking radioligand cells of the renal artery of the rabbit (ERBA-A), expressing recombinant human endothelin receptor-A containing tyrosinekinase leukocyte cells (HERBA-A) and expressing the recombinant human endothelin receptor-B cells K-1 Chinese hamster ovary (HERBA-B).

Membranes obtained from cultured cells by lysis of cells in a cold lyse buffer (5 mmol of 4-(2-hydroxyethyl)-1 - piperazine-econsultancy, 2 mmol ethylenediaminetetraacetic acid, the pH is 7.4) and homogenized using a homogenizer of the downs "A". The homogenate was centrifuged for twenty minutes at a temperature of 4oC and with acceleration 30,000 g. Precipitation of the membrane after centrifugation suspended in cold buffer containing 20 mmol Tris(hydroxymethyl)aminomethane, 2 mmol ethylenediaminetetraacetic acid, 200 µmol of Peaslake, 10 µmol containing phosphorus starch, 10 µmol leupeptin, 1 µmol of pepstatin (the pH is 7.4) and frozen at a temperature of -80oC before use. Membranes are thawed and homogenized using Polytron of Brinkmann, then diluted in buffer to tissue containing 20 mmol Tris(hydroxymethyl)aminomethane, 2 mmol ethylenediaminetetraacetic acid, 200 µmol of Peaslake and 100 µmol b is terasem 20 mmol Tris(hydroxymethyl)aminomethane, 2 mmol ethylenediaminetetraacetic acid, and 0.1% bovine serum albumin.

Testing competing binding start with combining membranes, [125] -ET-1 (40 pmol) and the competing ligand in a final volume of 250 μl and incubation for two hours at 37oC. the Test is finished by filtration through filters Whatman GF/B, which are pre-impregnated with buffer containing 50 mmol Tris(hydroxymethyl)aminomethane, and 0.2% bovine serum albumin and 100 µmol bacitracin (the pH is 7.4). Nonspecific binding is defined as binding in the presence of 100 nmol of endothelin-1.

Inhibition of in vitro-stimulated endothelin-1 release of arachidonic acid (CRA) in cultured vascular smooth muscle cells of the rabbit (endothelin-A) with compounds according to the invention

Antagonistic activity determined by the ability of added compounds to reduce stimulated endothelin allocation of arachidonic acid in cultured vascular smooth muscle cells. Contains [3H]-arachidonic acid environment is 1,2-dimethoxyethan /F 12 to+0.5% fetal calf serum g 0.25 MCI/ml [oC in the presence of 5% carbon dioxide. Wednesday sucked off and the cells washed once with buffer for analysis (balanced salt solution Hank + 10 mmol of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic + 1 mg/ml containing no fatty acid bovine serum albumin) and incubated for five minutes with 1 ml of preheated buffer for analysis. This solution is sucked off, then add 1 ml of pre-warmed buffer for analysis, and incubated further in the next five minutes. Similarly spend the final five-minute incubation. Repeat the same sequence of operations when 10 μl of the test compound (from 1 nmol to 1 Microm) and 10 μl of endothelin-1 (0.3 nmol) and the incubation continued for thirty minutes. This solution is then collected, add 10 ml of scintillation cocktail for the account and determine the amount of [3H]-arachidonic acid in a scintillation counter.

Antagonism in vitro-stimulated endothelin-1 vasoconstriction (VERA) in the femoral artery of the rabbit (endothelin-a) and stimulated sarafotoxin-6s vasoconstriction in the pulmonary artery of the rabbit (endothelin-B)

Male new Zealand rabbits mind connective tissue and cut into rings 4 mm wide. Endothelium dinoderus by placing the rings on the hypodermic tube (size 32 for femoral rings and $ 28 for pulmonary rings; small Desk, Inc., Miami, Florida), and careful of their rotation. Denuded rings contribute to the baths for bodies with a volume of 20 ml containing bicarbonate buffer Krebs (composition: 118,2 mmol of sodium chloride; 24,8 mmol of sodium bicarbonate; 4.6 mmol potassium chloride; 1.2 mmol of the heptahydrate of magnesium sulfate; 1.2 mmol of potassium dihydrophosphate; the dihydrate of calcium chloride; it was 0.026 mmol dimetrically salt ethylenediaminetetraacetic acid; 10.0 mmol dextrose), which support at a temperature of 37oC and continuously saturated with oxygen and 5% carbon dioxide (the pH is 7.4). Remaining unchanged tensile set at 3.0 g for femoral and 4.0 g for the pulmonary arteries; the ring is left in this state for 90 minutes for equilibration. Ring of vessels experiencing a lack of functional endothelium (i.e. lack of endothelium-dependent relaxation responses to carbachol (1.0 nmol) in norepinephrine (0.03 nmol compressed rings). Peptide agonists, endothelin-1 (femoral) and S6c (pulmonary), together added to ten-minute intervals. Endothelin antagonists coactively in relation to the binding of endothelin receptor characteristic of the compounds according to the present invention.

The compounds of formula (I) can be obtained in several ways. These methods are presented in the diagrams from the first to the twelfth and are illustrated in detail in the examples section of the description.

Scheme 1 illustrates the methodology used to obtain alkoxy-substituted sharenow. 1,2-Benzisothiazol-3(2H)-he (Burri K. F. [4 + 2] Reactions proceed with the isothiazol-3(2H)-one-1,1 - dioxide", Helv. Chim. Acta, 73, 69 - 80 (1990)) alkylate by alkylhalogenide, usually propyliodide, in the presence of a base, usually cesium carbonate in a dipolar aprotic solvent at room temperature. As a result of processing by the acid, usually triperoxonane acid, by boiling under reflux in a few days receive the intermediate 6-prophylaxisfor.

Scheme 2 represents a method of obtaining the appropriately substituted benzothiadiazides using the appropriate o-aminobenzoic acid. Diazotization of aniline in acid is usually carried out by treatment with an aqueous solution of sodium nitrite. Then add sulfur dioxide and chloride divalent copper and the mixture is stirred at room temperature for several days, during which deposited IU the s o,o'-dithio-Dibenzoyl acids includes the processing of diazotized o-aminobenzoic acid ethylxanthate potassium, basic hydrolysis and oxidation by air, as described Katz L, L. S. Karger, Scroeder W., Cohen M. , "hydrazine Derivatives. I. Benzylthio and bisbenzimidazole". J. Org. Chem., 18, 1380 - 1402 (1953). The disulfide is converted into sulphonylchloride by processing sulfurylchloride and potassium nitrate at room temperature (Park, I. J., Shin H.N., Kim Y. H. "Suitable one-step synthesis of sulphonylchloride of thiols using sulfurylchloride and metal nitrate". Chem. Lett., 1483 - 1486 (1992)). Adding methyl ester aminouksusnoy acid and base, typically triethylamine, a few hours later leads to the corresponding sulfonamida. As a result of processing of this adduct with sodium methylate in dimethylformamide and acidification with an aqueous solution of hydrogen chloride receive target intermediate benzothiazinone.

Scheme 3 illustrates the method used to convert a derivative of saccharin in the appropriate benzothiazinone. Derived saccharin N-alkylate using methylpropanoate in dimethylformamide using sodium hydride as the base. Adduct regroup in the appropriate benzothiazinone by treatment with sodium methylate in dimethylformamide at room tempeature. In this case, the processing sulphonylchloride using the appropriately substituted aniline results in sulfonamida, which after heating gives N-substituted saccharin. In the add METHYLCHLOROSILANE and sodium hydride receive intermediate benzothiazinone.

