Benzosulfimide pyrimidine derivatives or their salts, the pharmaceutical composition for treatment of diseases associated with the activity of endothelin

 

(57) Abstract:

Usage: in medicine. The inventive benzosulfimide pyrimidine derivatives f-ly 1, where R1is hydrogen, lower alkyl, lower alkyloxy; R2is hydrogen; R3is hydrogen, halogen, lower alkyl, trifluoromethyl, lower alkoxygroup; R2and R3together methylendioxy; R4is hydrogen, lower alkyl, trifluoromethyl, phenyl, furyl, pyrimidinyl, pyridyl, pyridyl-N-oxide; R5is hydrogen, lower alkanoyl; R6- R9is hydrogen, halogen, lower alkyl, lower alkyloxy-lowest allylthiourea or methylsulfinyl; R7together with R6or R8butadienyl or-OCH2O-; Z=-O, Vinylinum; X and Y=-O-and n is 2, 3 or 4 or their salts. Reagent 1: compound f-crystals 2. Reagent 2: MX(CH2)nYR5M is Alkali metal or reagent 1 f-crystals 3 or reagent 2 f-ly 4, where Q is aryl, a is an anion, followed by hydrogenation or their salts. Pharmaceutical composition for treatment of diseases associated with the activity endothelin containing as active principle benzosulfimide pyrimidine derivatives f crystals of 1 in an amount of 0.1 - 100 g/kg and a pharmaceutically acceptable carrier. The structure of the compounds of formulas 1, 2, 3, 4:

< / BR>
< / BR>
(R
< / BR>
where R1hydrogen, lower-alkyl, lower-alkoxy-group;

R2hydrogen;

R3hydrogen, halogen, lower-alkyl-, trifluoromethyl-, lower-alkoxy - group;

R2and R3together metridiochoerus;

R4hydrogen, lower-alkyl-, triptoreline, phenyl, furyl, pyrimidinyl, pyridyl, pyridyl N-oxide;

R5hydrogen, lower-alkanoyl;

R6R9hydrogen, halogen, lower-alkyl, lower-alkoxy, lower-alkylthio, group, methylsulfinyl;

R7together with R6or R8butadienyl or-OCH2O;

Z is-O-, vinile;

X and J-O-, and n is 2, 3 or 4,

and their salts.

Applied here, the expression "lower" means a group with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms. Alkyl groups, alkoxy - and ancilliary, as well as alkyl groups as components alkanoyl groups may be normal or isotrate. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, secondary, and tertiary butyl. Halogen means fluorine, chlorine, bromine and iodine, preferably chlorine is. Examples of aryl radicals are the Hairdryer is th-alkyl, lower-alkoxygroup, carboxyl, triptoreline. Examples of heteroaryl-radicals are, in particular monocyclic 5-, 6-membered heteroaromatic radicals with nitrogen or sulphur as heteroatoms, such as pyrimidinyl, pyridyl, diazines and thienyl such as pyrimidinyl, pyridyl, diazines and thienyl.

Compounds of the above formula I are inhibitors for endothelin receptors. The compounds of formula I can be applied for the treatment of diseases associated with the activity of endothelin, in particular, diseases of the cardiovascular system such as hypertension, ischemia, vasospasm and Angina pectoris (angina).

A special group of compounds within formula I are those compounds where Z is-O - and then those groups, where R7and R8means hydrogen and R6lower-alkoxygroup.

The compounds of formula I can be obtained in such a way that

a) compounds of the formula

< / BR>
where R1, R2, R3, R4and R6R9have the above mentioned meaning.

Hal represents halogen, interacts with the compound of the formula

MX(CH2)nJR5< / BR>
where X, J, n and R5have the above meaning and n have the abovementioned meaning, interacts with the compound of the formula

< / BR>
where R1R3have the above mentioned meaning;

Q means aryl and A is an anion, or

c) the compound of the formula

< / BR>
where R1R9, X, J and n have the abovementioned meaning, are subjected to hydrogenation and, in this case, the substituents present in the resulting compound of formula I modify and/or translate the obtained compound of formula I in salt.

