CN1064965C - Novel sulfonamides compound and its use as medicine - Google Patents

Abstract

The compounds of formula I are endothelin receptor inhibitors, wherein the substituents are described in the specification, and they can be used for the treatment of diseases related to endothelin activity, especially circulatory diseases such as hypertension, local ischemia, vasospasm and angina pectoris.

Description

New sulfonamide compounds and their use as medicines

The present invention relates to novel sulfonamide compounds and their use as medicines. In particular, the present invention relates to novel compounds of the formula

Wherein R ¹ refers to a heterocyclic group; R ² refers to hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkoxy lower alkyl, lower alkylsulfonyl lower alkoxy, phenyl, Lower alkylphenyl, lower alkoxyphenyl, lower alkylenedioxyphenyl, phenyl lower alkyl, lower alkylphenyl lower alkyl, lower alkoxyphenyl lower alkyl, lower alkylene Alkyldioxyphenyl lower alkyl, heterocyclyl or heterocyclyl lower alkyl; ^R means lower alkyl, lower alkoxy, formyl, halogenated lower alkyl, hydroxy lower alkyl, amino Lower alkyl or -CH ₂ OA-lower alkyl, -(CH ₂ ) _m -O-(CR ⁿ R ^b ) _n OH, -(CH ₂ ) _m -O-(CR ⁿ R ^b ) _n OR ⁹ , -(CH ₂ ) _m -O-(CR ⁿ R ^b ) _n NH ₂ or -(CH ₂ ) _m -O-(CR ^a R ^b ) _n -BR ⁹ ; R ⁴ -R ⁸ refers to hydrogen, lower alkanes Oxygen or halogen; R ⁹ means heterocyclyl; phenyl or phenyl substituted by lower alkyl, lower alkoxy and/or halogen, or lower alkyl; R ⁿ and R ^b mean hydrogen or lower alkane A means ketalized 1,2-dihydroxy-ethylene; B means -OC(O)O-, OC(O)NH-, -NHC(O)NH- or -NHC(O) O-; n means 2, 3 or 4; and m means 0 or 1.

The term "lower" as used herein means a group containing 1-7 carbon atoms, preferably 1-4 carbon atoms. Alkyl, alkoxy, alkylthio and alkyl as a constituent of alkanoyl may be straight-chain or branched. Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl are examples of such alkyl groups. Halogen means chlorine, bromine and iodine, preferably chlorine. Lower alkylenedioxyphenyl is, for example, ethylenedioxyphenyl. Ketalized 1,2-dihydroxyethylene is, for example, 2,2-dimethyl-1,3-dioxolane-4,5-diyl. Examples of heterocyclyl are especially monocyclic or bicyclic rings mono- or disubstituted or unsubstituted by eg lower alkyl, lower alkanoyl, halogen or by another heterocyclyl containing heteroatoms containing oxygen, nitrogen or sulfur. For example 2- and 3-furyl, pyrimidinyl, 2-, 3- and 4-pyridyl, 1,2- and 1,4-diazinyl, morpholino, 2- and 3-thienyl, isoxane Azolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzofuryl, benzothienyl, indolyl, purinyl, quinolinyl, isoquinolyl and quinazolinyl. Examples of heterocyclyl R ¹ are especially substituted or unsubstituted pyridyl, pyrimidinyl, thienyl and isoxazolyl. Examples of heterocyclyl R ² (sic) are especially pyrimidinyl and morpholino. Examples of heterocyclyl ^R9 are especially pyridyl, pyrimidinyl and furyl.

Preferred compounds of formula I are compounds wherein ^R is monocyclic S-, N- and/or O-heterocyclyl, especially unsubstituted or replaced by lower alkyl, halogen, amino, mono-lower alkylamino Or di-lower alkylamino or lower alkanoyl substituted pyridyl, pyrimidinyl, isoxazolyl, furyl and thienyl. In addition, preferably wherein ^R is hydrogen, pyrimidinyl, pyridyl, morpholino, thiomorpholino, piperidino, pyrrolidino, benzodioxolyl, lower Alkoxyphenyl or lower alkylthio compound of formula I, and [wherein] R ³ is -O-(CR ^a R ^b ) _n OH, -O-(CR ^a R ^b ) _n NH ₂ or -O( CH ₂ ) ₂ -BR ⁹ , and R ⁹ is a monocyclic N- and/or O-heterocyclyl (especially pyridyl, pyrazinyl or furyl) compound of formula I.

Of particular interest are those wherein R ¹ is pyridyl substituted by lower alkyl, R ² is morpholino, R ³ is -O(CH ₂ ) ₂ OC(O)NHR ⁹ , R ⁴ is lower alkoxy and R ⁵ -R ⁸ are hydrogen compounds of formula I. Preferred ^R9 groups are heterocyclyl, especially pyridyl such as 2-pyridyl.

The compounds of formula I above are endothelin receptor inhibitors. They are therefore useful in the treatment of diseases associated with endothelin activity, especially circulatory diseases such as hypertension, ischemia, vasospasm and angina.

The compound of formula I can be prepared by the following method: a) compound of formula II

Wherein R ¹ , R ² and R ⁴ -R ⁸ have the same meaning as before, and Hal is a halogen, reacting with the compound of the following formula

HO(CR ^a R ^b ) _n XH

wherein n, R ^a and R ^b have the same meanings as before, and X refers to O or NH, or b) the compound of formula III

Wherein R ² -R ⁸ have the same meaning as before, and react with the compound of the following formula

R ¹ SO ₂ Z

wherein R ¹ has the same meaning as before, and therefore Y represents halogen and Z represents amino, or Y represents amino and Z represents halogen, or c) the compound of formula IV

Wherein R ¹ , R ² , R ⁴ -R ⁸ , R ^a , R ^b , X, m and n have the same meanings as before, c1) react with isocyanates of formula R ⁹ NCO or carbamoyl chloride compounds of formula R ⁹ NCOCl, wherein R ⁹ has the same meaning as before, or c2) reacts with phosgene, and then reacts with an alcohol of formula R ⁹ OH; or reacts with a chloroformate of formula R ⁹ OC(O)Cl; or d) wherein R ³ represents halo The formula I compound of lower alkyl is reacted with the following formula compound

HO(CH) ₂ -A-lower alkyl

wherein A represents a ketalized 1,2-dihydroxy-ethylene group and, if desired, the substituents present on the resulting compound of formula I can be altered and/or converted into a salt.

In the reaction of a compound of formula II with a compound of formula HO(CR ^a R ^b ) _n XH, the compound of formula HO(CR ^a R ^b ) _n XH may conveniently be used in the form of an alkali metal alkoxide. Preference is therefore given to using the corresponding diols or aminoalcohols such as ethylene glycol or aminoethanol (when n=2) as solvents. The alkali metal alkoxide is preferably sodium alkoxide. The reaction is conveniently carried out under heating, for example to 40-120°C. In a preferred embodiment, the compound of the formula HO(CR ^a R ^b ) _n XH is used as the monosodium salt of ethylene glycol, propylene glycol or butylene glycol or as the monosodium salt of aminoethanol, aminopropanol or aminobutanol.

The reaction of a compound of formula III with a compound of formula R ¹ SO ₂ Z can be carried out according to known methods for the preparation of sulfonamides, for example in an inert organic solvent such as dimethylsulfoxide, conveniently under heating and under a protective atmosphere such as performed under an argon atmosphere.

The reaction of process c1) can be carried out according to known methods for the preparation of carbamates and ureas, respectively, from alcohols and amines. Thus, compounds of formula IV can be converted to compounds of formula I wherein B is -OC(O)NH- using isocyanates of formula R ⁹ NCO under heating in a suitable anhydrous organic solvent such as a hydrocarbon such as toluene. Isocyanates can be generated in situ from azides of formula R ⁹ CON ₃ by thermal decomposition. Likewise, compounds of formula I, wherein B is -NHC(O)NH-, can be obtained using compounds of formula IV, wherein B is NH.

According to process c2), a compound of formula IV, wherein B is oxygen, can be reacted with phosgene and then an alcohol of formula R ⁹ OH to give a compound of formula I, wherein A is a -OC(O)O- group. Phosgene can be replaced by phosgene salts such as diphosgene (Cl-COOCCl ₃ ) or triphosgene (CO(OCCl ₃ ) _2. Similarly starting from compounds of formula IV where B is NH, one can obtain where B is -NHC ( O) Compounds of formula I of O-. Phosgene can be conveniently used in the form of a solution in an inert anhydrous organic solvent (for example, a hydrocarbon such as toluene). The reaction with phosgene can be carried out at room temperature. The acid chloride obtained in the form of an intermediate , conveniently react directly with the alcohol ^R9OH under heating.

The reaction of method d) can be carried out under the reaction conditions required for method a) to obtain the compound of formula I wherein R ³ is -CH ₂ OA-lower alkyl.

The substituents present in the compounds of formula I thus obtained may be varied. Methyl ^R3 can thus be converted to formyl by oxidation. The oxidation reaction can be carried out according to methods known per se, eg with selenium dioxide. The formyl group in the compound thus obtained can be reduced to a hydroxymethyl group. The reduction reaction can be carried out according to methods known per se, for example with a reducing agent such as _NaBH4 . The methylol group can be converted to a halomethyl group by reaction with a halogenating agent such as POCl ₃ /PCl ₅ . Furthermore, N-heterocyclic groups such as pyridyl can be oxidized to N-oxides. All these reactions can be carried out by methods known per se. The compounds of formula I can be converted into salts, such as alkali salts such as sodium and potassium salts or alkaline earth metal salts such as calcium or magnesium salts, according to methods known per se.

If the compounds used as starting materials are not known or their preparation is described below, these compounds can be prepared analogously to known methods or as described in more detail hereinafter.

