Derivatives of aryl - and heteroarylboronic and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to new derivatives of aryl - and heteroarylboronic General formula I, where R1denotes a substituted phenyl or pyridyl, R2denotes a substituted phenyl, R3denotes hydrogen, (lower)alkyl, cyano, carboxy, esterified carboxylate, phenyl, 1H-tetrazolyl or the group,- CONR5R6, R5denotes hydrogen or the radical R7, R6represents -(CH2)mR7or R5and R6together with the nitrogen atom to which they are attached, denote morpholino, 2,6-dimethylmorpholine, piperidino, 4-(lower)alkylpiperazine, 4-(lower)alkoxyimino, 4-(lower)alkoxycarbonylmethyl or 4 formylpiperazine,7denotes phenyl, substituted phenyl, pyridyl, 1H-tetrazolyl, (lower)alkyl, cyano(lower)alkyl, hydroxy(lower)alkyl, di(lower)alkylamino(lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl or phenyl(lower)alkoxycarbonyl, Radenotes hydrogen or hydroxy, Rbrepresents hydrogen, Z represents hydroxy or the group-OR8or-OC(O)NR8, R8denotes pyridyl or pyrimidinyl and heteroarylboronic formula I have selective inhibitory activity against receptor A and endothelin B and are used to obtain drugs. Also described pharmaceutical composition based on compounds of the formula I. 2 C. and 25 C.p. f-crystals, 2 PL.

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

< / BR>
where

R1denotes phenyl, substituted phenyl or heterocyclyl;

R2denotes phenyl or substituted phenyl;

R3denotes hydrogen, (lower)alkyl, cyano, carboxy, esterified carboxylate, phenyl, substituted phenyl, heterocyclyl or the group,- CONR5R6or-NR5COR7;

R4denotes hydrogen or (lower) alkyl;

R5denotes hydrogen or the radical R7;

R6represents - (CH2)mR7; or

R5and R6together with the nitrogen atom to which they are attached, denote heterocyclyl radical;

R7denotes phenyl, substituted phenyl, cycloalkyl, heterocyclyl, (lower)alkyl, cyano(lower)alkyl, hydroxy(lower)alkyl, di(lower) alkylamino (lower) alkyl, carboxy(lower) alkyl, (lower) alkoxycarbonyl (lower) alkyl, (lower) alkoxycarbonyl (lower) alkyl or phenyl (lower) alkoxide ISSI)alkyl;

Z represents hydroxy, amino or a group-OR8, -OC(O)OTHER8, -OC(O)OR8, -NHC(O)OTHER8or-NHC(O)OR8;

R8means heterocyclyl, phenyl, substituted phenyl or (lower)alkyl;

A and Y each independently of one another denotes oxygen or sulfur;

X represents nitrogen or CH;

m is 0, 1 or 2; and

n is 0, 1 or 2;

and their pharmaceutically acceptable salts.

Examples heterocyclyl residues are mono - or bicyclic 5 - and 6-membered heterocyclic residues with oxygen, nitrogen or sulphur as heteroatoms, such as 2 - and 3-furyl, pyrimidinyl, 2-, 3 - and 4-pyridyl N-oxide pyridyl, 5-tetrazolyl, 2-tetrazol-5-yl-4-pyridyl, 1,2 - and 1,4-diazines, morpholino, 2 - and 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzofuranyl, Bastiani, indolyl, purinol, hinely, ethanolic and chinadoll, which can be substituted, for example, (lower)alkyl, (lower)alkanoyl, hydroxy, (lower)alkanoyloxy, (lower)alkoxy, (lower)alkoxycarbonyl, formyl, amino, mono - or di(lower) alkylamino or halogen. Phenyl may be substituted by (lower)alkyl, (lower) alkoxygroup, hydroxy (lower)alkyl, carboxypropyl, (lower)alkylenedioxy such, SSI)alkylaminocarbonyl, the phenyl and/or by halogen. The term "lower" used in the present description, refers to the group with 1-7 carbon atoms, preferably groups with 1-4 carbon atoms. Alkyl, alkoxy and allylthiourea, and alkyl groups that are part alkanoyl groups may be 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. Examples of esterified carboxylate are (lower) alkoxycarbonyl, aryloxyalkyl (primarily phenoxycarbonyl) and arelaxation (especially benzyl and ventilatsioonil). N - heterocyclic residues, formed by the radicals R5and R6, are preferably monocyclic 6-membered heterocyclyl residues, which may also contain an oxygen atom or nitrogen, such as morpholino, 2,6-dimethylmorpholine, piperidine, or piperazine derivatives, piperazine derivatives, substituted in position N4(lower)alkyl, formyl or (lower) alkoxycarbonyl.

In EP-A - 0658542, WO-A-95/26957, EP-A-0526708, EP-A-0601386 in Nature, volume 365, October 21, 1993, pp. 759-761, described sulfonamidnuyu compounds with different chemical is azulfidinenaprelan connection which can be used as antagonists thromboxane AND2< / BR>
In EP-A-0472053 described sulfonamidnuyu derivatives with antitumor activity.

In Arzneimittel-Forschung, vol 15, November 15, 1965, pp. 1309-1317, described sulfanilamidami possessing antibacterial activity.

In Biochemical and Biophysical Research Communications, vol 201, No. 1, 1994, pages 228-234, described sulfonamides having 5 - or 6-membered heteroaryl system with two heteroatoms, and at least one atom is nitrogen and the other represents a nitrogen, oxygen or sulfur. These compounds have selective activity against ETAthe endothelin receptor.

Preferred meanings of the radicals R1are phenyl and monocyclic heterocyclyl residues containing a nitrogen atom, such as pyridyl, especially 2-pyridyl which may be substituted, preferably monosubstituted. Examples of preferred values of the radical R1are, in particular, (lower)alkylphenyl, (lower)alkoxyphenyl, (lower)alkyldiphenyl, triptoreline, (lower)alkylenedioxy and (lower) alkylphenyl. Preferred meanings of the radicals R2are phenyl, semese is d, cyano, phenyl, 5-tetrazolyl, carboxy, (lower)alkoxycarbonyl and-CONR5R6where R5denotes hydrogen, a R6denotes phenyl, phenyl, substituted (lower)alkoxygroup, hydroxy-group, hydroxy(lower)alkyl, carboxypropyl, (lower) alkylenedioxy or phenyl, pyridium, 5-tetrazolyl, (lower)alkyl, cyano(lower)alkyl, hydroxy(lower)alkyl, di(lower) alkylamino (lower)alkyl, carboxy (lower)alkyl, (lower)alkoxycarbonyl (lower)alkyl, -(lower) alkoxycarbonyl (lower)alkyl or phenyl (lower) alkoxy-carbonyl; or NR5R6indicates morpholino, 2,6-dimethylmorpholine, piperidine, piperazine derivatives, N4- (lower)alkylpiperazine, N-formylpiperazine or N4- (lower)alkoxycarbonylmethyl. R4preferably denotes hydrogen. The preferred values of the radical Z is hydroxy or, when Radenotes hydrogen or (lower) alkyl, -OC(O)NR8where R8denotes phenyl or pyridyl. And Y preferably represent oxygen, n is preferably 0.

The compounds of formula I and their salts are inhibitors of endothelin receptors. Therefore, they can be used in the treatment of diseases, waeugene blood vessels and angina.

The compounds of formula I and their salts in accordance with the invention can be obtained

(a) the interaction of the compounds of formula II

< / BR>
where R2, R3, R4, Ra, Rb, A, X, Y, Z and n have the above values, and amino - or hydroxy-group, which are not necessarily contained in R3and Z, are in protected form, with a reactive derivative of sulfonic acid of the formula R1SO2OH; or

b) the interaction of the compounds of formula III

< / BR>
where R1-R4And X have the above meanings, in the presence of a base with the compound of the formula HalCH2(CRaRb)nCH2OH, where Hal represents halogen, and hydroxy-group(s) present(s) in the last connection, may be in protected form; or

the interaction of the compounds of formula I, where Z represents hydroxy or amino, and other amino - or hydroxy-group, which may be present in the molecule, are in protected form,

B1) with an isocyanate of formula R8NCO or carbamoylation formula R8NCOCl, where R8has the above values, or

B2) with phosgene and then with alcohol of formula R8OH; or ether of Harborview acid of formula R8OC(OP>5R6where R5and R6have the above meanings; or

d) the interaction of the compounds of formula I, where R3denotes cyano, and the other symbols have the above values, with NH4Cl and sodium azide; or

e) processing the compounds of formula IV

< / BR>
where R1-R4, RbAnd, X and Y have the above values, the oxidizing agent, if necessary, removing the amino - or hydroxyamine groups contained in the reaction product, and if necessary transform of the substituents contained in the obtained compound of the formula I and/or converting the resulting compounds of formula I in salt.

As reactive derivatives of sulfonic acid of the formula R1SO2OH to interact with the compound of the formula II can be considered, for example, halides, such as chlorides. The reaction can be accomplished well-known method used to obtain sulfonamides, for example, in an inert organic solvent, such as dimethylsulfoxide, usually by heating in an atmosphere of inert gas, for example, in an argon atmosphere. Reactive amino - or hydroxy-group present in the substituents R3and/or Z must fuck Irani. The introduction of such protective groups is usually carried out at an early stage in obtaining the considered source products. Cleavage of the protective groups in obtaining compounds of formula I can be carried out by conventional methods, for example, by treatment with an acid for removal of tetrahydropyranyl or tert - butoxycarbonyl groups.

In variant b) method, which is preferably used for obtaining compounds of formula I, where X denotes nitrogen, as coreagent for the compounds of formula III, it is advisable to use compounds in which Hal denotes iodine, and silver carbonate as the base. The reaction is usually carried out by heating in an inert organic solvent, for example toluene by heating to about 100oC.

The interaction in accordance with variant b) method can be carried out a well-known method used to obtain carbamates and ureas from alcohols and amines respectively. So, in option B1), the compound of formula I, where Z represents hydroxy, may be subject to interaction with the isocyanate of formula R8NCO in a suitable anhydrous organic solvent, e.g. a hydrocarbon, such as toluene is obtained in situ, for example, azide of the formula R8CON3by thermal decomposition. Accordingly, the compounds of formula I, where Z represents-NHC(O)OR8can be obtained from compounds of the formula I, where Z represents amino.

In accordance with option B2) a compound of formula I, where Z denotes oxygen, can be converted into a compound of formula I, where Z denotes the group-OC(O)OR8by interaction with phosgene and then with alcohol of formula R8OH. Instead of phosgene can be used fossanova salt, such as diphosgene (Cl-CCl3or triphosgene (CO(OCCl3)2). Similarly, the compounds of formula I, where Z represents-NHC(O)OR8receive from compounds of the formula I, where Z represents amino. The phosgene is usually used in the form of a solution in an inert anhydrous organic solvent, e.g. a hydrocarbon, such as toluene. Interaction with phosgene can be carried out at room temperature. The acid chloride obtained as an intermediate product, immediately subjected to interaction with alcohol R8OH, usually when heated.

The interaction in accordance with option g) may be carried out a well-known method for obtaining lat (THIEF) or dicyclohexylcarbodiimide, in an inert organic solvent, such as, for example, acetonitrile or tetrahydrofuran.

The interaction in accordance with option d) is carried out in a suitable solvent, such as dimethylformamide, typically by heating, to obtain the compounds of formula I, where R3denotes 2-tetrazolyl.

Under option e) obtain the compounds of formula I, where Raand Z represent hydroxy. The oxidation can be carried out, for example, with the use of osmium tetroxide in a solvent, such as acetone.

The substituents present in the thus obtained compound of formula I, can be modified. For example, the ether group can be amylene to the carboxyl group, for example, by treatment with aqueous alcoholic alkali. In addition, N-heterocyclyl residues, such as pyridyl, can be oxidized to N-oxides. All these reactions can be carried out in well known ways. The compounds of formula I can be converted into a well-known method in the salt, for example, salts of alkali metals such as Na and K, or salts of alkaline-earth metals such as Ca or Mg salts.

The compounds used as starting materials, in that case what and or how, described below in the examples. The compounds of formula II, where X is CH, can be obtained, for example, of ester 5-nitro-3,4 - dihydroxybenzoic acid. The sequence of reactions involving the replacement of 4-hydroxy-group chlorine, for example, by processing gloriouse agent such as oxalicacid, DMF, interaction with the compound of the formula HalCH2(CRaRb)nCH2ORxwhere Hal represents halogen and Rxdenotes a protective group, such as tetrahydropyranyl, and the others hydroxy-group are in protected form, interaction with phenol R2OH or thiophenols R2SH and restoration of the nitro group to the amino group leads to compounds of formula II, where X represents CH, Y represents oxygen and Z represents a protected hydroxy-group, R3indicates the esterified carboxypropyl, and R4denotes hydrogen. A similar technique can be used to obtain the corresponding compounds of formula II where Y represents sulfur. Esterified carboxypropyl in the thus obtained compounds can be converted into another radical R3a well-known manner. Alternate this with ISOE is sootvetstvuyushie the compounds of formula II, where R4represents (lower) alkyl.

The compounds of formula III, where X denotes nitrogen, can be obtained, for example, the interaction of the compounds of formula R3-C(NH)-CH2CN first with ethyl-MgBr, and then with the compound of the formula C(NH)-CH2CN with obtaining the compounds of formula R2ACH2COCl. Ring closure to obtain 2-hydroxy-3-AR2-4-amino-6-R3-pyridine carried out by treatment with a base such as sodium amide, in dioxane. Interaction with the compound of the formula R1SO2Cl leads to derivatization with O, N-disulphonyl from which sulfonylurea group can be selectively derived by heating to 60oC 1H. ethanolic NaOH. Thus obtained compound of the formula II can be converted into the desired compound of formula II with the compounds of formula Hal-CH2(CRaRb)nCH2ORxwhere Rxdenotes a protective group, such as tetrahydropyranyl, and the others hydroxy-group are in a protected form. The above sequence of reactions is preferably carried out using as initial products of the compounds in which R3means a Deputy,klizzie, or where unstable or reactive Deputy, such as, for example, carboxypropyl, is in the form of derivatives, for example, in the form of ester, and the Deputy further optionally functionally modified.

The compounds of formula I have a selective inhibitory action against the receptors and endothelin (ETAand ETB), which can be illustrated by the following examples of test methods.

1. Inhibition of binding of endothelin with recombinant ETAreceptors

cDNA encoding ETA-receptors in the human placenta, cloned (M. Adachi, Y.-Y. Yang, Y. Furuichi and S. Miyamoto, BBRC 180, 1265-1272) and expressed in the system of the baculovirus-insect cell. From the fermenter volume 23 l by centrifugation (3000 x 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.SUP>oC). 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 μl of125I-endothelin (specific activity 2200 CI/mmol) in the buffer for analysis (25000 pulses per minute to a final concentration of 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.

II. Inhibition of binding of endothelin to membranes of human placenta (ETBreceptor) (see Life Sci. 44: 1429 (1988))

The human placenta homogenized in 5 mm Tris buffer, pH of 7.4, containing 1 mm MgCI2and 250 mm Saharsa membranes, centrifuged at 72000 x g for 30 minutes and the precipitate is washed with 75 mm Tris buffer, pH of 7.4, containing 25 mm MgCl2. After that, the precipitate obtained in each case from 10 g of original tissue, suspended in 1 ml of 75 mm Tris buffer, pH of 7.4, containing 25 mm MgCl2and 250 mm sucrose, and lyophilizer at -20oC in the form of an aliquot of 1 ml

For analysis of binding lyophilized preparations of membranes subjected to thawing and after centrifugation at 20oC and 25,000 x 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 35 μg protein are incubated with 50 μl of125I-endothelin (specific activity 2200 CI/mmol) in the buffer for analysis (25000 pulses per minute to a final concentration of 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 against Alice 1 in the form of the IC50i.e., in the form of concentration [μm], which is required for 50% inhibition of specific binding125I-endothelin.

III. 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 by the observed shift of the curve to the right the dose-activity of endothelin-1 in the presence of different concentrations of antagonist. This shift to the right (or "doses" OD) corresponds to the rate of change of the values of the EU50endothelin-1 in the presence and in the absence of the antagonist, where the value of the EU50the concentration of endothelin needed to reduce tissue at half maximum.


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

Is EU50endothelin 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 their ability to inhibit the binding of endothelin to the compounds of formula I can be used as drugs for the treatment of diseases associated with an increased frequency of vasoconstriction (narrowing of blood vessels). Examples of such violations are high blood pressure, especially high pulmonary blood pressure and subarachnoid hemorrhage. In addition, the indications for which we can apply the compounds according to the invention are coronary disorders, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, cerebral infarction, migraine and Raynaud's syndrome. Compounds according to the invention can also be applied in case of 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, CH is ylospain, as well as other diseases associated with impaired 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 of from approximately 0.1 to 100 mg/kg of body weight per day. In the specified range of doses of the compounds of formula I are non-toxic. Preparations containing the compounds of formula I may contain inert additives or additives, which also pharmacodynamically active. Tablets or granules, for example, may contain a number of binders, fillers, carriers or solvents. Liquid preparations mo is the total 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, the abbreviation "CT" refers to room temperature, MeOH means methanol, and DMSO means dimethylsulfoxide.

