Sulfonamides and pharmaceutical drug

 

(57) Abstract:

Describes new connections - sulfonamides of General formula I, where R1selected from a monocyclic five or six-membered S, N and/or O-containing heterocyclic residue, such as pyridyl, pyrimidinyl, isoxazolyl, thienyl, thiazolyl, which can be unsubstituted or substituted by lower alkyl, halogen or lower alkanoyl; R2denotes hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkoxy-lower alkyl, lower alkylsulfonyl-lower alkoxy, phenyl, lower alkylphenyl, lower alkoxyphenyl, lower alkylenedioxy, phenyl-lower alkyl, lower alkylphenyl-lower alkyl, lower alkoxyphenyl-lower alkyl, lower alkylenedioxy-lower alkyl, monocyclic six-membered N and/or O-containing heterocyclic residue, such as pyrimidinyl, pyridyl, morpholino; R3denotes lower alkyl, lower alkoxy, formyl, halogen-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl or a residue-CH2On-A-lower alkyl, -(CH2)m-O-(CRaRb)nOH, -(CH2)m-O-(CRaRb)nOR9, -(CH2)m-O-(CH2)nNH2or -(CH2)m-O-(CRadenotes pyridyl, pyrimidinyl; Raand Rbrepresent hydrogen or lower alkyl; a represents Catalonian 1,2-dihydroxyethylene group; represents-OC(O)O-, -OC(O)NH-, -NHC(O)NH - or-NHC(O)O-; n denotes 2, 3 or 4, and m represents 0 or 1. The compounds of formula I are inhibitors of endothelin receptors, so they can be used as biologically active substances in the manufacture of drugs for the treatment of diseases associated with activity of the endothelium, in particular diseases of the circulatory system, such as hypertension, ischemia, vascular spasm and angina. 3 S. and 21 C.p. f-crystals.

The invention relates to new sulfonamide having the properties of an inhibitor of binding of endothelin, and pharmaceutical drugs based on them. The invention relates in particular to new compounds of the formula

< / BR>
where

R1means heterocyclyl selected from a monocyclic five-, six-membered S-, N - and/or O-containing heterocyclic residue, such as pyridyl, pyrimidinyl, isoxazolyl, thienyl, thiazolyl, which can be unsubstituted or substituted by lower alkyl, halogen or lower alkanoyl;

R2denotes hydrogen or the and phenyl, lower alkylphenyl, lower alkoxyphenyl, lower alkylenedioxy-phenyl, phenyl-lower alkyl, lower alkylphenyl-lower alkyl, lower alkoxyphenyl-lower alkyl, lower alkylenedioxy-lower alkyl, heterocyclyl - monocyclic six-membered N - and/or O-containing heterocyclic residue, such as pyrimidinyl, pyridyl, morpholino;

R3denotes lower alkyl, lower alkoxy, formyl, halogen-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl or a residue-CH2O-A lower alkyl, -(CH2)m-O-(CRaRb)nOH, -(CH2)m-O-(CRaRb)nOR9, -(CH2)m-O-(CH2)nNH2or -(CH2)m-O-(CRaRb)n-B-R9;

R4-R8denote hydrogen, lower alkoxy or halogen;

R9denotes pyridyl, pyrimidinyl;

Raand Rbrepresent hydrogen or lower alkyl;

A represents Catalonian 1,2-dihydroxyethylene group;

B represents-OC(O)O-, - OC(O)NH-, -NHC(O)NH - or-NHC(O)O-;

n denotes 2, 3 or 4 and

m denotes 0 or 1.

The closest analogue is the application EP-A-0526708, which describes the connection of a number of sulfonamides possessing properties of an unexpectedly high degree of antagonism in vitro.

The proposed compounds are non-toxic or of subtoxic.

Used here is the definition of "lower" means a group with the number of C-atoms 1-7, preferably 1-4 C-atoms. Alkyl groups, alkoxy - and ancilliary, as well as alkyl groups, which fragments alkanoyl groups may be linear or branched. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec - and tert-butyl. Under the halogen refers to fluorine, chlorine, bromine and iodine, preferably from chlorine them. Lower alkylenedioxy the remainder represents, for example, ethylenedioxythiophene balance. Metalizowana 1,2-dihydroxyethylene group represents, for example, 2,2-dimethyl-1,3-dioxolane-4,5-Delovoy group. Examples of these substituted heterocyclyl residues are substituted, for example, lower alkyl, lower alkanoyl, halogen. It is also possible heterocyclyl remains one - or disubstituted other heterocyclic residue or unsubstituted mono - or bicyclic 5 - and 6-membered heterocyclic residues containing as heteroatoms oxygen, nitrogen or sulfur as 2 - and 3-furyl, pyrimidinyl, 2-, 3 - and 4-pyridyl, 1,2 - and 1,4-diazines, mortarini, chenail, ethanolic and chinadoll. Examples heterocyclyl residues R1can serve primarily of substituted and unsubstituted pyridyl, pyrimidinyl, thienyl and isoxazolyl. Examples heterocyclyl residues R2are primarily pyrimidinyl, morpholino. As examples heterocyclyl residues R9you can also call in addition to pyridyl - pyrimidinyl and furyl. R9can also be a phenyl, possibly substituted lower alkyl, lower alkoxy and/or halogen, or lower alkyl.

The compounds of formula I can be classified as those in which R1represents a monocyclic S-, N - and/or O-heterocyclic residue, especially unsubstituted or substituted by lower alkyl, halogen, amino, mono - or di-lower alkyl-amino or lower alkanoyl pyridyl, pyrimidinyl, isoxazolyl, furyl or thienyl, and the compounds of formula I, where R2represents hydrogen, pyrimidinyl, pyridyl, morpholino, thiomorpholine, piperidine, pyrrolidine, benzodioxolyl, lower alkoxyphenyl or lower alkylthio, as well as such compounds, in which R3represents the balance-O-(CRaRb)nOH, -O-(CRaRb)nNH2Il is the current first of all, pyridyl, pyrazinyl or furyl.

Of particular interest are compounds of the formula I, in which R1represents a substituted lower alkyl pyridyloxy the remainder, R2represents morpholino, R3represents the balance - O(CH2)2OC(O)OTHER9, R4represents lower alkoxy and R5-R8are hydrogen. Preferred residues R9are heterocyclyl remains primarily pyridylamine remains as 2-pyridyl.

Compounds of the above formula I possess the properties of inhibitors of endothelin receptors. 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, vasospasm and angina.

The compounds of formula I can be obtained in the following way:

a) compound of the formula

< / BR>
where R1, R2and R4-R8have the meanings specified above, a Hal denotes halogen, is subjected to the interaction with the compound of the formula

HO(CRaRb)nXH

where n, Raand Rbhave the meanings specified above, and X denotes O or NH, or

is the influence with the compound of the formula

R1SO2Z

where R1has the meaning specified above, a Y and Z represent, respectively, halogen and amino group, or Y represents an amino group, and Z is halogen, or

in the connection formula

< / BR>
where R1, R2, R4-R8, Ra, Rb, X, m and n have the meanings indicated above is subjected to interaction

B1) with an isocyanate of formula R9NCO or carbamoylation formula R9NCOCl, where R9has the meaning specified above, or

B2) with phosgene and then with alcohol of formula R9OH, or ether of Harborview acid of formula R9OC(O)Cl; or

g) the compound of the formula I, in which R3represents a halogen-lower alkyl, are subjected to interaction with the compound of the formula HOCH2-A lower alkyl, where A is Catalonian 1,2-dihydroxyethylene group. Optionally contained in the obtained compound of formula I, the substituents modify and/or the resulting compound of formula I transferred to salt.

When conducting the compounds of formula II with the compound of the formula HO(CRaRb)nXH last it is advisable to apply as alcoholate of an alkali metal. As the solution is R ethylene glycol, or respectively aminoethanol, if n=2. As an alcoholate of an alkali metal is preferred sodium alcoholate. Reaction it is advisable to carry out when heated, for example, to a temperature of 40-120oC. In one preferred embodiment of the invention, the compound HO(CRaRb)nXH in the form of sodium salt is a mono-sodium salt of ethylene-, propylene - or butyleneglycol, respectively aminoethanol, aminopropanol or aminobutanol.

The interaction of the compounds of formula III with the compound of the formula R1SO2Z can be carried out by well-known methods used to obtain sulfonamides, for example in an inert organic solvent, such as dimethylsulfoxide, preferably by heating in a protective gas atmosphere, for example argon.

The reaction according to variant B1) of the method can be carried out by well-known methods, usually used to obtain carbamates and ureas from alcohols, amines respectively. Thus, the compound of formula IV using an isocyanate of formula R9NCO can be transformed into the corresponding anhydrous organic solvent, e.g. a hydrocarbon such as toluene, predpochtitel the om in situ, for example, azide of the formula R9CON3by thermal decomposition. Similarly, when using the compounds of the formula IV in which B represents NH, can be obtained the compounds of formula I with B denoting-NHC(O)NH-.

Under option B2) of the method of connection of the formula IV in which B is oxygen, with phosgene and then with alcohol of formula R9OH may be converted into the compound of the formula I in which A represents the residue-OC(O)O-. Instead of phosgene can be used fossanova salt, such as diphosgene (Cl-COOCCl3or triphosgene (CO(OCCl3)2). Similar by proceeding from compounds of formula IV with B representing NH, obtain the compounds of formula I with B denoting-NHC(O)O-. The phosgene it is reasonable to apply in the form of a solution in an inert anhydrous organic solvent, for example in a hydrocarbon, such as toluene. Interaction with phosgene can be performed at room temperature. Obtained as an intermediate product acid chloride is subjected directly interact with alcohol R9OH, preferably by heating.

The reaction according to variant d) of the method may be carried out in the same predstavljaet a residue-CH2O-A lower alkyl.