The inhibitory activity of the compound of formula I to the endothelin receptor can be confirmed by the following experimental method: I: the inhibitory effect of endothelin binding to the recombinant ETA receptor

The cDNA encoding human placental ETA receptor was cloned (M. Adachi, Y.-Y. Yang, Y. Furuichi and C. Miyamoto, BBRC180, 1265-1272) and expressed in the baculovirus insect cell system. After infection, baculovirus insect cells were isolated from 23 liters of fermentation by centrifugation (3000 x g, 15 min, 4°C) for 60 hours and resuspended in Tris buffer (5 mM, pH 7.4, 1 mM MgCl ₂ ). , and centrifuged again. The resuspended and centrifuged cells were suspended in 800 ml of the same buffer and lyophilized at -120°C. Cells disintegrate when the suspension in the hypotonic buffer mixture melts. After repeated lyophilization/thawing cycles, the suspension was stirred well and centrifuged (25000 xg, 15 min, 4°C). After suspending in Tris buffer (75 mM, pH 7.4, 25 mM MgCl ₂ , 250 mM sucrose), 1 ml aliquots (protein content about 3.5 mg/ml) were stored at -85°C.

For binding assays, lyophilized membrane preparations were melted and centrifuged at 25,000 g for 10 minutes at 20°C before being resuspended in assay buffer (50 mM Tris buffer, pH 7.4, containing 25 mM MnCl ₂ , 1 mM EDTA and 0. 5% bovine serum albumin). 100 μl of this membrane suspension containing 70 μg protein was incubated with 50 μl 1251-endothelin (specific activity 2200 Ci/mMol) in assay buffer (25,000 cpm, final concentration 20 mM) and 100 μl assay buffer containing different concentrations of test compounds . The cultivation was performed at 20°C for 2 hours or at 4°C for 24 hours. Free and membrane-bound radioligand was separated by filtration through glass fiber filters.

The inhibitory activity of the compounds of formula I demonstrated in this experiment is expressed in the table as IC50, i.e. the concentration [nM] required to inhibit 50% of the specific binding of 1251-endothelin.

Compounds of the Examples in Table 1 IC50[nM]34 0.351 0.4II. Inhibition of endothelin-induced contraction in isolated rat aortic rings

Rings 5 mm long were excised from the thoracic aorta of mature Wistar-Kyoto rats. Gently rub the inner surface to remove the inner skin. In a separate bath, each ring was immersed in 10 ml of Krebs-Henseleit solution at 37°C while bubbling with 95% oxygen and 5% carbon dioxide. The isometric stretching of each ring was measured. The loop was stretched to a pre-tension of 3 grams. After 10 min incubation with test compound or vehicle, cumulative doses of endothelin-1 were added. The activity of test compounds was determined by observing the rightward shift of the endothelin-1 dose-activity curve in the presence of different concentrations of antagonist. This rightward shift (or "dose ratio", DR) corresponds to the quotient of the EC50 values for endothelin-1, the concentration of endothelin required for half-maximal contraction, in the presence and absence of antagonist .

According to the following equation for the "dose ratio" DR of each individual dose-activity curve, a computer program was used to calculate the corresponding PA2 value, which is a measure of the activity of the test compound.

PA2=log(DR-1)-log(antagonist-concentration)

In the absence of the test compound, the EC50 value of endothelin was 0.3 nM.

Table 2 gives the PA2 values obtained with the compounds of formula I.

The compound of table 2 embodiment dose ratio (turn right) 34 9.751 9.2

Since the compound of formula I is capable of inhibiting endothelin binding, it can be used as a drug for the treatment of diseases associated with increased frequency of vasoconstriction. Examples of such diseases are hypertension, coronary disease, cardiac insufficiency, renal and myocardial ischemia, renal insufficiency, dialysis, cerebral ischemia, cerebral infarction, migraine, subarachnoid hemorrhage, Raynaud's syndrome and pulmonary high pressure. They may also be used in atherosclerosis, prophylaxis of restenosis after balloon dilation of vessels, inflammation, gastric and duodenal ulcers, ulcus cruris, Gram-negative sepsis, shock, glomerulonephritis, renal Colic, glaucoma, asthma, treatment and prevention of complications of diabetes and complications resulting from the administration of cyclosporine, and other diseases associated with endothelin activity.

The compounds of formula I can be administered orally, rectally, parenterally (eg intravenously, intramuscularly, subcutaneously, intrathecally or transdermally); or sublingually or in the form of ophthalmic preparations, or in the form of aerosols. Oral capsules, tablets, suspensions or solutions, suppositories, injections, eye drops, ointments or spray solutions are examples of administration forms.

Preference is given to administering intravenous, intramuscular or oral administration forms. The effective dose of a compound of formula I administered will depend on the nature of the particular active ingredient, the age and needs of the patient and the mode of administration. Generally, the dosage may be about 0.1-100 mg per kilogram of body weight per day. Formulations containing compounds of formula I may contain inert or pharmaceutically active additives. Tablets or granules may contain, for example, a series of binders, fillers, carriers or diluents. Liquid preparations may be presented as sterile water-miscible solutions. Capsules may contain, in addition to the active ingredient, filler or thickening agents. Furthermore, flavoring additives as well as substances acting as preservatives, stabilizers, wetting agents and emulsifiers and salts, buffers and other additives to improve the osmotic pressure may also be present.

The carriers and diluents may include organic or inorganic substances such as water, gelatin, lactose, starch, magnesium stearate, talc, acacia, and polyethylene glycols, among others. The first condition is that all adjuvants used in the preparation of the formulations are non-toxic.

The following examples illustrate the invention in more detail.

Example 1

At 50°C, 1.29 g of sodium was dissolved in 50 ml of ethylene glycol. Then, at the same temperature, 3.0 g of 5-tert-butyl-thiophene-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bis pyrimidin-4-ylamide, and the mixture was heated at 100°C for 4.5 hours. The clear solution was poured into ice/dilute hydrochloric acid solution, and the mixture was extracted 3 times with 0.21 each of ethyl acetate. The organic phase was washed 3 times with water, dried over sodium sulfate and finally evaporated on a rotary evaporator (sic). This gives 5-tert-butyl-thiophene-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2' as a pale yellow foam -bipyrimidin-4-ylamide. MS: 493 (M- _SO2 ). Preparation of starting compounds: a) Dissolve 2.0 g of 5-tert-butyl-thiophene-2-sulfonyl chloride in 30 ml of methanol at room temperature, treat with 50 ml of 25% ammonia, and heat to reflux for 4.5 hours. The mixture was concentrated on a rotary evaporator, the residue was treated with water, extracted with ethyl acetate (150 ml), dried over magnesium sulfate and concentrated again on a rotary evaporator. 5-tert-butyl-2-thiophene-2-sulfonamide was thus obtained as white crystals. MS: 219(M). Potassium salt was obtained using potassium tert-butoxide in methanol. b) 3.49 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine were dissolved in 125 ml of dimethylsulfoxide. 3.855 g of potassium (5-tert-butyl-thiophene-2-sulfonamide) was added at room temperature, and the solution was stirred at room temperature for 20 hours. It was treated with another 1.285 g of potassium (5-tert-butyl-thiophene-2-sulfonamide) and allowed to react for a further 2 hours at room temperature. While vigorously stirring, 200 ml of water were added to the reaction mixture, [and] then 200 ml of diethyl ether were added, whereby a fine, white crystalline precipitate formed, which was filtered off with suction. The crystals are suspended in dilute aqueous hydrochloric acid, stirred at room temperature for 0.5 h, filtered off with suction and dried under high vacuum. This gives 5-tert-butyl-thiophene-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide as white crystals solid. MS: 523.4 (M+H).

Example 2

3.23g of 5-tert-butyl-thiophene-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine- A solution of 4-ylamide, 1.71 g of 2-pyridine formic acid azide and 70 mg of p-dimethylaminopyridine in toluene (50 ml) was heated at 80°C for 2 hours. Toluene was removed on a rotary evaporator and the residue was partitioned between dichloromethane (0.51) and 1N hydrochloric acid solution (0.351). The organic phase was dried over magnesium sulfate and finally the solvent was removed on a rotary evaporator. The crude product was purified by chromatography on silica gel using dichloromethane/methanol (5/1) as eluent. This gives pyridin-2-ylcarbamate 2-[6-(5-tert-butyl-thiophen-2-ylsulfonylamino)-5-(2-methoxy-phenoxy)-2,2' -bipyrimidin-4-yloxy]-ethyl ester as a pale yellow solid which was recrystallized from dichloromethane/methanol. MS: 678.3 (M+H).

Example 3

26 mg of sodium are dissolved in 2 ml of ethanolamine at 50° C., 150 mg of the compound of example 1 b) are treated in portions at the same temperature, and the solution is heated at 100° C. for 4 hours. The mixture was then poured into ice/water and the pH was adjusted to 6 with 3N HCl, whereby a pale yellow crystalline solid was isolated which was filtered off with suction, washed with water and dried under high vacuum. Thus, 5-tert-butyl-thiophene-2-sulfonic acid 6-(2-amino-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-sulfonic acid was obtained as yellow crystals Bipyrimidin-4-ylamide. MS: 557.4 (M+H).

Example 4

100mg of 5-tert-butyl-thiophene-2-sulfonic acid 6-(2-amino-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine-4- The base amide was dissolved in 10 ml of toluene, treated with 53 mg of 2-pyridylcarboxylic acid azide, and the solution was heated at 120°C for 4 hours. Toluene was removed on a rotary evaporator and the residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and finally concentrated on a rotary evaporator. The residue is purified by chromatography on silica gel using dichloromethane/methanol (30/1) as eluent. This gives 5-tert-butyl-thiophene-2-sulfonic acid 5-(2-methoxy-phenoxy)-6-[2-(3-pyridin-2-yl-ureido)-ethoxy ]-2,2'-bipyrimidin-4-ylamide as a crystalline solid. MS: 677.4 (M+H).

