Sulfonamides and pharmaceutical composition

 

(57) Abstract:

The invention relates to new sulfonamide of General formula I, where R1-R8A and B have the meanings indicated in the formula, which are inhibitors of endothelin and can be used for the treatment of diseases associated with the activity of endothelin, such as high blood pressure, as well as to pharmaceutical compositions based on them. 2 S. and 11 C.p. f-crystals, 3 PL.

The present invention relates to new sulfonamides and their use as medicaments. In particular, the invention relates to new compounds of the formula

< / BR>
where R1denotes phenyl or phenyl substituted by halogen, (C1-C7)alkyl, (C1-C7)alkoxygroup, (C1-C7)alkylenedioxy, carboxyla or trifluoromethyl; or denotes heterocyclyl selected from mono - or bicyclic 5 - or 6-membered heterocyclic compounds with oxygen, nitrogen or sulfur as a heteroatom;

R2means tetrazolyl, tetrazolyl, substituted (C1-C7)alkyl, cyano, carboxyl, (C1-C7)alkoxycarbonyl, hydroxymethyl, formyl, carbarnoyl, thiocarbamoyl, amidino or hydroxyamides;
1-C7)alkoxygroup or halogen;

R9denotes hydrogen, benzyl, benzyl substituted in the phenyl ring by halogen, (C1-C7)alkyl, (C1-C7)alkoxygroup, (C1-C7)alkylenedioxy, carboxyla or trifluoromethyl; or denotes the group-C(O)other10;

R10means (C1-C7)alkyl, phenyl, phenyl substituted with halogen, (C1-C7)alkyl, (C1-C7)alkoxygroup, (C1-C7)alkylenedioxy, carboxyla or trifluoromethyl; or represents pyridyl or pyridyl substituted by one or two (C1-C7)alkyl groups;

Raand Rbdenote hydrogen or (C1-C7)alkyl;

n is 2, 3 or 4; and

A and B denote CH; or one of the symbols A or B is nitrogen and the other represents CH; or

R2denotes hydrogen, and one of the symbols A or B represents N-oxide (N--->O), and the other represents CH, and

to pharmaceutically acceptable salts of compounds of formula I.

Examples of fragments mono - or bicyclic 5 - or 6-membered heterocyclic compounds with oxygen, nitrogen or sulfur as heteroatom are such passages as 2 - and 3-furyl, 2-, 4 - and 5-pyrimidinyl, 2-, 3 - and 4-Lil, ethanolic and chinadoll, and these fragments can be substituted, for example, one or two (C1-C7)alkyl groups. Preferred are pyridyl or pyridyl substituted by one or two (C1-C7)alkyl groups.

The term "(C1-C7) "as used herein, denotes a group with 1-7, preferably 1-4 carbon atoms. Alkyl and alkoxygroup can have straight or branched chain. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec - and tert-butyl. Halogen denotes fluorine, chlorine, bromine and iodine, preferably chlorine is.

A preferred group of compounds of formula I includes those in which A and B denote CH or one of the symbols A and B is nitrogen. R1preferably denotes a phenyl group which is mono - or disubstituted, or pyridyloxy group, which is monogamist (C1-C7)alkyl, most preferably 2-pyridyloxy group, substituted C1-C7)alkyl. R2preferably indicates tetrazolyl group. R3preferably denotes-O(CH2)nOH, -O(CH2)nO-benzyl or-O(CH2)what about the 2. Among these compounds of most interest are those in which R4means (C1-C7)alkoxygroup, and R5-R8represent hydrogen; or R4denotes halogen, R7means (C1-C7)alkoxygroup, and R5, R6and R8denote hydrogen; A represents nitrogen and B is CH.

In EP-A-0510526 and EP-A-0526708 described sulfonamides with endothelin-inhibitory activity.

The compounds of formula I can be obtained

(a) the interaction of the compounds of formula II

< / BR>
where R12denotes a 3 - or 4-tianfeng or N-oxide 2 - or 4-pyridyl, Hal denotes halogen, and other symbols have the meanings indicated above, with the compound of the formula MO(CRaRb)n-OR91where M denotes an alkali metal, R91denotes hydrogen, benzyl or benzyl substituted in the phenyl ring by halogen, (C1-C7)alkyl, (C1-C7)alkoxygroup, (C1-C7)alkylenedioxy, carboxyla or trifluoromethyl, and Ra, Rband n have the meanings stated above; or

b) the interaction of the compounds of formula III

< / BR>
where R11denotes the N-oxide 2 - or 4-pyridyl, and other symbols is of formula I, in which R2denotes cyano, and the other symbols have the meanings indicated above, with an azide in the presence of an aprotic Lewis acid; or

g) converting the compounds of formula I in which R2denotes cyano, and the other symbols have the meanings indicated above, by interacting with the alcoholate of an alkali metal, and then with hydrazine in an appropriate amerson with subsequent treatment with nitrite and acid; or

d) the interaction of the compounds of formula I in which R9denotes hydrogen, with an isocyanate of formula R10NCO; or

e) transforming ceanography the compounds of formula I in which R2denotes cyano, and the other symbols have the meanings specified above, in amidinopropane, carbarnoyl, thiocarbamoyl, (C1-C7)alkoxycarbonyl, carboxyl, hydroxymethyl, formyl or hydroxyamides; or

g) alkylation tetrazolyl group of compounds of formula I in which R2means tetrazolyl and R9denotes benzyl, benzyl substituted in the phenyl ring by halogen, (C1-C7)alkyl, (C1-C7)alkoxygroup, (C1-C7)alkylenedioxy, carboxyla or trifluoromethyl; and removal the I formula I in salt.

The interaction of the compounds of formula II with the compound of the formula MO(CRaRb)n-OR91(option a) is usually carried out using as a solvent of the glycol corresponding to this connection, for example, ethylene glycol, when n is 2 and Raand Rbdenote hydrogen. The alkali metal M preferably represents sodium, and Hal preferably represents chlorine. The reaction is usually carried out by heating, for example, to a temperature of 40-100oC. In accordance with this variant of the method are the compounds of formula I in which R2denotes a cyano, and A and B denote CH; or R2denotes hydrogen, one of the symbols A or B represents N-oxide, and the other represents CH, and R9denotes the radical R91the above, and other symbols have the specified values.

Option b) N-oxide of formula II is preferably subjected to interaction with trimethylsilylcyanation and triethylamine. The reaction is usually carried out in acetonitrile by heating the reaction mixture to a temperature of reflux distilled. In accordance with this variant of the method are the compounds of formula I in which R2denotes cyano, one of the symbols A and B is nitrogen and the other is as azide, for example, sodium azide, guanidinium or trimethylsilane. As Lewis acids can be used ammonium salts, such as ammonium chloride. The reaction can be carried out in an aprotic polar solvent such as dimethylformamide or dimethylsulfoxide, usually by heating, for example, to a temperature of 60-100oC.

The interaction of the compounds of formula I in which R2denotes cyano, with hydrazine in accordance with option d) is performed with the help of aminoether, from which, using an excess of hydrazine get amerson, i.e., the connection corresponding to that of formula I, in which R2denotes-CH(NH)NHNH2. Amerson by nitrosation in turn aminoacid that spontaneously cyclizes to tetrazole. In accordance with the variants C) and d) are obtained the compounds of formula I in which R2means tetrazolyl, and other symbols have the specified values.

The interaction in accordance with variant e) can be carried out by a method well-known to obtain carbamates of alcohols and isocyanates, for example, in a suitable anhydrous organic solvent, e.g. a hydrocarbon, such as toluene, usually by heating. is piroski. In accordance with the method according to this variant obtain the compounds of formula I in which R9denotes the group-C(O)other10and other symbols have the specified values.

Transform ceanography R2the compounds of formula I in amidinopropane, carbarnoyl, thiocarbamoyl, (lower)alkoxycarbonyl, carboxyl, hydroxymethyl, formyl or hydroxyamides in accordance with variant e) can be carried out by a method well known for such transformations. For example, the cyano may be converted by treatment with an alcoholate of an alkali metal, e.g. sodium methylate in methanol, in aminoether (i.e., group C(NH)OCH3), which can be converted in situ by treatment with hydrochloric acid in alkylcarboxylic (for example, group-COOCH3), which can be Amylin to carboxylic acid in the treatment of an alcoholic solution of alkali. An alternative to this iminoethyl obtained in situ, can be converted by treatment with ammonium chloride in methanol to the corresponding amidinothiourea (R2denotes amidinopropane), which then can be converted by treatment with an aqueous solution of alkali and subsequent acidification in the corresponding carbamoyl connection (R2about the atrium can be obtained corresponding hydroxyamides compounds (R2denotes-C(NH)NHOH). The carboxyl group can be restored by treatment with reducing agents, such as dihydrobis(2 methoxyethoxy)sodium aluminate in toluene, to hydroxymethylene group, which in turn can be oxidized to a formyl group in the processing of oxidizing agents such as manganese dioxide. This sequence of reactions R3may not contain hydroxyl groups, i.e., R9cannot denote hydrogen, but may denote, for example, benzyl.