The substituents contained in the thus obtained compound of formula I, can be modified. So, a methyl group, R3by oxidation can be transformed into formulabuy group. The oxidation can be carried out by known methods, for example, with selenium dioxide. In the thus obtained compound formanova group can be restored to hydroxymethylene group. This recovery can be carried out by known methods, for example, using a reducing agent, as NaBH4. Hydroclimatology group can be converted by interaction with a halogenation agent POCl3/PCl5in halogenmethyl group. Next, N-heterocyclic residues, as pyridyl, can be oxidized to N-oxides. All these reactions may be carried out using known methods. The compounds of formula I by known methods can be converted into salts, for example alkali metal salts, such as sodium and potassium salts, or salts of alkaline-earth metals such as calcium salts and magnesium.

Used as the source of the connection, if they are unknown or if they are getting described below can be obtained analogously to known meuli I on endothelin receptors can be illustrated by a series of experiments, described below.

I. Inhibition of the binding of recombinant endothelin ETAreceptor

cDNA that encodes human ETAreceptor human placenta, clone (M. Adachi, Y.-Y. Yang, Y. Furuichi and C. Miyamoto, BBRC 180, 1265-1272) and Express the system baculovirus-insect cells.

Infected with the baculovirus insect cells from the fermenter volume 23 l after 60 h after infection centrifuged (3000 g, 15 min, 4oC), then resuspended in Tris buffer (5 mm, pH of 7.4, 1 mm MgCl2) and re-centrifuged. After re-resuspendable and centrifugation, the cells are suspended in 800 ml of the same buffer and frozen at a temperature of -120oC. the Destruction of cells occurs during thawing of the suspension in this hypotonic buffer mixture. After repeated cycle of freezing/thawing, the suspension is homogenized and centrifuged (25000 x g, 15 min, 4oC). After suspension in Tris-buffer (75 mm, pH of 7.4, 25 mm MgCl2, 250 mm sucrose) 1 ml aliquot of sample (protein content of approximately 3.5 mg/ml) incubated at a temperature of -85oC.

To test the binding frozen preparations membrane was thawed after a 10-minute UB>2, 1 mm etc and 0.5% bovine serum albumin). 100 μl of this membrane suspension containing 70 μg protein are incubated in the presence of 50 μl of125I-endothelin (specific activity 2200 CI/mmol) in a test buffer (25000 pulses per minute to a final concentration of 20 nm) and 100 μl of test buffer containing various concentrations of the test compounds. Incubation carried out for 2 h at a temperature of 20oC or for 24 h at a temperature of 4oC. Separation of free and membrane-bound radio-carried out by filtration through a glass fiber filter.

In table 1 revealed in this series of experiments the inhibitory activity of the compounds of formula I are represented as IC50i.e. as the concentration (nm) required to inhibit 50% of specific binding 125I-endothelin.

Table 1

The compound from example IC50[nm]

34 - 0,3

51 - 0,4

II. The inhibition induced by endothelin reductions on selected rings of rat aorta

From the thoracic aorta of adult rats Wistar-Kyoto cut ring width of 5 mm, Slight rubbing the inner surface of the endothelium was removed. Each ring was immersed at a temperature of 37oC in isolated is delali isometric tension rings. Rings were stretched under preliminary tension of 3 g after 10 min of incubation the test compound or binder was added to the cumulative dose of endothelin-1. The activity of the test compounds was determined on the basis of the observed shift of the curve to the right the dose-effect of endothelin-1 in the presence of different concentrations of antagonist. This shift to the right (or "dose ratio", DR) corresponds to the coefficient derived from the values of EC50endothelin-1 in the presence and in the absence of the antagonist, and the indicator EC50denotes the concentration of endothelin required for half maximal contraction.

On the basis of the "dose ratio" DR (dose ratio) using a suitable computer program for each curve dose - effect was derived from the following equation, based on which the expected corresponding value pA2, which is a measure of the activity of the test compounds.

pA2=log(DR-l)-log(concentration of antagonist)

EC50endothelin in the absence of the tested compounds is 0.3 nm.

The values of pA2obtained is described by using the compounds of formula I are presented in table 2.

Table 2

their ability to inhibit the binding of endothelin can be used as tools for the treatment of diseases, associated with processes that increase vasoconstriction. Examples of such diseases are high blood pressure, coronary disease, cardiac insufficiency, renal and myocardial ischemia, renal failure, dialysis, cerebral ischemia, infarction of the brain, migraine, subarachnoid hemorrhage, Raynaud's syndrome and pulmonary hypertension. The compounds of formula I can be used also in case of atherosclerosis, prevention of restenosis after balloon dilation, inflammation, ulcer and duodenal ulcers, leg ulcers, gram-negative sepsis, shock, glomerulonephritis, renal colic, glaucoma, asthma, therapy and prophylaxis of diabetic complications, and complications associated with therapy with cyclosporine, as well as diseases associated with the activity of endothelin.

The compounds of formula I can be administered for oral, rectal, parenteral, for example intravenous, intramuscular, subcutaneous, intrathecal or subcutaneous; or they can be administered sublingually or ophthalmic formulation or in the form of aerosols. Examples of applications can include capsules, tablets,or aerosol sprays.

The preferred form of injection is intravenous, intramuscular or oral. The effective dosage amounts, which are compounds of formula I, depends on the type and characteristics of the biologically active substance, the age and needs of the patient, as well as the form of the introduction. As a rule, the daily dose is prescribed at a rate of 0.1-100 mg/kg body weight. Preparations containing the compounds of formula I can contain inert or active in pharmacodynamic regarding supplements. So, for example, tablets or granules can contain a number of binders, fillers, carriers or diluents. Liquid preparations can be represented, for example, in the form of sterile, mixed with water solution. Capsules along with the biologically active substance may include additional fillers or thickeners. In addition, they can be added substances that improve the taste, substance, usually used as preservatives, stabilizers, water-saving tools and emulsifiers, further, salts for modifying the osmotic pressure, buffers and other additives.

The above-mentioned fillers and diluents can be a organic and inorganic in the Lee etc. The main condition for the application of all excipients in the manufacture of drugs - they should be non-toxic.

Below the invention is illustrated in the following examples.

Example 1

1.29 g of Na was dissolved in 50oC in 50 ml of ethylene glycol. Then at the same temperature portions were added 3.0 g of 6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-ylamide 5-tert - butylthiophene-2-sulfonic acids and heated for 4.5 h at 100oC. the Clear solution was poured into ice/dilute HCl, then was extracted three times respectively in portions of 0.2 l of ether acetic acid. The organic phase is washed three times with water, dried over sodium sulfate and finally evaporated in a rotary evaporator. The way it was obtained 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 5-tert - butylthiophene-2-sulfonic acids in the form of a pale yellow foamy substance. MS: 493 (M-SO2).

Obtaining initial connection:

a) 2.0 g of the chloride of 5-tert-butylthiophene-2-sulfonic acid dissolved at room temperature in 30 ml of ethanol, mixed with 50 ml of 25% ammonia solution and heated for 4.5 h under reflux. Then concentrated using a rotary evaporator,) who was interaval using a rotary evaporator. The result was obtained 5-tert-butylthiophene-2-sulfonamide in the form of white crystals. MS: 219 (M). With the help of potassium tert-butylate in methanol of them received a potassium salt.

b) 3,49 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine was dissolved in 125 ml of dimethylsulfoxide, was added at room temperature 3,855 g (5-tert-butylthiophene-2-sulfonamide)-K, after which the solution was stirred for 20 h at room temperature. Then mixed more with 1,285 g (5-tert-butylthiophene-2-sulfonamide)-K and the reaction proceeded for 2 h at room temperature. Then, with vigorous stirring, the reaction mixture was added first, 200 ml of water and then 200 ml of a simple ester, which formed the fine white precipitate, which was aspirated. The crystals are suspended in a dilute aqueous hydrochloric acid for 0.5 h and stirred at room temperature, then was filtered by suction and dried under high vacuum. The way it was obtained 6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4 - alamid 5-tert-butylthiophene-2-sulfonic acids in the form of a crystalline solid white. MS: OF 523.4 (M+H).

Example 2

A solution of 3.23 g of 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'- bipyrimidine in toluene (50 ml) was heated for 2 hours at a temperature of 80oC. Then the toluene was removed using a rotary evaporator and the residue was distributed between methylene chloride (0.5 l) and 1 N. HCl solution (0.35 l). The organic phase was dried over magnesium sulfate and finally the solvent was removed using a rotary evaporator. The crude product was chromatographically on kieselgel in the solvent system methylene chloride/MeOH (5: 1). The way it was obtained 2-[6-(5-tert-butylthiophene-2-ylsulphonyl)-5-(2 - methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid as a pale yellow solid, which was recrystallized from methylene chloride/MeOH. MS: 678,3 (M+H).

Example 3

26 mg of sodium was dissolved in 2 ml of ethanolamine in 50oC, was mixed at the same temperature portions with 150 mg of the compound from example 1, section b) and the solution was heated for 4 h at 100oC. and Then was poured into ice/water, was installed using 3 N. HCl to pH 6, then fell precipitate in the form of a crystalline solid of light yellow color, which was filtered by suction, washed with water and dried under high vacuum. The result was obtained 6-(2-aminoethoxy)-5-(2 - methoxyphenoxy)-2,2'- bipyrimidin-4-alamid 5-tert-butylthiophene-2-sulfonic acids in the form of yellow crystals. utiltiies-2-sulfonic acid dissolved in 10 ml of toluene, mixed with 53 mg of azide 2-pyridylcarbinol acid and the solution was heated for 4 hours at a temperature of 120oC. Then the toluene was removed using a rotary evaporator and the residue was distributed between ether acetic acid and water. The organic phase was dried over magnesium sulfate and finally concentrated using a rotary evaporator. The residue was chromatographically on kieselgel in the solvent system methylene chloride/methanol (30: 1). The way it was obtained 5-(2-methoxyphenoxy)-6-[2-(3-pyridine-2 - yureina)-ethoxy] -2,2'-bipyrimidin-4-alamid 5-tert - butylthiophene-2-sulfonic acids in the form of a crystalline solid. MS: 677,4 (M+H).