According to scheme 5 intermediate benzothiazinone benzylium usually using (3,4-methylendioxy)benzylchloride in dimethylformamide in the presence of a base, typically sodium hydride. N-Antilibanus adduct is treated with anhydride of triftoratsetata and pyridine in dichloromethane at room temperature for about one hour. This intermediate product is directly used in the subsequent reactions.

Scheme 6 illustrates the method used for the synthesis of 4-arylsulfonate-thisindicates. Usually by solution vinestreet in dimethylformamide add (3,4-methylendioxy)penalties. Adduct allocate by chromatography and omelet using an aqueous solution of lithium hydroxide.

Figure 7 presents the methodology used for the synthesis of 4-arylbenzothiazoles-dioxides. Usually (3,4-methylendioxy)phenylboric acid is introduced into the reaction mix in the presence of pellagra of lithium hydroxide.

Figure 8 depicts the method of derivatization source benzothiazepine-3-carboxylic acid. Acid activated with carbodiimide, usually 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-hydrochloride, and injected into the reaction mix with a sulfonamide, receiving the appropriate karbonyldichlorid. Similarly, the activated using carbonyldiimidazole and adding aqueous ammonia to obtain the corresponding amide. This amide dehydration using trichloroacetamide triethylamine, receiving the corresponding nitrile. The addition of sodium azide and ammonium chloride to the nitrile in dimethylformamide and holding for several hours at elevated temperature, typically at 100oC, leads to the corresponding tetrazole.

Figure 9 represents an alternative method of obtaining the target benzodiazepined. In this case, saccharin N-alkylate by adding a base, typically sodium hydride, and adding an alkylating agent, usually (3,4-methylendioxy)benzylchloride. Extension ring by adding chlormethiazole and sodium hydride in a dipolar aprotic solvent such as dimethyl sulfoxide, leads to N-alkilirovannami benzodi what's sharenow and therefore, the corresponding benzodiazepined. In this case, the resulting ortho-methylsulfonylamino produce after processing of the initial toluene derived using chlorosulfonic acid. Oxidation to the corresponding benzoic acid is achieved by using an aqueous solution of permanganate. The acid chloride and sulphonylchloride acid obtained after treatment with pentachloride phosphorus. Adding ammonium hydroxide leads to appropriate the saccharine.

In chart 11 presents the methodology used for the synthesis of substituted 2H-1,2-benzothiazin-3-carbonitrile-4-hydroxy-1,1-dioxide, and the sequence of stages required for the conversion of compounds of formula (I). In this case, arylsulfonate converted into the sulfonamide tsianuksusnogo acid by adding aminoacetonitrile. This sulfonamide is treated with sodium methylate, receiving the target benzothiazinone after treatment with acid (about alternative methods, see "Derived 1,2-benzothiazine"; patent application Spain 508671 authors: Fogh Ambros, Rafael Ortiz Hernandez, Jose Alfonso). This intermediate connection benzelius and derivatized to give the corresponding 4-aryl and 4-Arinsal is ultimately carboxylic acid. Tetrazol get through interaction with tributylammonium or ammonium chloride and sodium azide in dimethylformamide.

Figure 12 represents a method of obtaining benzisothiazol-3-he-dioxides, and, consequently, the corresponding benzothiadiazides, by oxidation of the corresponding 1,2-benzisothiazol-3-ones (see Bambas L. L. "the Chemistry of heterocyclic compounds"; Weissburger A. Willy - Interscience: new York, 4, 225 - 227 (1952); and Davis M., Adv. Heterocycl. Chem., 14, 43 (1972)). The reaction of diazotized o-benzoic acids with ethylxanthate potassium, followed by hydrolysis, usually with potassium hydroxide, and oxidation, usually with the help of iodine leads to the corresponding 2,2'-dithiosalicylic acid. By adding thionyl chloride and methyl ester aminouksusnoy acid obtain the corresponding amide, which cyclist to 1,2-benzothiazol-3-one. Oxidation of 1,2-benzisothiazol-3-it is up to benzisothiazol-3-one-1,1-dioxide is carried out using peracetic acid (Giadi F., and others, Farmaco Ed. Sci., 16, 509 - 526 (1961)).

In the diagrams at the end of the text, use the following abbreviations:

Ar is aryl

DMSO - dimethyl sulfoxide

DMF - dimethylformamide

CBI - carbonyldiimidazole

CT room temperature

Compounds according to the present invention can be obtained and introduced in the form of a variety of oral and parenteral dosage forms. Thus, the compounds according to the present invention can be administered by injection, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally or IPR. Compounds according to the present invention can also be administered by inhalation, for example, in the nose. Additionally, the compounds according to the present invention it is possible to enter percutaneous. The person skilled in the art it is known that removal of finished dosage forms may contain as an active ingredient or compound of formula (I) or the pharmaceutically acceptable salt of the compounds of formula (I).

Used to obtain pharmaceutical compositions of the compounds according to the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid dosage forms include powders, tablets, pills, capsules, pills, suppositories and dispergirujutsja granules. A solid carrier can be one or more substances which may also act as diluents, flavorings, binders, which defaults to a finely ground solid, which is mixed with finely ground active ingredient.

In tablets, the active ingredient is mixed with carrier having the necessary binding properties in appropriate proportions and compacted in the form of the desired shape and size.

The powders and tablets preferably contain from about five or ten to about seventy percent of the active compounds.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter and the like. The term "dosage form" means a finished dosage form of the active compound with encapsulating material as a carrier providing formation of a capsule in which the active component, with other carriers, is surrounded by media, being thus in Association with it. The same applies to those capsules and lozenges. Tablets, powders, capsules, pills, pills and lozenges can be used as solid dosage forms suitable for oral administration.

To obtain suppositories, nescopeck the homogeneous melt is dispersed active component. Homogeneous molten mixture is then poured into molds of suitable size, leave to cool and thus be cured.

Liquid dosage forms are solutions, suspensions and emulsions, for example, water-based or aqueous solutions of propylene glycol. Liquid dosage forms for parenteral injection may be in the form of a solution in an aqueous solution of polyethylene glycol.

Suitable for oral use aqueous solutions can be obtained by dissolving the active component in water and adding, if desired, suitable colorants, flavoring flavoring agents, stabilizers and thickeners.

Suitable for oral use water suspension can be obtained by dispersing finely ground active component in water with viscous substance, such as natural or synthetic gums, resins, methylcellulose, sodium salt of carboxymethylcellulose, and other well-known suspendresume agents.

Also suitable solid dosage forms that are intended to transform just before use in liquid dosage forms for oral administration. Such th component, dyes, flavouring flavouring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

Dosage form preferably is in the form of a single dose. In this form, the dosage form is divided into single doses containing appropriate quantities of the active component. A single dose may be in the packaging, and the packaging contains a specific number of dosage forms such as tablets, capsules and powders, Packed in vials or ampoules. A single dose is also in itself can be a capsule, plate, wafer, or toffee, or it can represent the appropriate number of any of them in the package.

The number of active component in a single dosage form can be modified or be set from 0.1 mg to 100 mg, preferably from 0.5 mg to 100 mg, in accordance with the specific use and effectiveness of the active component. If desired, the composition may also contain other therapeutically acceptable agents.