Example 1

a) of 2.08 g of methyl 3-amino-4- (2-methoxyphenoxy)-5-[2-(tetrahydropyran-2-yloxy)ethoxy] benzoate was dissolved in pyridine (30 ml) dropwise while cooling on ice, treated with a solution containing 2,09 g of 4-tert - butylbenzenesulfonamide in toluene (15 ml) and then stirred at RT for 20 hours. The reaction mixture was distributed between water and ethyl acetate, the organic phase is washed with 2n. HCl solution and susiecondevereux)-5-[2- (tetrahydropyran-2-yloxy)ethoxy] benzoate in the form of resin.

b) a Solution containing 4.6 g of methyl-3-(4-tert - butylbenzenesulfonamide)-4-(2-methoxyphenoxy)-5-[2- (tetrahydropyran-2-yloxy)ethoxy] benzoate in methanol (50 ml) was treated at RT with 4 ml of 2n. aqueous HCl and the solution is further stirred at RT for 2 h the Solvent was removed on a rotary evaporator and the residue was distributed between ethyl acetate and diluted secondary acidic potassium carbonate. The organic phase was dried over magnesium sulfate, the solvent was removed on a rotary evaporator and the crude product was chromatographically on silica gel using CH2/Cl2/ethyl acetate (5/1) as the eluent. In this way got to 2.57 g of methyl-3- (4-tert-butylphenylphosphine)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzoate as a white foam. MS: 528,4 (M-N).

Obtaining source materials:

in) 18,87 ml oxalicacid at -20oC was added dropwise to 16,95 ml of DMF. The mixture was allowed to react at -20oC for 10 minutes. Then it slowly dropwise added to the solution containing 15,63 g of methyl 3,4-dihydroxy-5-nitrobenzoate in DMF (100 ml), keeping the temperature of the reaction mixture between -10oC to -20oC. the Mixture was allowed to warm to room temperature and then kept the Wali in the icy water, were extracted at RT with ethyl acetate and the organic phase is washed three times with water, dried over sodium sulfate and concentrated on a rotary evaporator. The way it was obtained methyl 4 - chloro-3-hydroxy-5-nitrobenzoate in a solid yellow color, which is used in the next stage without additional purification.

g) 6,84 g methyl-4-chloro-3-hydroxy-5 - nitrobenzoate was dissolved in acetone (150 ml) was sequentially treated with CT 10,19 g of potassium carbonate and 11,19 g 2-(2 - iodoxy)tetrahydropyran and the mixture is boiled under reflux for 16 hours. The mixture is then poured into ice water, extracted with ethyl acetate, the organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was subjected to rapid chromatography on silica gel using as eluent hexane/simple ether (2/1). Thus was obtained the desired methyl-4-chloro - 3-nitro-5- [2-(tetrahydropyran-2-yloxy)ethoxy]benzoate in the form of a solid of light yellow color.

d) 4,28 g methyl-4-chloro-3-nitro-5-[2-(tetrahydropyran-2-yloxy) ethoxy] benzoate was dissolved in acetone (250 ml) was treated at RT 5.0 g of potassium carbonate, of 1.93 g of guaiacol and the mixture is boiled under reflux for 20 hours. s ' solution of sodium hydroxide, then water, dried over sodium sulfate and finally concentrated on a rotary evaporator. The crude product (6 g) was subjected to rapid chromatography on silica gel using as eluent hexane/simple ether (1/1). Thus was obtained the desired methyl-4-(2-methoxyphenoxy)-3-nitro-5-[2-(tetrahydropyran-2 - yloxy)ethoxy] benzoate in the form of powder light yellow color.

e) 4.3 g of methyl-4-(2-methoxyphenoxy)-3-nitro-5-[2- (tetrahydropyran-2 - yloxy)ethoxy]benzoate was dissolved in ethanol (250 ml) was treated with 0.75 g Raney Ni as catalyst and was first made at RT for 3.5 hours. The catalyst was filtered and the solution was concentrated on a rotary evaporator. The way it was obtained methyl 3-amino-4-(2-methoxyphenoxy)-5- [2- (tetrahydropyran-2-yloxy)ethoxy] benzoate in the form of a solid of light yellow color.

Example 2

to 2.57 g of methyl-3-(4-tert-butylphenylphosphine)-5-(2-hydroxyethoxy)- 4-(2-methoxyphenoxy) benzoate was dissolved in methanol (50 ml), treated with 19.4 ml of 1M NaOH solution and then kept at 65oC for 2 hours. The mixture was poured into ice water, acidified with dilute HCl solution (pH 1) and the product was extracted with ethyl acetate. The organic phase was dried over sulfate is pet - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzoic acid as a white foam. MS: 514,3 (M-N).

Example 3

77 mg of 3-(4-tert-butylbenzenesulfonamide)-5-(2 - hydroxyethoxy)-4-(2-methoxyphenoxy)benzoic acid was dissolved in acetonitrile (5 ml) were added in sequence 28 μl of n-ethyldiethanolamine, 73 mg hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium and 14 ál of the research, after which the mixture was stirred at RT for 2.5 hours. The mixture was distributed between ethyl acetate and water, the organic phase was dried over sodium sulfate, concentrated on a rotary evaporator and the residue was chromatographically on silica gel using CH2Cl2/MeOH (20/1) as eluent. The way it was obtained 4-tert-butyl-N-[3-(2-hydroxyethoxy)-2- (2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl] benzosulfimide in the form of a white foam. MS: 583,5 (M-N).

Example 4

By analogy with example 3 from 3-(4-tert-butylbenzenesulfonamide)-5- (2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzoic acid and piperidine was obtained 4-tert-butyl-N-[3-(2-hydroxyethoxy)-2- (2-methoxyphenoxy)-5-(piperidine-1-carbonyl)phenyl]benzosulfimide. MS: 581,4 (M-N).

Example 5

By analogy with example 3 from 3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzoic acid)-N-(2-pyridin-2 - retil)benzamide. MS: 681,4 (M-N).

Example 6

By analogy with example 3 from 3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4- (2-methoxyphenoxy)benzoic acid and benzylaminopurine received benzyl-[3-(4-tert-butylbenzenesulfonamide)-5-(2 - hydroxyethoxy)-4-(2-methoxyphenoxy)benzoylamine] acetate. MS: OF 661.4 (M-N).

Example 7

By analogy with example 3 from 3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4- (2-methoxyphenoxy)benzoic acid and aniline was obtained 3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)-N-phenylbenzene. MS: 589,4 (M-N).

Example 8

By analogy with example 3 from 3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzoic acid and aminoacetonitrile was obtained 3- (4-tert-butylbenzenesulfonamide)-N-lanmeter-5-(2 - hydroxyethoxy)-4-(2-methoxyphenoxy)benzamide. MS: 552,3 (M-N).

Example 9

By analogy with example 3 from 3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzoic acid and 2-diethylaminoethylamine was obtained 3-(4-tert-butylbenzenesulfonamide)-N-(2 - dimethylaminoethyl)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzamide. MS: 584,4 (M-N).

Example 10

By analogy with the example of the Il-(2-amino-ethyl)carbamate was obtained tert-butyl-(2-[3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzoylamine] ethyl) carbamate. MS: 656,3 (M+H).

Example 11

By analogy with example 3 from 3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzoic acid and 3-picolylamine was obtained 3-(4 - tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)-N-pyridin-3-ylmethylene. MS:640,4(M+H).

Example 12

By analogy with example 3 from 3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy) benzoic acid and benzylamine received N-benzyl - 3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzamide. MS: 603,3 (M-N).

Example 13

By alkaline saponification of benzyl-[3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy) -4-(2-methoxyphenoxy)benzoylamine] acetate was obtained [3-(4-tert-butylbenzenesulfonamide)-5-(2 - hydroxyethoxy)-4-(2-methoxyphenoxy)benzoylamine]acetic acid. MS: 571,2 (M-H).

Example 14

A solution containing 75 mg of 4-tert-butyl-N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5- (morpholine-4-carbonyl)phenyl] benzosulfimide, 40 mg of azide 2 - pyridylcarbinol acid and 7 mg para-dimethylaminopyridine in toluene (5 ml), kept at 80oC for 2 hours. The toluene was removed on a rotary evaporator and the residue was distributed Ino was removed on a rotary evaporator. The crude product was chromatographically on silica gel using CH2Cl2/ethyl acetate/MeOH (60/60/3) as eluent. The way it was obtained 2-[3-(4-tert - butylbenzenesulfonamide)-2-(2-methoxyphenoxy)-5-(morpholine-4 - carbonyl)phenoxy] ethyl ester pyridine-2-ylcarbamate acid. Solid white, 55 mg. MS: 705,5 (M-H).

Example 15

By analogy with example 14 3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4- (2-methoxyphenoxy)-N-(2-pyridin-2-retil)benzamide azide and 2-pyridylcarbinol acid was obtained 2- [3-(4-tert-butylbenzenesulfonamide)-2-(2-methoxyphenoxy)-5- (2-pyridin-2-iletileri)phenoxy] ethyl ester pyridine-2 - ylcarbamate acid. MS: 738,4 (M-H).

Example 16

By analogy with example 14 from 4-tert-butyl-N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5- (piperidine-1-carbonyl)phenyl]benzosulfimide azide and 2-pyridylcarbinol acid was obtained 2-[3-(4-tert - butylbenzenesulfonamide)-2-(2-methoxyphenoxy)-5-(piperidine-1-carbonyl)phenoxy] ethyl ester pyridine-2-ylcarbamate acid. MS: 701,3 (M-H).

Example 17

By analogy with example 14 N-benzyl - 3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzamide azide and 2-pirincci] ethyl ester pyridine-2-ylcarbamate acid. MS: 723,3 (M-H).

Example 18

By analogy with example 14 of benzyl-[3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzoylamine]acetate azide and 2-pyridylcarbinol acid was obtained benzyl-{3-(4-tert-butylbenzenesulfonamide)- 4-(2-methoxyphenoxy)-5-[2-(pyridine-2 - ylcarbamate)ethoxy] benzoylamine} acetate. MS: 781,4 (M-H).

Example 19

By analogy with example 14 3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)-N-pyridin-3-iletilmesine azide and 2 - pyridylcarbinol acid was obtained 2-{3-(4-tert-butylbenzenesulfonamide)- 2-(2-methoxyphenoxy)-5-[(pyridine-3-ylmethyl)carbarnoyl] phenoxy} ethyl ester pyridine-2-ylcarbamate acid. MS: 724,4 (M-H).

Example 20

By analogy with example 14 3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)-N-phenylbenzene azide and 2-pyridylcarbinol acid was obtained 2-[3-(4-tert-butylbenzenesulfonamide)-2-(2 - methoxyphenoxy)-5-phenylcarbamoyloxy] ethyl ester pyridine-2 - ylcarbamate acid. MS: 709,3 (M-H).

Example 21

a) 0,417 g of methyl 3-amino-4-(2-methoxyphenoxy)-5-[2-(tetrahydropyran-2 - yloxy)ethoxy]benzoate was dissolved in pyridine (7.5 ml), dropwise, the cooling is ATEM was stirred at RT for 20 hours. The reaction mixture was distributed between water and CH2Cl2, the organic phase is washed with 1M HCl solution and then a 1M solution of secondary acid, potassium carbonate and dried over magnesium sulfate. After removal of the solvent was obtained methyl 3-(5-isopropylpyridine-2-sulfonylamino)-4- (2-methoxyphenoxy)-5-[2-(tetrahydropyran-2-yloxy)ethoxy]benzoate (0.6 g) in the form of resin.

b) a Solution containing 0.6 g of methyl-3-(5-isopropylpyridine-2 - sulfonylamino)-4-(2-methoxyphenoxy)-5-[2-(tetrahydropyran-2 - yloxy)ethoxy]benzoate in methanol (10 ml) was treated at RT with 1 ml of 2M aqueous HCl and the solution is further stirred at RT for a further 1 hour. The solvent was removed on a rotary evaporator and the residue was distributed between ethyl acetate and diluted secondary acidic potassium carbonate. The organic phase was dried over magnesium sulfate, the solvent was removed on a rotary evaporator and the crude product was chromatographically on silica gel, using as eluent CH2Cl2/ethyl acetate (5/1). In this way received 0,459 g of methyl-3-(2-hydroxyethoxy)-5-(5-isopropylpyridine-2 - sulfonylamino)-4-(2-methoxyphenoxy)benzoate as a white foam. MS: 515,4 (M-H).

Example 22

0,459 g of methyl-3-(2-hydroxyethoxy)-5- (5-isopropylpyridine the ATEM kept at 80oC for 1.5 h the Mixture was poured into ice water, acidified with dilute HCl solution (pH 1) and the product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and the resulting solid was dried in high vacuum. The way it was obtained 3-(2 - hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)-4-(2 - methoxyphenoxy)benzoic acid as a white foam (0,474 g). MS: 510,4 (M-H).

Example 23

55 mg of 3-(2-hydroxyethoxy)-5-(5 - isopropylpyridine-2-sulfonylamino)-4-(2-methoxyphenoxy)benzoic acid was dissolved in acetonitrile (5 ml), at RT in the specified sequence was added to 19 μl of n-ethyldiethanolamine, 49 mg of hexaflurophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium and 10 ál of the research and then the mixture was stirred at RT for 16 hours. The mixture was distributed between ethyl acetate and water, the organic phase was dried over sodium sulfate, concentrated on a rotary evaporator and the residue was chromatographically on silica gel using CH2Cl2/MeOH (20/1) as eluent. The way it was received [3-(2 - hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(morpholine-4 - carbonyl)phenyl] amide 5-isopropylpyridine-2-sulfonic acid as a white foam. MS: 570,4 (M-H).

Example 25

By analogy with example 23 3-(2-hydroxyethoxy)- 5-(5-isopropylpyridine-2-sulfonylamino)-4-(2 - methoxyphenoxy)benzoic acid and 1-methylpiperazine received [3- (2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(4-methylpiperazin-1 - carbonyl)phenyl]amide 5-isopropylpyridine-2-sulfonic acid. MS: 583,4 (M-H).

Example 26

By analogy with example 23 3-(2 - hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)-4-(2 - methoxyphenoxy)benzoic acid and 2,6-dimethylmorpholine received [5-(2,6-dimethylmorpholine-4-carbonyl)-3-(2-hydroxyethoxy)-2-(2 - methoxyphenoxy)phenyl] amide 5-isopropylpyridine-2-sulfonic acid. MS: 598,3 (M-H).

Example 27

By analogy with example 23 3-(2-hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)-4- (2-methoxyphenoxy)benzoic acid and 2-pyridine-2-ylethylamine was obtained 3-(2-hydroxyethoxy)-5-(5-isopropylpyridine-2 - sulfonylamino)-4-(2-methoxyphenoxy)-N-(2-pyridin-2 - retil)benzamide. MS: 670,5 (M-H).

Example 28

By analogy with example 23 3-(2-hydroxyethoxy)-5-(5-isopropylpyridine-2 - sulfonylamino)-4-(2-methoxyphenoxy)benzoic acid and ethylpiperazin-1-carboxylate was obtained ethyl-4- [3-(2 - hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)-4-(2 - methoxyp is doxetaxel)-5- (5-isopropylpyridine-2-sulfonylamino)-4-(2 - methoxyphenoxy)benzoic acid and piperazine-1-carbaldehyde was obtained[5-(4-formylpiperazine-1-carbonyl)-3-(2-hydroxyethoxy) -2-(2-methoxyphenoxy)phenyl] amide 5-isopropylpyridine-2 - sulfonic acid. MS: 697,3 (M-H).

Example 30

By analogy with example 23 3-(2-hydroxyethoxy)-5-(5 - isopropylpyridine-2-sulfonylamino)-4-(2-methoxyphenoxy)benzoic acid and Propylamine was obtained 3-(2-hydroxyethoxy)-5-(5 - isopropylpyridine-2-sulfonylamino)-4-(2-methoxyphenoxy)-N - propylbenzamide. MS: 542,5 (M-H).

Example 31

A solution containing 50 mg of [3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(morpholine-4 - carbonyl)phenyl] amide 5-isopropylpyridine-2-sulfonic acid, 36 mg of azide 2-pyridylcarbinol acid and 5 mg of para - dimethylaminopyridine in toluene (5 ml), kept at 135oC (bath temperature) for 2 hours. The residue was distributed between ethyl acetate and 1N. HCl solution, the aqueous phase was extracted several times with methylene chloride and the organic phase was dried over magnesium sulfate. The solvent was finally removed on a rotary evaporator and the crude product was chromatographically on silica gel using CH2Cl2/MeOH (20/1) as eluent. The way it was obtained 2- [3-(5-isopropylpyridine-2-sulfonylamino)-2-(2-methoxyphenoxy)-5- (morpholine-4-carbonyl)phenoxy] ethyl ester pyridine-2-ylcarbamate acid. Solid white color. MS: 690,3 (M-H).