Example 5

At room temperature, to a solution of 162.5 mg 4-amino-6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine in 10 ml tetrahydrofuran was added 92 mg NaH (65% ), the solution was stirred at room temperature for 1.5 hours, and then 162.5 mg of 5-tert-butyl-thiophene-2-sulfonyl chloride was added at the same temperature. The mixture was stirred at room temperature for another 2 hours, poured into ice/water, extracted with ethyl acetate, the aqueous phase was acidified and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is purified by chromatography on silica gel using dichloromethane/methanol (20/1) as eluent. This gives 5-tert-butyl-N-[6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-thiophene-2-sulfonic Amide, yellow powder. MS: 463 (M- _SO2 ). Preparation of starting compounds: a) 2.09 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine (EP-A-0 526 708) were suspended in Into 75 ml of methanol, 150 ml of ammonia was condensed at 75°C via the feed tube. The reaction mixture was brought to room temperature overnight, concentrated under water jet vacuum and the residue was partitioned between a small amount of water and dichloromethane (500ml). The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was triturated with ether and the resulting solid was isolated and dried under high vacuum. 4-Amino-6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine is thus obtained as a fine, almost white powder. MS: 329(M). b) At room temperature, 6.55 g of sodium methylate was added to a solution of 4-amino-6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine in 200 ml of methanol, and then The solution was heated to reflux for 32 hours. Methanol was removed on a rotary evaporator, the residue was dissolved in dichloromethane and washed with 1N hydrochloric acid. The organic phase is dried over magnesium sulfate and finally the solvent is removed under water jet vacuum. The crude product was purified by chromatography on silica gel using dichloromethane/methanol (10/1) as eluent. 4-Amino-6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine is thus obtained as a lemon yellow powder. MS: 325(M).

Example 6

According to the method similar to Example 1, from sodium glycolate and 5-pentyl-thiophene-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bis Pyrimidin-4-ylamide yields 5-pentyl-thiophene-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bis Pyrimidin-4-ylamide as a white solid. MS: 570.3 (M+H). Preparation of starting compounds: a) from 2-pentyl-5-(tert-butylsulfonylamino)thiophene (EP-A-0 512 675) and ethanol/conc. sulfonamide) potassium, and salt formation with potassium tert-butoxide in methanol. b) According to a method similar to that of Example 1b), through (5-n-pentyl-thiophene-2-sulfonamide) potassium and 4,6-dichloro-5-(2-methoxy-phenoxy) -2,2'-bipyrimidine reaction to give 5-pentyl-thiophene-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine-4- amide as a white solid. MS: 545(M).

Example 7

According to a method similar to Example 2, from 2-pyridylcarboxylic acid azide and 5-pentyl-thiophene-2-sulfonic acid 6-(2-hydroxyl-ethoxy)-5-(2-methoxy -phenoxy)-2,2'-bipyrimidin-4-ylamide to give pyridin-2-ylcarbamate 2-[5-(2-methoxy-phenoxy)-6-(5-pentyl -thiophen-2-ylsulfonylamino)-2,2'-bipyrimidin-4-yloxy]-ethyl ester as a white solid. MS: 692.4 (M+H).

Example 8

According to a method similar to Example 2, from sodium glycolate and 5-(2,2-dimethyl-propionyl)-thiophene-2-sulfonic acid 6-chloro-5-(2-methoxy-benzene Oxy)-2,2'-bipyrimidin-4-ylamide to give 5-(2,2-dimethyl-propionyl)-thiophene-2-sulfonic acid 6-(2-hydroxy-ethoxy)- 5-(2-Methoxy-phenoxy)-2.2'-bipyrimidin-4-ylamide, pink powder. MS: 586.3 (M+H).

Preparation of starting compounds: a) In a manner analogous to that of Example 1b), through the potassium salt of 5-(2,2-dimethylpropionyl)thiophene-2-sulfonamide (Preparation: J Org. Chem., Vol 56,4260) reacts with 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine to give 5-(2,2-dimethyl-propionyl )-thiophene-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide as a crystalline solid. MS: 560.1 (M+H). Potassium salt was obtained using potassium tert-butoxide in methanol.

Example 9

According to a method similar to Example 2, from 2-pyridylcarboxylic acid azide and 5-(2,2-dimethyl-propionyl)-thiophene-2-sulfonic acid 6-(2-hydroxy-ethoxy )-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide to give pyridin-2-ylcarbamate 2-[6-[5-(2,2-di Methylpropionyl)-thiophen-2-ylsulfonylamino]-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yloxy]-ethyl ester, beige powder. MS: 704.3 (M+H).

Example 10

At 50°C, 1.75 g of sodium was dissolved in 70 ml of ethylene glycol. Then, at the same temperature, add 4.9 g of 5-isopropyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bis pyrimidin-4-ylamide and the mixture was heated at 100°C for 4 hours. The clear solution was poured into 200 ml of water, the pH was adjusted to 1 with 3N hydrochloric acid, the isolated yellow crystals (sic) were filtered off with suction, washed with water, then with ether, and finally dried under high vacuum. 5-Isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'- Bipyrimidin-4-ylamide. MS: 537.3 (M-H). Preparation of starting compounds: a) 4.0 g of 5-isopropylpyridine-2-sulfonamide were dissolved (sic) in 40 ml of methanol at room temperature, 2.308 g of potassium tert-butoxide were added and stirred for a further 20 minutes. It was then concentrated thoroughly on a rotary evaporator and the potassium salt thus obtained was dried under high vacuum. b) Dissolve 3.49g 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine in 125ml dimethyl sulfoxide, add 4.7g ( 5-isopropyl-pyridine-2-sulfonamide) potassium, and the solution was stirred at room temperature for 20 hours. Under vigorous stirring, it was poured into 350 ml of water and 90 ml of ether, and the pH of the solution was adjusted to 1 by adding 3N hydrochloric acid. The white crystalline precipitate is filtered off with suction, washed with water and then with diethyl ether. The crystals are suspended in dilute aqueous hydrochloric acid (100 ml water and 50 ml (sic) 1N hydrochloric acid), stirred for 5 minutes, filtered off with suction, washed with water and dried under high vacuum. 5-Isopropyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide was thus obtained as white crystals solid. MS: 511.3 (M+H).

Example 11

2.0g of 5-isopropyl-pyridine-2-sulfonic acid 6-(2-amino-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine- The 4-ylamide was dissolved in 80 ml of toluene, treated with 1.1 g of 2-pyridylcarboxylic acid azide, and the solution was heated at 90°C for 4 hours. It was concentrated on a rotary evaporator and the residue was partitioned between 1N hydrochloric acid and ethyl acetate. The organic phase is dried over magnesium sulfate, the solvent is finally removed under water jet vacuum and the residue is purified by chromatography on silica gel using dichloromethane/methanol (30/1) as eluent. This gives pyridin-2-ylcarbamate 2-[6-(5-isopropyl-pyridin-2-ylsulfonylamino)-5-(2-methoxy-phenoxy)-2,2' -bipyrimidin-4-yloxy]-ethyl ester as yellow crystals. MS: 657.3 (M+H).

To prepare the dihydrochloride salt, the compound is dissolved in dichloromethane and treated with the corresponding amount of 4.4N hydrochloric acid in ethanol at room temperature. The solution was concentrated on a rotary evaporator and the isolated crystalline solid was isolated and dried at 60° C. under high vacuum for 4 hours (sic).

Example 12

According to a method similar to Example 4, from 5-isopropyl-pyridine-2-sulfonic acid 6-(2-amino-ethoxy)-5-(2-methoxy-phenoxy)-2, 2'-bipyrimidin-4-ylamide and 2-pyridinylcarboxylic acid azide give the desired 5-isopropyl-pyridine-2-sulfonic acid 5-(2-methoxy-phenoxy)-6 -[2-(3-Pyridin-2-yl-ureido)-ethoxy]-2,2'-bipyrimidin-4-ylamide as yellow crystals. MS: 656.3 (M+H).

Following a procedure analogous to Example 3, the starting compound was obtained as a yellow foam from ethanolamine and the compound from paragraph b) of Example 10. MS: 538.3 (M+H).

Example 13

According to a method similar to Example 10, from pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide and ethylene glycol Pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide was obtained as white crystals. MS: 615.4 (M-H). Preparation of starting compound: a) 1.7g of 2-pyridylsulfonyl chloride (J Org.Chem., Vol.54,389) was dissolved in 30ml of ethanol, while cooling with ice, 30ml of 25% ammonia solution was added, and then The mixture was heated to reflux for 4 hours. The reaction solution was concentrated on a rotary evaporator, the residue was partitioned between ethyl acetate and water, the organic phase was dried over magnesium sulfate and finally concentrated on a rotary evaporator to isolate 2-pyridylsulfonamide as a beige crystalline solid. MS: 469.2 (M+H). Potassium tert-butoxide in methanol was used to obtain the potassium salt. b) According to a method similar to that of Example 10b), through (2-pyridylsulfonamide)-potassium and 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2' -bipyrimidine reaction to give pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide as white crystals. MS: 495.3 (M-H).

Example 14

According to a method similar to Example 11, from pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine- 4-ylamide and 2-pyridinylcarboxylic acid azide to give pyridin-2-ylcarbamate 2-[5-(2-methoxy-phenoxy)-6-pyridin-2-ylsulfonylamino)- 2,2'-bipyrimidin-4-yloxy]-ethyl ester, white crystal. MS: 615.4 (M-H).

Example 15

According to a method similar to Example 10, from pyridine-3-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide and ethylene glycol Pyridine-3-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide is obtained as white crystals. MS: 496(M). Preparation of starting compounds: a) According to a method similar to that of Example 13a), 3-pyridylsulfonyl chloride (J Org.Chem., Vol.54, 389) and ammonia were obtained as a white crystalline solid. Sulfonamide, potassium tert-butoxide in methanol to give the potassium salt. b) According to a method similar to that of Example 10b), through (3-pyridylsulfonamide)-potassium and 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2' -bipyrimidine reaction to give pyridine-3-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide as white crystals. MS: 470(M).