Alkylation of compounds of formula I in accordance with option g) may be carried out a well-known method, for example, by processing the (lower)alkylhalogenide in the presence of a base, such as tert-butyl potassium in tetrahydrofuran, and the thus obtained mixture of 1 - and 2-(lower)alkyldiethanolamine compounds of formula I may be separated by a well-known method, for example, chromatography. Acceptable hydroxyamine group represents, for example, alkylsilane protective group, such as dimethyl-tert-Boticelli and tetrahydropyranyl, which can be introduced into the reaction product and removed from the well known manner. In accordance with option g) corresponding to R9denotes hydrogen.

The compounds of formula I containing a carboxy or tetrazolyl group can be turned into a well-known method in pharmaceutically acceptable salt, for example, salts of alkali metals such as Na and K, or salts of alkaline-earth metals such as Ca or Mg salts, or salts of amines, such as monoethanolamine.

Compounds that are used as the original products, if they are not known to obtain or are not described in the present description, can be obtained by analogy with known methods or by the methods described below.

The above compounds of formula I are inhibitors of endothelin receptor. Therefore, they can be used for the treatment of diseases associated with the activity of endothelin, first of all diseases of the circulatory system, such as hypertension, ischemia, narrowing of blood vessels, angina.

The compounds of formula I have a selective inhibitory action against the endothelin receptors, which can be illustrated using the following test methods.

I. Inhibition of binding of endothelin with recombinant ETichi and C. Miyamoto, BBRC 180, 1265-1272) and expressed in the system of the baculovirus-insect cell. From the fermenter volume 23 l by centrifugation (3000 g, 15 min, 4oC) after 60 hours after infection emit insect cells infected with baculovirus, resuspended in Tris buffer (5 mm, pH of 7.4, 1 mm MgCl2and again centrifuged. After additional resuspendable and centrifugation, the cells are suspended in 800 ml of the same buffer and lyophilizer at -120oC. When thawing the suspension in this hypotonic buffer mixture occurs disintegration of the cells. After re-cycle freeze-drying/thawing, the suspension is homogenized and centrifuged (25000 g, 15 minutes, 4oC). After suspension in Tris-buffer (75 mm, pH of 7.4, 25 mm MgCl2, 250 mm sucrose) aliquots of 1 ml (protein content of approximately 3.5 mg/ml) stored at -85oC.

For analysis of binding lyophilized preparations of membranes subjected to thawing and after centrifugation at 20oC and 25,000 g for 10 minutes resuspending buffer for analysis (50 mm Tris-buffer, pH of 7.4, containing 25 mm MnCl2, 1 mm etc and 0.5% bovine serum albumin). 100 µl of this suspension of membranes containing 5 μg protein are incubated with 50 cconcentration 20 PM) and 100 μl of buffer for analysis, containing different concentrations of the tested compounds. Incubation is carried out at 20oC for 2 hours or at 4oC for 24 hours. Separation of free and membrane-bound radio-carried out by filtration through a glass fiber filter. Inhibiting activity of the compounds of formula I, defined using this testing method, are shown in table 1 in the form of the IC50i.e., in the form of concentration [nm], which is required for 50% inhibition of specific binding125I-endothelin.

II. The inhibition caused by endothelin reductions in selected rings of rat aorta

Rings with a length of 5 mm was cut off from the thoracic aorta of adult rats Wistar-Kyoto. The endothelium was removed by gently wipe the inner surface. Each ring was immersed at 37oC in 10 ml of Krebs-Henseleit in a separate tub, which was filled with gas, a composition of 95% O2and 5% CO2. Measured isometric stretching rings. The ring is pre-stretched with a tension of 3 g After incubation for 10 minutes with the test compound or with a carrier was added to the cumulative dose of endothelin-1. The activity of test compounds was evaluated is tagonist. This shift to the right (or "doses" OD) corresponds to the rate of change of the values of EC50endothelin-1 in the presence and in the absence of the antagonist, where the value EC50the concentration of endothelin needed to reduce tissue at half maximum.

The corresponding value pA2that is a measure of the activity of the tested compounds was determined by "relation doses" OD for each individual curve dose-activity using a computer program based on the following equation:

pA2= log (AR-1) - log (concentration of antagonist)

The value of EC50endothelin in the absence of test compounds is 0.3 nm.

The values of pA2obtained for compounds of formula I listed in table 2.

Due to its ability to inhibit the binding of endothelin to the compounds of formula I can be used as drugs for treatment of disorders associated with increased frequency of narrowing of the blood vessels. Examples of such violations are high blood pressure, coronary disorders, cardiac insufficiency, renal and myocardial ischemia, renal failure, dialysis, cerebral and the E. They can also be used with atherosclerosis, to prevent restenosis after called a catheter, the expansion of blood vessels, inflammation, gastric ulcer and duodenal ulcer, the ulcer cruris, sepsis caused by gram-negative bacteria, shock, glomerulonephritis, renal colic, glaucoma, asthma, and for treatment and prevention of complications in diabetes and complications with the introduction of cyclosporine, as well as other disorders associated with the activity of endothelin.

The compounds of formula I can be administered orally, rectally, parenterally, for example intravenously, intramuscularly, subcutaneously, podvoloshino or transdermal or sublingual or in the form of eye preparations or in the form of an aerosol. Examples of application forms are capsules, pills, suspensions or solutions for oral administration, suppositories, injectable solutions, eye drops, ointments or solutions in the form of aerosols.

The preferred form of administration is intravenous, intramuscular or oral administration. The dose at which the compounds of formula I administered in effective amounts depend on the specific nature of the active substance, the age and needs of the patient and the route of administration. In General, permitted dose pnye additive or additives, also which pharmacodynamically active. Tablets or granules, for example, may contain a number of binders, fillers, carriers or solvents. Liquid preparations may represent, for example, the form of sterile mixing with the water solution. Capsules in addition to the active substance may contain a filler or thickener. In addition, can also be improving the taste additives and substances commonly used as preservatives, stabilizers, preserving moisture, and emulsifying agents, salts for modifying the osmotic pressure, buffers and other additives.

The above-mentioned carriers and solvents may include organic or inorganic substances, for example, water, gelatin, lactose, starch, magnesium stearate, talc, gum Arabic, polyalkylene glycols, etc., it is Necessary that all adjuvants used in the manufacture of drugs were non-toxic.

Below the invention is illustrated in more detail by examples. In these examples, DMF refers to dimethylformamide, THF refers to tetrahydrofuran and EtOAC means ethyl acetate.

Example 1

a) 200 ml of dimethoxyethane and 110,9 g of 4-[4-(4-tert-butyltrichlorosilane 23,80 g of sodium in 660 ml of ethylene glycol. The solution is incubated under stirring at a temperature of 90oC for 20 hours, then cooled, poured into 2500 ml of H2O and then treated CH3COOH to obtain a pH of 5. The mixture is extracted with EtOAc three times, the organic phase is washed with H2O, dried over Na2SO4and evaporated under reduced pressure. The residue is recrystallized from CH3CN and then twice from a mixture of acetone and CH3CN. Thus obtained 4-[4-(4-tert-butylphenylphosphine)-6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)pyrimidine-2-yl] pyridine-1-oxide.