Example 32

By analogy with example 31 the acid azide and 2-pyridylcarbinol acid was obtained 2-[3-(5 - isopropylpyridine-2-sulfonylamino)-2-(2-methoxyphenoxy)-5- (piperidine-1-carbonyl)phenoxy] ethyl ester pyridine-2 - ylcarbamate acid. MS: 688,3 (M-H).

Example 33

By analogy with example 31 from [3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(4 - methylpiperazin-1-carbonyl)phenyl] amide 5-isopropylpyridine-2 - sulfonic acid azide and 2-pyridylcarbinol acid was obtained 2-[3-(5-isopropylpyridine-2-sulfonylamino)-2-(2-methoxyphenoxy) -5-(4 - methylpiperazin-1-carbonyl)phenoxy] ethyl ester pyridine-2 - ylcarbamate acid. MS: 703,3 (M-H).

Example 34

By analogy with example 31 from [5- (2, 6-dimethylmorpholine-4-carbonyl)-3-(2-hydroxyethoxy)-2- (2-methoxyphenoxy)phenyl] amide 5-isopropylpyridine-2-sulfonic acid azide and 2-pyridylcarbinol acid was obtained 2-[5-(2,6-dimethylmorpholine-4-carbonyl)-3-(5-isopropylpyridine-2 - sulfonylamino)-2-(2-methoxyphenoxy)phenoxy] ethyl ester pyridine-2-ylcarbamate acid. MS: 718,3 (M-H).

Example 35

By analogy with example 31 3-(2-hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)-4- (2-methoxyphenoxy)-N-(2-pyridin-2-retil)benzamide azide and 2 - pyridylcarbinol acid was obtained 2-[3-(5-isopropylpyridine-2 - sulfonylamino)-2-(2-methoxyphenoxy)-5-(2-pyridin-2 - iletileri)phenoxy]ethyl ester pyridine-2-ylcarbamate acid. MS: 725,3 (M-H).

Example 36

By analogy with example 31 from ethyl-4-[3-(2-Gerda 2-pyridylcarbinol acid was obtained ethyl-4- {3-(5-isopropylpyridine-2-sulfonylamino)-4-(2-methoxyphenoxy)-5- [2-(pyridine-2-ylcarbamate)ethoxy] benzoyl} piperazine-1 - carboxylate. MS: 761,3 (M-H).

Example 37

By analogy with example 31 from [5-(4-formylpiperazine-1-carbonyl)-3-(2-hydroxyethoxy)-2-(2 - methoxyphenoxy)phenyl] amide 5-isopropylpyridine-2-sulfonic acid azide and 2-pyridylcarbinol acid was obtained 2-[5-(4 - formylpiperazine-1-carbonyl)-3-(5-isopropylpyridine-2-sulfonylamino) -2-(2-methoxyphenoxy)phenoxy] ethyl ester pyridine-2 - ylcarbamate acid. MS: 717,3 (M-H).

Example 38

a) 1.04 g of methyl 3-amino-4-(2-methoxyphenoxy)-5-[2- (tetrahydropyran-2-yloxy)ethoxy]benzoate was dissolved in pyridine (30 ml) dropwise while cooling on ice, treated with a solution containing 1.1 g of benzo[1,3]dioxol-5-sulphonylchloride in toluene (10 ml) and then stirred at RT for 20 hours. The reaction mixture was poured into ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. After removal of solvent required methyl - 3-(benzo[1,3]dioxol-5-sulphonylamino)-4-(2-methoxyphenoxy)-5-[2- (tetrahydropyran-2-yloxy)ethoxy] benzoate in the form of resin.

b) a Solution containing 1.5 g of methyl-3-(benzo[1,3]dioxol-5 - sulphonylamino)-4-(2-methoxyphenoxy)-5-[2- (tetrahydropyran-2-yloxy)ethoxy]benzoate in methanol (50 ml) was treated at RT 3 ml of 5M aqueous HCl and then solution in ethyl acetate and washed with 2n. a solution of the secondary acid potassium carbonate. The organic phase was dried over magnesium sulfate, the solvent was removed on a rotary evaporator and the crude product (1.7 g) was chromatographically on silica gel using CH2Cl2/ethyl acetate (8/1) as eluent; the way it was obtained methyl 3-(benzo [1,3]dioxol-5-sulphonylamino) -5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzoate in the form of a solid white color. MS: 516,3 (M-H).

Example 39

of 1.17 g of methyl-3-(benzo[1,3]dioxol-5-sulphonylamino)-5-(2-hydroxyethoxy) -4-(2-methoxyphenoxy) benzoate was dissolved in methanol (20 ml) was treated with 9 ml of 1M NaOH solution and then boiled under reflux for 3 hours. The mixture was poured into ice water, acidified with dilute HCl solution to pH 1 and the product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and the resulting solid was dried in high vacuum. The way it was obtained 3-(benzo[1,3]dioxol-5-sulphonylamino)-5-(2-hydroxyethoxy)-4- (2-methoxyphenoxy)benzoic acid as a white foam. MS: 502,3 (M-H).

Example 40

50 mg of 3-(benzo[1,3] dioxol-5-sulphonylamino)-5-(2 - hydroxyethoxy)-4-(2-methoxyphenoxy)benzoic acid was dissolved in acetonitrile (5 ml), to which hospita benzotriazol-1 yloxy - Tris(dimethylamino)phosphonium and 10 ál of the research and then the mixture was stirred at RT for 3 hours. The mixture was distributed between ethyl acetate and water, the organic phase was dried over sodium sulfate, concentrated on a rotary evaporator and the residue was chromatographically on silica gel using CH2Cl2/MeOH (20/1) as eluent. In this way; received [3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5- (morpholine-4-carbonyl)phenyl]amide benzo [1,3] dioxol-5-sulfonic acid as a white foam. MS: 571,2 (M-H).

Example 41

By analogy with example 40 3-(benzo[1,3]dioxol-5 - sulphonylamino)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzoic acid and 1-ethoxycarbonylpyrimidine received ethyl-N-4-[3- (benzo[1,3]dioxol-5-sulphonylamino)-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzoyl]piperazine-1-carboxylate. MS: 642 (M-H).

Example 42

By analogy with example 40 3-(benzo[1,3]dioxol-5 - sulphonylamino)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzoic acid and isobutylamine received 3-(benzo[1,3] dioxol-5 - sulphonylamino)-5-(2-hydroxyethoxy)-N-isobutyl-4-(2 - methoxyphenoxy)benzamide. MS: 557,0 (M-H).

Example 43

By analogy with example 40 3-(benzo[1,3]dioxol-5 - sulphonylamino)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzoic acid and Isopropylamine received 3-(benzo[1,3] dioxol-5 - sulphonylamino)-5-(2-hydrox of 3-(benzo[1,3]dioxol-5 - sulphonylamino)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzoic acid and ethanolamine was obtained 3-(benzo [1,3] dioxol-5-sulphonylamino)-5-(2-hydroxyethoxy)-N- (2-hydroxyethyl)-4-(2-methoxyphenoxy)benzamide. MS: 545,2 (M-H).

Example 45

A solution containing 52 mg of methyl 3-(benzo [1,3] dioxol-5 - sulphonylamino)-4-(2-methoxyphenoxy)-5-[2-(tetrahydropyran - 2-yloxy)ethoxy] benzoate, 44 mg of azide 2-pyridylcarbinol acid and 5 mg of para-dimethylaminopyridine in toluene (5 ml), kept at 110oC (bath temperature) for 1.5 hours, the Residue was distributed between ethyl acetate and 1N. HCl solution, the aqueous phase was extracted several times with methylene chloride and the organic phase was dried over magnesium sulfate. The solvent was finally removed on a rotary evaporator and the crude product was chromatographically on silica gel using CH2/Cl2/ethyl acetate (210/1) as eluent. In this way received methyl-3-(benzo[1,3] dioxol-5-sulphonylamino)-4-(2-methoxyphenoxy)-5-[2-(pyridine-2-ylcarbamate) ethoxy] benzoate in the form of a solid white color. MS: 636,1 (M-H).

Example 46

By analogy with example 45 from [3-(2-hydroxyethoxy)-2-methoxyphenoxy)-5 -(morpholine-4-carbonyl)phenyl] amide benzo[1,3]dioxol-5-sulfonic acid azide and 2 - pyridylcarbinol acid was obtained 2-[3-(benzo [1,3] dioxol-5-sulphonylamino)-2-(2-methoxyphenoxy)-5- (morpholine-4-carbonyl)phenoxy] ethyl ester pyridine-2-ylcarbamate acid. MS: 691,3 (M-H).hydroxy) -4-(2-methoxyphenoxy)benzoyl] piperazine-1-carboxylate azide and 2-pyridylcarbinol acid was obtained ethyl-{3-(benzo [1,3] dioxol-5-sulphonylamino)-4-(2-methoxyphenoxy)-5- [2-(pyridine-2-ylcarbamate)ethoxy]benzoyl}piperazine-1 - carboxylate. MS: 702,2 (M-H).

Example 48

By analogy with example 45 3-(benzo[1,3]dioxol-5 - sulphonylamino)-5-(hydroxyethoxy)-N-isobutyl-4-(2 - methoxyphenoxy)benzamide azide and 2-pyridylcarbinol acid was obtained 2-[3-(benzo[1,3]dioxol-5-sulphonylamino) -5-isobutylamino-2-(2-methoxyphenoxy)phenoxy] ethyl ester pyridine-2-ylcarbamate acid. MS: 677,1 (M-H).

Example 49.

By analogy with example 45 3-(benzo [1,3] dioxol-5-sulphonylamino)-5-(2-hydroxyethoxy)-N-isopropyl-4-(2 - methoxyphenoxy)benzamide azide and 2-pyridylcarbinol acid was obtained 2-[3-(benzo[1,3]dioxol-5-sulphonylamino)-5 - isopropylcarbamate-2-(2-methoxyphenoxy)phenoxy] ethyl ester pyridine-2-ylcarbamate acid. MS: 663,1 (M-H).

Example 50

a) 2.14 g of methyl 3-amino-4-(2-methoxyphenoxy)-5-[2- (tetrahydropyran-2-yloxy)ethoxy]benzoate was dissolved in pyridine (30 ml) dropwise while cooling on ice, treated with a solution containing 1,488 g of 4-methoxybenzenesulfonamide in toluene (10 ml) and then stirred at RT for 20 hours. The reaction mixture was poured into ice/ZM HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. After removal of the solvent was obtained methyl-3-(4-methoxybenzylideneamino)-4-(2-methomyl-3-(4 - methoxybenzylideneamino)-4-(2-methoxyphenoxy)-5-[2- (tetrahydropyran-2-yloxy)ethoxy] benzoate in methanol (10 ml), was treated at RT with 10 ml of 5.5 M aqueous HCl and then the solution was stirred at RT for a further 5 hours. The solvent was removed on a rotary evaporator, the residue was dissolved in ethyl acetate and washed with 2n. a solution of the secondary acid potassium carbonate. The organic phase was dried over magnesium sulfate, the solvent was removed on a rotary evaporator and the crude product was chromatographically on silica gel using CH2Cl2/ethyl acetate (10/1) as eluent. In this way received methyl-3-(2-hydroxyethoxy)-5-(4-methoxybenzylideneamino)-4-(2 - methoxyphenoxy)benzoate in the form of a solid white color. MS: 502,3 (M-H).

Example 51.

0.88 g of methyl-3-(4-methoxybenzylideneamino)-4-(2-methoxyphenoxy)- 5-[2-(tetrahydropyran-2-yloxy)ethoxy] benzoate was dissolved in methanol (10 ml) was treated with 7 ml of 1M NaOH solution and then boiled under reflux for 1.5 hours the Mixture was poured into ice water, acidified with dilute HCl solution to pH 1 and the product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and the resulting solid was dried in high vacuum. The way it was obtained 3-(2 - hydroxyethoxy)-5-(4-methoxybenzylideneamino)-4-(2 - methoxyphenoxy)benilantoureiii)-4-(2-methoxyphenoxy)benzoic acid was dissolved in acetonitrile (5 ml), when CT is in the specified sequence was added to 19 μl of n-ethyldiethanolamine, 49 mg of hexaflurophosphate benzotriazol-1 - yloxytris(dimethylamino)phosphonium and 10 ál of the research and then the mixture was stirred at RT for 12 hours. The mixture was distributed between ethyl acetate and water, the organic phase was dried over sodium sulfate, concentrated on a rotary evaporator and the residue was chromatographically on silica gel using CH2Cl2/MeOH (30/1) as eluent. The way it was obtained N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl] -4-methoxybenzoyl-sulfonamide as a white foam: MS: 557,3 (M-H).

Example 53

A solution containing 50 mg of methyl 3-(2-hydroxyethoxy)-5-(4-methoxybenzylideneamino)-4-(2 - methoxyphenoxy)benzoate, 45 mg of azide 2-pyridylcarbinol acid and 5 mg of para-dimethylaminopyridine in toluene (5 ml), kept at 110oC (bath temperature) for 1 hour. The residue was distributed between ethyl acetate and 1N. HCl solution, the aqueous phase was extracted several times with methylene chloride and the organic phase was dried over magnesium sulfate. The solvent was finally removed on a rotary evaporator and the crude product was chromatographically on silica gel using CH2-4-(2-methoxyphenoxy)-5-[2-(pyridine-2-ylcarbamate)ethoxy]benzoate. Solid white color. MS: 622,2 (M-H).

Example 54

By analogy with example 53 N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(morpholin-4-carbonyl)phenyl] -4-methoxybenzenesulfonamide azide and 2-pyridylcarbinol acid was obtained 2-[3-(4-methoxybenzylideneamino)-2-(2-methoxyphenoxy)-5-(morpholine - 4-carbonyl)phenoxy] ethyl ester pyridine-2-ylcarbamate acid. MS: 677,3 (M-H).

Example 55

a) 0,626 g of methyl 3-amino-4-(2-methoxyphenoxy)-5-[2-(tetrahydropyran- -2-yloxy)ethoxy] benzoate was dissolved in pyridine (30 ml) dropwise while cooling on ice, treated with a solution containing 0,593 g of 4-methylsulfonylbenzoyl in toluene (10 ml) and then stirred at RT for 20 hours. The reaction mixture was poured into ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. After removal of the solvent was obtained methyl-4-(2-methoxyphenoxy) -3-(4-methylsulfonylamino)-5-[2 - tetrahydropyran-2-yloxy)ethoxy] benzoate in the form of a yellow oil.

b) a Solution containing 0,91 g methyl-4-(2-methoxyphenoxy)-3- (4-methylsulfonylamino)-5-[2-(tetrahydropyran-2 - yloxy)ethoxy]benzoate in methanol (30 ml) was treated at 0oC 5 ml of 5.5 M Ariele, the residue was dissolved in ethyl acetate and washed with 2n. a solution of the secondary acid potassium carbonate. The organic phase was dried over magnesium sulfate, the solvent was removed on a rotary evaporator and the crude product was chromatographically on silica gel using CH2Cl2/ethyl acetate (7/1) as eluent. In this way received methyl-3-(2-hydroxyethoxy) -4-(2-methoxyphenoxy)-5-(4-methylsulfonylamino)benzoate as a white foam. MS: 520,2 (M-H).

Example 56

0,78 g of methyl-3-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)-5-(4-methylsulfonylamino)benzoate was dissolved in methanol (30 ml) was treated with 9 ml of 1M NaOH solution and then boiled under reflux for 1.5 hours the Mixture was poured into ice water, acidified with dilute HCl solution (pH 1) and the product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and the resulting solid was dried in high vacuum. The way it was obtained 3-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)-5-(4 - methylsulfonylamino)benzoic acid as a white foam (0,79 g). MS: 504,2 (M-H).

Example 57

75 mg of 3-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)-5-(4 - methylsulfonylamino)be the of Diisopropylamine, 75 mg hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium and 14 ál of the research and then the mixture was stirred at RT for 20 hours. The mixture was distributed between ethyl acetate and water, the organic phase was dried over sodium sulfate, concentrated on a rotary evaporator and the residue was chromatographically on silica gel using CH2Cl2/MeOH (20/1) as eluent. The way it was obtained N-[3-(2-hydroxyethoxy) -2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl]-4 - methylsulfonylmethane (71 mg) as a white foam. MS: 573,3 (M-H).

Example 58

By analogy with example 57 3-(2-hydroxyethoxy)- 4-(2-methoxyphenoxy)-5-(4-methylsulfonylamino)benzoic acid and 1-ethoxycarbonylpyrimidine received ethyl-4-[3-(2 - hydroxyethoxy)-4-(2-methoxyphenoxy)-5-(4 - methylsulfonylamino)benzoyl]piperazine-1 - carboxylate. MS: 646,3 (M+H).

Example 59

A solution containing 63 mg of N-[3-(2-hydroxyethoxy)-2-(2 - methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl]-4 - methylsulfonylmethane, 48 mg of azide 2 - pyridylcarbinol acid and 5 mg of para-dimethylaminopyridine in toluene (15 ml), kept at 110oC (bath temperature) for 2 hours. The residue was distributed between meth is dried over magnesium sulfate. The solvent was finally removed on a mountain evaporator and the crude product was chromatographically on silica gel using CH2Cl2/MeOH (30/1) as eluent. This fact was obtained 2-[2-(2-methoxyphenoxy)-3-(4-methylsulfonylamino)-5- (morpholine-4-carbonyl)phenoxy] ethyl ester pyridine-2-ylcarbamate acid in a solid white color. MC: 693,1 (M-H).