Example 5

In the solution of 162,5 mg 4-amino-6-methoxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidine in 10 ml of tetrahydrofuran was added at room temperature to 92 mg of NaH (65%), stirred solution for 1.5 h at room temperature, and then at the same temperature was added 162,5 mg of 5-tert-butylthiophene-2-sulphonylchloride. Then continued stirring for 2 h at room temperature, was poured into ice/water, was extracted with ether acetic acid, the aqueous phase was acidified and extracted with methylene chloride. The combined organic phases were dried over selfactuating methylene chloride/methanol (20:1). The result was obtained 5-tert-butyl-N-[6-methoxy-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-yl]-thiophene-2-sulfonamide as a yellow powder. MS: 463 (M-SO2).

Obtaining input connections:

a) of 2.09 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (European application EP-A 0526708) suspended in 75 ml of ethanol and are condensed at a temperature of -75oC with the addition of 150 ml of ammonia that is injected through the tube. Over night the reaction mixture was allowed to cool to room temperature, then concentrated in a water jet vacuum and the residue was distributed between water and methylene chloride (500 ml). The organic phase was dried over sodium sulfate and concentrated using a rotary evaporator. The residue was mixed with simple ether, the solid was separated and dried under high vacuum. The result was obtained 4-amino-6-chloro-5-(2 - methoxyphenoxy)-2,2'-bipyrimidin in the form of a fine crystalline powder almost white. MS: 329 (M).

b) a solution of 2.0 g of 4-amino-6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine in 200 ml of methanol at room temperature was added 6,55 g of sodium methylate, after which the solution was heated for 32 hours under reflux. Then methanol UDA is. the content of inorganic fillers phase was dried over magnesium sulfate, then the solvent was removed in a water jet vacuum. The crude product was chromatographically on kieselgel in the solvent system methylene chloride/methanol (10:1). The way it was obtained 4-amino-6 - methoxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin in the form of a powder lemon-yellow color. MS: 325 (M).

Example 6

Analogously to example 1 from glycolate, sodium and 6-chloro-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-ylamide 5-pentylthiophene-2-sulfonic acids was obtained 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 5-pentylthiophene-2-sulfonic acids in the form of a solid white color. MS: 570,3 (M+H).

Obtaining input connections:

a) From 2-pentyl-5-(tert-butylsulfonyl)thiophene (European application EP-A 0512675) with ethanol/concentrated HCl and was received with use of potassium tert-butylate in methanol potassium salt of amide 5-n-pentylthio-2-sulfonic acids.

b) Analogously to example 1, section b), the interaction of the potassium salt of amide 5-n-pentylthio-2-sulfonic acids and 4,6-dichloro-5-(2 - methoxyphenoxy)-2,2'-bipyrimidine was obtained 6-chloro-5-(2 - methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 5-pentylthiophene-2-sulfonic acids in the form of a solid white color. MS: 545 (M).

Example 8

Analogously to example 1 from glycolate, sodium and 6-chloro-5-(2 - methoxyphenoxy)-2,2'-bipyrimidin-4-ylamide 5-(2,2-dimethylpropionic)- thiophene-2-sulfonic acids was obtained 6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 5-(2,2-dimethylpropionic)-thiophene-2-sulfonic acids in the form of a pink powder. MS: 586,3 (M+H).

Obtaining initial connection:

a) Analogously to example 1, section b), the interaction of the potassium salt of 5-(2,2-dimethylpropionic)thiophene-2-sulfonamida (receive: Journ. Org. Chem., volume 56, page 4260) and 4,6-dichloro-5-(2-methoxyphenoxy)- 2,2'-bipyrimidine was obtained 6-chloro-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-alamid 5-(2,2-dimethylpropionic)-thiophene-2 - sulfonic acids in the form of a crystalline solid. MS: 560,1 (M+H). With the help of potassium tert-butylate in methanol from this compound was obtained potassium salt.

Example 9

Analogously to example 2 of azide 2-pyridylcarbinol acid and 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-ylamide 5-(2,2-dimethylpropionic)-thiophene-2-sulfonic received as the target product 2-[6-[5-(2,2-dimethylpropionic)-thiophene-2 - ylsulphonyl] -5- (2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy] ethyl ester pyridine-2-ylcarbamate acid in the form of a square of ethylene glycol. Then at the same temperature portions was added 4.9 g of 6-chloro-5-(2-methoxyphenoxy) -2,2'-bipyrimidin-4-ylamide 5-isopropylpyridine-2-sulfonic acids and heated for 4 h to 100oC. the Clear solution was poured into 200 ml of water, using 3 N. HCl was set at pH 1, precipitated yellow crystals were filtered by suction, washed successively with water and simple ether, then dried under high vacuum. The way it was obtained 6-(2-hydroxyethoxy)-5- (2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 5-isopropylpyridine - 2-sulfonic acids in the form of a crystalline solid yellow color. MS: 537,3 (M-N).

Obtaining input connections:

a) 4.0 g of 5-isopropylpyridine-2-sulfonamida was dissolved in 40 ml of MeOH, was added at room temperature 2,308 g of potassium tert-butylate and stirred the solution for 20 minutes Then concentrated using a rotary evaporator and thus obtained potassium salt was dried under high vacuum.

b) 3,49 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine was dissolved in 125 ml of dimethylsulfoxide, was added at room temperature, 4.7 grams of potassium salt of 5-isopropylpyridine-2-sulfonamida, then stirred the solution for 20 h at room temperature. ZAT is constant additive 3 N. HCl to pH 1. The resulting crystalline white precipitate was aspirated and then washed with water and simple ether. The crystals are suspended in a dilute aqueous hydrochloric acid (100 ml of water and 50 ml of 1 N. HCl), was stirred for 5 min, was filtered by suction and repeatedly washed with water, then dried under high vacuum. The way it was obtained 6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 5 - isopropylpyridine-2-sulfonic acids in the form of a crystalline solid white. MS: 511,3 (M-N).

Example 11

2.0 g of 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4 - ylamide 5-isopropylpyridine-2-sulfonic acid dissolved in 80 ml of toluene was mixed with 1.1 g azide 2-pyridylcarbinol acid, after which the solution was heated for 4 hours at a temperature of 90oC. Then concentrated using a rotary evaporator and divided the remainder between 1 N. HCl and ether acetic acid. The organic phase was dried over magnesium sulfate, the solvent was removed in a water jet vacuum and the residue was chromatographically on kieselgel in the solvent system methylene chloride/methanol (30: 1). The way it was obtained 2-[6-(5-isopropylpyridine-2-ylsulphonyl)-5- (2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy] -e dihydrochloride compound was dissolved in methylene chloride and mixed with the proper amount of 4,4 N. HCl in ethanol at room temperature. The solution was concentrated using a rotary evaporator, precipitated crystalline solid was isolated and dried for 4 hours at a temperature of 60oC under high vacuum.

Example 12

Analogously to example 4 from 6-(2-aminoethoxy)-5-(2 - methoxyphenoxy)-2,2'-bipyrimidin-4-ylamide 5-isopropylpyridine-2 - sulfonic azide and 2-pyridylcarbinol acid was obtained as the desired product 5-(2-methoxyphenoxy)-6-[2-(3-pyridine-2 - yureina)-ethoxy]-2,2'-bipyrimidin-4-alamid 5-isopropylpyridine-2 - sulfonic acids in the form of yellow crystals. MS: 656,3 (M-N).

The original compound was obtained analogously to example 3 from ethanolamine and compounds of example 10, section b), as a yellow foamy substance. MS: 538,3 (M+H).

Example 13

Analogously to example 10 from 6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-ylamide pyridine-2 - sulfonic acids and ethylene glycol was obtained 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-alamid pyridine-2-sulfonic acids in the form of white crystals. MS: 615,4 (M-N).

Obtaining input connections:

a) 1.7 g of the chloride of 2-pyridylsulfonyl (Journ. Org. Chem., volume 54, page 389) was dissolved in 30 ml of ethanol, while cooling with ice was added 30 ml of 25% narrowly using a rotary evaporator, the residue was distributed between ether acetic acid and water, the organic phase was dried over magnesium sulfate and then concentrated using a rotary evaporator, resulting amide 2-pyridylsulfonyl fell in the form of a crystalline solid beige color. MS: 469,2 (M-N). This amide with the aid of potassium tert-butylate in methanol was obtained potassium salt.

b) Analogously to example 10, section b), the interaction of the potassium salt of 2-pyridinesulfonamide with 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'- bipyrimidine was obtained 6-chloro-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-alamid pyridine-2-sulfonic acids in the form of white crystals. MS: 495,3 (M-N).

Example 14

Analogously to example 11 from 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- 2,2'-bipyrimidin-4-ylamide pyridine-2-sulfonic azide and 2-pyridylcarbinol acid was obtained 2-[5-(2-methoxyphenoxy)-6-pyridin-2 - ylsulphonyl)-2,2'-bipyrimidin-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid in the form of white crystals. MS: 615,4 (M-N).

Example 15

Analogously to example 10 from 6-chloro-5-(2 - methoxyphenoxy)-2,2'-bipyrimidin-4-ylamide pyridine-3-sulfonic acids and ethylene glycol was obtained 6-(2-hydroxyethoxy)-5- (2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid pyridine-is but example 13, section (a) of the chloride of 3-pyridylsulfonyl (Journ. Org. Chem. volume 54, page 389) and ammonia received amide 2-pyridylsulfonyl in the form of a crystalline solid white color, which then by means of potassium tert-butylate in methanol was obtained potassium salt.

b) Analogously to example 10, section b), the interaction of the potassium salt of 3-pyridinesulfonamide with 4,6-dichloro - 5-(2-methoxyphenoxy)-2,2'-bipyrimidine received as the target product 6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4 - alamid pyridine-3-sulfonic acids in the form of white crystals. MS: 470 (M).

Example 16

Analogously to example 11 from 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2,2'-bipyrimidin-4-ylamide pyridine-3-sulfonic azide and 2-pyridylcarbinol acid was obtained 2-[5- (2-methoxyphenoxy)-6-pyridin-3-ylsulphonyl) -2,2'- bipyrimidin-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid in the form of white crystals. MS: 615,4 (M-N).