Getting the original product:

b) to 53.1 g of 4-lepirudin (98%) are added in one portion to a solution containing of 1.15 g of sodium in 200 ml of absolute MeOH. After 6 hours with vigorous stirring to 29.5 g of NH4Cl. The mixture is stirred at room temperature overnight. To it was added 600 ml of simple ether, after which the precipitate is filtered under vacuum and then dried at 50oC under reduced pressure. Thereby obtaining hydrochloride 4-amidinopropane (decomposition temperature 245-247oC).

in) 112,9 g of diethyl(2-methoxyphenoxy)malonate added dropwise during 30 minutes to a solution containing 27,60 g of sodium in 400 ml of MeOH. After that odnonefnoj temperature overnight and evaporated at a temperature of 50oC under reduced pressure. The residue is treated with 500 ml of simple ether and filtered by vacuum filtration. The filter cake is dissolved in 1000 ml of H2O and gradually treated with 50 ml of CH3COOH. The precipitate is filtered off by vacuum filtration, washed with 400 ml of H2O and dried at 80oC under reduced pressure. Thus obtained 5-(2-methoxyphenoxy)-2-(pyridin-4 - yl)pyrimidine-4,6-diol (or tautomer), tPLabove 250oC.

g) a Suspension containing 154, 6mm g of 5-(2-methoxyphenoxy)-2-(pyridin - 4-yl)pyrimidine-4,6-diol (or tautomer) in 280 ml of POCl3, incubated with vigorous stirring and at a temperature of 120oC in oil bath for 24 hours. The reaction mixture gradually changed, turning into a dark brown liquid which is evaporated under reduced pressure, after which the process three times with 500 ml of toluene and evaporated. The residue is dissolved in 1000 ml of CH2Cl2handle ice and H2O and then using 3h. NaOH adjust pH value of the aqueous phase, until it reaches 8. The organic phase is separated and the aqueous phase is extracted with CH2Cl2. United CH2Cl2-extracts dried over MgSO4, evaporated to half volume, process 1000 ml ACET 2 hours, the crystals are filtered vacuum filtration and dried at 50oC during the night. Thus obtained 4,6-dichloro-5-(2-methoxyphenoxy)- 2-(pyridin-4-yl)pyrimidine, tPL178-180oC.

d) a Solution containing of 17.4 g of 4,6-dichloro-5-(2-methoxyphenoxy)- 2-(pyridin-4-yl)pyrimidine in 100 ml of CH3CN, refluxed for 3 hours with 15 ml of a 32% solution of peracetic acid, then cooled and kept in the refrigerator over night. The crystals are filtered vacuum filtration and dried at 50oC under reduced pressure. Thus obtained 4-[4,6-dichloro-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-1-oxide, tPL189-190oC.

e) a Solution containing of 36.4 g of 4-[4,6-dichloro-5-(2-methoxyphenoxy) pyrimidine-2-yl] pyridine-1-oxide of 52.8 g of para-tert-butylbenzaldehyde potassium in 150 ml of absolute DMF, stirred at room temperature for 24 hours. Then it is drained by mechanical stirring in a mixture of 1500 ml of H2O and 1000 ml simple ether, thus obtaining a residue. The pH of the suspension was adjusted to 5 using the CH3COOH, filtered vacuum-filtered, the crystals washed with cold water, and then a simple ether and dried at a temperature of 50oC. are Thus obtained 4-[4-(4-tert-butylphenylphosphine)-6-x"ptx2">

Example 2

The solution containing 78,45 g of 4-[4-(4-tert-butylphenylphosphine)- 6-chloro-5-(2-methoxyphenoxy)pyrimidine-2-yl] pyridine-1-oxide, of 122.5 g of trimethylsilylacetamide, 127,8 g of triethylamine and 1200 ml of CH3CN, refluxed for 20 hours and then evaporated under reduced pressure. The oily residue is dissolved in 1000 ml of EtOAc and the solution washed with a mixture (9: 1) CH3COOH:H2O, then H2O. EtOAc extracts are dried over Na2SO4. After evaporation of the solvents the residue is dissolved in a mixture of CH3CN and CF3COOH (20:1). When this is separated crystalline precipitate. Thus obtained 4-tert-butyl-N-[2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)pyrimidine-4-yl]benzosulfimide, tPL176-179oC.

Example 3

The suspension containing 50.0 g of 4-tert-butyl-N-[2-(2-lepirudin-4-yl)- 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide, 46,33 g NH4Cl and 56,47 g NaN3in 1600 ml of DMF, incubated with vigorous stirring and at a temperature of 70oC for 24 hours. A large part of the solvent is distilled off under reduced pressure, the residue is dissolved in H2O, the solution is extracted four times at a pH of 6.5 simple ether, then treated CHthrowaway vacuum filtration. Thus obtained 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] benzosulfimide, tPL225-227oC.

Example 4

(a) heated to 90oC the solution containing 46,0 g of 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H - tetrazol-5-espiridion-4-yl)pyrimidine-4-yl]benzosulfimide in 600 ml of absolute dioxane, while stirring dropwise within 60 minutes add a cold solution containing 22,0 g 2-pyridylcarboxylic in 200 ml of dioxane. After 4 hours the solvent is evaporated under reduced pressure, the residue is dissolved in 300 ml EtOAc and incubated at room temperature overnight. The crystal mass is filtered off by vacuum filtration and washed with EtOAc. After repeated recrystallization from tetrahydrofuran and EtOAc and drying under reduced pressure during the first 3 days at a temperature of 45oC and then for 2 days at a temperature of 65oC get 2-[6-(4-tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2-(2-1H - tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy]ethylpyridine-2-ylcarbamate, tPL214oC, above which starts very slow decomposition.

b) 2-pyridylcarboxylic used is Kalinovo acid in 330 ml of absolute DMF and to 61.2 ml of triethylamine, for 30 minutes at a temperature of 10oC is treated dropwise to 99.7 ml diphenylphosphinite. After soaking for 2 hours at room temperature the greater part of the solution evaporated at 30oC under reduced pressure, the oily residue is treated with 200 ml of 5% sodium bicarbonate solution and completely extracted with simple ether. The ether extracts are combined, dried over MgSO4and evaporated at room temperature under reduced pressure. Yellowish oily residue is cooled in an ice bath at 0-5oC and the crystals washed with -20oC a simple mixture of ether and hexane (1: 1). Thus obtained 2-pyridylcarboxylic in the form of colorless crystals, tPL39-41oC.

Example 5

A solution containing of 47.8 g of 2-[6-(4-tert-butylphenylphosphine)- 5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4 - yloxy] ethylpyridine-2-ylcarbamate in 500 ml of absolute THF, is treated dropwise a cold solution containing 2.8 g of sodium in 50 ml of methanol, thus gradually formed a solid residue, which after stirring at room temperature for 1 hour, filtered off by vacuum filtration, dried at very low pressure at a temperature of 35oC decomposition temperature which is above 250oC.

Example 6

Tetrazol, completely similar to that described in example 3, get, starting with the same source materials as in example 3, the reaction is carried out in a single vessel (3 stage) under the following conditions:

2.4 ml of a 1.0 n solution of sodium methylate added at room temperature to a suspension containing 1,15 g (2 mmole) of 4-tert-butyl-N-[2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)pyrimidine-4-yl] benzosulfimide in 50 ml of absolute MeOH. Resulting clear yellow solution is maintained at a temperature of 40oC for 3 days.

The solution aminoether at room temperature is slowly added dropwise within 30 minutes to a suspension containing 302 mg (4.4 mmole) of H2N-NH2HCl in 10 ml of absolute MeOH, while gradually separated crystalline precipitate. Then the suspension is cooled to a temperature of 2oC with stirring and treated with 15 ml of 1.0 N. HCl. The clear yellowish solution (pH of 1.7) is treated dropwise with a solution of 800 mg (of 11.6 mmole) NaNO2in 10 ml of H2O so that the temperature did not exceed 5oC (pH of 2.7). After 1 hour, add 2 ml of 1N. HCl and then add a solution containing 200 mg (2.9 mmole) NaNO2in 2 ml of H2O. Rastaa the suspension is extracted with EtOAc. The combined EtOAc solutions first washed twice H2O, and then thoroughly extracted with 0.5 N. the solution of NaHCO3-H2O. the combined aqueous NaHCO3the solutions carefully treated with 3h. HCl (to pH 2) and the suspension extracted with EtOAc standard way. After evaporation of the solvent under reduced pressure, the crystalline residue remains, which is identical to the product obtained in example 3.

Example 7

a) In analogy to example 1A) from N-[6-chloro-5-(2-methoxyphenoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-yl] benzosulfimide and glycolate, sodium ethylene glycol receive N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-yl]benzosulfimide, tPL110-112oC (from EtOAc).

b) In analogy to example 2 from N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] benzosulfimide receive N-[2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)pyrimidine-4-yl]benzosulfimide.