When used in therapy as endothelin antagonists used in the treatment FAO about 100 mg/kg / day. Preferred is a range of daily dose from about 0.01 mg to about 10 mg/kg, the dose can be changed depending on the needs of the patient, the severity treatable condition and used for the connection. The appropriate dose in a particular case is determined by the physician. Usually the treatment is started with small doses that are less than the optimum dose of the compound. Then increase the dose by small increases until the optimum effect under the circumstances. For convenience, if desired, the daily dose may be divided and administered by the parts during the day.

Deriving dioxide benzothiazine the above formula (I) is illustrated by the following examples.

Example 1

Methyl ether 1,2-benzo-3H-isothiazol-1,1-dioxide-3-oxo-2-acetic acid

To a solution of 40 g (0,218 mol) of saccharin in 100 ml of dimethylformamide at a temperature of 0oC add 8,73 g (0,218 mol) of sodium hydride (60% dispersion in oil). Fifteen minutes later add 20.7 ml (0,218 mol) of methylpropanoate and the mixture is stirred at room temperature for eighteen hours. Then diluted with 250 ml of dichloromethane and washed twice in 180 ml of a saturated solution gfsu dried over magnesium sulfate, the solvent is removed in vacuo and the product crystallized from hot ethanol, receiving of 36.3 g (65%) of target compound.

Analysis for C10H9NO5S:

calculated % C 47,06 H 3,55 N 5,49

found, % 47,02 3,68 lower than the 5.37

Mass spectrum (chemical ionization): m/e 256;

Example 2

Methyl ester of 4-hydroxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

To 100 ml of methanol are added in several portions of 5.4 g (0.23 mol) of sodium. After dissolution of all sodium solution was concentrated in vacuo and trace amounts of methanol are removed in high vacuum. The sodium methylate are suspended in 65 ml of anhydrous dimethylformamide. 20 g (0,078 mol) Methyl ether, 1,2-benzo-3H-isothiazol-1,1 - dioxide-3-oxo-2-acetic acid are dissolved in 30 ml of dimethylformamide, cooled to a temperature of 0oC and within seven minutes add a freshly prepared suspension of sodium methylate. The solution is stirred for thirty minutes at a temperature of 0oC, then through the funnel to the reaction mixture 430 ml of 1 N. hydrochloric acid, precipitated precipitate was separated and washed with water. The precipitate is dried in a vacuum at a temperature of 52oC during the night, getting to 13.6 g (68 %) of target compound.

Analysis for C10H
Example 3

Methyl ester of 2-benzo[1,3]dioxol-5-yl-methyl-4 - hydroxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3 - carboxylic acid

To 1.48 g (of 5.84 mmol) of methyl ester of 4-hydroxy-1,1-dioxo - 1,2-dihydro-16-benzo[e] [1,2]thiazin-3-carboxylic acid in 10 ml of dimethylformamide add 0,257 g (6.4 mmol) of sodium hydride (60% dispersion in oil) and the mixture is stirred for five minutes, then add 2.2 g (6.4 mmol) of 3,4-methylenedioxyaniline in dichloromethane (concentration of 50 wt.%) and the mixture is stirred for eighteen hours at room temperature. Diluted with 100 ml ethyl acetate, washed twice in 80 ml water, 80 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, the solvent is removed in vacuo and the residue crystallized from a mixture of ethyl acetate with heptane, getting 1.63 g (72%) of target compound.

Analysis for C18H15NO7S:

calculated % C 55,52 H 3,88 N 3,60

found, % 55,45 3,72 3,49

Mass spectrum (chemical ionization): m/e 389.

Example 4

2-Benzo[1,3]dioxol-5-yl-methyl-1,1-dioxo-1,2-dihydro - 16-benzo[d]isothiazol-3-one

To 5.0 g (0,0273 mol) of saccharin in 10 ml of dimethylformamide under cooling in a bath with ice add 1.1 target 10 g (0,0293 mol) of 3,4-methylenedioxyaniline in dichloromethane (concentration of 50 wt. %) and the mixture is stirred for sixteen hours. The mixture is then diluted with 200 ml ethyl acetate containing 10% dichloromethane, and washed twice in 100 ml of 1 n hydrochloric acid. The organic phase is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The mixture is concentrated until, until crystals appear. After standing for sixteen hours by filtering off gain of 4.2 g of the product (49%).

Analysis for C15H11NO5S:

calculated % C H 56.78 has 3,49 to 4.41 N

found, % 56.26 vertical 3,50 4,56

Mass spectrum (chemical ionization): m/e 317.

Example 5

Methyl ester of 2-benzo[1,3] dioxol-5-yl-methyl-4-hydroxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

(alternative method)

To 1,115 g (3,517 mmol) of 2-benzo[1,3]dioxol-5-yl-methyl-1,1 - dioxo-1,2-dihydro-16-benzo[d] isothiazol-3-one in 6 ml of dimethyl sulfoxide add and 0.61 ml (of 6.96 mmol) of methyl 2-CHLOROACETATE. The mixture is heated to 40oC for one hour slowly add 0,562 g (14 mmol) of sodium hydride (60% dispersion in oil). The mixture was incubated for three hours at a temperature of 40oC, then cooled to room temperature and diluted with poiut saturated aqueous sodium chloride and dried over magnesium sulfate. After chromatography on silica gel with elution using chloroform and crystallization from a mixture of dichloromethane hexane get 0,596 g (44%) of the target product.

Analysis for C18H15NO7S:

calculated % C 55,52 H 3,88 N 3,60

found, % 55,62 3,85 3,52

Mass spectrum (chemical ionization): m/e 389.

Example 6

2-Tert. -butyl-1,1-dioxo-6-propyloxy-1,2-dihydro-16-benzo[d] isothiazol-3-one

To a solution of 0,454 g (1.78 mmol) of 2-tert.-butyl-6-hydroxy-1,1-dioxo-1,2-dihydro-16-benzo[d] isothiazol-3-one in 10 ml of dimethylformamide type of 1.16 g (of 3.56 mmol) of cesium carbonate and the mixture is stirred for ten minutes. Then add of 0.26 ml (or 2.67 mmol) of 1-iodopropane and the mixture is stirred for sixteen hours, then add 100 ml ethyl acetate and 50 ml of water. The organic layer was washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. After concentration in vacuo get 0,526 g (99%) of the desired product. Part of the product is crystallized from a mixture of diethyl ether and hexane, obtaining long colorless needles.

Analysis for C14H19NO4S:

calculated % C 56,55 H 6,44 N 4,71

found, % 56,72 6,46 4,66

Mass spectrum (chemical ioniza the thief 0,346 g (1,165 mmol) 2-tert.-butyl-1,1-dioxo-6 - propyloxy-1,2-dihydro-16-benzo[d]isothiazol-3-one in 10 ml triperoxonane acid is refluxed for forty-eight hours. The NMR spectrum of the reaction mixture shows the quantitative removal of the protective group. The mixture was concentrated in vacuo and the residue crystallized from a mixture of dichloromethane with methanol and hexane, obtaining 0,130 g (46%) of the target product.

Analysis for C10H11NO4S:

calculated % C 49,78 H 4,60 N 5,81

found, % 49,61 4,49 5,80

Mass spectrum (chemical ionization): m/e 242.

Example 8

5-Methoxy-1,1-dioxo-1,2-dihydro - 16-benzo[d]isothiazol-3-one

Receive according to scheme 10.

Analysis for C8H7NO4S:

calculated % C 45,07 H 3,31 N 6,57

found, % 45,23 3,31 6,52

Mass spectrum (chemical ionization): m/e 213.