Example 60

In analogy to example 59 from ethyl-4-[3-(2-hydroxyethoxy)-4- (2-methoxyphenoxy)-5-(4-methylsulfonylamino)benzoyl] piperazine-1-carboxylate azide and 2-pyridylcarbinol acid was obtained ethyl-4-{4-(2-methoxyphenoxy) -3-(4-methylsulfonylamino)-5- [2-(pyridine-2-ylcarbamate)ethoxy]benzoyl)piperazine-1 - carboxylate. MS: 764,0 (M-H).

Example 61

a) 1.04 g of methyl 3-amino-4-(2-methoxyphenoxy)-5-[2-(tetrahydropyran - 2-yloxy)ethoxy] benzoate was dissolved in pyridine (30 ml) dropwise while cooling on ice, treated with a solution containing 0,953 g of 4-methylbenzenesulfonamide in toluene (10 ml) and then stirred at RT for 20 hours. The reaction mixture was poured into ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. After removal of rest seat in a solid yellow color.

b) a Solution containing 1.42 g of methyl-4-(2-methoxyphenoxy)-3-[2- (tetrahydropyran-2-yloxy)ethoxy]-5-(toluene-4 - sulfoaluminate)benzoate in methanol (50 ml) was treated at RT 3 ml of 5.5 M aqueous HCl and then the solution was stirred at RT for a further 5 hours. The solvent was removed on a rotary evaporator, the residue was dissolved in ethyl acetate and washed with 2n. a solution of the secondary acid potassium carbonate. The organic phase was dried over magnesium sulfate, the solvent was removed on a rotary evaporator and the crude product was chromatographically on silica gel using CH2Cl2/ethyl acetate (9/1) as eluent. In this way got to 1.15 g of methyl-3-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)-5- (toluene-4-sulfonylamino)benzoate as a white foam. MS: 486,2 (M-H).

Example 62

1,069 g of methyl-3-(2-hydroxyethoxy)-4- (2-methoxyphenoxy)-5-(toluene-4-sulfonylamino)benzoate was dissolved in methanol (50 ml) was treated with 11 ml of 1M NaOH solution and then boiled under reflux for 20 hours. The mixture was poured into ice water, acidified with dilute HCl solution (pH 1) and the product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and the resulting solid was dried in high vacuum. Tabelas foam. MS: 472,5 (M-H).

Example 63

70 mg of 3-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)-5-(toluene-4 - sulfonylamino)benzoic acid was dissolved in acetonitrile (5 ml) at room temperature in a specified sequence was added 29 μl of n-ethyldiethanolamine, 75 mg hexaphosphate benzotriazol-1 yloxytris(dimethylamino)phosphonium and 14 ál of the research and then the mixture was stirred at RT for 16 hours. The mixture was distributed between ethyl acetate and water, the organic phase was dried over sodium sulfate, concentrated on a rotary evaporator and the residue was chromatographically on silica gel using CH2Cl2/MeOH (30/1) as eluent. The way it was obtained N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5- (morpholine-4-carbonyl)phenyl]-4-methylbenzenesulfonamide (71 mg) as a white foam. MS: 541,4 (M-H).

Example 64

A solution containing 57 mg of methyl 3-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)-5-(toluene-4-sulfonylamino)benzoate, 51 mg of azide 2-pyridylcarbinol acid and 5 mg of para-dimethylaminopyridine in toluene (5 ml), kept at 110oC (bath temperature) for 1 hour. The residue was distributed between ethyl acetate and 1N. HCl solution, the aqueous phase was extracted several times with methylene chloride and the organic fdoct was chromatographically on silica gel using CH2Cl2/ethyl acetate (12/1) as eluent. In this way received methyl-4-(2-methoxyphenoxy)-3-[2-(pyridine-2 - ylcarbamate)ethoxy]-5-(toluene-4-sulfonylamino)benzoate in the form of a solid white color. MC: 606,2 (M-H).

Example 65

By analogy with example 64 N-[3-(2-hydroxyethoxy)-2- (2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl] -4-methylbenzenesulfonamide azide and 2-pyridylcarbinol acid was obtained 2-[2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl) -3-(toluene-4-sulfonylamino)phenoxy] ethyl ester pyridine-2-ylcarbamate acid. MC: 661,3 (M-H).

Example 66

a) 1.13 g of methyl 3-amino-4-(2-chloro-5-methoxyphenoxy)- 5-[2-(tetrahydropyran-2-yloxy)ethoxy] benzoate was dissolved in a mixture of toluene/pyridine (20 ml/30 ml) dropwise while cooling on ice, treated with a solution containing of 1.05 g of 4-tert - butylbenzenesulfonamide in toluene (30 ml) and then stirred at RT for 24 hours. The reaction mixture was poured into ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. After removal of the solvent was obtained methyl-3-(4-tert-butylbenzenesulfonamide)-4-(2-chloro-5 - methoxyphenoxy)-5-[2-(tetrahydropyran-2-yloxy)ethoxy] benzoate in the form of a solid yellow color.

Obtaining source materials:

in) 3,59 g methyl-4-chloro-3-nitro-5-[2-(tetrahydropyran-2-yloxy)ethoxy] benzoate say the masters in acetone (200 ml) was treated at RT to 4.14 g of potassium carbonate and 1.9 g of 2-chloro-5-methoxyphenol and the mixture is then boiled under reflux for 20 hours. The mixture was poured into ice water and was extracted with ethyl acetate. The organic phase is washed three times with 5% sodium hydroxide solution and then with water, dried over sodium sulfate and finally concentrated on a rotary evaporator. The crude product (5.5 g) was subjected to rapid chromatography on silica gel using Gex is dapiran-2-yloxy)ethoxy] benzoate (3.5 g) in the form of powder light yellow color.

g) 3.5 g of methyl-(2-chloro-5-methoxyphenoxy)-3 - nitro-5-[2-(tetrahydropyran-2-yloxy)ethoxy] benzoate was dissolved in methanol (150 ml) was treated with 0.5 g of Raney Ni as catalyst and was first made at room temperature for 1.5 hours, the Catalyst was filtered and the solution was concentrated on a rotary evaporator. The way it was obtained methyl 3-amino-4- (2-chloro-5-methoxyphenoxy)-5-[2-(tetrahydropyran-2-yloxy)ethoxy] benzoate. Solid light yellow color.

Example 67

1.13 g of methyl-3-(4-tert-butylbenzenesulfonamide)-4-(2-chloro-5 - methoxyphenoxy)-5-(2-hydroxyethoxy)benzoate was dissolved in methanol (30 ml) was treated with 6 ml of 1M NaOH solution and then boiled under reflux for 6 hours. The mixture was poured into ice water, acidified with dilute HCl solution (pH 1) and the product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and the resulting solid was dried in high vacuum. The way it was obtained 3-(4-tert-butylbenzenesulfonamide)-4-(2-chloro-5-methoxyphenoxy)-5- (2-hydroxyethoxy)benzoic acid in the form of a solid crystalline substance of white color. MS: 548,3 (M-H).

Example 68

55 mg of 3-(4-tert-butylbenzenesulfonamide)-4-(2-chloro-5 - methox is lesti was added to 19 μl of n-ethyldiethanolamine, 49 mg of hexaflurophosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium and 10 ál of the research and then the mixture was stirred at RT for 2 hours. The mixture was distributed between ethyl acetate and water, the organic phase was dried over sodium sulfate, concentrated on a rotary evaporator and the residue was chromatographically on silica gel using CH2Cl2/MeOH (20/1) as eluent. The way it was obtained 4-tert-butyl-N-[2-(2-chloro-5-methoxyphenoxy) -3-(2-hydroxyethoxy)-5-(morpholine-4-carbonyl)phenyl]benzosulfimide (63 mg) as a white foam. MS: 617,3 (M-H).

Example 69

In analogy to example 68 3-(4-tert-butylbenzenesulfonamide)-4-(2-chloro-5 - methoxyphenoxy)-5-(2-hydroxyethoxy)benzoic acid and aniline was obtained 3-(4-tert-butylbenzenesulfonamide)-4-(2-chloro-5 - methoxyphenoxy)-5-(2-hydroxyethoxy) -N-phenylbenzene. MS: 623,3 (M-H).

Example 70

The solution containing 28 mg of methyl 3-(4-tert - butylbenzenesulfonamide)-4-(2-chloro-5-methoxyphenoxy)-5-(2 - hydroxyethoxy)benzoate, 22 mg of azide 2-pyridylcarbinol acid and 2 mg of para-dimethylaminopyridine in toluene (5 ml), kept at 110oC (bath temperature) for 1.5 hours, the Residue was distributed between ethyl acetate and 1N. HCl solution, the aqueous phase is repeatedly removed on a rotary evaporator and the crude product was chromatographically on silica gel using CH2Cl2/ethyl acetate (10/1) as eluent. In this way received methyl-3-(4-tert-butylbenzenesulfonamide)- 4-(2-chloro-5-methoxyphenoxy)-5-[2-(pyridine-2 - ylcarbamate)ethoxy] benzoate in the form of a solid white color. MS: 682,3 (M-H).

Example 71

By analogy with example 70 4-tert-butyl-N-[2-(2-chloro-5-methoxyphenoxy) -3-(2-hydroxyethoxy) - 5-(morpholine-4-carbonyl) phenyl] benzosulfimide azide and 2 - pyridylcarbinol acid was obtained 2-[3-(4 - tert-butylbenzenesulfonamide)-2-(2-chloro-5 - methoxyphenoxy)-5-morpholine-4-carbonyl)phenoxy] ethyl ester pyridine-2-ylcarbamate acid. MS: 737,2 (M-H).

Example 72

a) 1.12 g of methyl 3-amino-4-(2-chloro-5-methoxyphenoxy)-5-[2- (tetrahydropyran-2-yloxy)ethoxy] benzoate was dissolved in a mixture of toluene/pyridine (20 ml/30 ml) while cooling on ice, treated dropwise with a solution containing of 1.05 g of 5 - isopropylpyridine-2-sulphonylchloride in toluene (30 ml) and then stirred at room temperature for 24 hours. The reaction mixture was poured into ice/3M HCl, the product was extracted with ethyl acetate and the organic phase is washed with water and dried over magnesium sulfate. After removal of solvent received target methyl-4-(2-chloro-5-methoxyphenoxy)-3-(5-isopropylpyridine - 2-sulfonator, containing 2.0 g methyl-4-(2-chloro-5-methoxyphenoxy)-3-(5-isopropylpyridine-2 - sulfonylamino)-5-[2-(tetrahydropyran-2-yloxy)ethoxy] benzoate in methanol (10 ml) was treated at RT with 5 ml of 5.5 M aqueous HCl and then the solution was stirred at RT for a further 1 hour. The solvent was removed on a rotary evaporator, the residue was dissolved in ethyl acetate 1 washed 2n. a solution of the secondary acid potassium carbonate. The organic phase was dried over magnesium sulfate, the solvent was removed on a rotary evaporator and the crude product was chromatographically on silica gel using CH2Cl2/ethyl acetate (10/1) as eluent. In this way received methyl-4-(2-chloro-5-methoxyphenoxy)-3-(2 - hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)benzoate. MS: 549,2 (M-H).

Example 73

0,905 g methyl-4-(2-chloro-5-methoxyphenoxy)-3-(2 - hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)benzoate was dissolved in methanol (10 ml), was treated to 6.57 ml of 1M NaOH solution and then boiled under reflux for 1 hour. The mixture was poured into ice water, acidified with dilute HCl solution (pH 1) and the product was extracted with ethyl acetate. The organic phase is once washed with water, dried over sodium sulfate and concentrated. Received from the toxi)-5-(5-isopropylpyridine-2 - sulfonylamino)benzoic acid in the form of a crystalline solid white. MS: 535,3 (M-H).

Example 74

54 mg of 4-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy) -5-(5-isopropylpyridine-2-sulfonylamino)benzoic acid was dissolved in acetonitrile (5 ml), at RT in the specified sequence was added to 19 μl of n-ethyldiethanolamine, 49 mg of hexaflurophosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium and 10 ál of the research and then the mixture was stirred at RT for 2 hours. The mixture was distributed between ethyl acetate and water, the organic phase was dried over sodium sulfate, concentrated on a rotary evaporator and the residue was chromatographically on silica gel using CH2Cl2/MeOH (25/1) as eluent. The way it was received [2-(2-chloro-5-methoxyphenoxy) -3-(2-hydroxyethoxy)-5-(morpholine-4-carbonyl)phenyl] amide 5-isopropylpyridine-2-sulfonic acid (60 mg) as a white foam. MS: 604,2 (M-H).

Example 75

A solution containing 55 mg of methyl 4-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5- (5-isopropylpyridine-2-sulfonylamino)benzoate, 44 mg of azide 2-pyridylcarbinol acid and 4 mg of para - dimethylaminopyridine in toluene (5 ml), kept at 110oC (bath temperature) for 1 hour. The residue was distributed between ethyl acetate and 1N. HCl solution, the aqueous phase is several times extra the rotary evaporator and the crude product was chromatographically on silica gel using CH2Cl2/ethyl acetate (10/1) as eluent. In this way received methyl-4-(2-chloro-5-methoxyphenoxy)-3-(5 - isopropylpyridine-2-sulfonylamino)-5-[2-(pyridine-2 - ylcarbamate)ethoxy] benzoate in the form of a solid white color. MS: 669,2 (M-H).

Example 76

In analogy to example 75, from [2-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(morpholine-4-carbonyl)phenyl]amide 5 - isopropylpyridine-2-sulfonic acid azide and 2-pyridylcarbinol acid was obtained 2-[2-(2-chloro-5-methoxyphenoxy)-3-(5 - isopropylpyridine-2-sulfonylamino)-5- (morpholine-4-carbonyl)phenoxy] ethyl ester of pyridine-2 - ylcarbamate acid. MS: 605,0 (M-C6H4N2O).

Example 77

a) 135 mg of methyl 3-amino-4-(2-chloro-5-methoxyphenoxy)-5-[2- (tetrahydropyran-2-yloxy)ethoxy] benzoate was dissolved in pyridine (3 ml), was treated while cooling on ice, the solution containing 111 mg of 4-methoxybenzenesulfonamide in toluene (1 ml) and then stirred at RT for 20 hours. The reaction mixture was poured into ice/3M HCl, the product was extracted with ethyl acetate and the organic phase is washed with water and dried over magnesium sulfate. After removal of the solvent was obtained methyl-4-(2-chloro-5-methoxyphenoxy-3-(4 - methoxybenzylideneamino)-5-[2-(tetrahydrate-3-(4 - methoxybenzylideneamino)-5-[2-(tetrahydropyran-2 - yloxy)ethoxy] benzoate in methanol (5 ml), was treated at RT with 1 ml of 5.5 M aqueous HCl and then the solution was stirred at RT for a further 1.5 hours the Solvent was removed on a rotary evaporator, the residue was dissolved in ethyl acetate and washed with 2n. a solution of the secondary acid potassium carbonate. The organic phase was dried over magnesium sulfate, the solvent was removed on a rotary evaporator and the crude product was chromatographically on silica gel using CH2Cl2/ethyl acetate (10/1) as eluent. In this way received methyl-4-(2-chloro-5-methoxyphenoxy) -3-(2-hydroxyethoxy)-5-4-methoxybenzenesulfonamide)benzoate. MS: 536,2 (M-H).

Example 78

By analogy with example 73 by alkaline saponification of methyl-4-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(4 - methoxybenzenesulfonamide)benzoate 1M NaOH was obtained 4-(2-chloro - 5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(4 - methoxybenzenesulfonamide)benzoic acid. MS: TO 541.3 (M-H).

Example 79

In analogy to example 74 by condensation of 4-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(4 - methoxybenzenesulfonamide) benzoic acid with aniline was obtained 4-(2-chloro-5 - methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(4 - methoxybenzylideneamino)-N-phenylbenzene. MS: 597,2 (M-H).

Example 80

By analogy with n is a with benzo[1,3] dioxol-5-sulphonylchloride received methyl-3-(benzo[1,3]dioxol-5-sulphonylamino)-4-(2 - chloro-5-methoxyphenoxy)-5-[2-(tetrahydropyran-2 - yloxy)ethoxy] benzoate and then by processing 5.5 M HCl was obtained methyl 3-(benzo[1,3]dioxol-5-sulphonylamino) -4- (2-chloro-5 - methoxyphenoxy)-5-(2-hydroxyethoxy)benzoate. MS: 550,3 (M-H).

Example 81

By analogy with example 73 by alkaline saponification of methyl-3-(benzo[1,3]dioxol-5-sulphonylamino)-4-(2-chloro-5 - methoxyphenoxy)-5-(2-hydroxyethoxy)benzoate 1M NaOH was obtained 3-(benzo[1,3]dioxol-5-sulphonylamino)-4-(2-chloro-5 - methoxyphenoxy)-5-(2-hydroxyethoxy)benzoic acid. MS: 536,2 (M-H).