Example 8

a) In analogy to example 1A) from N-[6-chloro-5-(2-methoxyphenoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-yl] benzosulfimide receive N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4 - yl)pyrimidine-4-yl] -4-methylbenzenesulfonamide, tPL

Example 9

a) In analogy to example 1A) from N-[6-chloro-5-(2-methoxyphenoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-yl] benzosulfimide receive N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4 - yl)pyrimidine-4-yl] -4-methoxybenzenesulfonamide in the form of a white solid.

b) In analogy to example 2 from N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] -4 - methoxybenzenesulfonamide acid get N-[2-(2-lepirudin-4 - yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl]-4 - methoxybenzenesulfonamide.

Example 10

a) In analogy to example 1A) from N-[6-chloro-5-(2-methoxyphenoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-yl]benzosulfimide receive N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4 - yl)pyrimidine-4-yl] -4-methylsulfonylmethane, tPL146-150oC (from acetonitrile).

b) In analogy to example 2 from N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] -4 - methylsulfonylmethane receive N-[2-(2-lepirudin-4-yl)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl]-4 - methylsulfonylmethane.

Example 11

a) In analogy to example 1A) from 6-chloro-5-(2-methoxyphenoxy)- 2-(1-oksidoksi)-2-(1 - oxypyridine-4-yl)pyrimidine-4-alamid 1,3-benzodioxol-5-sulfonic acid, tPL174-175oC (from acetonitrile).

b) In analogy to example 2 from 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-ylamide 1,3-benzodioxol-5-sulfonic acid to obtain 2-(2-lepirudin-4-yl)- 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-alamid 1,3-benzodioxol-5-sulfonic acid.

Example 12

a) In analogy to example 1A) from N-[6-chloro-5-(2-methoxyphenoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-yl] -3,4-dimethoxybenzenesulfonamide receive N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxypyridine - 4-yl)pyrimidine-4-yl]-3,4-dimethoxybenzenesulfonamide, tPL189-191oC (from EtOAc).

b) In analogy to example 2 from N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] -3,4 - dimethoxybenzenesulfonamide receive N-[2-(2-lepirudin-4-yl)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl]-3,4 - dimethoxybenzenesulfonamide.

Example 13

a) In analogy to example 1A) from N-[6-chloro-5-(2-methoxyphenoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-yl] -2,5-dimethoxybenzenesulfonamide receive N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxypyridine - 4-yl)pyrimidine-4-yl]-2,5-dimethoxybenzenesulfonamide in the form of a white solid.

b) aneasyskypename receive N-[2-(2-lepirudin-4-yl)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl]-2,5 - dimethoxybenzenesulfonamide.

Example 14

a) In analogy to example 1A) from 6-chloro-5-(2-methoxyphenoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-ylamide pyridine-3-sulfonic acid to obtain 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1 - oxypyridine-4-yl)pyrimidine-4-alamid pyridine-3-sulfonic acid, tPL227-228oC (from EtOAc).

b) In analogy to example 2 from 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-ylamide pyridine-3-sulfonic acid to obtain 2-(2-lepirudin-4-yl)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-alamid pyridine-3-sulfonic acid.

Example 15

a) In analogy to example 1A) from 6-chloro-5-(2-methoxyphenoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-ylamide 5-methylpyridin-2-sulfonic acid to obtain 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1 - oxypyridine-4-yl)pyrimidine-4-alamid 5-methylpyridin-2-sulfonic acid, tPL188-190oC (from acetonitrile).

b) In analogy to example 2 from 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-ylamide 5-methylpyridin-2-sulfonic acid to obtain 2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine - 4-alamid 5-methylpyridin-2-sulfonic acid.

Example 16

(a) By analogy with the iSlate receive 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1 - oxypyridine-4-yl)pyrimidine-4-alamid 5-isopropylpyridine-2-sulfonic acid, tPL140-141oC (from EtOAc).

b) In analogy to example 2 from 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-ylamide 5-isopropylpyridine-2-sulfonic acid to obtain 2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine - 4-alamid 5-isopropylpyridine-2-sulfonic acid.

Example 17

a) In analogy to example 1A) from 4-tert-butyl-N-[6-chloro-5-(2-chloro - 5-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] benzosulfimide receive a 4-tert-butyl-N-[5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-yl] benzosulfimide, tPL228-230oC (from EtOAc).

b) In analogy to example 2 from 4-tert-butyl-N-[5-(2-chloro-5 - methoxyphenoxy)-6-(2-hydroxyethoxy)-2-(1-oxypyridine-4-yl)pyrimidine - 4-yl]benzosulfimide receive a 4-tert-butyl-N-[5-(2-chloro-5 - methoxyphenoxy)-2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)pyrimidine - 4-yl]benzosulfimide.

Example 18

a) In analogy to example 1A) from 6-chloro-5-(2-chloro-5-methoxyphenoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-ylamide 1,3-benzodioxol-4-sulfonic acid to obtain 5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-alamid 1,3-benzodioxol-4-sulfonic acid, tPL

Example 19

a) In analogy to example 1A) from 6-chloro-5-(2-chloro-5-methoxyphenoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-ylamide 5-isopropylpyridine-2-sulfonic acid to obtain 6-(2-hydroxyethoxy)-5-(2-chloro-5-methoxyphenoxy)- 2-(1-oxypyridine-4-yl)pyrimidine-4-alamid 5-isopropylpyridine-2-sulfonic acid, tPL204-206oC (from EtOAc).

b) In analogy to example 2 from 6-(2-hydroxyethoxy)-5-(2-chloro-5 - methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-ylamide 5-isopropylpyridine-2-sulfonic acid to obtain 2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2-chloro-5 - methoxyphenoxy)pyrimidine-4-alamid 5-isopropylpyridine-2-sulfonic acid.

Example 20

a) In analogy to example 1A from 2-[4-(4-tert-butylphenylphosphine)- 6-chloro-5-(2-methoxyphenoxy)pyrimidine-2-yl] pyridine-1-oxide receive 2-[4-(4-tert-butylphenylphosphine)-6-(2-hydroxyethoxy)- 5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-1-oxide in the form of an amorphous substance.

b) In analogy to example 2 from 2-[4-(4-tert-butylphenylphosphine)- 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-2-yl] pyridine-1-oxide receive a 4-tert-butyl-N-[2-(6-lepirudin-2-yl)-6-(2-hydroxyethoxy)- 5-(2-methoxyphenoxy)pyrimidine-4-yl]benzosulfimide.

Example 21

is lonarid receive N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H - tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] benzosulfimide in the form of a white substance, tPL205-207oC (from acetonitrile).

Example 22

By analogy with example 3 from N-[2-(2-lepirudin-4-yl)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl]-4 - methylbenzenesulfonamide receive N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] -4 - methylbenzenesulfonamide in the form of a white substance, tPL214-216oC (CH3CN).

Example 23

By analogy with example 3 from N-[2-(2-lepirudin-4-yl)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl]-4 - methoxybenzenesulfonamide receive N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] -4 - methoxybenzenesulfonamide in the form of a white substance, tPL218-220oC (from acetonitrile).

Example 24

By analogy with example 3 from N-[2-(2-lepirudin-4-yl)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] -4 - methylsulfonylmethane receive N-[6-(2-hydroxyethoxy)- 5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4 - yl]-4-methylsulfonylmethane in the form of a white substance.

Example 25

By analogy with example 3 from 2-(2-lepirudin-4-yl)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-ylamide 1,3-benzodioxol-5-sulphonic kiyoka-5-sulfonic acid in the form of a white substance, tPL227-229oC (CH3CN).

Example 26

By analogy with example 3 from N-[2-(2-lepirudin-4-yl)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] -3,4 - dimethoxybenzenesulfonamide receive N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl]- 3,4-dimethoxybenzenesulfonamide in the form of a white substance, tPL224-225oC (from acetonitrile).

Example 27

By analogy with example 3 from N-[2-(2-lepirudin-4-yl)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] -2,5 - dimethoxybenzenesulfonamide receive N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl]- 2,5-dimethoxybenzenesulfonamide in the form of a white substance.

Example 28

By analogy with example 3 from 2-(2-lepirudin-4-yl)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-ylamide pyridine-3-sulfonic acid to obtain 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-alamid pyridine-3-sulfonic acid in the form of a white substance.

Example 29

By analogy with example 3 from 2-(2-lepirudin-4-yl)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-ylamide 5-methylpyridin-2-sulfonic acid to obtain 6-(2-hydroxilic the IDA white matter, tPL239-241oC (CH3CN).

Example 30

By analogy with example 3 from 2-(2-lepirudin-4-yl)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-ylamide 5-isopropylpyridine-2-sulfonic acid to obtain 6-(2-hydroxyethoxy)- 5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-alamid 5-isopropylpyridine-2-sulphonic acid in the form of a white substance, tPL198-200oC (from acetonitrile). From this product using sodium methylate by analogy with example 5 receive the corresponding disodium salt as a white powder.