Example 9

2-Benzo[1,3] dioxol-5-yl-methyl-5-methoxy-1,1-dioxo-1,2-dihydro-16-benzo[d]-isothiazol-3-one

Receive in accordance with the method of example 3.

Analysis for C16H13NO6S:

calculated % C 55,33 H of 3.77 N 4,03

found, % 55,31 3,81 3,89

Mass spectrum (chemical ionization): m/e 347.

Example 10

Methyl ester (5-methoxy-1,1,3-trioxo-1,3 - dihydro-16-benzo[d] isothiazol-2-yl)acetic acid
found, % 45,93 3,90 4,78

Mass spectrum (chemical ionization): m/e 286.

Example 11

Dimethyl 2,2'-dithiobis(4,5-dimethoxybenzoic acid)

To a suspension of 1.50 g (7,11 mmol) methyl ester 2-amino-4,5-dimethoxybenzoic acid in 10 ml of acetic acid and 13 ml of concentrated hydrochloric acid at an internal temperature of 1-3oC slowly add a solution of 0.55 g (of 7.97 mmol) of sodium nitrite in 5 ml of water; after adding an aqueous solution of sodium nitrite solid dissolves. The solution is stirred for an additional thirty minutes and then thirty minutes later, the cooled solution is passed sulfur dioxide. Add 0,471 g (was 2.76 mmol) chloride dihydrate divalent copper in 5 ml of water and is colored green, the mixture is left to warm to room temperature for forty eight hours. After filtration and washing three times, 100 ml of water 0.800 to get g (49%) of the desired product in the form of a solid white color.

Analysis for C20H22O8S2:

calculated % C 52,85 H 4,88

found, % 52,64 4,89

Mass spectrum (chemical ionization): m/e 454.

Example 12

Dimethyl 6,6'-dithiobis(1,3-benzo-dioxol-5-carboxylic acid. Crystallized from a mixture of dichloromethane hexane.

Analysis for C18H14O8S2:

calculated % C 51,18 H 3,34

found, % 51,04 of 3.33

Example 13

Methyl ester 2-chlorosulfonyl-4,5-dimethoxybenzoic acid

To a suspension 0,170 g (0,374 mmol) of dimethyl 2,2'-dithiobis(4,5-dimethoxybenzoic acid) in 4 ml of acetonitrile at a temperature of 0oC add 0,095 g (0,940 mmol) of potassium nitrate and then added dropwise 0.075 ml (0,934 mmol) sulfurylchloride. After a short time forms a yellow coloured solution, which quickly falls copious precipitate. The mixture is stirred for one hour at a temperature of 0oC and then for four hours at room temperature. Add 10 ml of a saturated aqueous solution of sodium bicarbonate and 50 ml of ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After crystallization from a mixture of ethyl acetate with hexane get 0,119 g (54%) of the target product.

Analysis for C10H11O6SCl:

calculated % C 40,76 H 3,76

found, % 40,79 3,74

Mass spectrum (chemical ionization): m/e 294.

Example 14

Methyl ester of 6-chloraea 6,6'-dithiobis(1,3-benzodioxol-5-carboxylic acid).

Analysis for C9H7O6SCl:

calculated % C 38,79 H 2,53

found, % 39,19 2,42

Mass spectrum (chemical ionization): m/e 287.

Example 15

Methyl ester of 4,5-dimethoxy-2- (methoxycarbonylmethylene)-benzoic acid

To a solution 0,100 g (0,339 mmol) methyl ester 2-chlorosulfonyl-4,5-dimethoxybenzoic acid in 5 ml of dichloromethane type of 0.28 ml (2,012 mmol) of triethylamine and 0,128 g (1,02 mmol) methylphenethylamine.

The mixture is stirred for two hours and then diluted with 50 ml ethyl acetate and 50 ml of 1 N. hydrochloric acid. The organic fraction was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After crystallization from a mixture of dichloromethane hexane get 0,092 g (78%) of target compound.

Analysis for C13H17NO8S:

calculated % C 44,95 H 4,93 N 4,03

found, % 44,91 to 4.81 4.09 to

Mass spectrum (chemical ionization): m/e 347.

Example 16

Methyl ester of 6-(methoxycarbonylmethylene)benzo[1,3]dioxol-5-carboxylic acid

Receive in accordance with the method of example 15 from methyl ester 6-chlorosulfonyl-benzo[1,3]dioxol-5-carboxylic acid.

Analysis for C12H13NO

Example 17

Methyl ester of 4-hydroxy-6,7-dimethoxy-1,1-dioxo-1,2-dihydro-16-benzo[e]-[1,2]thiazin-3-carboxylic acid

To a solution of 0,555 g (1,60 mmol) of the methyl ester of 4,5-dimethoxy-2-(methoxy-carbonylmethyl)benzoic acid in 3 ml of anhydrous dimethylformamide add 0,345 g (6,39 mmol) and anhydrous freshly prepared sodium methylate. After adding sodium methylate appears red staining. The mixture is stirred for forty-five minutes and then diluted with 100 ml of 1 N. hydrochloric acid. Precipitated precipitated solid pale yellow color is separated and washed with water, getting 0,341 g (68%) of target compound.

Analysis for C12H13NO7S:

calculated % C 45,71 H 4,16 of 4.44 N

found, % 45,67 4,14 4,40

Mass spectrum (chemical ionization): m/e 316.

Example 18

Methyl ester of 8-hydroxy-5,5-dioxo-5,6-dihydro-1,3-dioxa-56-thia-6-azacyclopenta[b]naphthalene-7-carboxylic acid

Receive in accordance with the method of example 17 methyl ester 6-(methoxycarbonyl-methylsulfonyl)benzo[1,3]dioxol-5-carboxylic acid.

Analysis for C11H9NO7S:

calculated % C 44,15 H 3,03 N 4,68

found, % 44,14 2,87 4,24

Mass spectrum (hamiltoni-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 3 from methyl ester of 4-hydroxy-6,7-dimethoxy-1,1-dioxo-1,2-dihydro-16-benzo[e] [1,2] thiazin-3-carboxylic acid.

Analysis for C20H19NO9S:

calculated % C 53,45 H 4.26 deaths N 3,12

found, % 53,27 to 4.23 3,01

Mass spectrum (chemical ionization): m/e 449.

Example 20

Methyl ester of 6-benzo[1,3]dioxol-5-yl-methyl-8-hydroxy-5,5 - dioxo-5,6-dihydro-1,3-dioxa-56-thia-6-Aza-cyclopent[b]naphthalene-7 - carboxylic acid

Receive in accordance with the method of example 3 from methyl ester of 8-hydroxy-5,5-dioxo-5,6-dihydro-1,3-dioxa-56-thia-6-Aza - cyclopent[b] naphthalene-7-carboxylic acid.

Analysis for C19H15NO9S:

calculated % C 52,66 H 3,49 N 3,23

found, % 52,93 3,81 3,17

Mass spectrum (chemical ionization): m/e 433.

Example 21

Methyl ester of 2-benzo[1,3] dioxol-5-yl-methyl-4-hydroxy-6-methoxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 3 from methyl ester of 4-hydroxy-6-methoxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid.