Example 82

In analogy to example 74 by condensation of 3- (benzo[1,3]dioxol-5-sulphonylamino)-4-(2-chloro-5-methoxyphenoxy) -5-(2-hydroxyethoxy)benzoic acid with aniline was obtained 3- (benzo[1,3]dioxol-5-sulphonylamino)-4-(2-chloro-5-methoxyphenoxy) - 5-(2-hydroxyethoxy)-N-phenylbenzene. MS: 611,1 (M-H).

Example 83

By analogy with example 77 by condensation of methyl-3-amino-4-(2-chloro-5-methoxyphenoxy)-5- [2-(tetrahydropyran-2-yloxy)ethoxy] benzoate 4 - trifluoromethyl)benzosulphochloride received methyl-4-(2 - chloro-5-methoxyphenoxy)-3-[2-(tetrahydropyran-2 - yloxy)ethoxy] -5-(4-triftormetilfullerenov)benzoate and then by processing 5.5 M HCl was obtained methyl-4-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5- (4-triftormetilfullerenov)benzoate. MS: 574,2 (M-H).

Example 84

By analogy with example 73 by alkaline saponification of methyl-4-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(4 - trif is (4-triftormetilfullerenov)benzoic acid. MS: 560,2 (M-H).

Example 85

In analogy to example 74 by condensation of 4-(2 - chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(4 - triftormetilfullerenov)benzoic acid with aniline was obtained 4-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-N - phenyl-5-(4-triftormetilfullerenov)benzamide. MS: 635,1 (M-H).

Example 86

a) 0.35 mg of methyl 3-amino-4-(3-methoxyphenoxy)-5- [2-(tetrahydropyran-2-yloxy)ethoxy] benzoate was dissolved in pyridine (10 ml) while cooling on ice, treated dropwise with a solution containing 0.312 g of 4-tert-butylbenzenesulfonamide in toluene (3 ml) and then stirred at RT for 24 hours. The reaction mixture was poured into ice/3M HCl, the product was extracted with ethyl acetate, the organic phase is washed with 2 m KHCO solution3and dried over magnesium sulfate. After removal of solvent required methyl-3-(4-tert-butylbenzenesulfonamide)-4-(3-methoxyphenoxy)-5- [2-(tetrahydropyran-2-yloxy)ethoxy]benzoate in the form of a solid substance.

b) a Solution containing 0,566 g of methyl-3-(4-tert - butylbenzenesulfonamide)-4-(3-methoxyphenoxy)-5-[2- (tetrahydropyran-2-yloxy)ethoxy]benzoate in methanol (7 ml) was treated at RT with 5 ml of 5.5 M aqueous HCl and then the solution was stirred at RT in tn. a solution of the secondary acid potassium carbonate. The organic phase was dried over magnesium sulfate, the solvent was removed on a rotary evaporator and the crude product was chromatographically on silica gel using CH2Cl2/acetone (50/1) as the eluent. In this way received 0,113 g of methyl-3-(4-tert-butylbenzenesulfonamide)-5-(2 - hydroxyethoxy)-4-(3-methoxyphenoxy)benzoate. MS: CONSISTS 528.3 (M-H).

Obtaining source materials:

in) 3,57 metil-4-chloro-3-nitro-5- [2-(tetrahydropyran-2-yloxy)ethoxy]benzoate was dissolved in acetone (100 ml) was treated at RT 4.15 g of potassium carbonate, 2,82 ml 3-methoxyphenol and the mixture is then boiled under reflux for 20 hours. The mixture was poured into ice water and was extracted with ethyl acetate. The organic phase is washed three times with 5% sodium hydroxide solution and then with water, dried over sodium sulfate and finally concentrated on a rotary evaporator. The crude product (5.5 g) was subjected to rapid chromatography on silica gel using hexane/simple ether (1/1) as eluent. In this way received methyl-3-nitro-4-(3-methoxyphenoxy)-5-[2-(tetrahydropyran-2 - yloxy)ethoxy] benzoate in the form of powder light yellow color.

g) 3.5 metil-3-nitro-4-(3-methox is as a catalyst and was first made at room temperature for 1 hour. The catalyst was filtered and the solution was concentrated on a rotary evaporator. Thus was obtained the desired methyl 3-amino-4-(3-methoxyphenoxy)-5-[2-(tetrahydropyran-2 - yloxy)ethoxy] benzoate in the form of a solid of light yellow color.

Example 87

By analogy with example 73 by alkaline saponification of methyl-3- (4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4- (3-methoxyphenoxy)benzoate 1M NaOH was obtained 3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3-methoxyphenoxy) benzoic acid. MS: 514,2 (M-H).

Example 88

In analogy to example 74 by condensing 3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4- (3-methoxyphenoxy)benzoic acid with morpholine was obtained 4 - tert-butyl-N-[3-(2-hydroxyethoxy)-2-(3 - methoxyphenoxy)-5-morpholine-4-carbonyl)phenyl] benzosulfimide. MS: 583.3 (M-H).

Example 89

In analogy to example 74 by condensing 3-(4 - tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3 - methoxyphenoxy)benzoic acid with aniline was obtained 3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3 - methoxyphenoxy)-N-phenylbenzene. MS: 589,3 (M-H).

Example 90

In analogy to example 74 by condensing 3-(4-tert-butylbenzenesulfonyl the em-butylbenzenesulfonamide)-5-(2 - hydroxyethoxy)-4-(3-methoxyphenoxy)benzamide. MS: 665,1 (M-H).

Example 91

In analogy to example 74 by condensing 3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3 - methoxyphenoxy)benzoic acid with anisidine was obtained 3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3 - methoxyphenoxy)-N-(3-methoxyphenyl)benzamide. MS: 619,2 (M-H).

Example 92

In analogy to example 74 by condensing 3-(4-tert - butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3 - methoxyphenoxy)benzoic acid methyl ester of L-leucine was obtained methyl-2-[3-(4-tert-butylbenzenesulfonamide)-5-(2 - hydroxyethoxy)-4-(3-methoxyphenoxy)benzoylamine] -4 - methylpentanoate. MS: 641,3 (M-H).

Example 93

In analogy to example 74 by condensing 3-(4-tert-butylbenzoyl-sulfonylamino)-5-(2-hydroxyethoxy)-4- (3-methoxyphenoxy)benzoic acid with 3,4-methylenedioxyaniline received N-benzo [1,3] dioxol-5-yl-3-(4 - tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3 - methoxyphenoxy)benzamide. MS: 633,1 (M-H).

Example 94

37.5 mg of methyl 2-[3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4- (3-methoxyphenoxy)benzoylamine] -4-methylpentanoate was dissolved in methanol (5 ml) was treated at room temperature 0,23 ml of 1M NaOH solution and stirred is the pH was brought to 1 with dilute HCl solution and the product was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, the solvent was removed on a rotary evaporator and the residue was dried in high vacuum. The way it was obtained 2-[3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3 - methoxyphenoxy)benzoylamine] -4-methylpentanol acid in a solid white color. MS: 629,3 (M+H).

Example 95

By analogy with example 75 methyl-3- (4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3 - methoxyphenoxy)benzoate azide and 2-pyridylcarbinol acid was obtained methyl-3-(4-tert-butylbenzenesulfonamide)-4-(3-methoxyphenoxy)-5-[2- (pyridine-2-ylcarbamate)ethoxy] benzoate. MS: 648,1 (M-H).

Example 96

In analogy to example 75, from 4-tert-butyl-N-[3-(2-hydroxyethoxy)-2-(3-methoxyphenoxy)-5-(morpholine-4 - carbonyl)phenyl]benzosulfimide azide and 2 - pyridylcarbinol acid was obtained 2-[3-(4-tert-butylbenzenesulfonamide)- 2-(3-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenoxy] ethyl ester pyridine-2-ylcarbamate acid. MS: 705,2 (M-H).

Example 97

By analogy with example 75 3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4- (3-methoxyphenoxy)-N-(3-methoxyphenyl)benzamide azide and 2 - pyridylcarbinol acid was obtained 2-[3-(4-tert-butylbenzenesulfonyl MS: 739,2 (M-H).

Example 98

By analogy with example 75 3-(4-tert - butylbenzenesulfonamide)-5- (2-hydroxyethoxy)-4-(3-methoxyphenoxy)-N-phenylbenzene azide and 2 - pyridylcarbinol acid was obtained the desired 2-[3-(4 - tert-butylbenzenesulfonamide)- -2-(3-methoxyphenoxy)-5-phenylcarbamoyloxy] ethyl ester pyridine-2-ylcarbamate acid. MS: 711,3 (M+H).

Example 99

By analogy with example 86 by condensation of methyl-3-amino-4-(3 - methoxyphenoxy)-5-[2-(tetrahydropyran-2-yloxy)ethoxy] benzoate (4 - methoxybenzenesulfonamide received methyl-3-(4 - methoxybenzylideneamino)-4-(3-methoxyphenoxy)-5-[2- (tetrahydropyran-2-yloxy)ethoxy]benzoate and then after processing of 5.5 M HCl was obtained methyl-3-(2-hydroxyethoxy)-5-(4 - methoxybenzenesulfonamide)-4-(3-methoxyphenoxy)benzoate. MS:502,2 (M-H).

Example 100

By analogy with example 73 by alkaline saponification of methyl-3-(2-hydroxyethoxy)-5-(4 - methoxybenzylideneamino)-4-(3-methoxyphenoxy)benzoate 1M NaOH was obtained 3-(2-hydroxyethoxy)-5-(4-methoxybenzoyl sulfonylamino)-4-(3-methoxyphenoxy)benzoic acid. MS: 488,2 (M-H).

Example 101

In analogy to example 74 by condensation of 3- (2-hydroxyethoxy)-5-(4-methoxybenzylideneamino)-4-(3 - methoxyphenoxy)benzoic to same. MS: 563,2 (M-H).

Example 102

By analogy with example 75 3-(2-hydroxyethoxy)-5-(4 - methoxybenzylideneamino)-4-(3-methoxyphenoxy)-N - phenylbenzene azide and 2-pyridylcarbinol acid was obtained 2-[3- (4-methoxybenzylideneamino)-2-(3-methoxyphenoxy)-5 - phenylcarbamoyloxy] ethyl ester pyridine-2-ylcarbamate acid. MS: 683,1 (M-H).

Example 103

By analogy with example 86 by condensation of methyl-3-amino-4-(3 - methoxyphenoxy)-5-[2-(tetrahydropyran-2-yloxy)ethoxy]benzoate (4 - methylsulfonylmethane received methyl-4-(3 - methoxyphenoxy)-3-(4-methylsulfonylamino)-5-[2- (tetrahydropyran-2-yloxy)ethoxy]benzoate and then after processing of 5.5 M HCl was obtained methyl-3-(2-hydroxyethoxy)-4-(3-methoxyphenoxy) - 5-(4-methylsulfonylamino)benzoate. MS: 518,2 (M-H).

Example 104

By analogy with example 73 by alkaline saponification of methyl-3- (2-hydroxyethoxy)-4-(3-methoxyphenoxy)-5-(4 - methylsulfonylamino)benzoate 1M NaOH was obtained 3- (2-hydroxyethoxy)-4-(3-methoxyphenoxy)-5-(4 - methylsulfonylamino)benzoic acid. MS: 504,1 (M-H).

Example 105

In analogy to example 74 by condensation of 3-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)-5-(4 - hydroxy)-5-(4 - methylsulfonylamino)-N-phenylbenzene. MC: 579,2 (M-H).

Example 106

By hydrogenation of benzyl-{3-(4-tert - butylbenzenesulfonamide)-4-(2-methoxyphenoxy)-5-[2-(pyridine - 2-ylcarbamate)ethoxy] benzoylamine} acetate described in example 18, in methanol in the presence of palladium on coal at RT and at atmospheric pressure was obtained {3-(4 - tert-butylbenzenesulfonamide)-4-(2-methoxyphenoxy)-5-[2-(pyridine-2 - ylcarbamate)ethoxy] benzoylamine} acetic acid. MS:OF 693, 3 (M-H).

Example 107

A mixture containing 290 mg of para-tert-butyl-N- [2-(2-hydroxy)-3-(ortho methoxyphenoxy)-6-methyl-4 - pyridyl] benzosulfimide, 341 mg of gadatanili, 362 mg of silver carbonate and 25 ml of toluene was heated to 100oC and boiled for 5 hours under reflux, and then after 4 hours was added 150 mg of gadatanili. The reaction mixture was filtered and the filtrate was evaporated in vacuum. The residue was chromatographically on 30 g of silica gel. Using CH2Ck2+ 1% methanol was obtained 110 mg of pure amorphous para-tert-butyl-N-[2- (2-hydroxyethoxy)-3-(ortho methoxyphenoxy)-6-methyl-4 - pyridyl]benzosulfimide. MS: M t/e = 486.

IR spectrum: bands at 3211, 2963, 1600, 1498, 1339, 1252, 839, 751 cm-1.

Starting material was prepared as follows: 3 - aminocrotononitrile)crotononitrile, which was subjected to cyclization with NaNH2in dioxane at 100oC 2-hydroxy-3- (ortho methoxyphenoxy)-4-amino-6-methylpyridin. By interacting with 4-tert-butylbenzenesulfonamide in pyridine at 100oC was obtained 2-(para-tert-butylphenylmethyl)-3-(ortho methoxyphenoxy)-4- (para-tert-butylbenzaldehyde-6-methylpyridin. Treatment with sodium hydroxide in ethanol was obtained para-tert-butyl-N-[2-(2 - hydroxy)-3-(ortho methoxyphenoxy)-6-methyl-4-pyridyl] benzosulfimide in the form of amorphous substances,

MS spectrum: M t/e = 442.

NMR spectrum: 1,29(S) (9H, -C(CH3)3); 2,21 (5,6-methyl); 4,01 (s, OCH3)

Example 108

By analogy with example 107 of 270 mg of para-tert-butyl-N-[2-(2-hydroxy) -3-(3-methoxyphenoxy)-6-methyl-4-pyridyl] benzosulfimide received 122 mg of pure para-tert-butyl-N-[2-hydroxyethoxy)-3-(3-methoxyphenoxy)-6-methyl-4-pyridyl] benzosulfimide, tPL138-139oC (acetone/hexane).

IR spectrum: bands at 3259, 2963, 1601, 1490, 1340, 1177, 836, 571 cm-1.

Starting material was obtained in analogy to example 107 using M-methoxyphenylacetylene.

MS spectrum: M t/e = 442.

NMR spectrum: 1,32 (5,9 H, -C(CH3)3); is 2.09 (s, 3H, 6-methyl); of 3.75 (s, 3H, OCH3).

P mg of pure 4-tert-butyl-N-[2-(2-hydroxyethoxy)-3-(2-methoxyphenoxy) -6-fenspiride-4-yl] benzosulfimide.

IR spectrum: bands at 2964, 1597, 1339, 1168, 1100, 750 cm-1.

Starting material was obtained in analogy to example 107 using 3-amino-3-phenylacrylate and ortho - methoxyphenylacetylene.

MS spectrum: M t/e = 308.

IR spectrum: bands at 3442, 1617, 1499, 1251, 1217, 771 cm-1< / BR>
Example 110

By analogy with example 107 of 500 mg of N- [2-(2-hydroxy)-3-(2-methoxyphenoxy)-6-methylpyridin-4-yl] -5 - isopropylpyridine-2 - sulfonamida received 194 mg of pure N-[2-(2-hydroxyethoxy)-3- (2-methoxyphenoxy)-6-methylpyridin-4-yl]-5-isopropylpyridine-2 - sulfonamida in the form of an amorphous substance.

IR spectrum: bands at 3201, 2930, 1601, 1498, 1253, 1180, 847, 750 cm-1. Starting material was obtained in analogy to example 1, using 5 - isopropylpyridine-2-sulphonylchloride.

MS spectrum: M t/e = 429.

Example 111

A mixture containing 93 mg of N-[2-(2-hydroxyethoxy)-3-(2-methoxyphenoxy)- 6-methylpyridin-4-yl] -5-isopropylpyridine-2-sulfonamida, 43 mg azide pyridine-2-carboxylic acid, 10 ml of toluene and 10 mg of 4-dimethylaminopyridine, boiled under reflux for 90 minutes. The reaction mixture was evaporated in vacuo, dissolved in methylene chloride, washed with water, dried over magnesium sulfate and evaporated. The remainder of chromatographically)-3-(2-methoxyphenoxy)-6 - methylpyridin-2-yloxy] ethyl ester pyridine-2-ylcarbamate acid as an amorphous substance.

MS spectrum: M t/e = 594

IR spectrum: bands at 2963, 1734, 1596, 1438, 1181, 847 cm-1.

Example 112

By analogy with example 111 from 40 mg 4-tert-butyl-N-[2-(2 - hydroxyethoxy)-3-(2-methoxyphenoxy)-6-fenspiride-4-yl] benzosulfimide received 33 mg of pure 2-[4-(4-tert-butylbenzenesulfonamide)-3-(2 - methoxyphenoxy)-6-phenylpyridine-2-yloxy] ethyl ester pyridine-2-ylcarbamate acid as an amorphous substance.