Example 31

By analogy with example 3 from 4-tert-butyl-N-[5-(2-chloro-5 - methoxyphenoxy)-2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)pyrimidine - 4-yl]benzosulfimide receive a 4-tert-butyl-N-[5-(2-chloro-5 - methoxyphenoxy)-6-(2-hydroxyethoxy)-2-(2-1H-tetrazol-5-espiridion-4 - yl)pyrimidine-4-yl] benzosulfimide, tPL170-172oC (CH3CN). From this product using sodium methylate by analogy with example 5 receive the corresponding disodium salt as a white powder.

Example 32

By analogy with example 3 from 5-(2-chloro-5-methoxyphenoxy)-2-(2 - lepirudin-4-yl)-6-(2-hydroxyethoxy)pyrimidine-4-ylamide 1,3-benzodioxol-5-sulphonic kibandiko-5-sulfonic acid.

Example 33

By analogy with example 3 from 5-(2-chloro-5-methoxyphenoxy)-2-(2 - lepirudin-4-yl)-6-(2-hydroxyethoxy)pyrimidine-4-alamid 5-isopropylpyridine-2-sulfonic acid get [5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)-2-(2-1H-tetrazol-5 - espiridion-4-yl)pyrimidine-4-alamid 5-isopropylpyridine-2-sulfonic acid.

Example 34

By analogy with example 3 from 4-tert-butyl-N-[2-(6-lepirudin-2-yl)-6- (2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide receive a 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- 2-[6-(1H-tetrazol-5-yl)pyridin-4-yl] pyrimidine-4-yl] benzosulfimide, tPL248-251oC (decomposition) (from CH2Cl2+ CH3CN).

Example 35

By analogy with example 4 from N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4 - yl] benzosulfimide and 2-pyridylcarboxylic get 2-[5-(2-methoxyphenoxy)-6-phenylcarbonylamino-2-(2-1H-tetrazol-5 - espiridion-4-yl)pyrimidine-4-yloxy] ethylpyridine-2-ylcarbamate in the form of a white substance.

Example 36

By analogy with example 4 from N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] -4 - methylbenzenesulfonamide and 2-pyridylcarboxylic produces the one-2-ylcarbamate in the form of a white substance, tPL224-225oC (CH3CN).

Example 37

By analogy with example 4 from N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] -4 - methylbenzenesulfonamide and 3,4-methylenedioxyphenethylamine get 2-[5-(2-methoxyphenoxy)-6-(4-methylphenylsulfonyl)-2-(2 - 1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethyl-1,3-benzodioxol - 5-ylcarbamate, tPL198-199oC (CH3CN).

Example 38

By analogy with example 4 from N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] -4 - methoxybenzenesulfonamide and 2-pyridylcarboxylic get 2-[5-(2-methoxyphenoxy)-6-(4-methoxyphenylacetylene)-2-(2-1H - tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethylpyridine-2-ylcarbamate in the form of a white substance, tPL224-225oC (from EtOAc).

Example 39

By analogy with example 4 from N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] -4 - methoxybenzenesulfonamide and 3,4-methylenedioxyphenethylamine get 2-[5-(2-methoxyphenoxy)-6-(4-methoxyphenylacetylene)- 2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethyl-1,3 - benzodioxol-5-ylcarbamate, tPL198-200oC (from EtOAc).

Prim is kidin-4-yl] -4 - methylsulfonylmethane and 2-pyridylcarboxylic get 2-[5-(2-methoxyphenoxy)-6-(4-methylsulfonylamino)-2-(2 - 1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy]ethylpyridine-2-ylcarbamate.

Example 41

By analogy with example 4 from 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-alamid 1,3-benzodioxol-5-sulfonic acid and 2-pyridylcarboxylic get 2-[6-(1,3-benzodioxol-5-ylsulphonyl)-5-(2-methoxyphenoxy)-2-(2-1H - tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy]ethylpyridine-2-ylcarbamate, tPL194-196oC (from EtOAc).

Example 42

By analogy with example 4 from 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-ylamide 1,3-benzodioxol-5-sulfonic acid and 3,4-methylenedioxyphenethylamine get 2-[6-(1,3-benzodioxol-5-ylsulphonyl)-5-(2-methoxyphenoxy)- 2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethyl-1,3-benzodioxol - 5-ylcarbamate, tPL187-188oC (from EtOAc).

Example 43

By analogy with example 4 from N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] -3,4 - dimethoxybenzenesulfonamide and 2-pyridylcarboxylic get 2-[6-(3,4-dimethoxyphenylethylamine)-5-(2-methoxyphenoxy)-2-(2-1H - tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy]ethylpyridine-2-ylcarbamate.

Example 44

By analogy with example 4 from N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-is enocsi)-6-(2,5-dimethoxyphenylethylamine)-2-(2-1H - tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy]ethylpyridine-2-ylcarbamate.

Example 45

By analogy with example 4 from 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-ylamide pyridine-3-sulfonic acid and 2-pyridylcarboxylic get 2-[5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)-6-pyridin - 3-isalphanumeric-4-yloxy]ethylpyridine-2-ylcarbamate.

Example 46

By analogy with example 4 from 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-ylamide pyridine-3-sulfonic acid and 3,4-methylenedioxyphenethylamine get 2-[5-(2-methoxyphenoxy)-6-pyridin-3-ylsulphonyl-2-(2-1H - tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy]ethyl-1,3-benzodioxol-5 - ylcarbamate.

Example 47

By analogy with example 4 from 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-ylamide 5-methylpyridin-2-sulfonic acid and 2-pyridylcarboxylic get 2-[5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-ylsulphonyl)- 2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy]ethylpyridine-2-ylcarbamate.

Example 48

By analogy with example 4 from 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-ylamide 5-isopropylpyridine-2-sulfonic acid and 2-pyridin-4-yl)pyrimidine-4-yloxy]ethylpyridine-2-ylcarbamate.

Example 49

By analogy with example 4 from 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- 2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-ylamide 5-isopropylpyridine-2 - sulfonic acid and 3,4-methylenedioxyphenethylamine get 2-[6-(5-isopropylpyridine-2-ylsulphonyl)-5-(2-methoxyphenoxy)-2-(2-1H - tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethyl-1,3-benzodioxol-5 - ylcarbamate.

Example 50

By analogy with example 4 from 4-tert-butyl-N-[5-(2-chloro-5 - methoxyphenoxy)-6-(2-hydroxyethoxy)-2-(2-1H-tetrazol-5-espiridion-4 - yl)pyrimidine-4-yl] benzosulfimide and 2-pyridylcarboxylic get 2-[6-(4-tert-butylphenylphosphine)-5-(2-chloro-5-methoxyphenoxy)- 2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy]ethylpyridine-2 - ylcarbamate.

Example 51

By analogy with example 4 of [5-(2-chloro-5-methoxyphenoxy)-6-(2 - hydroxyethoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] amide 1,3-benzodioxol-5-sulfonic acid and 2-pyridylcarboxylic get 2-[6-(1,3-benzodioxol-5-ylsulphonyl)-5-(2-chloro-5 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4 - yloxy]ethylpyridine-2-ylcarbamate.

Example 52

By analogy with example 4 of [5-(2-chloro-5-methoxyphenoxy)-6-(2 - hydroxyethoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrim the Jn-2-ylsulphonyl)- 2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy]ethylpyridine-2 - ylcarbamate.

Example 53

By analogy with example 4 from 4-tert-butyl-N-[6-(2-hydroxyethoxy)- 5-(2-methoxyphenoxy)-2-[6-(1H-tetrazol-5-yl)pyridin-2-yl] pyrimidine-4 - yl] benzosulfimide get 2-[6-(4-tert-butylphenylphosphine)-5-(2-methoxyphenoxy)- 2-(2-1H-tetrazol-5-espiridion-2-yl)pyrimidine-4-yloxy] ethylpyridine-2 - ylcarbamate.

Example 54

By analogy with example 1 from benzyloxyethanol Na and 4-[4-(4-tert-butylphenylphosphine)-6-chloro-5-(2-methoxyphenoxy) pyrimidine-2-yl]pyridine-1-oxide receive N-[6-(2-benzyloxyethyl)-5-(2 - methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] -4-tert - butylbenzenesulfonamide, tPL170-171oC (CH3CN), and the interaction with trimethylsilylcyanation in boiling triethylamine by analogy with paragraph (a) of example 1 to obtain N-[6-(2-benzyloxyethyl)-2-(2-lepirudin-4-yl)-5-(2-methoxyphenoxy) pyrimidine-4-yl] -4-tert-butylbenzenesulfonamide.