Example 17

213 mg of 6-[2-(tert-butyldimethylsilyloxy) -ethoxy]-5-(2-chloro-5 - methoxyphenoxy)-pyrimidine-4-ylamine was dissolved in 15 ml of tetrahydrofuran, mixed at room temperature with 92 mg of NaH (65%), was stirred for 2 h at room temperature and then added portions 155 mg of 5-tert-butylthiophenol water and was extracted twice with a total of 200 ml of acetic ether. After the usual processing of the organic phase protected silloway group the crude product was chromatographically on kieselgel in the solvent system methylene chloride/acetic ether (8:1).

The obtained foamy substance brownish color (219 mg) was dissolved in 15 ml of acetonitrile were mixed at room temperature with 1.5 ml of 40% HF solution and was stirred for 2 h Then the reaction mixture was distributed between ether acetic acid and polysystem NaCl solution and the organic phase was treated according to a conventional technique. The crude product was chromatographically on kieselgel in the solvent system methylene chloride/acetic ether (4:1) and recrystallized from simple ether/hexane. The result was obtained 5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)- pyrimidine-4-alamid 5-tert-butylthiophene-2-sulfonic acids in the form of white crystals. MS: 449 (M-SO2).

Obtaining initial connection:

a) 3-methoxyphenol as recommended by Julia M. and I. de Rosnay, Chemie Therapeutique 5 (1965), page 334, transformed using sulfurylchloride 2-chloro-5 - methoxyphenol.

b) of 18.2 g of 2-chloro-5-methoxyphenol was dissolved in 150 ml of dry methanol. Then added sequentially 9.3 g MeONa and 25 g of dimethyl ether of hormonology chatok distributed in a separating funnel between toluene and water and washed to a neutral state. After crystallization in ethanol was obtained (2-chloro-5 - methoxy)peroxidation in the form of white crystals with TPL68-69oC.

in) of 1.43 g of Na was dissolved in 70 ml of MeOH. Then was added 5.8 g (2-chloro-5-methoxy)peroxydiethylacetate and to 2.29 g formamidine; the reaction mixture was stirred for 1.5 hours while heating under reflux. The solvent is then drove away, the residue was dissolved in H2O, the aqueous phase was extracted with acetic ether, the organic phase was separated, and the aqueous phase was acidified with acetic acid to pH 4, the resulting 5-(2-chloro-5 - methoxy)phenoxy-4,6(1H,5H)-pyrimidinedione fell in the form of a white powder. MS: m/e = 268 (M).

g) a Mixture of 3.75 g of 5-(2-chloro-5-methoxy)phenoxy-4,6(1H,5H)- pyrimidinedione, of 5.4 g of N-ethyldiethanolamine, 12.5 ml POCl3in 20 ml of dioxane was stirred for 18 hours while heating under reflux. After distillation of the volatile components, the residue was distributed between acetic ether and H2O and washed to a neutral state. After removal of the solvent the compound was purified on kieselgel using CH2Cl2as eluent. After crystallization from EtOH was obtained 4,6-dichloro-5-(2-chloro-5-methoxyphenoxy)-pyrimidine in the form of white crystals with TPL88-8 the Nola at a temperature of -78oC was added about 500 ml of NH3. Then the reaction mixture was stirred for 15 h at -78oC for 50 h at room temperature, after which it was evaporated. The residue was distributed between ethyl acetate and water and the organic phase was subjected to normal processing. In this way received 8,53 g of 6-chloro-5-(2-chloro-5-methoxyphenoxy)-pyrimidine-4 - ylamine in the form of yellow crystals. MS: 285 (M).

e) 8,53 g obtained above by compounds were added to a solution of 0.82 g of sodium in 100 ml of ethylene glycol at a temperature of 50oC. the Solution was heated for 20 h to 100oC, after which he distributed among Polynesians solution of NH4Cl and CH2Cl2and processed according to normal procedures. The result has been to 8.3 g of 2- [6-amino-5-(2-chloro-5-methoxyphenoxy)-4-pyrimidine-4-yloxy] -1 - ethanol as a white solid, which without further purification was similaraly. With this purpose, the above material (8,3 g) was dissolved in 300 ml of methylene chloride, mixed sequentially with 8,15 g dimethylaminopyridine and at room temperature from 10.05 g of tert-butyldimethylchlorosilane. The reaction solution was stirred for 5 h at room temperature, and then filtered, the solution was concentrated, the residue was subjected to normal processing. By subsequent crystallization from methylene chloride/hexane was obtained 7 g of 6-[2- (tert-butyldimethylsilyloxy)-ethoxy]-5-(2-chloro-5 - methoxyphenoxy)-pyrimidine-4-ylamine. MS: 410 (M-CH3).

Example 18

Analogously to example 2 from 5-(2-chloro-5-methoxyphenoxy)-6-(2 - hydroxyethoxy)-pyrimidine-4-ylamide 5-tert-butylthiophene-2 - sulfonic azide and 2-pyridylcarbinol acid was obtained 2-[6- (5-tert-butylthiophene-2-ylsulphonyl)-5-(2-chloro-5 - methoxyphenoxy)-pyrimidine-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid in the form of white crystals. MS: 634,3 (M+H).

Example 19

Analogously to example 2 from the compound of example 17 azide and 4-pyridylcarbinol acid was obtained 2-[6-(5-tert-butylthiophene-2 - ylsulphonyl)- 5-(2-chloro-5-methoxyphenoxy)-pyrimidine-4-yloxy] -ethyl ester pyridine-4-ylcarbamate acid in the form of white crystals. MS: 634,3 (M+H).

Example 20

Analogously to example 17, and 6-[2-(tert - butyldimethylsilyloxy)-ethoxy] -5-(2-methoxyphenoxy)-pyrimidine-4 - ylamine was used as a component of the reaction, was obtained 6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)-pyrimidine-4-alamid 5-tert - butylthiophene-2-sulfonic acids in the form of a solid white color. MS: 479 (M).

Example 21

To a solution of La achieve complete solubility was added 1 ml of DMSO. The reaction proceeded further for 3 hours at a temperature of 90oC. After cooling to room temperature the reaction mixture was acidified aqueous citric acid to pH 4, after which the compound obtained was extracted with acetic ether. After the distillation of acetic ether was led from ethanol N-[5-(2-chloro-5-methoxyphenoxy) -6-(2-hydroxyethoxy)-pyrimidine-4-yl] -5-isopropylpyridine-2-sulfonamide. As a result received 175 mg of white crystals which decomposed at 180oC.

Obtaining initial connection:

306 mg of 4,6-dichloro-5-(2-chloro-5-methoxyphenoxy)-pyrimidine, 320 mg of 5-isopropyl-2-pyridine-sulfonamida and 180 mg of potassium tert-butylate were dissolved in 2 ml of DMSO and then carried out the reaction for 3 hours at a temperature of 90oC. After cooling to room temperature the reaction mixture was acidified aqueous citric acid; the compound was extracted with acetic ether and after removal of the solvent was led from ethanol. In this way received 250 mg of N-[6-chloro - 5-(2-chloro-5-methoxyphenoxy)-pyrimidine-4-yl] -5-isopropylpyridine - sulfonamida in the form of white crystals with aPL174-175oC.

Example 22

100 mg of N-[5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)- pyrimidine-4-yl] -5-isopropylpyridine-2-sulfona 2 hours at a temperature of 95oC, and when this was released N2. After removal of the solvent the compound was led from ethanol. The result has been 115 mg of 2-[5-(2 - chloro-5-methoxyphenoxy)-6-(5-isopropylpyridine-2-ylsulphonyl) - pyrimidine-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid in the form of white crystals with aPL190-191oC.

Example 23

Analogously to example 21 was obtained 5-isopropyl-N-[6-(2 - hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(3-methoxyphenyl)- pyrimidine-4-yl] -pyridine-2-sulfonamide. TPL139-140oC (from ethanol).

Obtaining initial connection:

Analogously to example 21, section two, received 400 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(3 - methoxyphenyl)-pyrimidine-4-yl] -5-isopropylpyridine-2-sulfonamide from 330 mg of 4,6-dichloro-2-(3-methoxyphenyl)-5-(2-methoxyphenoxy)- pyrimidine and 420 mg of potassium salt of 5-isopropylpyridine-2-sulfonamida.

Example 24

Analogously to example 22 of 115 mg of 5-isopropyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(3 - methoxyphenyl)-pyrimidine-4-yl] -pyridine-2-sulfonamida and 38.5 mg azide 2-pyridylcarbinol acid was obtained 120 mg of 2-[6-(5 - isopropylpyridine-2-ylsulphonyl)-5-(2-methoxyphenoxy)-2-(3 - methoxyphenyl)-pyrimidine-4-yloxy]ethyl ester pyridine-2-ylcarbamate acid. Tis phenoxy)-2 - methylsulfonylamino-4-yl] -5-isopropylpyridine-2-sulfonamide from 4,6-dichloro-2-methylsulfanyl-5-(2-methoxyphenoxy)-pyrimidine and potassium salt 5-isopropylpyridine-2-sulfonamida. TPL192oC (from ethanol).

b) the above connection using glycolate, sodium transformed into 5-isopropyl-N-[6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2 - methylsulfonylamino-4-yl]-pyridine-2-sulfonamide. TPL76-78oC (from EtOH).

Example 26

Analogously to example 22 was received 106 mg of 2-[6-(5-isopropylpyridine-2-ylsulphonyl)-5-(2 - methoxyphenoxy)-2-methylsulfonylamino-4-yloxy]-ethyl ester pyridine-2-ylcarbamate acid of 100 mg 5-isopropyl-N- [6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-methylsulfonylamino-4-yl] - pyridine-2-sulfonamida azide and 2-pyridylcarbinol acid. TPL213-214oC (from ethanol).