Analysis for C19H17NO8S:

Rimer 22

Methyl ester of 2-benzo[1,3]dioxol-5-yl-methyl-1,1-dioxo-4-(tripterocalyx)-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

A solution of 0.40 g (1,03 mmol) of methyl ether benzo[1,3]dioxol-5-yl-methyl-4-hydroxy-1,1-dioxo-1,2-dihydro - 16-benzo[e][1,2]thiazin-3-carboxylic acid and 0.42 ml (5,14 mmol) of pyridine in 5 ml of dichloromethane at a temperature of 0oC and under nitrogen atmosphere is treated with the help of 0.21 ml (1,23 mmol) of anhydride of triftoratsetata and the reaction mixture is stirred at a temperature of 0oC for two hours. The solution is diluted with ethyl acetate, washed twice 1 N. hydrochloric acid, saturated aqueous sodium chloride, dried over magnesium sulfate and the solvent is evaporated. After drying in high vacuum over night get crude, triplet. It is passed through a layer of silica gel, elwira mixture of hexane to ethyl acetate in the ratio of 1:1; after evaporation and drying under high vacuum, get the target connection.

Analysis for C19H14NO9S2F3:

calculated % C 43,77 H 2,71 N 2,69

found, % 44,15 2,84 2,59

Mass spectrum (chemical ionization): m/e 521.

Example 23

Methyl ester of 2-benzo[1,3] dioxol-levy ether 2-benzo[1,3]dioxol-5-yl-methyl-1,1-dioxo-4- (tripterocalyx)-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid contribute in a mixture of 10 ml of toluene and 2 ml of dimethylformamide and treated with 0.35 g (of 1.65 mmol) (3,4,5-trimetoksi)phenylboric acid, 0,23 g (1,67 mmol) of potassium carbonate and 0,19 g (0.16 mmol) of Tetra(triphenylphosphine)- palladium. The reaction mixture is refluxed for two hours, cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over magnesium sulfate and the solvent is evaporated. The residue is purified by chromatography on silica gel, elwira mixture of hexane to ethyl acetate in the ratio of 1:1. The oil obtained is treated with diethyl ether, separating the precipitated precipitated solid and dried, obtaining the product in the form of not-quite-white solid.

Analysis for C27H25NO9S:

calculated % C 59,42 to 4.41 H N 2,67

found, % 59,04 4,42 2,48

Mass spectrum (chemical ionization): m/e 539;

the melting point of 182 to 183oC.

Example 24

2-Benzo[1,3] dioxol-5-yl-methyl-1,1-dioxo-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

A solution of 0.28 g (0.05 MAGAZIN-3-carboxylic acid in a mixture of 10 ml of tetrahydrofuran, 3 ml methanol and 3 ml of water is treated with 0.33 g (7,78 mmol) of lithium hydroxide and the reaction mixture was stirred at room temperature overnight. The solution is diluted with ethyl acetate, washed with 1 N. hydrochloric acid, saturated aqueous sodium chloride, dried over magnesium sulfate and the solvent is evaporated. The resulting foam is crystallized from a mixture of dichloromethane with diisopropyl ether.

Mass spectrum (chemical ionization): m/e 525.

Example 25

4-Benzo[1,3] dioxol-5-yl-2-methyl-1,1-dioxo-1,2-dihydro-16- benzo[e] [1,2]teasn-3-carboxylic acid

Receive in accordance with the method of example 23 methyl ester of 2-methyl-1,1-dioxo-4-(tripterocalyx)-1,2 - dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid and the saponification is carried out by the method of example 24.

Analysis for C17H13NO6S:

calculated % C 56,82 H 3,65 N 3,90

found, % 56,68 3,69 3,79

Mass spectrum (chemical ionization): m/e 389;

the melting point of 204,0 to 205,0oC.

Example 26

4-Benzo[1,3] dioxol-5-yl-2-benzo[1,3] dioxol-5-yl-methyl-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 23 methyl ester 2-benzoi acid and the saponification is carried out by the method of example 24.

Mass spectrum (chemical ionization): m/e 479;

the melting point of 229 to 230oC.

Example 27

4-Benzo[1,3] dioxol-5-yl-2-benzyl-1,1-dioxo-1,2-dihydro-16-benzo[e] [1,2]-thiazin-3-carboxylic acid

Receive in accordance with the method of example 23 methyl ester of 2-benzyl-1,1-dioxo-4-(tripterocalyx)-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid and the saponification is carried out by the method of example 24.

Mass spectrum (chemical ionization): m/e 435.

Example 28

4-Benzo[1,3] dioxol-5-yl-2-(4-methoxybenzyl)-1,1 - dioxo-1,2-dihydro-16-benzo[e]-[1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 23 methyl ester 2-(4-methoxybenzyl)-1,1-dioxo-4-(tripterocalyx)-1,2-dihydro-16-benzo[e] [1,2]thiazin-3-carboxylic acid and the saponification is carried out by the method of example 24.

Mass spectrum (chemical ionization): m/e 465;

the melting temperature of from 200 to 201oC.

Example 29

4-Benzo[1,3] dioxol-5-yl-1,1-dioxo-2-(3,4,5 - trimethoxybenzyl)-1,2-dihydro-16-benzo[e][1,2]thiazin-3 - carboxylic acid

Receive in accordance with the method of example 23 methyl ester 1,1-dioxo-4-(tripterocalyx)-2-(3,4,5 - trimethoxybenzyl the>

Analysis for C26H23NO9S:

calculated % C 59,42 to 4.41 H N 2,67

found, % 56,23 of 4.38 2,40 H2O 4,42

Mass spectrum (chemical ionization): m/e 525;

the melting point of 211,0 to 212,0oC.

Example 30

4-Benzo[1,3] dioxol-5-yl-2-(2-carboxymethoxy-4 - methoxybenzyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3 - carboxylic acid

Receive in accordance with the method of example 23 methyl ester 2-(2-ethoxycarbonylmethoxy-4-methoxybenzyl)-1,1-dioxo-4- (tripterocalyx)-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid and the saponification is carried out by the method of example 24.

Analysis for C26H21NO10S:

calculated % C 57,88 to 3.92 H N 2,60

found, % 57,62 3,90 2,54

Mass spectrum (chemical ionization): m/e (M-C10H11O4) 345;

the melting point of 192oC.

Example 31

4-Benzo[1,3] dioxol-5-yl-2-(6-chloro - benzo[1,3]dioxol-5-yl-methyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 23 methyl ester of 2-(6-chloro-benzo[1,3] -dioxol-5-yl-methyl)-1,1-dioxo-4- (tripterocalyx)-1,2-dihydro-16-benzo[e] [1,2]thiazin-3-carboxylic acid and the saponification is carried out on IU is oxol-5-yl-2-(7-methoxy-benzo[1,3] dioxol-5-yl-methyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 23 methyl ester of 2-(7-methoxy-benzo-[1,3]dioxol-5-yl-methyl)-1,1-dioxo-4- (tripterocalyx)-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid and the saponification is carried out by the method of example 24.

Mass spectrum (chemical ionization): m/e 509;

the melting point of 181 to 182oC.

Example 33

2-Benzo[1,3] dioxol-5-yl-methyl-4-(3,4-acid) 1,1 - dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 23 methyl ester of 2-(benzo[1,3] dioxol-5-yl-methyl)-1,1-dioxo-4- (tripterocalyx)- 1,2-dihydro-16-benzo[e] -[1,2]thiazin-3-carboxylic acid 3,4-dimethoxyphenylacetic acid and the saponification is carried out by the method of example 24.

Mass spectrum (chemical ionization): m/e 495;

the melting point of 267 to 268oC.