MS spectrum: M t/e = 668.

IR spectrum: bands at 2964, 1735, 1596, 1439, 1169, 777 cm-1.

Example 113

A solution containing 280 mg of 4-tert-butyl-N-[3- (2-tetrahydropyranyloxy)-2-(2-methoxyphenoxy) phenyl] benzosulfimide and 1.0 g of para-toluensulfonate acid in 20 ml of methanol was kept at RT for 90 minutes. To obtain a product solution was evaporated in vacuo, the residue was distributed between methylene chloride and saturated sodium bicarbonate solution and the organic phase was dried and evaporated in vacuum. The residue was recrystallized from acetone-hexane. The way it was obtained 170 mg of pure 4-tert-butyl-S- [3-(2-hydroxyethoxy)-2-(2 - methoxyphenoxy)vinylbenzenesulfonic, tPL131-132oC.

IR spectrum: bands at 3496, 2967, 1507, 1499, 1335, 1168, 750 cm-1.

Original Wei under 100oC for 12 hours with a mixture that contains 188 mg of sodium hydroxide, 700 mg of guaiacol and 200 mg of copper powder in 15 ml DMSO. Using conventional processing and chromatography was obtained 1.0 g of pure 2-(2-methoxyphenoxy) -3-(2-tetrahydropyranyloxy)nitrobenzene, MS spectrum: M t/e = 359.

Using a catalytic reduction using hydrogen/Raney Nickel in ethanol was obtained 2-(2-methoxyphenoxy)-3-(2 - tetrahydropyranyloxy)aniline, IR bands at 3369, 2942, 1623, 1327, 870 cm-1.

Interaction with para-tert-butylbenzenesulfonamide in pyridine/toluene at room temperature was obtained pure 4-tert-butyl-N-[3-(2-tetrahydropyranyloxy)-2- (2-methoxyphenoxy)phenyl] benzosulfimide. MS: M t/e = 555.

Example 114

By analogy with example 111 4-tert-butyl-N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)phenyl] benzosulfimide was obtained pure 2-[3-(4-tert - butylphenylphosphine)-2-(2-methoxyphenoxy)phenoxy]ethyl ester pyridine-2-ylcarbamate acid, tPL118-119oC (acetone/hexane).

IR spectrum: bands at 2964, 1733, 1594, 1498, 1254, 769 cm-1.

Example 115

A solution containing 250 mg of 2-(2-methoxyphenoxy)- 3-(2-tetrahydropyranyloxy)aniline, 183 mg normal processing of received 335 mg oil, which was dissolved in 20 ml of methanol and maintained with 1.0 g of para-toluensulfonate acid at RT for 1 hour. After the usual treatments received 250 mg of pure 5 - isopropyl-N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)phenyl] pyridyl-sulfonamida in the form of an amorphous substance.

IR spectrum: bands at 2931, 1602, 1339, 1175, 1021, 764 cm-1< / BR>
Example 116

By analogy with example 111 5-isopropyl-N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)phenyl] -2-pyridinesulfonamide was obtained pure 2- [3-(5-isopropylpyridine-2-sulfonylamino)-2-(2 - methoxyphenoxy)phenoxy]ethyl ester pyridine-2-ylcarbamate acid, tPL163oC (acetone/hexane).

IR spectrum: bands at 2963, 1732, 1591, 1500, 1304, 1253, 1034, 748 cm-1.

Example 117

By analogy with example 111 from 2-(2-chloro-5-methoxyphenoxy)-3-(2-tetrahydropyranyloxy) aniline with 4-tert-butylbenzenesulfonamide and by acid saponification was obtained 4-tert-butyl-N-[2-(2-chloro-5-methoxyphenoxy)-3-(2 - hydroxyethoxy)phenyl] benzosulfimide, tPL131-134oC.

Starting material was obtained in accordance with example 113 2-chloro-3-(2 - tetrahydropyranyloxy) nitrobenzene and 2-chloro-5-methoxyphenol and subsequent reduction of nitro group.

PL204-206oC (methylene chloride/hexane).

Example 119

a) 0.14 mg of methyl 3-amino-5-(2,3 - dihydroxypropane)-4-(3-methoxyphenoxy)benzoate was dissolved in pyridine (4.5 ml) while cooling on ice, treated dropwise with a solution containing 0.16 g of 4-tert-butylbenzenesulfonamide in toluene (1.5 ml) and then stirred at room temperature for 5 hours. The reaction mixture was distributed between water and ethyl acetate and the organic phase is washed with 2n. HCl solution and dried over magnesium sulfate. After removal of solvent the residue was chromatographically on silica gel using methylene chloride/methanol (40/1) as eluent. In this way received 121 mg of methyl 3-(4-tert-butylbenzenesulfonamide) -5- (2,3-dihydroxypropane)-4-(3-methoxyphenoxy)benzoate in the form of resin.

MS: 558,2 (M-H).

Obtaining source materials:

b) to 3.67 g of methyl 4-chloro-3-hydroxy-5-nitrobenzoate was dissolved in acetone (100 ml) at room temperature was treated in sequence to 6.57 g of potassium carbonate and $ 2.68 ml allylbromide and the mixture is boiled under reflux for 17 hours. Then the reaction mixture was diluted with ethyl acetate, poured into water and the organic phase was isolated, dried over sulfate in the form of a solid crystalline substance.

MS: 231 (M).

in) of 5.3 g of methyl-3-allyloxy-4-chloro-5-nitrobenzoate was dissolved in acetone (100 ml) was treated at room temperature to 6.57 g of potassium carbonate and 3,66 g 3-methoxyphenol and the mixture is boiled under reflux for 24 hours. The mixture was poured into ice water and was extracted with ethyl acetate. The organic phase is washed three times with 5% sodium hydroxide solution and then with water, dried over sodium sulfate and finally concentrated on a rotary evaporator. The crude product (6.2 g) was chromatographically on silica gel with hexane/simple ether (3/1). In this way received methyl-3 - allyloxy-4-(3-methoxyphenoxy)-5-nitrobenzoate in the form of a solid crystalline substances lemon-yellow color.

MS: 359 (M).

g) 0.35 g of methyl-3-allyloxy-4-(3-methoxyphenoxy)-5-nitrobenzoate was dissolved in acetone/water (5 ml) and treated at room temperature 4-N-oxide 4-methylmorpholine (0,165 g), followed by osmium tetroxide (1 mg) dissolved in 1 ml of distilled water. The mixture was stirred at room temperature for 3 hours, treated with sodium pyrosulfite (0.17 g) and stirred at room temperature for a further 1 h the Resulting brown precipitate was filtered cher is cetate and washed with aqueous 1N. HCl and then with water. After drying the organic phase over magnesium sulfate, it was concentrated on a rotary evaporator and the residue was chromatographically on silica gel using methylene chloride/methanol (30/1) as eluent. In this way received methyl-3-(2,3 - dihydroxypropane)-4-(3-methoxyphenoxy)-5-nitrobenzoate resin.

MS: 393 (M).

d) 0.33 g of methyl-3-(2,3-dihydroxypropane)-4- (3-methoxyphenoxy)-5-nitrobenzoate was dissolved in methanol (10 ml) was treated with Raney Ni as catalyst and was first made at room temperature for 1 hour. The catalyst was filtered and the solution was concentrated on a rotary evaporator. The way it was obtained methyl 3-amino-5-(2,3-dihydroxypropane)-4- (3-methoxyphenoxy)benzoate in the form of a solid crystalline substance is light yellow in color.

MS:364 (M+H).

Example 120

0.15 g of methyl-3-(4-tert-butylbenzenesulfonamide)-5-(2,3 - dihydroxypropane)-4-(3-methoxyphenoxy)benzoate was dissolved in methanol (8 ml) was treated with 1.6 ml of 1N. NaOH solution and then boiled under reflux for 16 hours. The mixture was poured into ice water, acidified with dilute HCl solution to pH 1 and the product was extracted with ethyl acetate. The organic phase was dried over sulfa-tert - butylbenzenesulfonamide)-5-(2,3-dihydroxypropane)-4-(3 - methoxyphenoxy)benzoic acid as a white foam.

MS: 544,2 (M-H).

Example 121

54 mg of 3-(4-tert-butylbenzenesulfonamide)-5- (2,3-dihydroxypropane)-4-(3-methoxyphenoxy)benzoic acid was dissolved in methylene chloride (5 ml) at room temperature in a specified sequence was added 40 μl of N - ethyldiethanolamine, 30 mg of the acid chloride of bis(2-oxoacetate - nil)phosphinic acid and 11 μl of aniline, and then the mixture was stirred at room temperature for 12 hours. The mixture was dissolved in ethyl acetate, then washed first with water and then 1N. aqueous HCl and the organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographically on silica gel using CH2Cl2/MeOH (30/1) as eluent. The way it was obtained 3-(4-tert-butylbenzenesulfonamide)-5- (2,3-dihydroxypropane)-4-(3-methoxyphenoxy)-N-phenylbenzene in the form of a white foam.

MS: 619,3 (M-H).

Example 122

By analogy with example 119 from methyl 3-amino-5-(2,3 - dihydroxypropane)-4-(3-methoxyphenoxy)benzoate and 4 - methoxybenzenesulfonamide received methyl-3-(2,3 - dihydroxypropane)-5-(4-methoxybenzylideneamino)-4-(3 - methoxyphenoxy)benzoate in the form of resin.

MS: 532,1 (M-H).

Example 123

And what about) -4-(3-methoxyphenoxy) benzoate was obtained 3-(2,3-dihydroxypropane) -5-(4-methoxybenzylideneamino)-4-(3-methoxyphenoxy)benzoic acid as a white foam.

MS: 518 (M-H).

Example 124

By analogy with example 121 reaction mix 3- (2,3-dihydroxypropane)-5-(4-methoxybenzylideneamino)-4- (3-methoxyphenoxy)benzoic acid with aniline was obtained 3-(2,3 - dihydroxypropane)-5-(4-methoxybenzylideneamino)-4-(3 - methoxyphenoxy)-N-phenylbenzene in the form of foam.

MS:593,2 (M-H).

Example 125

By analogy with example 119 from methyl 3-amino-5- (2,3-dihydroxypropane)-4-(3-methoxyphenoxy)benzoate and 4 - methylmercaptopropionaldehyde received methyl-3- (2,3 - dihydroxypropane)-4-(3-methoxyphenoxy)-5-(4 - methylsulfonylamino)benzoate in the form of foam.

MS: 548,1 (M-H).

Example 126

By analogy with example 120 by acid saponification of methyl-3-(2,3-dihydroxypropane) -4-(3-methoxyphenoxy)-5- (4-methylsulfonylamino)benzoate was obtained 3- (2,3-dihydroxypropane)-4-(3-methoxyphenoxy)-5-(4 - methylsulfonylamino)benzoic acid in a solid white color.

MS: 534,1 (M-H).

Example 127

By analogy with example 121 reaction mix 3-(2,3 - dihydroxypropane)-4-(3-methoxyphenoxy)-5-(4 - methylsulfonylamino)benzoic acid with aniline was obtained 3-(2,3-dihydroxy> MS: 609,1 (M-H).

Example 128

By analogy with example 121 reaction mix 3-(4-tert-butylbenzenesulfonamide)-5-(2,3-dihydroxypropane) -4-(3-methoxyphenoxy)benzoic acid with 5 - aminotetrazole was obtained 3-(4-tert-butylbenzenesulfonamide)- -5-(2,3-dihydroxypropane)-4-(3-methoxyphenoxy)-N-(1H-tetrazol-5-yl)benzamide in a solid white color.

MS: 543,2 (M-CHN4-H).

Example 129

By analogy with example 121 reaction mix 3-(2,3 - dihydroxypropane)-4-(3-methoxyphenoxy)-5-(4 - methylsulfonylamino)benzoic acid with 1 - acetoxyeurifurane received ethyl-4- [3-(2,3 - dihydroxypropane)-4-(3-methoxyphenoxy)-5-(4 - methylsulfonylamino)benzoyl]piperazine-1 - carboxylate as a white foam.

MS: 674,3 (M-H).

Example 130

By analogy with example 121 reaction mix 3-(2,3 - dihydroxypropane)-4-(3-methoxyphenoxy)-5-(4 - methylsulfonylamino)benzoic acid with morpholine was obtained N-[3-(2,3-dihydroxypropane)-2-(3-methoxyphenoxy)-5- (morpholine-4-carbonyl)phenyl] -4-methylsulfonylmethane in the form of a white foam.

MS: 603,3 (M-H).

Example 131

Methyl-3-(4-tert-butylphenylphosphine)-5-(2-hidroxi alali 30 mg of 60% suspension of NaH and the mixture was stirred at room temperature for 20 minutes, then was treated with 2-chloropyrimidine (40 mg). The reaction mixture was stirred at room temperature for 18 hours, poured on ice water, was added a saturated solution of NH4Cl and the mixture was extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and finally concentrated on a rotary evaporator. The residue was chromatographically on silica gel using methylene chloride/ethyl acetate (7/1) as eluent. In this way received methyl-3-(4-tert-butylbenzenesulfonamide)-4-(2-methoxyphenoxy)-5- [2-(pyrimidine-2-yloxy)ethoxy]benzoate in the form of foam.

MS: 608,2 (M+H).

Example 132

By analogy with example 131 4-tert-butyl-N-[3- (2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl) phenyl] benzosulfimide and 2-chloropyrimidine was obtained 4-tert - butyl-N-{2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)-3-[2- (pyrimidine-2-yloxy)ethoxy]phenyl}benzosulfimide in the form of a white foam.

MS: 661,3 (M-H).

Example 133.

By analogy with example 131 4-tert-butyl-N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)- 5-(morpholine-4-carbonyl)phenyl] benzosulfimide and 2-chloropyridine was obtained 4-tert-butyl-N-{ 2-(2-methoxyphenoxy)-5-(morpholine-4 - carbonyl)-3-[2-(pyridine-2-ilok from 3-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)-5-(4 - methylsulfonylamino)-N-phenylbenzene and 2 - chloropyrimidine was obtained 4-(3-methoxyphenoxy)-3-(4 - methylsulfonylamino)-N-phenyl-5-[2-(pyrimidine-2-yloxy)ethoxy] benzamide in the form of a solid substance.

MS: 657,4 (M-H).

Example 135

By analogy with example 131 3-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)-5-(4-methylsulfonylamino)-N-phenylbenzene and 2-chloropyridine was obtained 4-(3-methoxyphenoxy)-3-(4-methylsulfonylamino)-N-phenyl-5-[2-(pyridine-2-yloxy)ethoxy]benzamide in the form of a solid substance.

MS: 656,3 (M-H).

Example 136

By analogy with example 121 reaction mix 3-(2 - hydroxyethoxy)-4-(3-methoxyphenoxy)-5-(4 - methylsulfonylamino)benzoic acid with morpholine was obtained N-[3-(2-hydroxyethoxy)-2-(3 - methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl]-4 - methylsulfonylmethane.

MS:575 (M+H).

Example 137

By analogy with example 131 N-[3-(2-hydroxyethoxy)-2-(3-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl] -4 - methylsulfonylmethane and 2-chloropyrimidine was obtained N- { 2-(3-methoxyphenoxy)-5-(morpholine-4-carbonyl)-3-[2-(pyrimidine-2 - yloxy)ethoxy] phenyl} -4-methylsulfonylmethane in the form of foam.

MS: 651,3 (M-H).

Example 138

By analogy with example 131 N- [3-(2-hydroxyethoxy)-2-(3-methoxyphenoxy)-5-(morpholine-4 - carbonyl)phenyl] -4-methylsulfonylmethane and 2 - chloropyridine was obtained N-{2-(3-methoxyp the s.

MS: 650,3 (M-H).

Example 139

a) 2.2 g of 3-amino-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzonitrile was dissolved in pyridine (45 ml), under ice cooling was treated dropwise with a solution containing a 3.06 g of 4-tert-butylbenzenesulfonamide in toluene (15 ml) and then stirred at room temperature for 12 hours. The reaction solution was distributed between aqueous hydrochloric acid (pH 1) and ethyl acetate and the organic phase was dried over magnesium sulfate. After removal of solvent on a rotary evaporator, the crude product was chromatographically on silica gel using methylene chloride/ethyl acetate (8/1) as eluent. In this way they obtained 1.19 g of 4-tert-butyl-N-[5-cyan-3-(2-hydroxyethoxy)-2- (2-methoxyphenoxy)phenyl] benzosulfimide in the form of foam.

MS: 495,1 (M-H).

Obtaining source materials:

b) to obtain a complex of Vilsmeier DMF (11.5 ml) was cooled to -20oC, the same temperature caution was added dropwise to 12.9 ml oxalicacid and the mixture was allowed to react at -20oC for 10 minutes. Then slowly dropwise added a solution containing 9 g of 3,4-dihydroxy-5-nitrobenzonitrile (obtained according to J. Med. Chem. 849, 1989) in DMF (11.5 ml), keeping the temperature reactionarily in an oil bath at 100oC (bath temperature) for 5 hours. The reaction solution dark color was poured into ice water, extracted with ethyl acetate and the organic phase is washed three times with water, dried over sodium sulfate and concentrated on a rotary evaporator. The way it was obtained 4-chloro-3-hydroxy-5-nitrobenzonitrile in the form of a powder beige color that was used in the next stage without additional purification.