Example 27

a) From 4,6-dichloro-2-(1,3-benzodioxol-5-yl)-5-(2-methoxyphenoxy)- pyrimidine and 5-isopropylpyridine-2-sulfonamida potassium was obtained N-[6-chloro-2-(1,3-benzodioxol-5-yl)-5-(2-methoxyphenoxy)- pyrimidine-4-yl] -5-isopropylpyridine-2-sulfonamide.

b) This compound using glycolate, sodium translated into N-[2-(1,3 - benzodioxol-5-yl)-6-(2-hydroxyethoxy)-5 (2-methoxyphenoxy)- pyrimidine-4-yl]-5-isopropylpyridine-2-sulfonamide. TPL184oC (from EtOH).

Example 28

Analogously to example 22 was obtained 110 mg of 2-[2- (1,3-benzodioxol-5-yl)-6-(5-isopro the Sol-5-yl)-6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-pyrimidine-4-yl] -5-isopropylpyridine-2-sulfonamida azide and 2-pyridylcarbinol acid. TPL184oC (from ethanol).

Example 29

a) From 4,6-dichloro-2-morpholine-4-Yeremina and 5-isopropylpyridine-2-sulfonamida potassium was obtained N-[6-chloro-5-(2 - chloro-5-methoxyphenoxy)-2-morpholine-4-Yeremey-4-yl]-5 - isopropylpyridine-2-sulfonamide.

b) the Interaction of this compound with glycolate, sodium was obtained N-[5-(2-chloro-5 - methoxyphenoxy)-6-(2-hydroxyethoxy)-2-morpholine-4-Yeremey-4 - yl]-5-isopropylpyridine-2-sulfonamide. TPL189-190oC (from EtOH).

Example 30

Analogously to example 22 116 mg of N-[5-(2-chloro-5 - methoxyphenoxy)-6-(2-hydroxyethoxy) -2-morpholine-4-Yeremey-4 - yl]-5-isopropylpyridine-2-sulfonamida were subjected to interaction with azide 2-pyridylcarbinol acid, resulting in the 2-[5-(2 - chloro-5-methoxyphenoxy) -6-(5-isopropylpyridine-2 - ylsulphonyl)-2-morpholine-4-Yeremey-4-yloxy] ethyl ester pyridine-2-ylcarbamate acid. Then received from ethanol 106 mg of white crystals which decomposed at a temperature of 240oC.

Example 31

Analogously to example 21 from [6-chloro-5- (2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl] -amide 5-methylpyridin-2 - sulfonic acids and glycolate, sodium was obtained 6-(2-hydroxyethoxy)-5- (2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 5-methylpyridin-2-5-methylpyridin was diazotisable and transformed into 2-bromo-5-methylpyridin according to the method of F. H. Case (JACS 68 (1946), page 2574).

b) 4.8 g of this compound was subjected to interaction in 40 ml of propylene glycol from 7.4 g of sodium hydrosulfide at 150oC. After cooling to room temperature the reaction mixture was added dropwise 5 ml of acetic acid, after which the resulting 2-mercapto-5-methylpyridin precipitated as a yellow powder.

in the two-phase mixture of 40 ml of CH2Cl220 ml of 37% aqueous HCl and 3 g of 2-mercapto-5-methylpyridine after cooling to -10oC was added dropwise within 30 min to 50 ml of a 1.2 molar solution of sodium hypochlorite. Then the organic phase was extracted three times with H2O by shaking. After removal of the solvent was obtained 5-methylpyridin-sulfochloride in the form of a yellowish liquid.

g) the Interaction of this sulfochloride with 25% solution of NH4OH received a 5-methylpyridin-2-sulfonamide.

d) 0.7 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine, 520 mg of 5-methylpyridin-2-sulfonamida and 320 mg of potassium tert-butylate were dissolved in 2 ml of DMSO and stirred for 3 hours at a temperature of 80oC. After the usual separation of the reaction mixture is received 410 mg [6-chloro-5-(2-methoxyphenoxy) -2,2'-bipyrimidin-4 - yl]-amide 5-methylpyridin-2-sulfonylated-4-ylamide 5-methylpyridin-2-sulfonic acids and 30 mg of azide 2-pyridylcarbinol acid received 100 mg of 2-[5-(2 - methoxyphenoxy)-6-(5-methylpyridin-2-ylsulphonyl)-2,2'- bipyrimidin-4-yloxy]ethyl ester pyridine-2-ylcarbamate acid in the form of beige crystals. TPL: decomposition at 198oC.

Example 33

a) Analogously to example 22 of 712 mg of 4,6-dichloro-5- (2-methoxyphenoxy)-2-morpholine-4-Yeremina and 5-methylpyridin-2 - sulfonamida potassium was obtained 580 mg of 6-chloro-5-(2-methoxyphenoxy)-2 - morpholine-4-Yeremey-4-ylamide 5-methylpyridin-2-sulfonic acids.

b) the Interaction of this compound with glycolate, sodium was obtained 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-morpholine-4 - Yeremey-4-alamid 5-methylpyridin-2-sulfonic acids. TPL195-196oC. (from ethanol).

Example 34

Analogously to example 22 was received 117 mg of 2-[5-(2-methoxyphenoxy) -6-(5-methylpyridin-2-ylsulphonyl)-2 - morpholine-4-Yeremey-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid 105 mg of 6-(2-hydroxy-ethoxy)-5-(2 - methoxyphenoxy)-2-morpholine-4-Yeremey-4-ylamide 5-methylpyridin - 2-sulfonic azide and 2-pyridylcarbinol acid. TPL: decomposition at 175oC.

Example 35

105 mg of 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-morpholine-4-Yeremey-4-ylamide 5-methylpyridin - 2-sulfonic acids in 2 ml of dichloromethane was mixed with 3 ml of 1.9 molar solution of phosgene in toluene. After 1 h at room temperature ended completely the formation of chloroformiate, PEFC is balali 0.5 g of 3-(hydroxymethyl) furan, and further the reaction proceeded at a temperature of 60oC for 3 hours After the usual separation of a mixture of the compound obtained was purified by kieselgel (system eluents dichloromethane/simple diethyl ether 4:1 in volume). The result obtained 65 mg furan-3-ymetray ether-{2-[5-(2- methoxyphenoxy)-6-(5-methylpyridin-2-sulfonylamino)-2-morpholine - 4-Yeremey-4-yloxy] -ethyl ester} carboxylic acid. MS: 640,5 [(M-N)-].

Example 36

of 9.2 g of 4-[4-chloro-5-(2-chloro-5 - methoxyphenoxy)-6-methylpyrimidin-2-yl]-the research and 17.8 g of 5-isopropylpyridine-2-sulfonamide-potassium in 130 ml of dry dimethyl sulfoxide was heated in an argon atmosphere for 16 h to a temperature of 120oC. Then the sulfoxide drove away, the residue was distributed between ethyl acetate and 1 N. hydrochloric acid and the organic phase is washed until neutral state. Next, the organic phase was dried, the solvent evaporated and the residue was recrystallized from ethanol. In this way they obtained 10.3 g of 5-(2-chloro-5-methoxyphenoxy)-6-methyl-2-morpholine-4-Yeremey-4 - ylamide 5-isopropylpyridine-2-sulfonic acids. MS: M = 534.

Example 37

1 g obtained in example 36 compound and 2.1 g of selenium dioxide in 40 ml of dioxane was stirred in an autoclave at a temperature of 170oC for 7 h and Then the reaction mixture was filtered actuarial evaporated and the residue was purified on kieselgel using acetic ether/hexane. In this way received of 0.53 g of 5-(2-chloro-5 - methoxyphenoxy)-6-formyl-2 - morpholine-4-Yeremey-4-ylamide 5-isopropylpyridine-2 - sulfonic acids. TPL194oC.

Example 38

0.1 g obtained in example 37 compound in 3 ml of ethanol was mixed with of 0.014 g of sodium borohydride. The reaction mixture was stirred at a temperature of 80oC for 1 h, after which the ethanol was off and the residue was distributed between chloroform and 1 N. HCl. The organic phase is washed with water and dried, the solvent evaporated and the residue was chromatographically on kieselgel using chloroform/methanol. After recrystallization from dichloromethane/ethanol received 0,072 g of 5-(2-chloro-5 - methoxyphenoxy)-6-hydroxymethyl-2-morpholine-4-Yeremey-4 - ylamide 5-isopropylpyridine-2-sulfonic acids. TPL105oC.

Example 39

0.2 g obtained in example 38 compound in 3.5 ml of POCl3mixed with 0.083 g PCl5for 2 h at a temperature of 20oC, then POCl3drove away and the residue was distributed between acetic ether and aqueous sodium bicarbonate. The organic phase is washed with water, dried and the solvent evaporated. The residue was chromatographically on kieselgel using chloroform/methanol and then recrystallized from dihl the amide 5-isopropylpyridine-2 - sulfonic acids. TPL205oC.

Example 40

In the solution glycolate, sodium, consisting of 0.35 g of ethylene glycol and 0,021 g of sodium was added 0,130 g of the compound obtained in example 39. The reaction mixture was stirred in an argon atmosphere for 2 h at a temperature of 80oC, after which the ethylene glycol drove away and the residue was distributed between ethyl acetate and 1 N. hydrochloric acid. The organic phase is washed with water, dried over sodium sulfate and the solvent was removed by distillation. The residue was recrystallized from a simple ether/petroleum ether. The way it was received in 0.104 g of 5-(2 - chloro-5-methoxyphenoxy) -6-(2-hydroxyethoxymethyl)-2-morpholine-4 - Yeremey-4-ylamide. TPL166oC.

Example 41

Analogously to example 2 from the obtained in example 40 compound was obtained 2-[5-(2-chloro-5 - methoxyphenoxy)-6-(5-isopropylpyridine-2-sulfonylamino)-2 - morpholine-4-Yeremey-4-ylethoxy] -ethyl ester pyridine-2-ylcarbamate acid. MS: (M-N)-= 713.