Example 16

According to a method similar to Example 11, from pyridine-3-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine- 4-ylamide and 2-pyridinylcarboxylic acid azide to give pyridin-2-ylcarbamate 2-[5-(2-methoxy-phenoxy)-6-pyridin-3-ylsulfonylamino)- 2,2'-bipyrimidin-4-yloxy]-ethyl ester, white crystal. MS: 615.4 (M-H),

Example 17

213mg 6-[2-(tert-butyl-dimethyl-silanoxy (silanoxy))-ethoxy]-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine-4 The -ylamine was dissolved in 15 ml tetrahydrofuran, treated with 92 mg sodium hydride (65%) at room temperature, stirred at room temperature for 2 hours, and then 155 mg 5-tert-butyl-thiophene-2-sulfonyl chloride was added in portions. The solution was stirred at room temperature for 2 hours, poured into ice water and extracted twice with a total of 200 ml of ethyl acetate. After the usual work-up of the organic phase, the silyl-protected crude product is purified by chromatography on silica gel using dichloromethane/ethyl acetate (8/1) as eluent.

The resulting brown foam (219mg) was dissolved in 15ml acetonitrile, treated with 1.5ml HF solution (40%) at room temperature and stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and half-saturated sodium chloride solution, and the organic phase was worked up as usual. The crude product was purified by chromatography on silica gel using dichloromethane/ethyl acetate (4/1) as eluent and recrystallized from ether/hexane. This gives 5-tert-butyl-thiophene-2-sulfonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl Amide, white crystal. MS: 449 (M- _SO2 ). Preparation of starting compounds: a) Follow M. Julia and I. The method of de Rosnay, Chimie Therapeutique 5 (1969), 334, conversion of 3-methoxyphenol to 2-chloro-5-methoxyphenol with sulfuryl chloride. b) Dissolve 18.2 g of 2-chloro-5-methoxyphenol in 150 ml of absolute ethanol. 9.3 g of sodium methoxide was added, followed by 25 g of dimethyl chloromalonate. The reaction mixture was stirred at 50°C for 2 hours. After distilling off the solvent, the residue was partitioned between toluene and water in a separatory funnel and washed neutrally. After crystallization from ethanol, (2-chloro-5-methoxy)phenoxy-dimethylmalonate is obtained as white crystals, melting point 68-69°C. c) Dissolve 1.43 g of sodium in 70 ml of methanol. Then 5.8 g of (2-chloro-5-methoxy)phenoxy-dimethylmalonate and 2.29 g of formamidine were added; the reaction mixture was stirred at reflux for 1.5 hours. The solvent was then distilled off, the residue was dissolved in water, the aqueous phase was extracted with ethyl acetate, the organic phase was discarded, the aqueous phase was acidified to pH 4 with acetic acid, and 5-(2-chloro-5-methoxy)phenoxy Base-4,6-(1H,5H)-pyrimidinedione, white powder. MS: m/e = 268 (M). d) 3.75g of 5-(2-chloro-5-methoxy)phenoxy-4,6-(1H,5H)-pyrimidinedione, 5.4g of N-ethyldiisopropylamine, A mixture of 12.5 ml _POCl3 in 20 ml dioxane was stirred at reflux for 18 hours. After distilling off the volatile constituents, the residue was partitioned between ethyl acetate and water and washed neutrally. After distilling off the solvent, the compound is purified on silica gel using dichloromethane as eluent. 4,6-Dichloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine is obtained as white crystals with a melting point of 88-89° C. after recrystallization from ethanol. e) At -78°C, add about 500ml of _NH3 to 9.9g of 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine from Example 1d) in 400ml solution in ethanol. Thereafter, the reaction mixture was stirred at -78°C for 15 hours. and stirred at room temperature for 50 hours and finally evaporated. The residue was partitioned between ethyl acetate and water and the organic phase was worked up. 6-Chloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-ylamine is thus obtained as yellow crystals. MS: 285(M). f) Add 8.53 of the compound obtained above to a solution of 0.82 g of sodium in 100 ml of ethylene glycol at 50°C. The solution was heated to 100°C for 20 hours. It was then partitioned between half saturated _NH4Cl solution and dichloromethane and worked up. Thus obtained 8.3 g of 2-[6-amino-5-(2-chloro-5-methoxy-phenoxy)-4-pyrimidin-4-yloxy]-1-ethanol as a white solid without Purification involves silylation. To this end, the abovementioned substance (8.3 g) was dissolved in 300 ml of dichloromethane, treated with 8.15 g of dimethylaminopyridine and finally with 10.05 g of tert-butyldimethylsilyl chloride at room temperature. The reaction solution was stirred at room temperature for 5 hours. It was then filtered, the solution was concentrated, the evaporated residue was partitioned between half-saturated _NH4Cl solution and ethyl acetate, and the organic phase was worked up. Then crystallization from dichloromethane/hexane gave 7 g of 6-[2-(tert-butyl-dimethyl-silyloxy)-ethoxy]-5-(2-chloro-5-methoxy- phenoxy)-pyrimidin-4-ylamine. MS: 410 (M- _CH3 ).

Example 18

According to a method similar to Example 2, from 5-tert-butyl-thiophene-2-sulfonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy )-pyrimidin-4-ylamide and 2-pyridinylcarboxylic acid azide to give pyridin-2-ylcarbamate 2-[6-(5-tert-butyl-thiophen-2-ylsulfonylamino)-5-( 2-Chloro-5-methoxy-phenoxy)-bipyrimidin-4-yloxy]-ethyl ester as white crystals. MS: 634.3 (M+H).

Example 19

According to a method similar to that of Example 2, the compound of Example 17 and 4-pyridylcarboxylic acid azide were used to obtain pyridin-4-ylcarbamic acid 2-[6-(5-tert-butyl-thiophene-2-ylsulfonic acid Amido)-5-(2-chloro-5-methoxy-phenoxy)-bipyrimidin-4-yloxy]-ethyl ester, white crystals. MS: 634.3 (M+H).

Example 20

According to a method similar to Example 17, with 6-[2-(tert-butyl-dimethyl-silyloxy)-ethoxy]-5-(2-methoxy-phenoxy)-pyrimidine- 4-ylamine as a reaction component to give 5-tert-butyl-thiophene-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidine-4 -ylamide as a white solid. MS: 479(M).

Example 21

To a sodium glycolate solution obtained from 1.5 ml of ethylene glycol and 46 mg of sodium was added 180 mg of the compound obtained in the above procedure. Add 1ml DMSO to dissolve completely. The mixture was reacted at 90°C for 3 hours. After cooling to room temperature, the reaction medium is acidified to pH 4 with aqueous citric acid and the resulting compound is extracted with ethyl acetate. After distilling off the ethyl acetate, crystallization from ethanol gave N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl ]-5-Isopropyl-pyridine-2-sulfonamide. 175 mg of white crystals were obtained, which decomposed at 180°C. Preparation of starting compound: 306 mg of 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine, 320 mg of 5-isopropyl-2-pyridine-sulfonamide and 180 mg of tert Potassium butoxide was dissolved in 2 ml of DMSO, which was reacted at 90°C for 3 hours. After cooling to room temperature, the reaction medium is acidified with aqueous citric acid; the compound is extracted with ethyl acetate and, after distilling off the solvent, crystallized from ethanol. 250 mg of N-[6-chloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-5-isopropyl-pyridine-sulfonamide was obtained as white crystals, melting point 174-175°C.

Example 22

100mg N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-5-isopropyl-pyridine- 2-Sulphonamide and 38.5 mg of 2-pyridyl-formic acid azide were dissolved in 1 ml of anhydrous dioxane. The solution was stirred at 95°C for 2 hours, whereby nitrogen gas was evolved. After distilling off the solvent, the compound was crystallized from ethanol. 115 mg of pyridin-2-yl-carbamate 2-[5-(2-chloro-5-methoxy-phenoxy)-6-(5-isopropyl-pyridin-2-ylsulfonylamino)- Pyrimidin-4-yloxy]-ethyl ester, white crystal, melting point 190-191°C.

Example 23

According to a method similar to Example 21, 5-isopropyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(3- Methoxy-phenyl)-pyrimidin-4-yl]-pyridine-2-sulfonamide, melting point 139-140°C (crystallization from ethanol). Preparation of starting compounds:

According to the method similar to the second paragraph of Example 21, from 330 mg 4,6-dichloro-2-(3-methoxy-phenyl)-5-(2-methoxy-phenoxy)-pyrimidine and 420mg (5-isopropyl-pyridine-2-sulfonamide) potassium, to obtain 400mg N-[6-chloro-5-(2-methoxy-phenoxy)-2-(3-methoxy-benzene Oxy)-pyrimidin-4-yl]-5-isopropyl-pyridine-2-sulfonamide.

Example 24

According to the method similar to Example 22, from 115mg 5-isopropyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(3 -methoxy-phenyl)-pyrimidin-4-yl]-pyridine-2-sulfonamide and 38.5 mg of 2-pyridyl-formic acid azide to give 120 mg of pyridin-2-yl-carbamic acid 2-[6 -(5-Isopropyl-pyridin-2-ylsulfonylamino)-5-(2-methoxy-phenoxy)-2-(3-methoxy-phenyl)-pyrimidin-4-yl Oxygen] - ethyl ester, melting point 158-160 ° C (crystallization from ethanol).

Example 25a) According to a method similar to Example 21, from 4,6-dichloro-2-methylsulfanyl (sulphanyl)-5-(2-methoxy-phenoxy)-pyrimidine and (5 -isopropyl-pyridine-2-sulfonamide) potassium to give N-[6-chloro-5-(2-methoxy-phenoxy)-2-methylsulfanyl-pyrimidin-4-yl] -5-Isopropyl-pyridine-2-sulfonamide, melting point 192°C (crystallization from ethanol). b) Conversion of this compound to 5-isopropyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-methanol with sodium glycolate Sulfuryl-pyrimidin-4-yl]-pyridine-2-sulfonamide, melting point 76-78°C (crystallization from ethanol).

Example 26

According to the method similar to Example 22, from 100mg 5-isopropyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-methyl Sulfuryl-pyrimidin-4-yl]-pyridine-2-sulfonamide and 2-pyridyl-formic acid azide to give 106 mg of pyridin-2-yl-carbamic acid 2-[6-(5-isopropyl- Pyridin-2-ylsulfonylamino)-5-(2-methoxy-phenoxy)-2-methylsulfanyl-pyrimidin-4-yloxy]-ethyl ester. Melting point 213-214°C (crystallization from ethanol).