Example 55

By analogy with example 3 from N-[6-(2-benzyloxyethyl)-2-(2 - lepirudin-4-yl)-5-(2-methoxyphenoxy)pyrimidine-4-yl] -4-tert - butylbenzenesulfonamide receive N-[6-(2-benzyloxyethyl)-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] -4 - tert-butylbenzenesulfonamide in the form of an amorphous substance, tPL173-175oC.Example 57

By analogy with example 3 of the nitrile obtained in example 56, receive [6-(2-benzyloxyethyl)-5-(2-methoxyphenoxy)-2-(2-1H - tetrazol-5-espiridion-4-yl] amide 5-methylpyridin-2-sulfonic acid, tPL202-204oC (CH3CN).

Example 58

By analogy with example 1 from benzyloxyethanol sodium and 6-chloro-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-ylamide 5-isopropylpyridine-2-sulfonic acid get [6-(2-benzyloxyethyl)-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4 - yl)pyrimidine-4-yl] amide 5-isopropylpyridine-2-sulfonic acid and from her interaction with trimethylsilylcyanation in boiling triethylamine by analogy with example 2, we can get the corresponding nitrile, namely, N-[6-(2-benzyloxyethyl)-2-(2-lepirudin-4-yl)-5-(2-methoxyphenoxy) pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid.

Example 59

By analogy with example 3 from 4-isopropyl-N-[2-(2-lepirudin-4-yl)- okefenokee)-2-[2-(1H-tetrazol - 5-yl)pyridin-4-yl] pyrimidine-4-yl] amide 5-isopropylpyridine-2-sulfonic acid, tPL236-237oC (CH3CN).

Example 60

By analogy with example 6 from 4-tert-butyl-N-[2-(2-lepirudin-4-yl)- 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide receive appropriate iminoethyl and out of engagement with NH4Cl in CH3OH at room temperature to obtain 4-tert-butyl-N-[2-[2-(aminoiminomethyl)pyridine-4-yl] -6-(2-hydroxyethoxy)- 5-(2-methoxyphenoxy)pyrimidine-4-yl]benzosulfimide.

Example 61

By analogy with example 6 from 4-tert-butyl-N-[2-(2-lepirudin-4-yl)- 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide receive appropriate iminoethyl and out of engagement with NH2OHHCl in CH3OH at room temperature to obtain 4-tert-butyl-N-[2-[2-(hydroxyquinolinato)pyridine-4-yl] - 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl]benzosulfimide.

Example 62

By analogy with example 6 from 4-tert-butyl-N-[2-(2-lepirudin-4-yl)- 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide receive appropriate iminoethyl and out of engagement with 3h. HCl at room temperature produces ethyl-4-[4-(4-tert-butylphenylphosphine)- 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)Piri, 1H. a methanol solution of sodium hydroxide at room temperature and acidification of the reaction mixture with acetic acid to obtain the corresponding 4-[4-(4-tert-butylphenylphosphine)-6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-2-yl]pyridine-2-carboxylic acid.

Example 64

a) In analogy with example 1, the interaction of 4-tert-butyl-N-[6 - chloro-(3-tianfeng)-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide and sodium salt of ethylene glycol receive a 4-tert-butyl-N-[2-(3-tianfeng)- 6-(hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl]benzosulfimide in the form of a white substance, tPL197-198oC (from EtOAc).

Obtaining source materials:

By analogy with paragraph (b) of example 1 by the interaction of 1,3-dicyanate with sodium methylate in methanol followed by treatment with ammonium chloride, a 3-lebensmittelsicherheit and out of engagement with diethyl-(2-methoxyphenoxy)malonate get rat. -3-[5-(2-methoxyphenoxy)-4,6-dioxo-1,4,5,6-tetrahydropyrimidin-2 - yl] benzonitrile in the form of a white substance. From this compound by using PCl5and POCl3receive 3-[4,6-dichloro-5-(2-methoxyphenoxy) pyrimidine-2-yl] benzonitrile, tPL155-156oC (from EtOAc). By interacting with 4-tert-butsashvili.

Example 65

By analogy with example 3, the interaction of 4-tert-butyl-N-[2-(3 - tianfeng)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4 - yl] benzosulfimide, of sodium azide and ammonium chloride in DMF receive a 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(3-1H - tetrazol-5-ylphenyl)pyrimidine-4-yl]benzosulfimide in the form of a solid substance.

Example 66

By analogy with example 4, the interaction of 4-tert-butyl-N-[6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(3-1H-tetrazol-5-ylphenyl)pyrimidine - 4-yl] benzosulfimide and-pyridylcarbonyl get 2-[6-(4-tert-butylphenylmethyl)-5-(2-methoxyphenoxy)-2-(3-1H - tetrazol-5-ylphenyl)pyrimidine-4-yloxy]ethylpyridine-2-ylcarbamate, tPL138-139oC.

Example 67

By analogy with example 1, the interaction of 4-tert-butyl-N-[6-chloro-2-(3 - tianfeng)-5-(2-methoxyphenoxy)pyrimidine-4-yl]benzosulfimide and sodium salt of benzyloxyethanol receive N-[6-(2-benzyloxyethyl)-2-(3-tianfeng)- 5-(2-methoxyphenoxy)pyrimidine-4-yl] -4-tert-butylbenzenesulfonamide, tPL120-122oC (from EtOAc).

Example 68

By analogy with example 3, the interaction of N-[6-(2-benzyloxyethyl)- 2-(3-tianfeng)-5-(2-methoxyphenoxy)pyrimidine-4-yl] -4-tert - butylbenzenesulfonamide, espiramicina-4-yl] -4-tert-butylbenzenesulfonamide in the form of a light yellow foam.

Example 69

By analogy with example 1, the interaction of 4-tert-butyl-N-[6-chloro - 2-(4-tianfeng)-5-(2-methoxyphenoxy)pyrimidine-4-yl]benzosulfimide and sodium salt of ethylene glycol receive a 4-tert-butyl-N-[2-(4-tianfeng)- 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl]benzosulfimide in the form of a light brown substance, tPL169-170oC (from EtOAc).

Obtaining source materials:

The interaction of 1,4-dicyanate with sodium methylate in methanol followed by treatment with ammonium chloride receive a 4-lebensmittelsicherheit, which is used in the next stage without additional purification and interaction with diethyl-(2-methoxyphenoxy)malonate get rat.-4-[5-(2-methoxyphenoxy)-4,6-dioxo-1,4,5,6-tetrahydropyrimidin - 2-yl]benzonitrile in the form of a yellow substance, tPL> 250oC. From this compound by using PCl5and POCl3receive 4-[4,6-dichloro-5-(2-methoxyphenoxy)pyrimidine-2-yl]benzonitrile in the form of a brownish substance, tPL179-180oC (from EtOAc). By interacting with 4-tert-butylbenzenesulfonamide potassium finally get 4-tert-butyl-N-[6-chloro-2-(4-tianfeng)-5-(2-methoxyphenoxy) pyrimidine-4-yl]benzosulfimide.

Example 70

By analogy encasulated, of sodium azide and ammonium chloride in DMF receive a 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(4-1H - tetrazol-5-ylphenyl)pyrimidine-4-yl]benzosulfimide in the form of a white substance.

Example 71

By analogy with example 1, the interaction of 4-tert-butyl-N-[6-chloro - 2-(4-tianfeng)-5-(2-methoxyphenoxy)pyrimidine-4-yl]benzosulfimide and sodium salt of benzyloxyethanol receive N-[6-(2-benzyloxyethyl)- 2-(4-tianfeng)-5-(2-methoxyphenoxy)pyrimidine-4-yl]-4-tert - butylbenzenesulfonamide, tPL158-159oC (from EtOAc).

Example 72

By analogy with example 3, the interaction of N-[6-(2-benzyloxyethyl)- 2-(4-tianfeng)-5-(2-methoxyphenoxy)pyrimidine-4-yl] -4-tert - butylbenzenesulfonamide, of sodium azide and ammonium chloride in DMF receive N-[6-(2-benzyloxyethyl)-5-(2-methoxyphenoxy)-2-(4-1H - tetrazol-5-ylphenyl)pyrimidine-4-yl] -4-tert-butylbenzenesulfonamide in the form of foam.