Example 42

Analogously to example 2 from the obtained in example 38 compound was obtained 5-(2 - chloro-5-methoxyphenoxy)-6-(5-isopropylpyridine-2-ylsulphonyl)-2 - morpholine-4-Yeremey-4-ymetray ether pyridine 2-ylcarbamate acid. MS: (M-N)-= 669.

the l-Na was obtained (RS)-5-(2-chloro-5 - methoxyphenoxy)-6-(2,2-dimethyl-1,3-dioxolane-3-ileocecal)-2 - morpholine-4-Yeremey-4-alamid 5-isopropylpyridine-2-sulfonic acids. MS: (M-N)-= 663.

Example 44

A solution of 0.05 g obtained in example 43 compound in 2 ml of dioxane was mixed with 2 ml of 1 N. HCl and heated for 15 min to a temperature of 80oC.

After evaporation the residue was chromatographically on kieselgel using chloroform/methanol and the way it was obtained (RS)-5-(2-chloro-5-methoxyphenoxy)-6-(2,3-dihydroxypropyl)-2 - morpholine-4-Yeremey-4-alamid 5-isopropylpyridine-2-sulfonic acids. TPL116oC, MS: (M-N)-= 623.

Example 45

345 mg of sodium was dissolved at a temperature of 80oC in 50 ml of abs. of ethylene glycol. After a short cooling the solution was added 1.56 g of 6-chloro-5-(2-methoxyphenoxy)-2-morpholine-4-Yeremey-4-ylamide 5 - isopropylpyridine-2-sulfonic acids. The resulting solution was stirred for 24 h at a temperature of 140oC, the solvent was removed under high vacuum and the residue was dissolved in 40 ml of water. After 4 h at a temperature of 5oC was filtered by suction, the crystals are suspended in 40 ml of water was stratified using acetic ether, and with stirring, was introduced dropwise 1 N. aqueous HCl until the pH was reduced to 3.5. The aqueous phase was extracted three times with acetic ether, and the organic phase was washed two who began crystallization (approximately 5 ml). Then filtered by suction, washed with simple ether and dried. The result has been 1,144 g (70%) of white crystals of 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2 - morpholine-4-Yeremey-4-ylamide 5-isopropylpyridine-2-sulfonic acids. TPL157-160oC, MS: (M-N)-= 544,4.

Obtaining initial connection:

A solution of 1.18 g of 4,6-dichloro-5-(2 - methoxyphenoxy)-2-morpholine-4-Yeremina and 2.12 g (8,88 mmol) 5-isopropylpyridine-2-sulfonamide potassium salt in 25 ml dry DMSO was heated for 3 h to a temperature of 80oC until dichloride is not fully reacted. Then DMSO was removed under high vacuum, the residue was dissolved in 60 ml of water and the aqueous solution washed three times with diethyl ether. Then the solution was acidified using 1 N. HCl to pH 3.5 and the product was extracted three times with acetic ester. The organic phase was sequentially washed twice with water and once with saturated sodium chloride solution, and then were combined, dried over sodium sulfate and evaporated. The crystalline residue to fully remove track 5-isopropylpyridine-2-sulfonamida was twice degenerately with absolute diethyl ether. The remaining crystals were filtered off and dried. The result has been 1.66 g (96%) of 6-chloro-5-(2-methoxyphenol-176oC. MS: (M-N)-= 518,3.

Example 46

Analogously to example 45 after 10 h of implementation of the reaction at a temperature of 120oC with the addition of DMSO as a dissolving agent (glycol/DMSO 5: 2) was obtained 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2-morpholine-4-Yeremey-4-alamid 5-tert - butylthiophene-2-sulfonic acids in the form of a solid foamy substance of white color with the release of 54%. MS: 565,5 (M+N)+.

Example 47

Analogously to example 45 after 3 h of reaction at a temperature of 140oC was obtained 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2 - morpholine-4-Yeremey-4-alamid 2.5-dichlorothiophene-3-sulfonic acids in the form of white crystals with a yield of 43%. TPL180-183oC, MS: 575,3 (M-N)-.

Example 48

Analogously to example 45 after 3.5 h the implementation of the reaction at a temperature of 140oC was obtained 6-(2-hydroxyethoxy)- 5-(2-methoxyphenoxy)-2-morpholine-4-Yeremey-4-alamid 3,5 - dimethylisoxazol-4-sulfonic acids in the form of white crystals with aPL144-147oC. MS: 520,4 (M-N)-.

Example 49

110 mg of sodium was dissolved at a temperature of 50oC in 2.5 ml of ethylene glycol. After cooling to room temperature the solution was added 260 mg of 6-chloro-5-(2 - methoxyphenoxy)-2,2'-bipyrimidin-4-ilamed and the solid residue was dissolved in 20 ml of water. The addition of 0.3 ml of acetic acid the product was besieged. After filtration, washing with water and drying under high vacuum at a temperature of 50oC received 182 mg (67%) of pale beige crystals of 6-(2-hydroxyethoxy)-5-(2 - methoxyphenoxy)-2,2'-bipyrimidin-4-ylamide 2.5-dichlorothiophene-3 - sulfonic acids. TPL157-160oC, MS: M+(569), 470 (M+-(SO2+Cl)).

Obtaining initial connection:

The solution of 0,349 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine and 0,405 g 2,5-dichlorothiophene-3-sulfonamide potassium salt in 5 ml of dry DMSO was kept for 16 h at room temperature. Then added 0,112 g of potassium tert-butylate, after which the reaction was continued for 5 hours Then the reaction mixture was poured into 40 ml of ice water and for removal of excess reagent was extracted with 40 ml of diethyl ether. From the aqueous phase using vysalivaniya a saturated solution of sodium chloride (20 ml) was obtained 6-chloro-5-(2 - methoxyphenoxy)-2,2'-bipyrimidin-4-alamid-sodium salt of 2,5-dichlorothiophene-3-sulfonic acids by filtration and washing with simple ether (0.54 g powder beige color).

To get free sulfonamida sodium salt is suspended in water and the suspension was acidified with acetic acid, the practical phase was twice washed with a saturated solution of sodium chloride, dried over MgSO4and evaporated under reduced pressure. The residue is briefly washed with diethyl ether and hexane and then dried. The result has been 0,30 g (54%) of a beige powder with TPL140oC (decomposition). MS: 444 (M-(SO2+Cl)).

In a similar way, using 3,5-dimethylisoxazole-4-sulfonamide-potassium was obtained 6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 3,5-dimethylisoxazol-4-sulfonic acids with 71% yield as a beige, slightly stained in a reddish color powder with TPL184-187oC. MS: M+=488,393 (M-(SO2+OCH3)).

Example 50

Analogously to example 49 was obtained 6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 3,5-dimethylisoxazol-4 - sulfonic acids in the form of a beige powder with TPL200-204oC. MS: 514 (M+), 450 (M+-SO2), 419 (450-CH3O).

Example 51

The solution of 888 mg of pyridine-2-carbonylated in 15 ml of abs.dioxane was kept for 15 min at a temperature of 80oC. After a short cooling was added 1,09 g of the compound obtained in example 45, and withstood the solution for 4 hours at a temperature of 90oC. Then evaporated until dry, the residue was dissolved in acetic ether, and was twice pteromalid, the resulting product is precipitated in the form of crystals. For complete cleaning chromatography was performed on kieselgel using EtOAc/CH2Cl2(1:1) and in this way received 931 mg (70%) of white crystals of 2-[6-(5-isopropylpyridine-2 - ylsulphonyl)-5-(2-methoxyphenoxy)-2-morpholine-4-Yeremey-4-yloxy] - ethyl ester pyridine-2-ylcarbamate acid with TPL200-202oC. MS: 664,4 (M-N)-IR (KBr) 1730 cm-1(carbamate).

Example 52

Analogously to example 51 from the obtained in example 49 connection with the release of 61% was obtained 2-[6-(2,5-dichlorothiophene 3 ylsulphonyl)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy] - ethyl ester pyridine-2-ylcarbamate acid in the form of white crystals with TPL194-197oC. MS: 690,1 (M+N)+IR (KBr) 1732 cm-1(carbamate).

Example 53

Analogously to example 51 from the obtained in example 50 connection with the release of 68% was obtained 2-[5-(2-methoxyphenoxy)-6-(3,5-dimethylisoxazol-4-ylsulphonyl)-2,2'- bipyrimidin-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid in the form of light yellow crystals with TPL217-218oC. MS: 635,3 (M+N)+IR (KBr) 1736 cm-1(carbamate).

Example 54

Analogously to example 51 from the obtained in example 46 connection with the release of 90% of the new ester of pyridine-2-ylcarbamate acid in the form of a foamy substance of white color. MS: 683,5 (M-N)-.

Example 55

Analogously to example 51 from the obtained in example 47 connection with the release of 55% was obtained 2-[6-(2,5-dichlorothiophene-3-ylsulphonyl)-5-(2-methoxyphenoxy)-2 - morpholine-4-Yeremey-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid in the form of white crystals with aPL194-196oC. MS: 695,3 (M-N)-.

Example 56

Analogously to example 51 from the obtained in example 48 connection with the release of 70% was obtained 2-[6-(3,5 - dimethylisoxazol-4-ylsulphonyl)-5-(2-methoxyphenoxy)-2 - morpholine-4-Yeremey-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid in the form of white crystals with aPL106-109oC. MS: 640,4 (M-N)-.

Example 57

6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-morpholine-4-Yeremey - 4-alamid 5-isopropylpyridine-2-sulfonic acids (54,5 mg) was dissolved in N,N-dimethylacetamide (5 ml) was added at room temperature to 14.4 mg of 60% suspension of NaH was stirred for 20 min at room temperature and was mixed with 2-chloropyrimidine (11.7 mg). Then the reaction mixture was continued to stir for 18 h at room temperature, poured on ice water, was added a saturated solution of NH4Cl and extracted with acetic ester. The organic phase pronyuk was chromatographically on kieselgel in the solvent system methylene chloride/methanol (100:1). In this way received {5-(2 - methoxyphenoxy)-2-morpholine-4-yl-6-[2-(pyrimidine-2-yloxy)- ethoxy] -pyrimidine-4-yl} -amide 5-isopropylpyridine-2-sulfonic acids in the form of white crystals. MS: 624 (M+H).