MS: 197,1 (M-H).

in) of 3.96 g of 4-chloro-3-hydroxy-5 - nitrobenzonitrile was dissolved in acetone (150 ml) at room temperature was treated in sequence 6,91 g of potassium carbonate and of 7.68 g of 2-(2-iodoxy)tetrahydropyran and the mixture is boiled under reflux for 22 hours. Then the mixture was poured into ice water, extracted with ethyl acetate and the organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was subjected to rapid chromatography on silica gel using hexane/ethyl acetate (3/1) as eluent. The way it was obtained 4-chloro-3-nitro-5-[2- (tetrahydropyran-2-yloxy)ethoxy] benzonitrile resin light yellow color.

MS: 326 (M).

g) 2,60 g of 4-chloro-3-nitro-5-[2- (tetrahydropyran-2-yloxy)ethoxy]benzonitrile was dissolved in Aceto the first refrigerator for 20 hours. The mixture was poured into ice water and was extracted with ethyl acetate. The organic phase is washed three times with 5% sodium hydroxide solution and then with water, dried over sodium sulfate and finally concentrated on a rotary evaporator. The crude product was subjected to rapid chromatography on silica gel with hexane/ethyl acetate (2/1). The way it was obtained 4-(2 - methoxyphenoxy)-3-nitro-5-[2-(tetrahydropyran-2 - yloxy)ethoxy]benzonitrile in the form of a yellow resin.

MS: 414 (M).

d) 3.5 g of 4-(2-methoxyphenoxy)-3-nitro-5-[2-(tetrahydropyran-2 - yloxy)ethoxy] benzonitrile was dissolved in ethanol (100 ml) at room temperature slowly dropwise added to the solution of the dichloride dihydrate tin (7.6 g) in 37% HCl (17 ml) and the mixture is then stirred at room temperature for 12 hours. The mixture was poured into ice water, the pH was brought to 7 and the product was extracted with ethyl acetate. After customary treatment of the organic phase was obtained 3-amino-5-(2-hydroxyethoxy)-4-(2 - methoxyphenoxy)benzonitrile in the form of a crystalline solid.

MS: 300 (M).

Example 140

4-tert-butyl-N-[5-cyan-3- (2-hydroxyethoxy)-2-(2-methoxyphenoxy)phenyl] benzosulfimide (124 mg) was dissolved in N,N-dimethylformamide, Amrapali at 70oC for 24 hours. N,N-dimethylformamide was removed in high vacuum, the residue was distributed between water/ethyl acetate and the organic phase is repeatedly washed with a saturated solution of sodium chloride, and finally dried over magnesium sulfate and evaporated on a rotary evaporator. The crude product was purified on silica gel using methylene chloride/methanol (5/1) as the eluent. The way it was obtained 4-tert-butyl-N-[3-(2-hydroxyethoxy)-2- (2-methoxyphenoxy)-5-(1H-tetrazol-5-yl)phenyl]benzosulfimide in the form of a white foam.

MS: 538,1 (M-H).

Example 141

a) of 0.89 g of 3-amino-5-(2-hydroxyethoxy)-4-(3 - methoxyphenoxy)benzonitrile was dissolved in pyridine (15 ml) while cooling on ice, treated dropwise with a solution containing 1.23 g of 4-tert-butylbenzenesulfonamide in toluene (5 ml) and then stirred at room temperature for 12 hours. The reaction solution was distributed between aqueous acid (pH 1) and ethyl acetate and the organic phase was dried over magnesium sulfate. After removal of solvent on a rotary evaporator, the crude product was chromatographically on silica gel using methylene chloride/ethyl acetate (5/1) as the eluent. The way it was received and 0.61 g of 4-tert-butyl-N-[5-cyan-3-(2-hydroxyethoxy)ASS="ptx2">

Obtaining source materials:

b) to 2.57 g of 4-chloro-3-nitro-5-[2-(tetrahydropyran-2-yloxy)ethoxy]benzonitrile was dissolved in acetone (100 ml) was treated at room temperature 3,24 g of potassium carbonate and 1.48 g nanometrology ester resorcinol and the mixture is boiled under reflux for 20 hours. The mixture was poured into ice water and was extracted with ethyl acetate. The organic phase is washed three times with 5% sodium hydroxide solution and then with water, dried over sodium sulfate and finally concentrated on a rotary evaporator. The crude product was subjected to rapid chromatography on silica gel with hexane/ethyl acetate (2/1). The way it was obtained 4-(3 - methoxyphenoxy)-3-nitro-5-[2-(tetrahydropyran-2 - yloxy)ethoxy]benzonitrile in the form of a crystalline solid.

b) 2.0 g of 4-(3-methoxyphenoxy)-3-nitro-5-[2- (tetrahydropyran-2-yloxy)ethoxy]benzonitrile was dissolved in ethanol (60 ml) at room temperature slowly dropwise added to the solution of the dichloride dihydrate tin (4.5 g) in 37% HCl (12 ml) and the mixture is then stirred at room temperature for 12 hours. The mixture was poured into ice water, the pH was brought to 7 and the product was extracted with ethyl acetate. After customary treatment of the organic.

MS: 301,2 (M+H).

Example 142

In analogy to example 140 interaction of 4 - tert-butyl-N-[5-cyan-3-(2-hydroxyethoxy)-2-(3 - methoxyphenoxy)phenyl] benzosulfimide with sodium azide in N,N - dimethylformamide was obtained 4-tert-butyl-N-[3-(2-hydroxyethoxy)-2- (3-methoxyphenoxy)-5-(1H-tetrazol-5-yl)phenyl] benzosulfimide in the form of a white foam.

MS: 538,2 (M-H).

Example 143

a) 0.25 g of N-[3 - allyloxy-5-cyan-2-(2-methoxyphenoxy)phenyl]-4 - tert-butylbenzenesulfonamide was dissolved in acetone (10 ml) and treated at room temperature 4-N-oxide 4 - methylmorpholine (0,082 g) and osmium tetroxide (1 mg) dissolved in 1 ml of distilled water. The mixture was stirred at room temperature for 44 hours to complete the reaction again was treated OsO4(1 mg in 3 ml water) and stirred at room temperature for 6 hours Then added sodium pyrosulphite (of 0.085 g) and the mixture was stirred at room temperature for a further 1 h the Resulting brown precipitate was filtered through dicalite and washed with acetone. The filtrate was concentrated on a rotary evaporator and the residue was dissolved in ethyl acetate and washed with aqueous 1N. HCl and then with water. After drying the organic phase over sulfation/methanol (20/1) as eluent. The way it was obtained 4-tert-butyl-N-[5-cyan-3-(2,3 g dihydroxypropane) -2-(2-methoxyphenoxy) phenyl] benzosulfimide in a solid white color.

MS: 525,1 (M-H).

Obtaining source materials:

b) 1.98 g of 4-chloro-3-hydroxy-5-nitrobenzonitrile was dissolved in acetone (100 ml) at room temperature was treated in sequence to 4.14 g of potassium carbonate and of 1.27 ml allylbromide and the mixture is boiled under reflux for 20 hours. Then the reaction mixture was diluted with ethyl acetate, poured into water and the organic phase was isolated, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographically on silica gel using hexane/simple ether (4/1) as eluent. The way it was received 3 allyloxy-4-chloro-5-nitrobenzonitrile in the form of a crystalline solid.

MS: 238 (M).

in) of 2.27 g of 3-allyloxy-4-chloro-5-nitrobenzonitrile was dissolved in acetone (100 ml) was treated at room temperature 3.94 g of potassium carbonate and 1.76 g of guaiacol and the mixture is boiled under reflux for 20 hours. The mixture was poured into ice water and was extracted with ethyl acetate. The organic phase is washed three times with 5% hydroxide solution narny product chromatographically on silica gel using hexane/ethyl acetate (4/1). The way it was received 3 allyloxy-4-(2-methoxyphenoxy)-5-nitrobenzonitrile in the form of a crystalline solid.

MS: 326 (M).

g) 3,59 g 3 allyloxy-4-(2-methoxyphenoxy)-5-nitrobenzonitrile was dissolved in ethanol (120 ml) at room temperature slowly dropwise added to the solution of the dichloride dihydrate tin (8,55 g) in 37% HCl (25 ml) and the mixture is then stirred at room temperature for 12 hours. The mixture was poured into ice water, the pH was brought to 7 and the product was extracted with ethyl acetate. After customary treatment of the organic phase was received 3 allyloxy-5-amino-4-(2-methoxyphenoxy)benzonitrile in a solid white color.

MS: 296 (M+H).

d) 0.3 g of 3-allyloxy-5-amino-4-(2-methoxyphenoxy)benzonitrile was dissolved in pyridine (9 ml) under ice cooling was treated dropwise with a solution, containing 0.42 g of 4-tert-butylbenzenesulfonamide in toluene (3 ml) and then stirred at room temperature for 12 hours. The reaction mixture was distributed between aqueous hydrochloric acid (pH 1) and ethyl acetate and the organic phase was dried over magnesium sulfate. After removal of solvent on a rotary evaporator, the crude product was chromatographically on silica gel, solvency)phenyl]-4 - tert-butylbenzenesulfonamide in a solid white color.

MS: 491,2 (M-H).

Example 144

4-tert-butyl-N-[5-cyan-3-(2,3 - dihydroxypropane)-2-(2-methoxyphenoxy) phenyl] benzosulfimide (131 mg) was dissolved in N,N-dimethylformamide (2.5 ml) was treated at room temperature with ammonium chloride (134 mg), and then sodium azide (162 mg) and the mixture is kept at 70oC for 24 hours. Added another portion of sodium azide (162 mg) and the mixture was stirred at 70oC for a further 16 hours. N. N-dimethylformamide was removed in high vacuum, the residue was distributed between water/ethyl acetate and the organic phase is repeatedly washed with a saturated solution of sodium chloride, and finally dried over magnesium sulfate and evaporated on a rotary evaporator. The crude product was purified on silica gel using methylene chloride/methanol (3/1) as eluent. The way it was obtained 4-tert-butyl-N-[3-(2,3-dihydroxypropane)-2-(2 - methoxyphenoxy)-5-(1H-tetrazol-5-yl)phenyl] benzosulfimide in the form of a white foam.

MS: 568,3 (M-H).

Example 145

a) In analogy to example 143 by oxidation of N- [3-allyloxy-5-cyan-2-(3-methoxyphenoxy)phenyl] -4-tert-butylbenzenesulfonamide by osmium tetroxide was obtained 4-tert-butyl-N-[5-cyan-3-(2,3 - dihydroxypropane)-2-(3-methoxyphenoxy) phenyl] benzols is By analogy with paragraph C) example 143 3 - allyloxy-4-chloro-5-nitrobenzonitrile and nanometrology ester resorcinol received 3 allyloxy-4-(3-methoxyphenoxy)-5 - nitrobenzonitrile.

MS: 326 (M).

C) By analogy with paragraph g) of example 143 3-allyloxy-4- (3-methoxyphenoxy)-5-nitrobenzonitrile by restoring the received 3-allyloxy-5-amino-4-(3-methoxyphenoxy)benzonitrile in the form of a crystalline solid.

MS: 296 (M+H).

d) By analogy with paragraph d) of example 143 3-allyloxy-5-amino-4-(3-methoxyphenoxy)benzonitrile the reaction mix with 4-tert-butylbenzenesulfonamide was obtained N-[3-allyloxy-5-cyan-2-(3-methoxyphenoxy)phenyl] -4-tert-butylbenzenesulfonamide in the form of a crystalline solid.

MS: 491,2 (M-H).

Example 146

By analogy with example 144 4-tert-butyl-N-[5-cyan-3-(2,3 - dihydroxypropane)-2- (3-methoxyphenoxy)phenyl] benzosulfimide by cyclization with sodium azide in N,N-dimethylformamide as a solvent was obtained 4-tert-butyl-N- [3-(2,3-dihydroxypropane)-2-(3-methoxyphenoxy)-5-(1H-tetrazol - 5-yl)phenyl]benzosulfimide in the form of a crystalline solid.

MS: 568,3 (M-H).

An example of a

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

Ingredients Quantity per tablet

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

Lactose - 125,0 mg

Cockadoodie ingredients can be obtained in a standard way:

Ingredients Quantity per 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

Solutions for injections may have the following composition:

The compound of formula I - 3.0 mg

Gelatin - 150,0 mg

Phenol - 4,7 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 shaking. This aerosol container contains approximately 100 single doses, which can be fed from the tank separately.

1. Derivatives of aryl - and getresultdata formula I

< / BR>
where R1- substituted phenyl or pyridyl;

R2- substituted phenyl;

R3is hydrogen, (lower)alkyl, cyano, carboxy, esterified carboxylate, phenyl, 1H-tetrazolyl or the group,- CONR5R6;

R5is hydrogen or the radical R7;

R6represents -(CH2)mR7; or

R5and R6
R7is phenyl, substituted phenyl, pyridyl, 1H-tetrazolyl, (lower)alkyl, cyano(lower)alkyl, hydroxy(lower)alkyl, di(lower)alkylamino(lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl or phenyl(lower)alkoxycarbonyl;

Rais hydrogen or hydroxy;

Rbis hydrogen;

Z is hydroxy or the group-OR8or-OC(O)other8;

R8- pyridyl or pyrimidinyl;

X is nitrogen or CH;

m = 0, 1, or 2;

n = 0, 1, or 2,

and their pharmaceutically acceptable salts.

2. Connection on p. 1, in which R3denotes hydrogen, (lower)alkyl, carboxy, esterified carboxylate, phenyl, 1H-tetrazolyl or the group,- CONR5R6; R7denotes phenyl, substituted phenyl, pyridyl, 1H-tetrazolyl, (lower)alkyl, cyano(lower)alkyl, hydroxy(lower) alkyl, carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl or (lower)alkoxycarbonyl(lower) alkyl; Z represents hydroxy or the group-OC(O)other8; R1, R2, R4, R5, R6, R8, Ra, Rb, X, m and n have the values pointed to by the LASS="ptx2">

4. Connection on p. 3 in which R1denotes phenyl or substituted phenyl.

5. Connection on p. 4, in which Z represents-OC(O)other8.

6. Connection on p. 4, in which Z represents hydroxy.

7. Connection on p. 5:

2-[3-(4-tert-butylbenzenesulfonamide)-2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenoxy]ethyl ester pyridine-2-ylcarbamate acid,

2-[3-(4-tert-butylbenzenesulfonamide)-2-(2-methoxyphenoxy)-5-(2-pyridin-2-iletileri)phenoxy] ethyl ester pyridine-2-ylcarbamate acid,

2-[3-(4-tert-butylbenzenesulfonamide)-2-(2-methoxyphenoxy)-5-(piperidine-1-carbonyl)phenoxy] ethyl ester pyridine-2-ylcarbamate acid,

2-[5-benzylcarbamoyl-3-(4-tert-butylbenzenesulfonamide)-2-(2-methoxyphenoxy)phenoxy]ethyl ester pyridine-2-ylcarbamate acid,

benzyl-{ 3-(4-tert-butylbenzenesulfonamide)-4-(2-methoxyphenoxy)-5-[2-(pyridine-2-ylcarbamate)ethoxy]benzoylamine}acetate

2-{ 3-(4-tert-butylbenzenesulfonamide)-2-(2-methoxyphenoxy)-5-[(pyridine-3-ylmethyl)carbarnoyl]phenoxy}ethyl ester pyridine-2-ylcarbamate acid,

2-[3-(4-tert-butylbenzenesulfonamide)-2-(2-methoxyphenoxy)-5-phenylcarbamoyloxy]ethyl ester pyridine-2-ilıca is lexi)ethoxy]benzoate,

2-[3-(benzo[1,3] dioxol-5-sulphonylamino)-2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenoxy]ethyl ester pyridine-2-ylcarbamate acid,

ethyl-4-{ 3-(benzo[1,3] dioxol-5-sulphonylamino)-4-(2-methoxyphenoxy)-5-[2-(pyridine-2-ylcarbamate)ethoxy]benzoyl}piperazine-1-carboxylate,

2-[3-(benzo[1,3] dioxol-5-sulphonylamino)-5-isobutylamino-2-(2-methoxyphenoxy)phenoxy]ethyl ester pyridine-2-ylcarbamate acid,

2-[3-(benzo[1,3] dioxol-5-sulphonylamino)-5-isopropylcarbamate-2-(2-methoxyphenoxy)phenoxy]ethyl ester pyridine-2-ylcarbamate acid,

methyl-3-(4-methoxybenzylideneamino)-4-(2-methoxyphenoxy)-5-[2-(pyridine-2-ylcarbamate)ethoxy]benzoate,

2-[3-(4-methoxybenzylideneamino)-2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenoxy]ethyl ester pyridine-2-ylcarbamate acid,

ethyl-4-{ 4-(2-methoxyphenoxy)-3-(4-methylsulfonylamino)-5-[2-(pyridine-2-ylcarbamate)ethoxy]benzoyl}piperazine-1-carboxylate,

methyl-4-(2-methoxyphenoxy)-3-[2-(pyridine-2-ylcarbamate)ethoxy] -5-(toluene-4-sulfonylamino)benzoate,

2-[2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)-3-(toluene-4-sulfonylamino)phenoxy]ethyl ester pyridine-2-ylcarbamate acid,

methyl-3-(4-tert-butive is albenzaalbenza)-2-(2-chloro-5-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenoxy]ethyl ester pyridine-2-ylcarbamate acid,

methyl-3-(4-tert-butylbenzenesulfonamide)-4-(3-methoxyphenoxy)-5-[2-(pyridine-2-ylcarbamate)ethoxy]benzoate,

2-[3-(4-tert-butylbenzenesulfonamide)-2-(3-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenoxy]ethyl ester pyridine-2-ylcarbamate acid,

2-[3-(4-tert-butylbenzenesulfonamide)-2-(3-methoxyphenoxy)-5-(3-methoxyphenylacetyl)phenoxy]ethyl ester pyridine-2-ylcarbamate acid,

2-[3-(4-tert-butylbenzenesulfonamide)-2-(3-methoxyphenoxy)-5-phenylcarbamoyloxy]ethyl ester pyridine-2-ylcarbamate acid,

2-[3-(4-methoxybenzylideneamino)-2-(3-methoxyphenoxy)-5-phenylcarbamoyloxy]ethyl ester pyridine-2-ylcarbamate acid,

{ 3-(4-tert-butylbenzenesulfonamide)-4-(2-methoxyphenoxy)-5-[2-(pyridine-2-ylcarbamate)ethoxy]benzoylamine}acetic acid,

2-[3-(4-tert-butylphenylphosphine)-2-(2-methoxyphenoxy)phenoxy] ethyl ester pyridine-2-yl his carbamino acid,

2-[3-(4-tert-butylphenylphosphine)-2-(2-chloro-5-methoxyphenoxy)]ethyl ester pyridine-2-yl his carbamino acid,

2-[2-(2-methoxyphenoxy)-3-(4-methylsulfonylamino)-5-(morpholine-4-carbonyl)phenoxy] ethyl ester pyridine-2-yl his carbamino acid.