Example 27a) from 4,6-dichloro-2-(1,3-benzodioxol-5-yl)-5-(2-methoxy-phenoxy)-pyrimidine and (5-Isopropyl-pyridine-2-sulfonamide) potassium to give N-[6-chloro-2-(1,3-benzodioxol-5-yl)-5-(2 -methoxy-phenoxy)-pyrimidin-4-yl]-5-isopropyl-pyridine-2-sulfonamide. b) Conversion of this compound to N-[2-(1,3-benzodioxol-5-yl)-6-(2-hydroxy-ethoxy)-5 with sodium glycolate -(2-Methoxy-phenoxy)-pyrimidin-4-yl]-5-isopropyl-pyridine-2-sulfonamide, melting point 184°C (crystallization from ethanol).

Example 28

According to a method similar to Example 22, from 116mg N-[2-(1,3-benzodioxol-5-yl)-6-(2-hydroxyl-ethoxy)-5- (2-Methoxy-phenoxy)-pyrimidin-4-yl]-5-isopropyl-pyridine-2-sulfonamide and 2-pyridyl-formic acid azide to give 110 mg of pyridin-2-yl- Carbamic acid 2-[2-(1,3-benzodioxol-5-yl)-6-(5-isopropyl-pyridin-2-ylsulfonylamino)-5-(2 -methoxy-phenoxy)-pyrimidin-4-yloxy]-ethyl ester. Melting point 184°C (crystallization from ethanol).

Example 29a) From 4,6-dichloro-2-morpholin-4-yl-pyrimidine and (5-isopropyl-pyridine-2-sulfonamide) potassium, N-[6-chloro-5-( 2-Chloro-5-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-5-isopropyl-pyridine-2-sulfonamide. b) This compound is reacted with sodium glycolate to give N-[5-(2-oxo-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-morpholine- 4-yl-pyrimidin-4-yl]-5-isopropyl-pyridine-2-sulfonamide, melting point 189-190°C (crystallization from ethanol).

Example 30

According to a method similar to Example 22, 116 mg of N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethyl Oxy)-2-morpholin-4-yl-pyrimidin-4-yl]-5-isopropyl-pyridine-2-sulfonamide is converted to pyridin-2-yl-carbamic acid 2-[5-(2- Chloro-5-methoxy-phenoxy)-6-(5-isopropyl-pyridin-2-ylsulfonylamino)-2-morpholin-4-yl-pyrimidin-4-yloxy]-ethyl base ester. Crystallization from ethanol gave 106 mg of white crystals which decomposed at 240°C.

Example 31

According to a method similar to Example 21, from 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine-4- base]-amide and sodium glycolate to give 5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2, 2'-bipyrimidin-4-ylamide, melting point 190°C (crystallization from ethanol). Preparation of starting compounds: a) Follow F. H． The method of Case (JACS 68 (1946), 2547) diazotizes 2-amino-5-picoline and converts it to 2-bromo-5-picoline. b) 4.8 g of this compound in 40 ml of propylene glycol were reacted with 7.4 g of sodium hydrosulfide at 150°C. After cooling to room temperature, 5 ml of acetic acid was added dropwise to the reaction mixture, and 2-mercapto-5-picoline was isolated as a yellow powder. c) With 30 minutes, add 50ml of 1.2 mole sodium hypochlorite dropwise to the biphasic mixture of 40ml of dichloromethane, 20ml of 37% aqueous hydrochloric acid and 3g of 2-mercapto-5-picoline cooled to -10°C. Then, the organic phase was extracted 3 times with water. After distilling off the solvent, 5-methylpyridinesulfonyl chloride was obtained as a pale yellow liquid. d) Reaction of sulfonyl chloride with 25% ammonium hydroxide solution gives 5-picoline-2-sulfonamide. e) put O. 7g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine, 520mg of 5-picoline-2-sulfonamide and 320mg of potassium tert-butoxide were dissolved in 2ml of DMSO , which was stirred at 80°C for 3 hours. After conventional work-up of the reaction mixture, 410 mg of 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine-4- base]-amide.

Example 32

According to a method similar to Example 22, from 105 mg of 5-methyl-pyridine-2-sulfonic acid (6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2 , 2'-bipyrimidin-4-yl]-amide and 30 mg of 2-pyridyl-formic acid azide to give 100 mg of pyridin-2-yl-carbamic acid 2-[5-(2-methoxy-phenoxy )-6-(5-Methyl-pyridin-2-ylsulfonylamino)-2,2'-bipyrimidin-4-yloxy]-ethyl ester as beige crystals. Melting point: decomposes at 198°C.

Example 33a) According to a method similar to Example 22, from 712 mg of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine and (5- Methyl-pyridine-2-sulfonamide) potassium to obtain 580 mg of 5-methyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2-morpholine-4- Base-pyrimidin-4-ylamide. b) Reaction of this compound with sodium glycolate gives 5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)- 2-Morpholin-4-yl-pyrimidin-4-ylamide. Melting point 195-196 ° C (crystallization from ethanol).

Example 34

According to a method similar to Example 22, from 105 mg of 5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2- Morpholin-4-yl-pyrimidin-4-yl-amide and 2-pyridyl-carboxylic acid azide to give 117 mg of pyridin-2-yl-carbamic acid 2-[5-(2-methoxy-phenoxy )-6-(5-Methyl-pyridin-2-ylsulfonylamino)-2-morpholin-4-yl-pyrimidin-4-yloxy]-ethyl ester.

Example 35

105 mg of 5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2- Methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl-amide. After 1 hour at room temperature, the chloroformate was completely formed. Then, the excess reagent was distilled off; the residue was dissolved in a mixture of chloroform and pyridine; 0.5 g of 3-(hydroxymethyl)-furan was added, and the mixture was reacted at 60°C for 3 hours. After conventional work-up, the compound was purified on silica gel (dichloromethane-diethyl ether in a volume ratio of 4:1 was used as eluent). 65 mg furan-3-ylmethyl formate 2-[5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-2-morpholine- 4-yl-pyrimidin-4-yloxy]-ethyl ester, MS: 640.5 [M-H)-].

Example 36

At 120°C under an argon atmosphere, 9.2 g of 4-[4-chloro-5-(2-chloro-5-methoxy-phenoxy)-6-methanol in 130 ml of anhydrous dimethyl sulfoxide Base-pyrimidin-2-yl]-morpholine and 17.8 g of potassium 5-isopropyl-pyridine-2-sulfonamide were heated for 16 hours. Afterwards, dimethyl sulfoxide was distilled off, the residue was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic phase was neutrally washed. The organic phase is dried, the solvent is evaporated and the residue is recrystallized from ethanol. 10.3 g of 5-isopropyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2-morpholin-4-yl-pyrimidine- 4-ylamide, MS: M=534.

Example 37

1 g of the compound obtained in Example 36 and 2.1 g of selenium dioxide in 40 ml of dioxane were stirred at 170°C for 7 hours in an autoclave. The reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The organic phase was dried, the solvent was evaporated and the residue was purified on silica gel with ethyl acetate/hexane. 0.53 g of 5-isopropyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-formyl-2-morpholin-4-yl-pyrimidine- 4-yl amides, melting point 194 ° C.

Example 38

0.1 g of the compound obtained in Example 37 in 3 ml of ethanol was treated with 0.014 g of sodium borohydride. The reaction mixture was stirred at 80°C for 1 hour. Thereafter, ethanol was distilled off, and the residue was partitioned between chloroform and 1N hydrochloric acid. The organic phase is washed with water and dried, the solvent is evaporated and the residue is purified by chromatography on silica gel using chloroform-methanol as eluent. After recrystallization from dichloromethane-ethanol, 0.072 g of 5-isopropyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-hydroxymethyl was obtained -2-morpholin-4-yl-pyrimidin-4-ylamide, melting point 105°C.

Example 39

0.2 g of the compound obtained in Example 38 in 3.5 ml _POCl3 were stirred with 0.083 g _PCl5 for 2 hours at 20°C. Afterwards, _POCl3 was distilled off and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate (sic). The organic phase is washed with water, dried and the solvent is evaporated. The residue was purified by chromatography on silica gel using chloroform-methanol as eluent. 0.150 g of 5-isopropyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-hydroxymethyl-2-morpholin-4-yl-pyrimidine was obtained -4-yl amides, the melting point is 205°C.

Example 40

A sodium glycolate solution was obtained from 0.35 g of ethylene glycol and 0.021 g of sodium, and 0.130 g of the compound obtained in Example 39 was added thereto. The reaction mixture was stirred at 80°C under argon atmosphere for 2 hours. Afterwards, ethylene glycol was distilled off and the residue was partitioned between ethyl acetate and iN hydrochloric acid. The organic phase is washed with water, dried over sodium sulfate and the solvent is distilled off. The residue was recrystallized from ether-petroleum ether. Obtained 0.104g 5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxymethyl)-2-morpholin-4-yl-pyrimidin-4-yl Amide, melting point 166 ° C.

Example 41

According to a method similar to Example 2, pyridin-2-yl-carbamic acid 2-[5-(2-chloro-5-methoxy-phenoxy)-6-(5 -Isopropyl-pyridine-2-sulfonylamino)-2-morpholin-4-yl-pyrimidin-4-ylmethoxy]-ethyl ester, MS: (M-H)-=713.

Example 42

According to a method similar to Example 2, pyridin-2-yl-carbamic acid 5-(2-chloro-5-methoxy-phenoxy)-6-(5-isopropyl) was prepared from the compound obtained in Example 38 yl-pyridin-2-ylsulfonylamino)-2-morpholin-4-yl-pyrimidin-4-ylmethyl ester, MS: (M-H)-=669.