Example 58

a) Analogously to example 45 interaction [6-chloro-2-(3-methoxybenzyl)-5-(2 - methoxyphenoxy)-pyrimidine-4-yl] -amide 5-isopropylpyridine-2 - sulfonic acids with Na in ethylene glycol was obtained [6-(2 - hydroxyethoxy)-2-(3-methoxybenzyl)-5-(2-methoxyphenoxy)- pyrimidine-4-yl] -amide 5-isopropylpyridine-2-sulfonic acids in the form of a white foamy substance. MS: 579,3 (M-N).

Obtaining input connections:

b) 10.8 g of 3-methoxyphenylacetonitrile was dissolved in ethanol (100 ml) and saturated solution of hydrogen chloride at room temperature. Then was stirred for 12 h at room temperature, cooled the solution to 0oC was aspirated and the precipitated crystals. The crude product was recrystallized from acetone/diethyl ether. The result is obtained the hydrochloride of the ethyl ester of 2-(3-methoxyphenyl)-iminoxyl acid in the form of a solid crystalline substance of white color. MS: 193 (M).

b) Hydrochloride of the ethyl ester of 2-(3-methoxyphenyl)-iminoxyl acid (12 g) was dissolved in ethanol (100 ml) and -75oC was mixed with Aravali using a rotary evaporator. The residue is suspended in acetone, obtaining the suspension, the precipitated crystals were pumped out and dried under high vacuum. The result is obtained the hydrochloride of 2-(3-methoxyphenyl)-acetamidine in the form of a solid crystalline substance of white color. MS: 164 (M).

g) 2.3 g of Na was dissolved in methanol (40 ml) was added at room temperature sequentially hydrochloride 2-(3-methoxyphenyl)-acetamidine (10 g) and dimethyl (2-methoxyphenoxy)malonic acid (12,67 g) and was stirred for 5 h at room temperature. Then concentrated using a rotary evaporator and the crude product was placed in the water. The aqueous phase was washed with acetic ether, then set to pH 1 and the precipitated crystals were filtered by suction, and then dried under high vacuum. The result was obtained 2-(3-methoxybenzyl)-5-(2-methoxyphenoxy)-pyrimidine-4,6-diol in the form of beige crystals. MS: 354 (M).

d) 2-(3-methoxybenzyl)-5-(2-methoxyphenoxy)-pyrimidine-4,6-diol (14 g) was dissolved in acetonitrile (150 ml), mixed at room temperature with collidine (5,24 ml), phosphoroxychloride (21,7 ml) and was stirred for 9 h at room temperature. Then the mixture was poured into ice water and was extracted with acetic ether. Organic is astoral in hexane/diethyl ether, was filtered and the filtrate was concentrated using a rotary evaporator. The result was obtained 4,6-dichloro-2-(3-methoxybenzyl)-5-(2-methoxyphenoxy)- pyrimidine in the form of light brown crystals. MS: 390 (M).

e) Analogously to example 45 interaction of 4,6-dichloro-2-(3 - methoxybenzyl)-5-(2-methoxyphenoxy)-pyrimidine, 5-isopropylpyridine-2-sulfonamide potassium salt was obtained [6-chloro-2- (3-methoxybenzyl)-5-(2-methoxyphenoxy)-pyrimidine-4-yl] -amide 5-isopropylpyridine-2-sulfonic acids in the form of a foamy substance is yellow. MS: 553,1 (M-N).

Example 59

a) Analogously to example 45 interaction [6-chloro-2-(3-methoxybenzyl)-5-phenoxypyridine-4-yl] - amide 5-isopropylpyridine-2-sulfonic acids with Na in ethylene glycol was obtained [6-(2-hydroxyethoxy)-2-(3-methoxybenzyl)- 5-phenoxypyridine-4-yl] -amide 5-isopropylpyridine-2-sulfonic acids in the form of light yellow crystals. MS: 549,2 (M-N).

Obtaining input connections:

b) Analogously to example 58 d) by condensation of the hydrochloride of 2-(3-methoxyphenyl)-acetamidine with dimethyl ether of proksimalnami acid was obtained 2-(3-methoxybenzyl)-5-phenoxypyridine - 4,6-diol in the form of a foamy substance is yellow. MS: 324 (M).

C) Analogously to example 58 d) the chlorination of 2-(3-IU is rimidine in the form of yellow crystals. MS: 360 (M).

d) Analogously to example 45 interaction of 4,6-dichloro-2-(3-methoxybenzyl)-5 - phenoxypyridine with 5-isopropylpyridine-2-sulfonamide potassium salt was obtained [6-chloro-2-(3-methoxybenzyl)-5-phenoxypyridine-4 - yl] - amide 5-isopropylpyridine-2-sulfonic acids in the form of a foamy substance is yellow. MS: 523 (M-N).

d) [6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-methoxyphenyl)- pyrimidine-4-yl]amide 5-methylthiazole-2-sulfonic acid

< / BR>
Aspects (ISP): m/e 545,1 (M+1).

(e)[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyridin-4-yl - pyrimidine-4-yl]amide 5-isopropylpyridine-2 sulfonic acid.

By analogy with example 45 from (6-chloro-5-(2-methoxyphenoxy)-2-pyridine-4-Yeremey-4-yl] amide 5-isopropylpyridine-2-sulfonic acid and sodium ethylene glycol obtained [6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- 2-pyridine-4-Yeremey-4-yl] amide 5-isopropylpyridine-2-sulphonic acid in the form of white crystals. So pl. 163-164oC.

Obtaining source materials:

The original product was obtained from 4,6-dichloro-5-(2-methoxyphenoxy)-2-pyridin-4-yl)pyrimidine and the potassium salt of 5-isopropylpyridine-2-pyridin-4-yl)pyrimidine and the potassium salt of 5-isopropylpyridine-2-sulfonamida similarly to the described method.

oC tribromide boron (50 mg) in methylene chloride (2 ml). Then was stirred for 2 h at 0oC and during the next 4 h at room temperature, and then concentrated using a rotary evaporator and was chromatographically balance kieselgel in the solvent system methylene chloride/acetic ether. The way it was received [2-(3-hydroxybenzyl)-6-(2-hydroxyethoxy)-5 - phenoxypyridine-4-yl]-amide 5-isopropylpyridine-2-sulfonic acids in the form of white crystals. MS: 525,1 (M-N).

An example of a

Tablets containing the following ingredients can be manufactured in the usual manner.

Ingredients 1 tablet

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

Lactose - 125,0 mg

Corn starch is 75.0 mg

Talc - 4.0 mg

Magnesium stearate 1.0 mg

Example B

Capsules containing the following ingredients can be manufactured in the usual manner.

Ingredients per 1 capsule

The compound of formula I - 25.0 mg

Lactose - 150,0 mg

Corn starch - 20.0 mg

Talc - 5.0 mg

The example IN

Injectable solutions may have the following composition:

The compound of formula I - 3.0 mg

Gelatin - 150,0 mg

Phenol - 4,7 mg

Water for injection solutions - until Then, this slurry fill the canister, fitted with a metering valve. Through this valve into the canister serves under pressure of 5.0 g of freon 12. As a result of shaking the freon is dissolved in a mixture of megliola and benzyl alcohol. This spray contains approximately 100 single doses, which can be assigned to a gradual acceptance.

1. Sulfonamides of General formula I

< / BR>
where R1selected from a monocyclic five or six-membered S, N and/or O-containing heterocyclic residue, such as pyridyl, pyrimidinyl, isoxazolyl, thienyl, thiazolyl, which can be unsubstituted or substituted by lower alkyl, halogen or lower alkanoyl;

R2denotes hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkoxy-lower alkyl, lower alkylsulfonyl-lower alkoxy, phenyl, lower alkylphenyl, lower alkoxyphenyl, lower alkylenedioxy, phenyl-lower alkyl, lower alkylphenyl-lower alkyl, lower alkoxyphenyl-lower alkyl, lower alkylenedioxy-lower alkyl, monocyclic six-membered N and/or O-containing heterocyclic residue, such as pyrimidinyl, pyridyl, morpholino;

R3denotes lower alkyl, lower alkoxy, formyl, halogen-lower alkyl, hydroxy-lower alkyl, amino/SUB>)m- O - (CRaRb)nOR9, - (CH2)m- O - (CH2)nNH2or -(CH2)m- O - (CRaRb)n- B - R9;

R4- R8denote hydrogen, lower alkoxy or halogen;

R9denotes pyridyl, pyrimidinyl;

Raand Rbrepresent hydrogen or lower alkyl;

A represents Catalonian 1,2-dihydroxyethylene group;

B represents-OC(O)O-, -OC(O)NH-, NHC(O)NH or NHC(O)O-;

n = 2, 3, or 4;

m = 0 or 1.

2. Connection on p. 1, where R2denotes hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkoxy-lower alkyl, lower alkylsulfonyl-lower alkoxy, phenyl, lower alkoxyphenyl, lower alkylenedioxy or monocyclic six-membered N and/or O-containing heterocyclic residue, such as pyrimidinyl, pyridyl, morpholino; R3denotes lower alkyl, lower alkoxy, formyl, halogen-lower alkyl, hydrocy-lower alkyl, amino-lower alkyl or a residue - CH2O-A lower alkyl, - (CH2)m- O - (CRaRb)n- OH, - (CH2)m- O - (CH2)nNH2or- (CH2)m- O - (CRaRb)n- B - R9; R1, R41denotes unsubstituted or substituted by lower alkyl, halogen or lower alkanoyl pyridyl, pyrimidinyl.

4. Join one of the PP.1 to 3, where R2denotes hydrogen, pyrimidinyl, pyridyl, morpholino.

5. Join one of the PP.1 to 4, where R3represents the balance-O - (CRaRb)n- OH, - O - (CH2)nNH2or a residue - O - (CH2)2- B - R9and R9denotes pyridyl.