8. Connection p. ethylbenzothiazoline)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzoic acid,

3-(4-tert-butylbenzenesulfonamide)-4-(2-chloro-5-methoxyphenoxy)-5-(2-hydroxyethoxy)-N-phenylbenzene,

4-tert-butyl-N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl]benzosulfimide,

4-tert-butyl-N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(piperidine-1-carbonyl)phenyl]benzosulfimide,

3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)-N-(2-pyridin-2-retil)benzamid,

benzyl-[3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzoylamine]acetate

3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)-N-phenylbenzene,

3-(4-tert-butylbenzenesulfonamide)-N-lanmeter-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzamid,

3-(4-tert-butylbenzenesulfonamide)-N-(2-dimethylaminoethyl)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzamid,

tert-butyl-{ 2-[3-(4-tributylphosphine)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzoylamine]ethyl}carbamate,

3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)-N-pyridin-3-ylmethylene,

N-benzyl-3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzamid,

[3-(4-tert-butylbenzenesulfonyl is ffonline)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzoate,

3-(benzo[1,3] dioxol-5-sulphonylamino)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzoic acid,

[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl] amide benzo [1,3]dioxol-5-sulfonic acid,

ethyl-N-4-[3-(benzo[1,3] dioxol-5-sulphonylamino)-5-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)benzoyl]piperazine-1-carboxylate,

3-(benzo[l, 3]dioxol-5-sulphonylamino)-5-(2-hydroxyethoxy)-N-isobutyl-4-(2-methoxyphenoxy)benzamid,

3-(benzo[1,3] dioxol-5-sulphonylamino)-5-(2-hydroxyethoxy)-N-isopropyl-4-(2-methoxyphenoxy)benzamid,

3-(benzo[1,3] dioxol-5-sulphonylamino)-5-(2-hydroxyethoxy)-N-(2-hydroxyethyl)-4-(2-methoxyphenoxy)benzamid,

methyl-3-(2-hydroxyethoxy)-5-(4-methoxybenzylideneamino)-4-(2-methoxyphenoxy)benzoate,

3-(2-hydroxyethoxy)-5-(4-methoxybenzylideneamino)-4-(2-methoxyphenoxy)benzoic acid,

N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl]-4-methoxybenzenesulfonamide,

methyl-3-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)-5-(4-methylsulfonylamino)benzoate,

3-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)-5-(4-methylsulfonylamino)benzoic acid,

N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl]-4-methylphenylimino)benzoyl]piperazine-1-carboxylate,

methyl-3-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)-5-(toluene-4-sulfonylamino)benzoate,

3-(2-hydroxyethoxy)-4-(2-methoxyphenoxy)-5-(toluene-4-sulfonylamino)benzoic acid,

N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl]-4-methylbenzenesulfonamide,

methyl-3-(4-tert-butylbenzenesulfonamide)-4-(2-chloro-5-methoxyphenoxy)-5-(2-hydroxyethoxy)benzoate,

3-(4-tert-butylbenzenesulfonamide)-4-(2-chloro-5-methoxyphenoxy)-5-(2-hydroxyethoxy)benzoic acid,

4-tert-butyl-N-[2-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(morpholine-4-carbonyl)phenyl]benzosulfimide,

methyl-4-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(4-methoxybenzenesulfonamide)benzoate,

4-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(4-methoxybenzenesulfonamide)benzoic acid,

4-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(4-methoxybenzylideneamino)-N-phenylbenzene,

methyl-3-(benzo[1,3] dioxol-5-sulphonylamino)-4-(2-chloro-5-methoxyphenoxy)-5-(2-hydroxyethoxy)benzoate,

3-(benzo[1,3] dioxol-5-sulphonylamino)-4-(2-chloro-5-methoxyphenoxy)-5-(2-hydroxyethoxy)benzoic acid,

3-(benzo[1,3] dioxol-5-sulphonylamino)-4-(2-chloro-5-methoxyphenoxy)-5-(2-hydroxyethoxy)-N-phenylbenzene,

meth is ethoxyphenoxy)-3-(2-hydroxyethoxy)-5-(4-triftormetilfullerenov)benzoic acid,

4-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-N-phenyl-5-(4-triftormetilfullerenov)benzamid,

methyl-3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)benzoate,

3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)benzoic acid,

4-tert-butyl-N-[3-(2-hydroxyethoxy)-2-(3-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl]benzosulfimide,

3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)-N-phenylbenzene,

N-biphenyl-2-yl-3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)benzamid,

3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)-N-(3-methoxyphenyl)benzamide,

methyl-2-[3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)benzoylamine]-4-methylpentanoate,

N-benzo[1,3] dioxol-5-yl-3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)benzamid,

2-[3-(4-tert-butylbenzenesulfonamide)-5-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)benzoylamine]-4-methylpentanoic acid,

methyl-3-(2-hydroxyethoxy)-5-(4-methoxybenzylideneamino)-4-(3-methoxyphenoxy)benzoate,

3-(2-hydroxyethoxy)-5-(4-methoxybenzenesulfonyl is okefenoke)-N-phenylbenzene,

methyl-3-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)-5-(4-methylsulfonylamino)benzoate,

3-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)-5-(4-methylsulfonylamino)benzoic acid,

3-(2-hydroxyethoxy)-4-(3-methoxyphenoxy)-5-(4-methylsulfonylamino)-N-phenylbenzene,

4-tert-butyl-N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)vinylbenzenesulfonic,

4-tert-butyl-N-[2-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)phenyl] benzosulfimide,

methyl-3-(4-tert-butylbenzenesulfonamide)-5-(2,3-dihydroxypropane)-4-(3-methoxyphenoxy)benzoate,

3-(4-tert-butylbenzenesulfonamide)-5-(2,3-dihydroxypropane)-4-(3-methoxyphenoxy)benzoic acid,

3-(4-tert-butylbenzenesulfonamide)-5-(2,3-dihydroxypropane)-4-(3-methoxyphenoxy)-N-phenylbenzene,

methyl-3-(2,3-dihydroxypropane)-5-(4-methoxybenzylideneamino)-4-(3-methoxyphenoxy)benzoate,

3-(2,3-dihydroxypropane)-5-(4-methoxybenzylideneamino)-4-(3-methoxyphenoxy)benzoic acid,

3-(2,3-dihydroxypropane)-5-(4-methoxybenzylideneamino)-4-(3-methoxyphenoxy)-N-phenylbenzene,

methyl-3-(2,3-dihydroxypropane)-4-(3-methoxyphenoxy)-5-(4-methylsulfonylamino)benzoate,

3-(2,3-dihydroxypropane)-4-(3-methoxyphenoxy)-5-(4-methylsulfonylamino)-N-phenylbenzene,

3-(4-tert-butylbenzenesulfonamide)-5-(2,3-dihydroxypropane)-4-(3-methoxyphenoxy)-N-(1H-tetrazol-5-yl)benzamid,

ethyl-4-[3-(2,3-dihydroxypropane)-4-(3-methoxyphenoxy)-5-(4-methylsulfonylamino)benzoyl]piperazine-1-carboxylate,

N-[3-(2,3-dihydroxypropane)-2-(3-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl]-4-methylsulfonylmethane,

N-[3-(2-hydroxyethoxy)-2-(3-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl]-4-methylsulfonylmethane,

4-tert-butyl-N-[5-cyan-3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)phenyl] benzosulfimide,

4-tert-butyl-N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(1H-tetrazol-5-yl)phenyl]benzosulfimide,

4-tert-butyl-N-[5-cyan-3-(2-hydroxyethoxy)-2-(3-methoxyphenoxy)phenyl] benzosulfimide,

4-tert-butyl-N-[3-(2-hydroxyethoxy)-2-(3-methoxyphenoxy)-5-(1H-tetrazol-5-yl)phenyl]benzosulfimide,

4-tert-butyl-N-[5-cyan-3-(2,3-dihydroxypropane)-2-(2-methoxyphenoxy)phenyl]benzosulfimide,

4-tert-butyl-N-[3-(2,3-dihydroxypropane)-2-(2-methoxyphenoxy)-5-(1H-tetrazol-5-yl)phenyl]benzosulfimide,

4-tert-butyl-N-[5-cyan-3-(2,3-dihydroxypropane)-2-(3-methoxyphenoxy)phenyl]benzosulfimide,

4-tert-butyl-N-[3-(2,3-dihydroxypropane)-2-(3-methoxyphenoxy)-5-(1H-teirei.

10. Connection on p. 9, in which Z represents the group-OC(O)other8.

11. Connection on p. 9, in which Z represents hydroxy.

12. Connection on p. 10:

2-[3-(5-isopropylpyridine-2-sulfonylamino)-2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenoxy]ethyl ester pyridine-2-ylcarbamate acid,

2-[3-(5-isopropylpyridine-2-sulfonylamino)-2-(2-methoxyphenoxy)-5-(piperidine-1-carbonyl)phenoxy] ethyl ester pyridine-2-ylcarbamate acid,

2-[3-(5-isopropylpyridine-2-sulfonylamino)-2-(2-methoxyphenoxy)-5-(4-methylpiperazin-1-carbonyl)phenoxy] ethyl ester pyridine-2-ylcarbamate acid,

2-[5-(2,6-dimethylmorpholine-4-carbonyl)-3-(5-isopropylpyridine-2-sulfonylamino)-2-(2-methoxyphenoxy)phenoxy]ethyl ester pyridine-2-ylcarbamate acid,

2-[3-(5-isopropylpyridine-2-sulfonylamino)-2-(2-methoxyphenoxy)-5-(2-pyridin-2-iletileri)phenoxy] ethyl ester pyridine-2-ylcarbamate acid,

ethyl-4-{ 3-(5-isopropylpyridine-2-sulfonylamino)-4-(2-methoxyphenoxy)-5-[2-(pyridine-2-ylcarbamate)ethoxy]benzoyl)piperazine-1-carboxylate,

2-[5-(4-formylpiperazine-1-carbonyl)-3-(5-isopropylpyridine-2-sulfonylamino)-2-(2-methoxyphenoxy)phenoxy] ethyl ester pyridine-2-ylcarbamate acid,

moat

2-[2-(2-chloro-5-methoxyphenoxy)-3-(5-isopropylpyridine-2-sulfonylamino)-5-(morpholine-4-carbonyl)phenoxy] ethyl ester pyridine-2-ylcarbamate acid,

2-[3-(5-isopropyl-2-pyridinesulfonamide)-2-(2-methoxyphenoxy)]ethyl ester pyridine-2-ylcarbamate acid.

13. Connection on p. 11:

methyl-3-(2-hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)-4-(2-methoxyphenoxy)benzoate,

3-(2-hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)-4-(2-methoxyphenoxy)benzoic acid,

[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)phenyl] amide 5-isopropylpyridine-2-sulfonic acid,

[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(piperidine-1-carbonyl)phenyl]amide 5-isopropylpyridine-2-sulfonic acid,

[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)-5-(4-methylpiperazin-1-carbonyl)phenyl]amide 5-isopropylpyridine-2-sulfonic acid,

[5-(2,6-dimethylmorpholine-4-carbonyl)-3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)phenyl]amide 5-isopropylpyridine-2-sulfonic acid,

3-(2-hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)-4-(2-methoxyphenoxy)-N-(2-pyridin-2-retil)benzamid,

ethyl-4-[3-(2-hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)-4-(2-methoxyphenoxy)benzoyl]piperazine-pyridin-2-sulfonic acid,

3-(2-hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)-4-(2-methoxyphenoxy)-N-propylbenzamide,

methyl-4-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)benzoate,

4-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(5-isopropylpyridine-2-sulfonylamino)benzoic acid,

[2-(2-chloro-5-methoxyphenoxy)-3-(2-hydroxyethoxy)-5-(morpholine-4-carbonyl)phenyl]amide 5-isopropylpyridine-2-sulfonic acid,

5-isopropyl-N-[3-(2-hydroxyethoxy)-2-(2-methoxyphenoxy)phenylenedimaleimide.

14. Connection under item 1 or 2, in which X denotes nitrogen.

15. Connection on p. 14, in which R1denotes a substituted phenyl.

16. Connection on p. 15, in which Z represents the group-OC(O)other8.

17. Connection on p. 15, in which Z represents hydroxy.

18. Connection on p. 16:

2-[4-(4-tert-butylbenzenesulfonamide)-3-(2-methoxyphenoxy)-6-phenylpyridine-2-yloxy]ethyl ester pyridine-2-ylcarbamate acid.

19. Connection on p. 17:

para-tert-butyl-N-[2-(2-hydroxyethoxy)-3-(ortho methoxyphenoxy)-6-methyl-4-pyridyl]benzosulfimide,

para-tert-butyl-N-[2-(2-hydroxyethoxy)-3-(3-methoxyphenoxy)-6-methyl-4-pyridyl]benzosulfimide,

the deposits on p. 14, in which R1denotes a substituted pyridyl.

21. Connection on p. 20, in which Z represents the group-OC(O)other8.

22. Connection on p. 20, in which Z represents hydroxy.

23. Connection on p. 21:

2-[4-(5-isopropylpyridine-2-sulfonylamino)-3-(2-methoxyphenoxy)-6-methylpyridin-2-yloxy]ethyl ester pyridine-2-ylcarbamate acid.

24. Connection on p. 22:

N-[2-(2-hydroxyethoxy)-3-(2-methoxyphenoxy)-6-methylpyridin-4-yl] -5-isopropylpyridine-2-sulfonamide.

25. Connection on p. 4, in which Z denotes OR8.

26. Connection on p. 25:

methyl-3-(4-tert-butylbenzenesulfonamide)-4-(2-methoxyphenoxy)-5-[2-(pyrimidine-2-yloxy)ethoxy]benzoate,

4-tert-butyl-N-{ 2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)-3-[2-(pyrimidine-2-yloxy)ethoxy]phenyl}benzosulfimide,

4-tert-butyl-N-{ 2-(2-methoxyphenoxy)-5-(morpholine-4-carbonyl)-3-[2-(pyridine-2-yloxy)ethoxy]phenyl}benzosulfimide,

4-(3-methoxyphenoxy)-3-(4-methylsulfonylamino)-N-phenyl-5-[2-(pyrimidine-2-yloxy)ethoxy]benzamide,

4-(3-methoxyphenoxy)-3-(4-methylsulfonylamino)-N-phenyl-5-[2-(pyridine-2-yloxy)ethoxy]benzamide,

N-{ 2-(3-methoxyphenoxy)-5-(morpholine-4-carbonyl)-3-[2-(pyrimi is)-3-[2-(pyridine-2-yloxy)ethoxy]phenyl}-4-methylsulfonylmethane.

27. Pharmaceutical composition having antagonistic activity on the endothelin-containing compound according to any one of paragraphs.1 - 26 and conventional carriers and adjuvants.

Priority points:

20.12.94 - PP.2 - 24;

31.10.95 - PP.1, 25 - 27.

 

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