Example 43

According to the method similar to Example 40, from the compound obtained in Example 39 and (RS)-2,2-dimethyl-1,3-dioxolane-4-sodium methoxide, 5-isopropyl- Pyridine-2-sulfonic acid (RS)-5-(2-chloro-5-methoxy-phenoxy)-6-(2,2-dimethyl-1,3-dioxolane-3- (methoxy-methyl)-2-morpholin-4-yl-pyrimidin-4-ylamide, MS: (M-H)-=663.

Example 44

A solution of 0.05 g of the compound prepared in Example 43 in 2 ml of dioxane was treated with 2 ml of 1N hydrochloric acid and heated to 80°C for 15 minutes. After evaporation, the residue was purified by chromatography on silica gel using chloroform-methanol as eluent to give 5-isopropyl-pyridine-2-sulfonic acid (RS)-5-(2-chloro-5-methoxy -Phenoxy)-6-(2,3-dihydroxy-propoxymethyl)-2-morpholin-4-yl-pyrimidin-4-ylamide, melting point 116°C, MS: (M-H)-= 623.

Example 45

At 80°C, 345 mg of sodium was dissolved in 50 ml of dry ethylene glycol. The solution was placed slightly cold, and 1.56g of 5-isopropyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl- Pyrimidin-4-ylamide. The resulting solution was stirred at 140°C for 24 hours, the solvent was removed under high vacuum, and the residue was dissolved in 40 ml of water. After 4 hours at 5°C, the mixture was filtered with suction, the crystals were suspended in 40 ml of water, dissolved in ethyl acetate and treated dropwise with 1N aqueous hydrochloric acid with stirring until the pH dropped to 3.5. The aqueous phase was extracted three times with ethyl acetate, and the organic phase was washed twice with water and once with saturated sodium chloride solution. The combined organic phases were dried and concentrated to give crystals (about 5ml). The crystals are filtered off with suction, washed with ether and dried. 1.144 g (70%) of 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholine were obtained -4-yl-pyrimidin-4-ylamide, white crystal, melting point 157-160°C, MS: (M-H)-=544.4. Preparation of starting compounds:

At 80°C, 1.18g 4,6-dichloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine and 2.12g (8.88mmol) 5- A solution of isopropyl-pyridine-2-sulfonamide potassium salt in 25 mL of anhydrous DMSO was heated for 3 hours until complete disappearance of the dichloride. DMSO was removed under high vacuum, the residue was dissolved in 60 ml of water, and the aqueous solution was washed 3 times with diethyl ether. The solution was then acidified to pH 3.5 with 1N hydrochloric acid, and the product was extracted three times with ethyl acetate. The organic phases are washed twice with water and finally once with saturated sodium chloride solution, combined, dried over sodium sulfate and evaporated. The crystallized residue was digested with anhydrous ether to completely remove traces of 5-isopropyl-pyridine-2-sulfonamide. The remaining crystals were filtered off and dried. Obtained 1.66 g (96%) of 5-isopropyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine-4 -Amide, white crystal, melting point 168-176°C, MS: (M-H)-=518.3.

Example 46

According to a method similar to Example 45, under the condition of adding DMSO as a solubilizer (ethylene glycol: DMSO 5:2), after a period of 10 hours of reaction at 120 ° C, 5-tert-butylthiophene-2- 6-(2-Hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide sulfonic acid as a white solid foam, yielding Yield 54%, MS: 565.5 (M+H)+.

Example 47

According to a method similar to Example 45, after a period of 3 hours of reaction at 140 ° C, 2,5-dichlorothiophene-3-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2- Methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide, white crystals, yield 43%, MS: 575.3 (M-H)-.

Example 48

According to the method similar to Example 45, after a period of 3.5 hours of reaction at 140 ° C, 3,5-dimethylisoxazole-4-sulfonic acid 6-(2-hydroxy-ethoxy)- 5-(2-Methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-ylamide, white crystals, melting point 144-147°C, MS: 520.4(M-H)-.

Example 49

At 50°C, 110 mg of sodium was dissolved in 2.5 ml of ethylene glycol. The solution was cooled to room temperature, and 260 mg of 2,5-dichlorothiophene-3-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide was added . After heating at 50°C for 2 hours, the ethylene glycol was removed under high vacuum and the solid residue was dissolved in 20 ml of water. The product was precipitated by adding 0.3 ml of acetic acid. After filtration, washing with water, and drying under high vacuum at 50 °C, 182 mg (67%) of 2,5-dichlorothiophene-3-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2 -Methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide, beige crystal, melting point 157-160°C, MS: M+(569), 470(M+-(SO ₂ +Cl) ). Preparation of starting compounds:

0.349g 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine and 0.405g 2,5-dichlorothiophene-3-sulfonamide potassium salt The solution in 5 ml of anhydrous DM-SO was kept at room temperature for 16 hours. Then 0.112 g of potassium tert-butoxide was added and the reaction was complete within 5 minutes. The reaction mixture was poured into 40 ml of ice-water and extracted with 40 ml of ether to remove excess reagent. The aqueous phase was salted out with saturated sodium chloride solution (20ml), filtered and washed with ether to isolate 2,5-dichlorothiophene-3-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy base)-2,2'-bipyrimidin-4-ylamide (0.54 g beige powder).

To obtain the free sulfonamide, the sodium salt is suspended in water, the suspension is acidified with acetic acid and extracted with ethyl acetate with the addition of a small amount of dichloromethane. The organic phase is washed twice with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was washed briefly with ether and hexane, then dried. This gave 0.30 g (54%) of a beige powder of melting point 140° C. (decomposition). MS: 444 (M+-( _SO2 +Cl)).

Similarly, 3,5-dimethylisoxazole-4-sulfonic acid 6-chloro-5-(2-methoxy-benzene Oxy)-2,2'-bipyrimidin-4-ylamide, yield 71%, beige, reddish powder, melting point 184-187°C. MS: M+=488,393 (M-( _SO2 + _OCH3 )).

Example 50

According to a method similar to Example 49, 3,5-dimethylisoxazole-4-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy) was obtained -2,2'-bipyrimidin-4-ylamide, a beige powder with a melting point of 200-204°C. MS: 514 (M+), 450 (M+ _-SO2 ), 419 (450- _CH3O ).

Example 51

A solution of 888 mg of pyridine-2-carbonyl azide in 15 ml of dry dioxane was heated at 80°C for 15 minutes. The solution was allowed to cool slightly, 1.09 g of the compound prepared in Example 45 was added, and the solution was heated at 90°C for 4 hours. Afterwards, it is evaporated to dryness, the residue is dissolved in ethyl acetate, washed twice with water and once with saturated sodium chloride solution, the organic phases are combined, dried and concentrated, whereby the product is isolated as crystals. For final purification, it was chromatographed on silica gel using ethyl acetate/dichloromethane (1:1) as eluent, thus yielding 931 mg (70%) of pyridin-2-ylcarbamate 2 -[6-(5-Isopropyl-pyridin-2-ylsulfonylamino)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxy ] Ethyl ester, white crystal, melting point 200-202°C. MS: 664.4(M-H)-. IR (KBr) 1730 cm-1 (urethane).

Example 52

According to the method similar to Example 51, from the compound prepared in Example 49, pyridin-2-ylcarbamate 2-[6-(2,5-dichlorothiophen-3-ylsulfonylamino)-5-( 2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yloxy]ethyl ester, white crystal, melting point 194-197°C, MS: 690.1(M+H)+, IR (KBr) 1732 cm-1 (carbamate), 61% yield.

Example 53

According to the method similar to Example 51, from the compound prepared in Example 50, pyridin-2-ylcarbamate 2-[5-(2-methoxy-phenoxy)-6-(3,5-di Methyl-isoxazol-4-ylsulfonylamino)-2,2'-bipyrimidin-4-yloxy]ethyl ester, pale yellow crystal, melting point 217-218°C, MS: 635.3(M +H)+, IR(KBr) 1736cm-1 (carbamate), yield 68%.

Example 54

According to the method similar to Example 51, from the compound prepared in Example 46, pyridin-2-ylcarbamate 2-[6-(5-tert-butylthiophene-2-ylsulfonylamino)-5-(2 -Methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxy]ethyl ester, white foam, MS: 683.5 (M-H)-, yield 90%.

Example 55

According to the method similar to Example 51, from the compound prepared in Example 47, pyridin-2-ylcarbamate 2-[6-(2,5-dichlorothiophen-3-ylsulfonylamino)-5-( 2-Methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxy]ethyl ester, white crystal, melting point 194-196°C. MS: 695.3 (M-H)-, 55% yield.

Example 56

According to a method similar to Example 51, from the compound prepared in Example 48, pyridin-2-ylcarbamate 2-[6-(3,5-dimethyl-isoxazol-4-ylsulfonylamino) was obtained -5-(2-Methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxy]ethyl ester, white crystal, melting point 106-109°C. MS: 640.4(M-H)-, 70% yield.