Example 34

4-Benzo[1,3] dioxol-5-yl-2-(2-Chlorobenzyl)-1,1 - dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 24 from the methyl ester of 2-(2-Chlorobenzyl)-1,1-dioxo-4-(tripterocalyx)-1,2 - dihydro-16-benzo[e]-[1,2] thiazin-3-carboxylic acid is ANO, % C 58,79 H 3,43 N 2,84

found, % 58,53 3,61 2,84

Mass spectrum (chemical ionization): m/e 470.

Example 35

N-(4-Benzo[1,3] dioxol-5-yl-2-benzo[1,3]dioxol-5-yl-methyl-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3 - carbonyl)benzosulfimide

To a solution of 0.25 g (0,56 mmol) 4-benzo[1,3]dioxol-5-yl-2 - benzo[1,3]dioxol-5-yl-methyl-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid in 5 ml of dichloromethane added 0.10 g (of 0.65 mmol) benzosulfimide, 0.12 g (of 0.65 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 0.05 g of dimethylaminopyridine. The mixture is stirred for three days and then diluted with 50 ml ethyl acetate and 20 ml of water. The organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuum. After chromatography on silica gel with elution with a mixture of dichloromethane with ethyl acetate to obtain 0.15 g (46%) of target compound.

Mass spectrum (chemical ionization): m/e 618.

Example 36

2-Benzo[1,3] dioxol-5-yl-4-(3-methoxyphenyl)-1,1-dioxo-1,2-dihydro-16-benzo[e]-[1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 23 methyl ester of 2-(benzo[1,3] dioxol-5-yl-methyl)-1,1-dioxo-4- (cryptomodule carried out according to the method of example 24.

Analysis:

calculated % C 61,93 H 4,11 N 3,01

found, % 61,50 4,40 2,90

Mass spectrum (chemical ionization): m/e 465.

Example 37

4-Benzo[1,3] dioxol-5-yl-2-benzo[1,3]dioxol-5-yl-methyl-6,7-dimethoxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 23 methyl ester 2-benzo[1,3] dioxol-5-yl-methyl-6,7-dimethoxy-1,1-dioxo-4- (tripterocalyx)-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid and the saponification is carried out by the method of example 24.

Analysis for C26H21NO10S:

calculated % C 57,88 to 3.92 H N 2,60

found, % 57,64 3,94 of 2.51

Mass spectrum (chemical ionization): m/e 539.

Example 38

4-Benzo[1,3] dioxol-5-yl-2-benzo[1,3]dioxol-5-yl-methyl-6-methoxy-1,1-dioxo-1,2-dihydro - 16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 23 methyl ester 2-benzo[1,3] dioxol-5-yl-methyl-6-methoxy-1,1-dioxo-4- (tripterocalyx)-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid and the saponification is carried out by the method of example 24.

Analysis for C25H19NO9S:

calculated % C 58,94 H 3,76 N 2,75

found, % 58,63 3,86 2,64

Mass spectrum (chemical ioniz the 3-dioxa-56-thia-6-Aza - cyclopent[b]naphthalene-7-carboxylic acid

Receive in accordance with the method of example 23 methyl ester 6-benzo[1,3] dioxol-5-yl-methyl-5,5-dioxo-8- (tripterocalyx)-5,6-dihydro-1,3-dioxa - 56thia-6-Aza - cyclopent[b]naphthalene-7-carboxylic acid and the saponification is carried out by the method of example 24.

Analysis for C25H17NO10S:

calculated % C 57,36 H 3,27 N 2,68

found, % 56,25 to 3.52 2,53

Mass spectrum (chemical ionization): m/e 523.

Example 40

Methyl ester of 2-benzo[1,3]dioxol-5-yl-methyl-4- (benzo[1,3]dioxol-5-yl-sulfanyl)-1,1-dioxo-1,2-dihydro-16-benzo[e] [1,2] thiazin-3-carboxylic acid

To methyl ether, 2-benzo[1,3]dioxol-5-yl-methyl-4 - hydroxy-1,1-dioxo-1,2-dihydro-16-benzo[e] [1,2] thiazin-3 - carboxylic acid in 6 ml dichloromethane and 0.65 ml (of 7.75 mmol) of pyridine type of 0.32 ml (1,71 mmol) of anhydride of triftoratsetata. This mixture is stirred for thirty minutes at room temperature, then diluted with 100 ml ethyl acetate, washed with twice 50 ml of 1 N. hydrochloric acid, 50 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated in vacuum, obtaining the crude methyl ester of 2-benzo[1,3]d is Borovoy acid. The solution of this complex ester in 3 ml of dimethylformamide is added to 0.31 g (2.0 mmol) of 1,3-benzodioxol-5-thiolate sodium {obtained by dissolving 0.31 g (2.0 mmol) of 1,3-benzodioxol-5-thiol in 3 ml of dimethylformamide and stirring with of 0.081 g (2.0 mmol) of sodium hydride in five minutes} in 3 ml of dimethylformamide. After stirring at room temperature for sixteen hours the mixture is diluted with 100 ml ethyl acetate, washed with twice 50 ml of 1 N. a solution of sodium hydroxide, 50 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. After chromatography on a column of silica gel with elution with 25% solution of ethyl acetate in hexane obtain 0.64 g (79%) of target compound in the form of foam.

Analysis for C25H19NO8S2:

calculated % C 57,14 H 3,64 N 2,67

found, % 56,93 3,93 of 2.51

Mass spectrum (chemical ionization): m/e 525.

Example 41

4-(Benzo[1,3] dioxol-5-yl-sulfanyl)-2-methyl-1,1 - dioxo-1,2-dihydro-16-benzo[e]-[1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 40 methyl ester 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-16- benzo[e][1,2]thiazin-3-carboxylic acid and amyraut by the method Deno, % 51,94 3,34 3,60

Mass spectrum (chemical ionization): m/e 391.

Example 42

2-Benzo[1,3] dioxol-5-yl-methyl-4-(benzo(1,3] dioxol-5-yl-sulfanyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

To 0,467 g (0.89 mmol) of methyl ester of 2-benzo[1,3]dioxol-5-yl-methyl-4-(benzo-[1,3]dioxol-5-yl-sulfanyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]-thiazin-3-carboxylic acid in a mixture of 5 ml of tetrahydrofuran, 2 ml methanol and 2 ml water is added and 0.46 g (0,19 mmol) of lithium hydroxide. Stirred at room temperature for five hours, diluted with 80 ml of water and 10 ml of 50% hydrochloric acid, then extracted with three 80 ml of chloroform, dried over magnesium sulfate and remove the solvent, obtaining 0.4 g (88%) of target compound in the form of foam.

Analysis for C24H17NO8S2:

calculated % C 56,35 H 3,35 N 2,74

found, % 55,78 3,43 2,58

Mass spectrum (chemical ionization): m/e 511.

Example 43

4-(Benzo[1,3] dioxol-5-yl-sulfanyl)-2-benzyl-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 40 from the methyl ester of 2-benzyl-4-hydroxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid, and washed the,67 N 3,00

found, % 58,74 3,91 2,68

Mass spectrum (chemical ionization): m/e 467.

Example 44

4-(Benzo[1,3] dioxol-5-yl-sulfanyl)-2-(4 - methoxybenzyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 40 methyl ester 4-hydroxy-2-(4-methoxybenzyl)-1,1-dioxo-1,2-dihydro - 16-benzo[e] [1,2]thiazin-3-carboxylic acid and amyraut by the method of example 42.

Analysis for C2H19NO7S2:

calculated % C 57,94 H 3,85 N 2,82

found, % 57,97 4,12 2,59

Mass spectrum (chemical ionization): m/e 498.