Example 73

a) a Solution containing 2.1 g (3.4 mmole) of 4-tert-butyl-N-[6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4 - yl)pyrimidine-4-yl] benzosulfimide in 40 ml of absolute THF, is treated with 2 ml of 1-(tert-butyldimethylsilyl)imidazole and incubated at a temperature of 50oC with stirring for 1 hour. The solution vparivayut receive a 4-tert-butyl-N-[6-[2-(tert-butyldimethylsilyloxy)ethoxy]-5-(2 - methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4 - yl]benzosulfimide, tPL237-239oC (decomposition).

b) a Solution containing 366,5 mg (0.5 mmole) of 4-tert-butyl-N-[6-[2-(tert - butyldimethylsilyloxy)ethoxy]-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5 - espiridion-4-yl)pyrimidine-4-yl] benzosulfimide in 30 ml of absolute THF, is treated at room temperature to 112.2 mg (1 mmol) of potassium tert-butylate and the suspension is incubated at a temperature of 40oC and stirring for 30 minutes. To the clear solution add 1 ml of ethylbromide and the solution maintained at a temperature of 40oC for 4 days. After this, the solution evaporated under reduced pressure, the residue is dissolved in a mixture of methylene chloride and simple ether (1:1) and the organic solution washed three times with 0.5 N. NaHCO3and then water. The organic extracts are dried over sodium sulfate and evaporated under reduced pressure. The remainder chromatographic on silica gel with cyclohexane-EtOAc (1: 1). First get 100 mg 4-tert-butyl-N-[6-[2-(tert-butyldimethylsilyloxy)ethoxy - 2-[2-(2-ethyl-2H-tetrazol-5-yl)pyridin-4-yl]-5-(2-methoxyphenoxy)pyrimidine - 4-yl] benzosulfimide, and then 100 mg 4-tert-butyl-N-[6-[2-(tert - butyldimethylsilyloxy)-2-[2-(1-ethyl-1H-tetrazol-5-yl)pyridin-4-yl]- 5-(2-methoxyphenoxy)pyrimidine-4-yl]benzosulfimide.

pyridine - 4-yl]-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide in 4 ml of a mixture of CH3CN/H2O (1:1), treated with 5 drops triperoxonane acid and incubated at room temperature for 24 hours. 3 Quiroga acetonitrile is evaporated at a temperature of 30oC under reduced pressure and the aqueous phase is treated first 1H. NaOH, then glacial acetic acid to pH 4 and extracted with simple ether. The organic extracts are washed with H2O, dried over sodium sulfate and evaporated under reduced pressure. Thus obtained 4-tert-butyl-N-[2-[2-(2-ethyl-2H-tetrazol-5-yl)pyridin-4-yl] -6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide in the form of a yellowish foam. Similarly, from 4-tert-butyl-N-[6-[2-(tert - butyldimethylsilyloxy)-2-[2-(1-ethyl-1H-tetrazol-5-yl)pyridin-4-yl] - 5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide receive a 4-tert-butyl-N-[2-[2-(1-ethyl-1H-tetrazol-5-yl)pyridin-4-yl] -6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide in the form of a yellowish foam.

An example of a

Tablets containing the following ingredients can be obtained in a standard way:

Ingredients per tablet, mg:

The compound of formula I - 10,0-100,0

Lactose - 125,0

Corn starch - 75,0

Talc - 4,0

Magnesium stearate - 1,0

Example B

The compound of formula I - 25,0

Lactose - 150,0

Corn starch - 20,0

Talc - 5,0

The example IN

Solutions for injections may have the following composition:

a)

The compound of formula I, for example, the disodium salt of 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H - tetrazol-5-espiridion-4-yl)pyrimidine-4-yl]benzosulfimide - 3.0 mg

Gelatin - 150,0 mg

Water for injection to 1.0 ml

b)

The compound of formula I, for example, disodium salt of 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion - 4-yl)pyrimidine-4-ylamide 5-methylpyridin-2-sulfonic acid 5.0 mg

Gelatin - 150,0 mg

Water for injection to 1.0 ml

in)

The compound of formula I, for example, disodium salt of 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion - 4-yl)pyrimidine-4-ylamide 5-isopropylpyridine-2-sulfonic acid 5.0 mg

Gelatin - 150,0 mg

Water for injection to 1.0 ml

Example D

500 mg of the compounds of formula I is suspended in 3.5 ml of Myglyol 812 and 0.08 g of benzyl alcohol. This suspension fill capacity, fitted with a metering valve. 5.0 g of freon 12 under pressure is injected into the container through the valve. Freon is dissolved in a mixture of Myglyol-benzyl alcohol by streifendienst.

As can be seen from the description, all of the compounds of formula I are characterized by the values of the IC50less than 50 PM and pA2higher than 8,1.

In table.3 summarizes the data for the values IC50and pA2for a number of other compounds.

In this table are reflected compounds 11b and 15b (corresponding examples), in which R2denotes cyano, and which exhibit the same activity as other compounds of this circle. These compounds, where R2is cyano, serve and intermediate substances, transformation which results in other claims active derivatives of sulfonamides.

1. The compounds of formula I

< / BR>
where R1denotes phenyl or phenyl substituted by halogen, (C1- C7)alkyl, (C1- C7)alkoxygroup, (C1- C7)alkylenedioxy, carboxyla or trifluoromethyl, or denotes heterocyclyl selected from mono - or bicyclic 5 - or 6-membered heterocyclic compounds with oxygen, nitrogen or sulfur as a heteroatom;

R2means tetrazolyl, tetrazolyl, substituted (C1- C7)alkyl, cyano, carboxyl, (C1- C7)alkoxycarbonyl, hydroxymethyl, formyl, b)n-OR9;

R4- R8denote hydrogen, (C1- C7)alkoxygroup or halogen;

R9denotes hydrogen, benzyl, benzyl substituted in the phenyl ring by halogen, (C1- C7)alkyl, (C1- C7)alkoxygroup, (C1- C7)alkylen-deoxyribo, carboxyla or trifluoromethyl, or denotes the group-C(O)other10;

R10means (C1- C7)alkyl, phenyl, phenyl substituted with halogen, (C1- C7)alkyl, (C1- C7)alkoxygroup, (C1- C7)alkylenedioxy, carboxyla or trifluoromethyl, or represents pyridyl or pyridyl substituted by one or two (C1- C7)alkyl groups;

Raand Rbdenote hydrogen or (C1- C7)alkyl;

n is 2, 3 or 4;

A and B denote CH or one of the symbols A or B is nitrogen and the other represents CH;

or pharmaceutically acceptable salts of compounds of formula I.

2. Connection on p. 1, in which A and B denote CH.

3. Connection on p. 1, in which one of the symbols A or B is nitrogen.

4. Connection on p. 1, in which A stands for nitrogen, and B is CH.

5. Connection one - 5, in which R1denotes phenyl or pyridyl, which monogamist (C1- C7)alkyl, R3denotes-O(CH2)nOH, -O(CH2)nO-benzyl, -O(CH2)nOC(O)OTHER10and n is 2.

7. Join one of the PP. 1 to 5, in which R4means (C1- C7)alkoxygroup and R5- R8denote hydrogen, or R4denotes halogen, R7means (C1- C7)alkoxygroup and R5, R6and R8denote hydrogen.

8. Connection on p. 5, a 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-alamid 5-methylpyridin-2-sulfonic acid, 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-alamid 5-isopropylpyridine-2-sulfonic acid.