Example 57

5-Isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine- The 4-ylamide (54.5 mg) was dissolved in N,N-dimethylacetamide (5 ml), 14.4 mg of 60% NaH suspension was added at room temperature, and the mixture was stirred for 20 minutes. Finally, 2-chloropyrimidine (11.7 mg) was added. The reaction mixture was stirred at room temperature for 18 hours and poured into ice water. Saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and evaporated, and the residue is purified by chromatography on silica gel with dichloromethane/methanol (100/1) as eluent. This gives 5-isopropyl-pyridine-2-sulfonic acid {5-(2-methoxy-phenoxy)-2-morpholin-4-yl-6-[2-(pyrimidin-2-yl O)-ethoxy]-pyrimidin-4-yl}-amide, white crystals. MD: 624(M+H)

Example 58a) According to a method similar to Example 45, by adding 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-2-(3-methoxy-benzyl)-5-(2- Reaction of methoxy-phenoxy)-pyrimidin-4-yl]-amide with sodium in ethylene glycol affords 5-isopropyl-pyridine-2-sulfonic acid [6-(2-hydroxy-ethoxy yl)-2-(3-methoxy-benzyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide as a white foam. MS: 579.3 (M-H) Preparation materials: b) Dissolve 10.8 g of 3-methoxyphenylacetonitrile in ethanol (100 ml) at room temperature and saturate the solution with hydrogen chloride. The mixture was then stirred at room temperature for 12 hours, the solution was cooled to 0°C, and the precipitated crystals were sucked off. Recrystallized in acetone/ether. Ethyl 2-(3-methoxy-phenyl)-acetylimidate hydrochloride was thus obtained as a white crystalline solid. MS: 193 (M) c) Dissolve 2-(3-methoxy-phenyl)-acetylimidate ethyl ester hydrochloride (12g) in ethanol (100ml) at -75°C with 14ml of liquid ammonia deal with. The mixture was allowed to come to room temperature over 5 minutes, then evaporated on a rotary evaporator. The residue was suspended in acetone, the precipitated crystals were sucked off and dried under high vacuum. 2-(3-Methoxy-phenyl)-acetamidine hydrochloride is thus obtained as a white solid. Complexion 64 (M) d) Sodium (2.3g) was dissolved in methanol (40ml), and 2-(3-methoxy-phenyl)-acetamidine hydrochloride (10g) and (2 -methoxyphenoxy)-dimethyl malonate (12.67 g). The mixture was stirred at room temperature for 5 hours, concentrated on a rotary evaporator, and the crude product was poured into water. The aqueous phase was washed with ethyl acetate, the pH was adjusted to 1, the precipitated crystals were sucked off and dried under high vacuum. 2-(3-Methoxy-benzyl)-5-(2-methoxy-phenoxy)-pyrimidine-4,6-diol is thus obtained as beige crystals. MS: 354 (M)e) 2-(3-Methoxy-benzyl)-5-(2-methoxy-phenoxy)-pyrimidine-4,6-diol (14 g) was dissolved in acetonitrile (150ml). Collidine (5.24ml) and phosphorus oxychloride (21.7ml) were added at room temperature, and the mixture was stirred at room temperature for 9 hours. The mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with half-saturated potassium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue was dissolved in hexane/ether, filtered, and the filtrate was evaporated on a rotary evaporator, thus giving 4,6-dichloro-2-(3-methoxy-benzyl)-5-(2-methoxy Base-phenoxy)-pyrimidine, as light brown crystals. MS: 390 (M) f) According to the method similar to Example 45, by adding 4,6-dichloro-2-(3-methoxy-benzyl)-5-(2-methoxy-phenoxy base)-pyrimidine with potassium 5-isopropyl-pyridine-2-sulfonamide to give 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-2-(3-methoxy-benzyl) -5-(2-Methoxy-phenoxy)-pyrimidin-4-yl]-amide as a yellow foam. MS: 553.1 (M-H)

Example 59a) According to a method similar to Example 45, by adding 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-2-(3-methoxy-benzyl)-5-phenoxy )-pyrimidin-4-yl]-amide reacts with sodium in ethylene glycol to give 5-isopropyl-pyridine-2-sulfonic acid [6-(2-hydroxy-ethoxy)-2-(3 -Methoxy-benzyl)-5-phenoxy)-pyrimidin-4-yl]-amide as pale yellow crystals. MS: 549.2 (M-H) Preparation materials: b) According to the method similar to Example 58d, by 2-(3-methoxy-phenyl)-acetamidine hydrochloride and dimethyl phenoxypropionate Reaction afforded 2-(3-methoxy-benzyl)-5-phenoxy)-pyrimidine-4,6-diol as a yellow foam. MS: 324 (M) c) According to a method similar to Example 58 e), 2-(3-methoxy-benzyl)-5-phenoxypyrimidine-4,6-diol chloride was prepared by using phosphorus oxychloride 4,6-dichloro-2-(3-methoxy-benzyl)-5-phenoxy-pyrimidine was obtained as yellow crystals. MS: 360 (M) d) According to a method similar to Example 45, by combining 4,6-dichloro-2-(3-methoxy-benzyl)-5-phenoxy-pyrimidine with 5-iso Propyl-pyridine-2-sulfonamide potassium reaction gives 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-2-(3-methoxy-benzyl)-5-phenoxy)- Pyrimidin-4-yl]-amide as a yellow foam. MS: 523(M-H)

Example 60

5-Isopropyl-pyridine-2-sulfonic acid [6-(2-hydroxy-ethoxy)-2-(3-methoxy-benzyl)-5-phenoxy)-pyrimidine-4- ]-amide (55mg) was dissolved in anhydrous dichloromethane (3ml). Boron tribromide (50 mg) in dichloromethane (2 ml) was added at 0 °C and reacted for a further 4 hours at room temperature, evaporated on a rotary evaporator, and the residue was washed with dichloromethane/ethyl acetate on silica gel As eluent, purified by chromatography. This gives 5-isopropyl-pyridine-2-sulfonic acid [2-(3-hydroxy-benzyl)-6-(2-hydroxy-ethoxy)-5-phenoxy-pyrimidin-4-yl ]-amide as white crystals. MS: 525.1 (M-H)

Example A

Tablets containing the following ingredients were prepared according to the conventional method: ingredients 10.0-100.0mg lactose 125.0mg cornstarch 75.0mg talc 4.0mg magnesium stearate 1.0 mg compound of formula I per tablet

Example B

Capsules containing the following ingredients were prepared according to conventional methods: ingredients compound formula Ⅰ 25.0mg lactose 150.0mg cornstarch 20.0mg talc 5.0mg

Example C

Injection with the following composition: compound of formula Ⅰ 3.0mg gelatin 150.0mg phenol 4.7mg water for injection added to 1. oml

Example D

500 mg of the compound of formula I were suspended in 3.5 ml of Myglyol 812 and 0.08 g of benzyl alcohol. The suspension is filled into containers fitted with dosing valves. Charge 5.0 g of Freon 12 through the valve under pressure. Shake to dissolve Freon in the Myglyol-benzyl alcohol mixture. The spray container contains approximately 100 individual doses, which are as many as possible for individual use.

Claims (25)