Example 45 4-(Benzo[1,3] dioxol-5-yl-sulfanyl)-2-(3,4,5 - trimethoxybenzyl)-1,1-dioxo-1,2-dihydro-16- benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 40 methyl ester 4-hydroxy-1,1-dioxo-2-(3,4,5-trimethoxybenzyl)-1,2-dihydro-16-benzo[e] [1,2]thiazin-3-carboxylic acid and amyraut by the method of example 42.

Analysis for C26H23NO9S2:

calculated % C 56,01 H 4,16 N OF 2.51

found, % 55,97 4,47 2,36

Mass spectrum (chemical ionization): m/e 557.

Example 46

4-(Benzo[1,3] dioxol-5-yl-sulfanyl)-2-(6-chloro - benzo[1,3] dioxol-5-yl-methyl)-1,1-dioxo-1,2-dihydro-16- benzo[e,3] -dioxol-5-yl-methyl)-4-hydroxy-1,1-dioxo-1,2 - dihydro-16-benzo[e] -[1,2]thiazin-3-carboxylic acid and amyraut by the method of example 42.

Analysis for C24H16NO8S2Cl:

calculated % C 52,80 H 2,95 N TO 2.57

found, % 52,91 2,87 2,42

Mass spectrum (chemical ionization): m/e 544;

the melting point of 203 to 204oC.

Example 47

4-(Benzo[1,3] dioxol-5-yl-sulfanyl)-2-(7-methoxy - benzo[1,3]dioxol-5-yl-methyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2] thiazin-3-carboxylic acid

Receive in accordance with the method of example 40 from the methyl ester of 2-(7-methoxy-benzo-[1,3] dioxol-5-yl-methyl)-4-hydroxy-1,1-dioxo - 1,2-dihydro-16-benzo[e] [1,2] thiazin-3-carboxylic acid and amyraut by the method of example 42.

Mass spectrum (chemical ionization): m/e 541.

Example 48

2-Benzo[1,3] dioxol-5-yl-methyl-4-(3,4 - dimethoxyphenylacetone)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 40 methyl ester 4-hydroxy-2-(3,4-dimethoxybenzyl)-1,1-dioxo-1,2-dihydro-16-benzo[e] [1,2] thiazin-3-carboxylic acid and amyraut by the method of example 42.

Analysis for C25H21NO8S2:

calculated % C 56,92 H 4,01 N 2,65

found, % 57,02 4,10 2,59

Mass spectrum (chemical is ioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 40 methyl ester 2-benzo[1,3] dioxol-5-yl-methyl-4-hydroxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid and amyraut by the method of example 42.

Analysis for C24H19NO7S2:

calculated % C 57,93 H 3,85 N 2,82

found, % 57,73 was 4.02 2,63

Mass spectrum (chemical ionization): m/e 497.

Example 50

2-Benzo[1,3] dioxol-5-yl-methyl-4-(benzo[1,3] dioxol-5-yl-sulfanyl)-6,7-dimethoxy-1,1-dioxo-1,2 - dihydro-16-benzo[e] [1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 40 methyl ester 2-benzo[1,3] dioxol-5-yl-methyl-4-hydroxy-6,7-dimethoxy-1,1-dioxo-1,2-dihydro-16-benzo[e] [1,2] thiazin-3-carboxylic acid and amyraut by the method of example 42.

Analysis for C27H23NO10S2:

calculated % C 54,64 H 3,70 N 2,45

found, % 54,96 4,08 2,09

Mass spectrum (chemical ionization): m/e 571.

Example 51

2-Benzo[1,3] dioxol-5-yl-methyl-4-(benzo[1,3]dioxol-5-yl-sulfanyl)-6-methoxy-1,1-dioxo-1,2 - dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 40 methyl ester 2-benzo[1,3] dioxol-5-yl-meta example 42.

Mass spectrum (chemical ionization): m/e 541.

Example 52

6-Benzo[1,3] dioxol-5-yl-methyl-8- (benzo[1,3]dioxol-5-yl-sulfanyl)-5,5-dioxo-5,6-dihydro-1,3 - dioxa - 56-thia-6-Aza-cyclopent[b]naphthalene-7-carboxylic acid

Receive in accordance with the method of example 40 methyl ester 6-benzo[1,3] dioxol-5-yl-methyl-8-hydroxy-5,5-dioxo-5,6 - dihydro-1,3-dioxa - 56-thia-6-Aza-cyclopent[b]-naphthalene-7-carboxylic acid and the saponification is carried out by the method of example 42.

Mass spectrum (chemical ionization): m/e 555.

Example 53

4-(Benzo[1,3] dioxol-5-yl-sulfanyl)-2-(2-Chlorobenzyl)-1,1 - dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Receive in accordance with the method of example 40 methyl ester 2-(2-Chlorobenzyl)-1,1-dioxo-4-(tripterocalyx)-1,2 - dihydro-16-benzo[e][1,2] thiazin-3-carboxylic acid and the saponification is carried out by the method of example 42.

Analysis for C23H16NO6S2Cl:

calculated % C 55,03 H 3,21 N 2,79

found, % 54,82 3,85 2,46

Mass spectrum (chemical ionization): m/e 501.

Example 54

2-(2-Benzo[1,3] dioxol-5-yl-methyl)-4-(benzo[1,3] dioxol-5-yl-sulfinil)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

Puteti)-4-(benzo[1,3]dioxol-5-yl-sulfanyl)-1,1-dioxo-1,2-dihydro-16-benzo[e] [1,2]thiazin-3-carboxylic acid in dichloromethane and stirring for ten minutes to obtain methyl ester of 2-(2-benzo[1,3] dioxol-5-yl-methyl)-4-(benzo[1,3]dioxol-5-yl-sulfanyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid, which amyraut by the method of example 42.

Analysis for C24H17NO9S2:

calculated % C 54,64 3,25 H N 2,66

found, % 54,75 3,38 2,61

Mass spectrum (chemical ionization): m/e 527.

Example 55

2-Benzo[1,3] dioxol-5-yl-1,1-dioxo-1,2-dihydro - 16-benzo[d]isothiazol-3-one

To a solution of 9.5 g (to 36.5 mmol) of 3,4-methylenedioxyaniline and of 3.53 ml (43,6 mmol) of pyridine in 20 ml of chloroform at a temperature of 0oC add 9.5 g (to 36.5 mmol) of 90% methyl-2-(chlorosulfonyl)benzoate portions six times for forty-five minutes, then stirred at room temperature for three days. The reaction mixture was diluted with ethyl acetate and washed with 1 N. hydrochloric acid. After drying over magnesium sulfate and removal of solvent the crude sulfonamide was dissolved in 100 ml of a mixture of xylenes and process with the help of 0.61 ml (of 7.64 mmol) of pyridine and 0,93 g (of 7.64 mmol) dimethylaminopropylamine and refluxed for vosemnadcat is really, washed with water and dried, obtaining the target compound.

Analysis for C14H9NO5S:

calculated % C 55,44 H 2,99 N 4,62

found, % 55,43 is 3.08 4,70

Mass spectrum (chemical ionization): m/e 303.