9. Connection on p. 5, a 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] benzosulfimide, 2-[6-(4-tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethylpyridine-2 - ylcarbamate, N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] benzosulfimide, N-[-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] -4-methoxybenzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] -4-methylsulfonylmethane, 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-alamid 1,3-benzodioxol-5-sulfonic acid, N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] -3,4-dimethoxybenzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] -2,5-dimethoxybenzenesulfonamide, 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-alamid pyridine-3-sulfonic acid, 4-tert-butyl-N-[5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] benzosulfimide, [5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] amide 1,3-benzodioxol-5-sulfonic acid [5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] amide 5-isopropylpyridine-2-sulfonic acid, 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[6-(1H-tetrazol-5-yl)pyridin-2-yl] pyrimidine-4-yl] benzosulfimide, 2-[5-(2-methoxyphenoxy)-6-phenylcarbonylamino-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethylpyridine-2-yl is terpyridine-2-ylcarbamate, 2-[5-(2-methoxyphenoxy)-6-(4-methylphenylsulfonyl)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethyl-1,3-benzodioxol-5-ylcarbamate, 2-[5-(2-methoxyphenoxy)-6-(4-methoxyphenylacetylene)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethylpyridine-2-ylcarbamate, 2-[5-(2-methoxyphenoxy)-6-(4-methoxyphenylacetylene)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethyl-1,3-benzodioxol-5-ylcarbamate, 2-[5-(2-methoxyphenoxy)-6-(4-methylsulfonylamino)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethylpyridine-2-ylcarbamate, 2-[6-(1,3-benzodioxol-5-ylsulphonyl)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy]ethylpyridine-2-ylcarbamate, 2-[6-(1,3-benzodioxol-5-ylsulphonyl)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethyl-1,3-benzodioxol-5-ylcarbamate, 2-[6-(3,4-dimethoxyphenylethylamine)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethylpyridine-2-ylcarbamate, 2-[5-(2-methoxyphenoxy)-6-(2,5-dimethoxyphenylethylamine)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-2-yloxy] ethylpyridine-2-ylcarbamate, 2-[5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)-6-pyridin-3-isalphanumeric-4-yloxy] ethylpyridine-2-ylcarbamate, 2-[5-(2-methoxyphenoxy)-6-PI is methoxyphenoxy)-6-(5-methylpyridin-2-ylsulphonyl)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethylpyridine-2-ylcarbamate, 2-[6-(5-isopropylpyridine-2-ylsulphonyl)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethylpyridine-2-ylcarbamate, 2-[6-(5-isopropylpyridine-2-ylsulphonyl)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethyl-1,3-benzodioxol-5-ylcarbamate, 2-[6-(4-tert-butylphenylphosphine)-5-(2-chloro-5-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethylpyridine-2-ylcarbamate, 2-[6-(1,3-benzodioxol-5-ylsulphonyl)-5-(2-chloro-5-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yloxy] ethylpyridine-2-ylcarbamate, 2-[5-(2-chloro-5-methoxyphenoxy)-6-(5-isopropylpyridine-2-ylsulphonyl] -2-(2-1H-tetrazol-5-espiridion-2-yl)pyrimidine-4-yloxy]ethylpyridine-2-ylcarbamate, 2-[6-(4-tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-2-yl)pyrimidine-4-yloxy] ethylpyridine-2-ylcarbamate, N-[6-(2-benzyloxyethyl)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl)pyrimidine-4-yl] -4-tert-butylbenzenesulfonamide, [6-(2-benzyloxyethyl)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-espiridion-4-yl] amide 5-methylpyridin-2-sulfonic acid [6-(2-benzyloxyethyl)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-yl)pyridin-4-yl] pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid, 4-tert-butyl-N-[2-[2-(1-this is">

10. Connection on p. 1, a 4-tert-butyl-N-[2-(3-tianfeng)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide, 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(3-1H-tetrazol-5-ylphenyl)pyrimidine-4-yl] benzosulfimide, 2-[6-(4-tert-butylphenylmethyl)-5-(2-methoxyphenoxy)-2-(3-1H-tetrazol-5-ylphenyl)pyrimidine-4-yloxy] ethylpyridine-2-ylcarbamate, N-[6-(2-benzyloxyethyl)-2-(3-tianfeng)-5-(2-methoxyphenoxy)pyrimidine-4-yl] -4-tert-butylbenzenesulfonamide, N-[6-(2-benzyloxyethyl)-5-(2-methoxyphenoxy)-2-(3-1H-tetrazol-5-ylphenyl)pyrimidine-4-yl]-4-tert-butylbenzenesulfonamide, 4-tert-butyl-N-[2-(4-tianfeng)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide, 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(4-1H-tetrazol-5-ylphenyl)pyrimidine-4-yl] benzosulfimide, N-[6-(2-benzyloxyethyl)-2-(4-tianfeng)-5-(2-methoxyphenoxy)pyrimidine-4-yl] -4-tert-butylbenzenesulfonamide, N-[6-(2-benzyloxyethyl)-5-(2-methoxyphenoxy)-2-(4-1H-tetrazol-5-ylphenyl)pyrimidine-4-yl] -4-tert-butylbenzenesulfonamide.

11. Connection on p. 2, a 4-tert-butyl-N-[2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide, N-[2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)pyrimidine-4-yl] -4-methylbenzenesulfonamide, N-[2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] -4-methoxybenzenesulfonamide, N-[2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] -4-methylsulfonylmethane, 2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-alamid 1,3-benzodioxol-5-sulfonic acid, N-[2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] -3,4-dimethoxybenzenesulfonamide, N-[2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] -2,5-dimethoxybenzenesulfonamide, 2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-alamid pyridine-3-sulfonic acid, 2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-alamid 5-methylpyridin-2-sulfonic acid, 2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-alamid 5-isopropylpyridine-2-sulfonic acid, 4-tert-butyl-N-[5-(2-chloro-5-methoxyphenoxy)-2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)pyrimidine-4-yl] benzosulfimide, 5-(2-chloro-5-methoxyphenoxy)2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)pyrimidine-4-alamid 1,3-benzodioxol-5-sulfonic acid, 5-(2-chloro-5-methoxyphenoxy)2-(2-lepirudin-4-yl)-6-(2-hydroxyethoxy)pyrimidine-4-alamid 5-isopropylene the l] benzosulfimide, N-[6-(2-benzyloxyethyl)-2-(2-lepirudin-4-yl)-5-(2-methoxyphenoxy)pyrimidine-4-yl] -4-tert-butylbenzenesulfonamide, N-[6-(2-benzyloxyethyl)-2-(2-lepirudin-4-yl)-5-(2-methoxyphenoxy)pyrimidine-4-yl] amide 5-isopropylpyridine-2-sulfonic acid, 4-tert-butyl-N-[2-[2-(aminoiminomethyl)pyridine-4-yl]-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide, 4-tert-butyl-N-[2-[2-(hydroxyquinolinato)pyridine-4-yl] -6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-4-yl] benzosulfimide, ethyl-4-[4-(4-tert-butylphenylphosphine)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-2-yl] pyridine-2-carboxylate, 4-[4-(4-tert-butylphenylphosphine)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-2-yl] pyridine-2-carboxylic acid.

12. Connection on p. 1, representing N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] benzosulfimide, N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] -4-methylbenzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] -4-methoxybenzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] -4-methylsulfonylmethane, 6-(2-hydroxyethoxy)-5-(2-methoxyethoxyethoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] -3,4-dimethoxybenzenesulfonamide, N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl] -2,5-dimethoxybenzenesulfonamide, 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-alamid pyridine-3-sulfonic acid, 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-alamid 5-methylpyridin-2-sulfonic acid, 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-alamid 5-isopropylpyridine-2-sulfonic acid, 4-tert-butyl-N-[5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-yl]benzosulfimide, 5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-alamid 1,3-benzodioxol-4-sulfonic acid, 5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)-2-(1-oxypyridine-4-yl)pyrimidine-4-alamid 5-isopropylpyridine-2-sulfonic acid.

13. Pharmaceutical composition having the properties of an inhibitor of binding of endothelin comprising the active substance and the usual carriers and adjuvants, characterized in that the active substance it contains compounds of the formula I according to any one of paragraphs.1 - 12.

 

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The invention relates to compounds intended for use in the pharmaceutical industry as active ingredients in the manufacture of medicines

The invention relates to a new derived tetrazole having effect in reducing blood sugar and lipid in the blood, and it contains the tool for use in the treatment of diabetes and hyperlipemia

The invention relates to new derivatives of 5-arylindole formula I, where R1matter referred to in the description, A, B, C, and D each represent a carbon or one of them represents a nitrogen; R2, R3, R4, R5each independently represents hydrogen, C1- C6-alkyl, phenyl, halogen, cyano,- (CH2)mNR14R15, -(CH2)mOR9, -(CH2)mNR14COR9, -(CH2)mNR14CONHR9, -CO2R9; R6represents hydrogen, -OR10; R7, R8, R14, R15each independently represents hydrogen, C1- C6-alkyl, (CH2)xOR11; R9represents hydrogen, C1- C6-alkyl, phenyl; R10is1- C10-alkyl; R11is1- C6-alkyl; n = 0,1 or 2; m = 0, 1, 2 or 3; x = 2 or 3; the dotted line indicates the optional single bond or their pharmaceutically acceptable salts

The invention relates to compounds intended for use in the pharmaceutical industry as active ingredients in the manufacture of medicines
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