6. Connection on p. 6, where R9represents a 2-pyridyl.

7. Connection on p. 6, where R3represents the balance-O(CH2)2- B - R9and B denotes a -(O)C(O)NH-.

8. Connection on p. 7, which is

2-[6-(5-isopropylpyridine-2-ylsulphonyl)-5-(2-methoxyphenoxy)-2-morpholine-4-Yeremey-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid.

9. Connection on p. 7, which is

2-[6-(5-tert. -butylthiophene-2-ylsulphonyl)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy]-ethyl ester pyridine-2-ylcarbamate acid,

2-[5-(2-methoxyphenoxy)-6-(5-pentylthiophene-2-ylsulphonyl)-2,2'-bipyrimidin-4-yloxy]-ethyl ester pyridine-2-ylcarbamate acid,

2-[6-[5-(2,2-timetype inovas acid,

2-[6-(5-isopropylpyridine-2-ylsulphonyl)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy]-ethyl ester pyridine-2-ylcarbamate acid,

2-[5-(2-methoxyphenoxy)-6-pyridin-2-ylsulphonyl)-2,2'-bipyrimidin-4-yloxy]-ethyl ester pyridine-2-ylcarbamate acid,

2-[5-(2-methoxyphenoxy)-6-pyridin-3-ylsulphonyl)-2,2'-bipyrimidin-4-yloxy]-ethyl ester pyridine-2-ylcarbamate acid,

2-[6-(5-tert. -butylthiophene-2-ylsulphonyl)-5-(2-chloro-5-methoxyphenoxy)-pyrimidine-4-yloxy]-ethyl ester pyridine-2-ylcarbamate acid,

2-[6-(5-isopropylpyridine-2-ylsulphonyl)-5-(2-methoxyphenoxy)-2-(3-methoxyphenyl)-pyrimidine-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid,

2-[6-(5-isopropylpyridine-2-ylsulphonyl)-5-(2-methoxyphenoxy)-2-methylsulfonylamino-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid,

2-[2-(1,3-benzodioxol-5-yl)-6-(5-isopropylpyridine-2-ylsulphonyl)-5-(2-methoxyphenoxy)-pyrimidine-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid,

2-[5-(2-chloro-5-methoxyphenoxy)-6-(5-isopropylpyridine-2-ylsulphonyl)-2-morpholine-4-Yeremey-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid,

2-[5-(2-methoxyphenoxy)-6-(5-methylpyridin-2-insult is(5-methylpyridin-2-ylsulphonyl)-2-morpholine-4-Yeremey-4-yloxy]-ethyl ester pyridine-2-ylcarbamate acid,

2-[5-(2-chloro-5-methoxyphenoxy)-6-(5-isopropylpyridine-2-sulfonylamino)-2-morpholine-4-Yeremey-4-ylethoxy] -ethyl ester pyridine-2-ylcarbamate acid,

5-(2-chloro-5-methoxyphenoxy)-6-(5-isopropylpyridine-2-ylsulphonyl)-2-morpholine-4-Yeremey-4-ymetray ether pyridine-2-ylcarbamate acid,

2-[6-(2,5-dichlorothiophene-3-ylsulphonyl)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy]-ethyl ester pyridine-2-ylcarbamate acid,

2-[5-(2-methoxyphenoxy)-6-(3,5-dimethylisoxazol-4-ylsulphonyl)-2,2'-bipyrimidin-4-yloxy]-ethyl ester pyridine-2-ylcarbamate acid,

2-[6-(5-tert. -butylthiophene-2-ylsulphonyl)-5-(2-methoxyphenoxy)-2-morpholine-4-Yeremey-4-yloxy]-ethyl ester pyridine-2-ylcarbamate acid,

2-[6-(2,5-dichlorothiophene-3-ylsulphonyl)-5-(2-methoxyphenoxy)-2-morpholine-4-Yeremey-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid,

2-[6-(3,5-dimethylisoxazol-4-ylsulphonyl)-5-(2-methoxyphenoxy)-2-morpholine-4-Yeremey-4-yloxy] -ethyl ester pyridine-2-ylcarbamate acid.

10. Connection on p. 6, where R9represents a 4-pyridyl.

11. Connection on p. 10, which represents a 2-[6-(5-tert.-butylthiophene-2-ylsulphonyl)-5-(2-chloro-5-mo p. 5, where R3represents the balance-O(CH2)2- B - R9and B represents -(O)C(O)O-.

13. Connection on p. 12 representing {5-(2-methoxyphenoxy)-2-morpholine-4-yl 6-[2-(pyrimidine-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide 5-isopropylpyridine-2-sulfonic acids.

14. Connection on p. 5, where R3represents the balance-O(CH2)2- B - R9and B represents the balance-NHC(O)NH-.

15. Connection on p. 14, which represents an

5-(2-methoxyphenoxy)-6-[2-(3-pyridine-2-yureina)-ethoxy] -2,2'-bipyrimidin-4-alamid 5-tert.-butylthiophene-2-sulfonic acids,

5-(2-methoxyphenoxy)-6-[2-(3-pyridine-2-yureina)-ethoxy] -2,2'-bipyrimidin-4-alamid 5-isopropylpyridine-2-sulfonic acids.

16. Connection PP.1 to 4, where R3is hydroxyethoxy.

17. Connection on p. 16, which represents an

6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 5-tert.-butylthiophene-2-sulfonic acids,

6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 5-pentylthiophene-2-sulfonic acid,

6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 5-(2,2-dimethylpropionic)-thiophene-2-sulfonic acids,

6-(2-hydroxyethoxy)-5-(2-methoxide)-2,2'-bipyrimidin-4-alamid pyridine-3-sulfonic acids,

5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)-pyrimidine-4-alamid 5-tert.-butylthiophene-2-sulfonic acids,

6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-pyrimidine-4-alamid 5-tert.-butylthiophene-2-sulfonic acids,

N-[5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)-pyrimidine-4-yl] -5-isopropylpyridine-2-sulfonamide,

5-isopropyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(3-methoxyphenyl)-pyrimidine-4-yl]-pyridine-2-sulfonamide,

5-isopropyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-methylsulfonylamino-4-yl]-pyridine-2-sulfonamide,

N-[2-(1,3-benzodioxol-5-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-pyrimidine-4-yl]-5-isopropylpyridine-2-sulfonamide,

N-[5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)-2-morpholine-4-Yeremey-4-yl]-5-isopropylpyridine-2-sulfonamide,

6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 5-methylpyridin-2-sulfonic acids,

6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-morpholine-4-Yeremey-4-alamid 5-methylpyridin-2-sulfonic acids,

6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-morpholine-4-Yeremey-3-alamid 5-isopropylpyridine-2-sulfonic acids,

6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-morpholine-4-Yeremey-4-alamid 5-tert.-butylthiophene-2-sulfonic acids,

6-(2-hydroxic the ISQ)-5-(2-methoxyphenoxy)-2-morpholine-4-Yeremey-4-alamid 3,5-dimethylisoxazol-4-sulfonic acids,

6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 2.5-dichlorothiophene-3-sulfonic acids,

6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 3,5-dimethylisoxazol-4-sulfonic acids,

[6-(2-hydroxyethoxy)-2-(3-methoxybenzyl)-5-(2-methoxyphenoxy)-pyrimidine-4-yl]-amide 5-isopropylpyridine-2-sulfonic acids,

[6-(2-hydroxyethoxy)-2-(3-methoxybenzyl)-5-phenoxypyridine-4-yl] -amide 5-isopropylpyridine-2-sulfonic acids,

[2-(3-hydroxybenzyl)-6-(2-hydroxyethoxy)-5-phenoxypyridine-4-yl]-amide 5-isopropylpyridine-2-sulfonic acids.

18. Connection PP.1 to 4, where R3is aminoethoxy.

19. Connection on p. 18, which represents a 6-(2-aminoethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-alamid 5-tert. -butylthiophene-2-sulfonic acids.

20. Connection PP.1 to 4, where R3denotes lower alkyl, lower alkoxy, formyl, halogen-lower alkyl, hydroxy-lower alkyl or-CH2O-A lower alkyl.

21. Connection on p. 20, which represents

5-(2-chloro-5-methoxyphenoxy)-6-methyl-2-morpholine-4-Yeremey-4-alamid 5-isopropylpyridine-2-sulfonic acids,

5-(2-chloro-5-methoxyphenoxy)-6-formyl-2-morpholine-4-Yeremey-4-alamid,

5-(2-chloro-5-methoxyphenoxy)-6-chloromethyl-2-morpholine-4-Yeremey-4-alamid 5-isopropylpyridine-2-sulfonic acids,

5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxymethyl)-2-morpholine-4-Yeremey-4-alamid.

22. The compounds of formula II

< / BR>
where R1, R2and R4- R8shall have the meaning specified in paragraph 1, and Hal represents halogen.

23. Sulfonamides on PP.1 - 21 as inhibitors of binding of endothelin.

24. The pharmaceutical preparation having the properties of an inhibitor of binding of endothelin comprising the active substance and the usual fillers and excipients, characterized in that the active substance contains one of the compounds according to paragraphs.1 - 21 of claims.

Priority points:

25.11.94 - PP.1 - 24 for compounds of formula 1, 11 and pharmaceutical compositions based on compounds of the formula I, where R1, R4- R9, Ra, Rb, A, B, m, n have the values corresponding to the values specified in paragraph 1 of the claims, except for R2phenyl-lower alkyl, lower alkylphenyl-lower alkyl, lower alkoxyphenyl-lower alkyl, lower alkylenedioxy-lower alkyl, and R3- (CH2)m- O - (CRaRb)n- R9;

09.10.95 - PP.1 - 24 for compounds of formulas I, II and pharmaceutical compositions based on compounds pokazannym in paragraph 1 of the claims, R2means phenyl-lower alkyl, lower alkylphenyl-lower alkyl, lower alkoxyphenyl-lower alkyl, lower alkylenedioxy-lower alkyl, and R3means - (CH2)m- O - (CRaRb)n- R9.

 

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