Example 56

Methyl ester of 2-benzo[1,3] dioxol-5-yl-4-hydroxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid

To a solution of 2 g (6,59 mmol) of 2-benzo[1,3]dioxol-5-yl-1,1 - dioxo-1,2-dihydro-16-benzo[d] isothiazol-3-one in 11 ml of dimethyl sulfoxide added to 1.16 ml (13,2 mmol) of methyl 2-CHLOROACETATE and the mixture is heated to a temperature of 40oC, then for one hour added in several portions of 1.05 g (of 26.4 mmol) of sodium hydride (60% dispersion in oil). The reaction mixture was kept at a temperature of 40oC over the next three hours, acidified with 1 N. hydrochloric acid, extracted with ethyl acetate, the extract washed with saturated aqueous sodium chloride and dried over magnesium sulfate. By chromatography receive the target product.

Analysis for C17H13NO7S:

calculated % C 54,40 H 3,49 N OF 3.73

found, % 54,11 3,66 3,60

Mass spectrum (chemical ionization): m/e 375.1

1. Derivatives dioxide benzothiazine General formula I

< / BR>
DG is five deputies;

Rbmeans from one to four substituents, independently from each other selected from the group comprising hydrogen, chlorine, methylenedioxy, Ethylenedioxy, group or SIG and co2Or SIG, where R denotes hydrogen, alkyl with 1 to 6 carbon atoms or phenyl;

Rdmean group CO2R, SO3R, NRR1where R has the above significance, and R1has the meaning given for the radical R;

n means an integer from zero to two;

--- means simple or double bond;

X is (CH2)nor S(O)nwhere n has the above meaning,

or their pharmaceutically acceptable salts accession acid or base.

2. Derivatives of dioxane benzothiazine General formula I on p. 1, where R2means or alkyl with 1 to 5 carbon atoms; each of Randand Rwithmeans from one to five substituents, and Rbmeans from one to four substituents, independently from each other selected from the group comprising hydrogen, chlorine, methylenedioxy, Ethylenedioxy; Rdmeans carboxyl; n means an integer from zero to one; --- indicates a double bond; X is (CH2)nor sulfonyl.

3. Proizvol of Randand Rwithmeans from one to five substituents, independently from each other selected from the group including hydrogen and chlorine; Rbmeans from one to four substituents, independently from each other selected from the group including hydrogen and chlorine; Rand, Rb, Rwithalso, independently from each other, can mean up to two substituents from the group comprising methylendioxy and Ethylenedioxy; n means an integer zero or one; --- means of the double bond and X is (CH2)nor sulfur.

4. Derivatives dioxide benzothiazine General formula I on p. 1, representing a compound selected from the group including:

4-benzo[1,3] dioxol-5-yl-2-methyl-1,1-dioxo-1,2-dihydro-16-benzo[e] [1,2]-thiazin-3-carboxylic acid;

4-benzo[1,3] dioxol-5-yl-2-benzo[1,3] dioxol-5-yl-methyl-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

4-benzo[1,3] dioxol-5-yl-2-benzyl-1,1-dioxo-1,2-dihydro-16-benzo[e] [1,2]-thiazin-3-carboxylic acid;

4-benzo[1,3] dioxol-5-yl-2-(4-methoxybenzyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

4-benzo[1,3] dioxol-5-yl-1,1-dioxo-2-(3,4,5-trimethoxybenzyl)-1,2-dihydro-16-benzo[e][1,2]t the 16-benzo[e][1,2]thiazin-3-carboxylic acid;

4-benzo[1,3] dioxol-5-yl-2-(6-chlorobenzo[1,3] dioxol-5-yl-methyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

4-benzo[1,3] dioxol-5-yl-2-(7-methoxybenzo[1,3] dioxol-5-yl-methyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-4-(3,4-acid) 1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-1,1-dioxo-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

N-(4-benzo[1,3] dioxol-5-yl-2-benzo[1,3]dioxol-5-yl-methyl-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carbonyl)-benzosulfimide;

4-benzo[1,3] dioxol-5-yl-2-benzo[1,3]dioxol-5-yl-methyl-6-methoxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

2,4-bis-benzo[1,3] dioxol-5-yl-6,7-dimethoxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

4-benzo[1,3] dioxol-5-yl-2-(2-Chlorobenzyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-4-(benzo[1,3] dioxol-5-yl)-7-methoxy-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid and

2-benzo[1,3] dioxol-5-yl-m is ptx2">

5. Derivatives dioxide benzothiazine General formula I on p. 1, representing a compound selected from the group including:

4-(benzo[1,3] dioxol-5-yl-sulfanyl)-2-methyl-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-4-(benzo[1,3] dioxol-5-yl-sulfanyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

4-(benzo[1,3] dioxol-5-yl-sulfanyl)-2-(4-methoxybenzyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

4-(benzo[1,3] dioxol-5-yl-sulfanyl)-2-(carboxymethoxy-4-methoxybenzyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

4-(benzo[1,3] dioxol-5-yl-sulfanyl)-2-(7-methoxybenzo[1,3] dioxol-5-yl-methyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-4(3,4-dimethoxyphenylacetone)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-4(3-methoxybenzenesulfonyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

2-benzo[1,3] dioxol-5-yl-methyl-4(benzo[1,3] dioxol-5-yl-sulfanyl)-6,7-dimethoxy-1,1-dioxo-1,2-dihydro-16-benzo[e] [1,2] thiazin-3-carboxylic acid;

2-be is in-3-carboxylic acid;

4-(benzo[1,3] dioxol-5-yl-sulfanyl)-2-(2-Chlorobenzyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid;

2-(2-benzo[1,3] dioxol-5-yl-methyl)-4-(benzo[1,3] dioxol-5-yl-sulfanyl)-1,1-dioxo-1,2-dihydro-16-benzo[e][1,2]thiazin-3-carboxylic acid and

methyl ester of 2-benzo[1,3]dioxol-5-yl-methyl-1,1-dioxo-4-(triptorelin-sulfonyloxy)-1,2-dihydro-16-benzo[e] [1,2] thiazin-3-carboxylic acid.

6. Pharmaceutical composition having activity of inhibiting endothelin receptor containing the active substance on the basis of heterocyclic compounds and pharmaceutically acceptable carrier, characterized in that it as a heterocyclic compound contains a compound of General formula I

< / BR>
where R2means or alkyl with 1 to 7 carbon atoms;

each of Randand Rwithmeans from one to five substituents;

Rbmeans from one to four substituents, independently from each other selected from the group comprising hydrogen, chlorine, methylenedioxy, Ethylenedioxy, group or SIG and co2Or SIG, where R denotes hydrogen, alkyl with 1 to 6 carbon atoms or phenyl;

Rdmean group CO2R, SO3R, NRR1where R them is from zero to two;

--- means simple or double bond;

X is (CH2)nor S(O)nwhere n has the above meaning,

or its pharmaceutically acceptable salt accession acid or base in a therapeutically effective amount.

7. The method of inhibition of endothelin receptor by introducing the patient of the active substance on the basis of heterocyclic compounds, characterized in that the heterocyclic compound is administered a compound of General formula I

< / BR>
where R2means or alkyl with 1 to 7 carbon atoms;

each of Randand Rwithmeans from one to five substituents;

Rbmeans from one to four substituents, independently from each other selected from the group comprising hydrogen, chlorine, methylenedioxy, Ethylenedioxy, group or SIG and co2Or SIG, where R denotes hydrogen, alkyl with 1 to 6 carbon atoms or phenyl;

Rdmean group CO2R, SO3R, NRR1where R has the above significance, and R1has the meaning given for the radical R;

n means an integer from zero to two;

--- means simple or double bond;

X is (CH2)nor S(O)nwhere policiesto in the form of a single dose.

 

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< / BR>
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