1. Formula I compound Wherein R ¹ refers to a heterocyclic group; R ² refers to hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkoxy lower alkyl, lower alkylsulfonyl lower alkoxy, phenyl, Lower alkylphenyl, lower alkoxyphenyl, lower alkylenedioxyphenyl, phenyl lower alkyl, lower alkylphenyl lower alkyl, lower alkoxyphenyl lower alkyl, lower alkylene Alkyldioxyphenyl lower alkyl, heterocyclyl or heterocyclyl lower alkyl; ^R means lower alkyl, lower alkoxy, formyl, halogenated lower alkyl, hydroxy lower alkyl, amino Lower alkyl or -CH ₂ OA-lower alkyl, -(CH ₂ ) _m -O-(CR ^a R ^b ) _n OH, -(CH ₂ ) _m -O-(CR ^a R ^b ) _n OR ⁹ , -(CH ₂ ) _m -O-(CR ^a R ^b ) _n NH ₂ , -(CH ₂ ) _m -O-(CR ^a R ^b ) _n -BR ⁹ ; R ⁴ -R ⁸ means hydrogen, lower alkanes Oxygen or halogen; R ⁹ means heterocyclyl; phenyl or phenyl substituted by lower alkyl, lower alkoxy and/or halogen, or lower alkyl; R ^a and R ^b mean hydrogen or lower alkane A means ketalized 1,2-dihydroxy-ethylene; B means -OC(O)O-, OC(O)NH-, -NHC(O)NH- or -NHC(O) O-; n means 2, 3 or 4; and m means 0 or 1. 2. The compound according to claim ¹ , wherein R is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkoxy lower alkyl, lower alkylsulfonyl lower alkoxy, phenyl, lower alkane Oxyphenyl, lower alkylene dioxaphenyl or heterocyclyl, R is ^lower alkyl, lower alkoxy, formyl, halogenated lower alkyl, hydroxy lower alkyl, amino lower alkyl or -CH ₂ OA-lower alkyl, -(CH ₂ ) _m -O-(CR ^a R ^b ) _n OH, -(CH ₂ ) _m -O-(CR ^a R ^b ) _n NH ₂ or -(CH ₂ ) _m -O-(CR ^a R ^b ) _n -BR ⁹ ; and R ¹ , R ⁴ -R ⁹ , R ^a , R ^b , A, B, n and m are as defined in claim 1 . 3. A compound according to claim ¹ , wherein R is pyridyl, pyrimidinyl, isoxazolyl, furyl or thienyl, which are unsubstituted or replaced by lower alkyl, halogen, amino, mono-lower alkylamino or di Substituted by lower alkylamino or lower alkanoyl. 4. A compound according to any ^one of claims 1-3, wherein R is hydrogen, pyrimidinyl, pyridyl, morpholino, thiomorpholino, piperidino, pyrrolidino, benzodioxa Cyclopentenyl, lower alkoxyphenyl or lower alkylthio. 5. A compound according to any one of claims 1-3, wherein R ³ is -O-(CR ^a R ^b ) _n OH, -O-(CR ^a R ^b ) _n NH ₂ or -O(CH ₂ ) ₂ -BR ⁹ , and R ⁹ is pyridyl, pyrimidinyl or furyl. 6. A compound according to claim 5, wherein ^R3 is -O( _CH2 ) ₂ - ^BR9 , and B is -(O)C(O)NH-. 7. A compound according to claim 6, wherein ^R9 is 2-pyridyl. 8. A compound according to claim 7 which is pyridin-2-ylcarbamate 2-[6-(5-isopropyl-pyridin-2-ylsulfonylamino)-5-(2-methoxy-phenoxy) -2-morpholin-4-yloxy]ethyl ester. 9. A compound according to claim 7, which is Pyridin-2-ylcarbamate 2-[6-(5-tert-butyl-thiophen-2-ylsulfonylamino)-5-(2-methoxy-phenoxy)-2,2′-bipyrimidine -4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[5-(2-methoxy-phenoxy)-6-(5-pentyl-thiophen-2-ylsulfonylamino)-2,2'-bipyrimidine- 4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[6-[5-(2,2-dimethylpropionyl)-thiophen-2-ylsulfonylamino]-5-(2-methoxy-phenoxy) -2,2'-bipyrimidin-4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[6-(5-isopropyl-pyridin-2-ylsulfonylamino)-5-(2-methoxy-phenoxy)-2,2′-bipyrimidine -4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[5-(2-methoxy-phenoxy)-6-pyridin-2-ylsulfonylamino)-2,2′-bipyrimidin-4-yloxy]ethyl base ester, Pyridin-2-ylcarbamate 2-[5-(2-methoxy-phenoxy)-6-pyridin-3-ylsulfonylamino)-2,2′-bipyrimidin-4-yloxy]ethyl base ester, Pyridin-2-ylcarbamate 2-[6-(5-tert-butyl-thiophen-2-ylsulfonylamino)-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine-4 -yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[6-(5-isopropyl-pyridin-2-ylsulfonylamino)-5-(2-methoxy-phenoxy)-2-(3-methoxy Base-phenyl)-pyrimidin-4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[6-(5-isopropyl-pyridin-2-ylsulfonylamino)-5-(2-methoxy-phenoxy)-2-methylsulfanyl -pyrimidin-4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[2-(1,3-benzodioxol-5-yl)-6-(5-isopropyl-pyridin-2-ylsulfonylamino) -5-(2-methoxy-phenoxy)-pyrimidin-4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[5-(2-chloro-5-methoxy-phenoxy)-6-(5-isopropyl-pyridin-2-ylsulfonylamino)-2-mol Lin-4-ylpyrimidin-4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[5-(2-methoxy-phenoxy)-6-(5-methyl-pyridin-2-ylsulfonylamino)-2,2'-bipyrimidine- 4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[5-(2-methoxy-phenoxy)-6-(5-methyl-pyridin-2-ylsulfonylamino)-2-morpholin-4-yl pyrimidin-4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[5-(2-chloro-5-methoxy-phenoxy)-6-(5-isopropyl-pyridin-2-ylsulfonylamino)-2-mol Lin-4-ylpyrimidin-4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 5-(2-chloro-5-methoxy-phenoxy)-6-(5-isopropyl-pyridin-2-ylsulfonylamino)-2-morpholine-4 -ylpyrimidin-4-ylmethyl ester, Pyridin-2-ylcarbamate 2-[6-(2,5-dichlorothiophen-3-ylsulfonylamino)-5-(2-methoxy-phenoxy)-2,2′-bipyrimidine -4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[5-(2-methoxy-phenoxy)-6-(3,5-dimethyl-isoxazol-4-ylsulfonylamino)-2,2 '-bipyrimidin-4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[6-(5-tert-butylthiophen-2-ylsulfonylamino)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl pyrimidin-4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[6-(2,5-dichlorothiophen-3-ylsulfonylamino)-5-(2-methoxy-phenoxy)-2-morpholine-4- Pyrimidin-4-yloxy]ethyl ester, Pyridin-2-ylcarbamate 2-[6-(3,5-Dimethyl-isoxazol-4-ylsulfonylamino)-5-(2-methoxy-phenoxy)-2-mol Lin-4-ylpyrimidin-4-yloxy]ethyl ester. 10. A compound according to claim 6, wherein ^R9 is 4-pyridyl. 11. A compound according to claim 10 which is pyridin-4-ylcarbamate 2-[6-(5-tert-butyl-thiophen-2-ylsulfonylamino)-5-(2-chloro-5-methoxy- phenoxy)-pyrimidin-4-yloxy]ethyl ester. 12. A compound according to claim 5, wherein ^R3 is -O( _CH2 ) ₂ - ^BR9 , and B is -(O)C(O)O-. 13. A compound according to claim 12, which is Furan-3-ylmethyl formate 2-[5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-2-morpholine-4- Pyrimidin-4-yloxy]ethyl ester, 5-isopropyl-pyridine-2-sulfonic acid {5-(2-methoxy-phenoxy)-2-morpholin-4-yl-6-[2-(pyrimidin-2-yloxy)- Ethoxy]-pyrimidin-4-yl}-amide. 14. A compound according to claim 5, wherein ^R3 is -O( _CH2 ) ₂ - ^BR9 , and B is -NHC(O)NH-. 15. A compound according to claim 14, which is 5-tert-butyl-thiophene-2-sulfonic acid 5-(2-methoxy-phenoxy)-6-[2-(3-pyridin-2-yl-ureido)-ethoxy]-2 , 2'-bipyrimidin-4-ylamide, 5-Isopropyl-pyridine-2-sulfonic acid 5-(2-methoxy-phenoxy)-6-[2-(3-pyridin-2-yl-ureido)-ethoxy]-2 , 2'-bipyrimidin-4-ylamide. 16. A compound according to any one of claims 1-3, wherein ^R3 is hydroxyethoxy. 17. A compound according to claim 16, which is 5-tert-butyl-thiophene-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2′-bipyrimidin-4-ylamide , 5-pentyl-thiophene-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide, 5-(2,2-Dimethyl-propionyl)-thiophene-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2 '-bipyrimidin-4-ylamide, 5-Isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2′-bipyrimidin-4-ylamide , Pyridine-3-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide, 5-tert-butyl-thiophene-2-sulfonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-ylamide, 5-tert-butyl-thiophene-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamide, N-[5-(2-Chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-5-isopropyl-pyridine-2- Sulfonamide, 5-isopropyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(3-methoxy-phenyl)-pyrimidine- 4-yl]-pyridine-2-sulfonamide, 5-isopropyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-methylsulfanyl-pyrimidin-4-yl]- Pyridine-2-sulfonamide, N-[2-(1,3-benzodioxol-5-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy) -pyrimidin-4-yl]-5-isopropyl-pyridine-2-sulfonamide, N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-5 -Isopropyl-pyridine-2-sulfonamide, 5-Methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-ylamide, 5-Methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine-4- base amides, 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine-4 -ylamide, 5-tert-butylthiophene-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl- Pyrimidin-4-ylamide, 2,5-dichlorothiophene-3-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholine- 4-yl-pyrimidin-4-ylamide, 3,5-Dimethylisoxazole-4-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl- Pyrimidin-4-ylamide, 2,5-dichlorothiophene-3-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'- Bipyrimidin-4-ylamide, 3,5-Dimethylisoxazole-4-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2′-bipyrimidine-4 -yl amides, 5-Isopropyl-pyridine-2-sulfonic acid [6-(2-hydroxy-ethoxy)-2-(3-methoxy-benzyl)-5-(2-methoxy-phenoxy )-pyrimidin-4-yl]-amide, 5-Isopropyl-pyridine-2-sulfonic acid [6-(2-hydroxy-ethoxy)-2-(3-methoxy-benzyl)-5-phenoxy-pyrimidin-4-ylamide , 5-Isopropyl-pyridine-2-sulfonic acid [2-(3-hydroxy-benzyl)-6-(2-hydroxy-ethoxy)-5-phenoxy-pyrimidin-4-yl]-amide . 18. A compound according to any one of claims 1-3, wherein R ³ is aminoethoxy. 19. A compound according to claim 18, which is 5-tert-butyl-thiophene-2-sulfonic acid 6-(2-amino-ethoxy)-5-(2-methoxy-phenoxy)-2,2′-bipyrimidin-4-ylamide . 20. A compound according to any one of claims 1-3, wherein ^R3 is lower alkyl, lower alkoxy, formyl, halogenated lower alkyl, hydroxy lower alkyl or _-CH2OA -lower alkyl. twenty one. A compound according to claim 20, which is 5-Isopropyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2-morpholin-4-yl-pyrimidin-4-ylamide , 5-(2-Chloro-5-methoxy-phenoxy)-6-formyl-2-morpholin-4-yl-pyrimidin-4-ylamide, 5-Isopropyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-hydroxymethyl-2-morpholin-4-yl-pyrimidin-4-yl amides, 5-Isopropyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-chloromethyl-2-morpholin-4-yl-pyrimidin-4-yl amides, 5-(2-Chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxymethyl)-2-morpholin-4-yl-pyrimidin-4-ylamide. twenty two. A pharmaceutical composition, which contains the compound of any one of claims 1-21 and commonly used carriers and adjuvants. twenty three. The preparation method of the compound of any-item in the claim 1-21 is characterized in that: a) formula II compound Wherein the meanings of R ¹ , R ² and R ⁴ -R ⁸ are as defined in the corresponding items in claims 1-21, and Hal is a halogen, reacting with the compound of the following formula HO(CR ^a R ^b ) _n XH wherein n, R ^a and R ^b meanings are as defined in the corresponding items in claims 1-21, and X refers to O or NH, or b) the compound of formula III

Wherein the meanings of R ² -R ⁸ are respectively as defined in the corresponding items in claims 1-21, reacting with the compound of the following formula R ¹ SO ₂ Z wherein R ¹ meanings are as defined in the corresponding items in claims 1-21, and therefore Y represents halogen and Z represents amino, or Y represents amino and Z represents halogen, or c) the compound of formula IV

The meanings of R ¹ , R ² , R ⁴ -R ⁸ , R ^a , R ^b , X, m and n are as defined in the corresponding items in claims 1-21, c1) is the same as the isocyanate of formula R ⁹ NCO or formula The carbamoyl chloride reaction of R ⁹ NCOCl, wherein the meaning of R ⁹ is as defined in the corresponding item in claims 1-21, or c2) reacts with phosgene, and then reacts with an alcohol of formula R ⁹ OH; or reacts with formula R ⁹ OC (O) Cl chloroformate reaction; or d) wherein R ³ represents the reaction of a compound of formula I of halogenated lower alkyl with a compound of the following formula HO(CH) ₂ -A-lower alkyl wherein A represents a ketalized 1,2-dihydroxy-ethylene group and, if desired, the substituents present on the resulting compound of formula I can be altered and/or converted into a salt. twenty four. Use of a compound according to any one of claims 1-21 as an active ingredient for the manufacture of a medicament for the treatment of a disease associated with endothelin activity, said disease being a circulatory disease. 25． The use of claim 24, wherein said circulatory disease is hypertension, ischemia, vasospasm and angina pectoris.