The interaction of the compounds of formula II with the compound of the formula III is advisable to carry out with the use of glycol, the underlying compound III, with ethylene glycol in the case when n is 2. As the alkali metal M is used primarily sodium. It is advisable to conduct the reaction under heating, for example up to 40 120oC. In a preferred embodiment, the monosodium salt of ethylene-, propylene - or butyleneglycol used as the compounds of formula III.

The interaction of the compounds of formula IV with the compound of the formula V can be carried out according to the standard technique under normal conditions of the Wittig reaction. Arrowy radical Q is a predominantly phenyl, examples of the anion A - may serve as Cl-, Br-, HSO-4and tailorshop. It is reasonable cooperation the AI of a strong base, such as utility, sodium hydride or the sodium salt of dimethyl sulfoxide or of potassium tert-butylate, mainly in the presence of ethylene oxide, in this case, substituted lower alkyl such as 1,2-butylenes, in this case, in a solvent, such as ether (simple), such as diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon, e.g. benzene, at temperatures between room temperature and the boiling temperature of the reaction mixture.

The reactive groups of the components of the reaction, interferome Wittig reaction such as carboxyl or amino group, it is advisable to protect intermedial, such as ether carboxylic acid or tert.-butoxycarbonylamino. Hydrogenation of the compounds of formula VI can be carried out as usual for the hydrogenation of olefinic double bonds, for example with hydrogen under normal or elevated pressure in the presence of catalysts of noble metals such as palladium, in particular palladium on media such as Pd/c.

In the thus obtained compound of formula I can be modified present in the substituents. A hydroxyl group can be, for example, ameriface is the SCP (simple ether), for example, in tetrahydropyranyloxy or ester group (ester), such as acetate. Metalcorp can be oxidized in methylsulfinyl or methylsulfonyl group.

All these processes take place in accordance with known methods.

The compounds of formula I can be converted into salts, for example alkali, such as sodium or potassium.

The initial compounds of formula II can be obtained as follows.

< / BR>
When the alkylation of phenol VII with diethyl ether hormonology acid get connection VIII, which with acetate of formamidine or homologous compound, such as the acetate of acetamidine, condense to pyrimidinediamine IX. Together with the oxychloride porcelain him get dichloroethylene X, which when interacting with the stoichiometric quantity of compound XI gives compound II. All of these reactions interactions are standard and can be conducted by conventional methods for such reactions and under conditions well known to the experts.

The compounds of formula IV can be obtained by the below diagram.

< / BR>
Condensation of the ether allylmalonic acid acetate of formamidine or R4-Saet dichloropyrimidine XII, which condense alkali salt R1, R2, R3- benzosulfimide at rearrangement of double bonds of the allyl before joining XIII.

Interaction of compound XIII with a compound III leads to the formation of compounds XIV. Oxidative cleavage of the double bond of the side chain of propanil in connection XIV gives, finally, the aldehyde IV.

The inhibitory effect of compounds of the formula I on the endothelin receptors may be shown in the below described the experience:

1. Inhibition of endothelin-communication on the membrane of human placenta (cf Vgl. Life Sci 44 1429/1989).

Human placenta homogenized in 5 mmol Tris-buffer at pH of 7.4, containing 1 mmol MgCl2and 250 mmol of sucrose. Homogenized centrifuged at 3000 g for 15 min at 4oC, adosados contained in plasmamembrane functions, centrifuged at 72000g for 30 min and the precipitate is washed with 75 mmol of trisbuffered at a pH of 7.4, containing 25 mmol MgCl2. Then the precipitate obtained from 10 g of the main fabric, suspended in 1 ml of 75 Smolnogo Tris buffer at a pH of 7.4, containing 25 mmol MgCl2and 250 mmol of sucrose and frozen in 1 ml aliquot of the divider Fold at -20oC.

To associate a method Assay (Assay) thawed saeaut in Assay-buffer (50 mmol Tris-buffer, a pH of 7.4, containing 25 mmol MnCl21 mmol ethylendiaminetetraacetic acid and 0.5% serum albumin bovine). 100 l of this membrane suspension containing 70 g of protein, incubated with 50 l1251-endothelin (specific activity 2200 CI/mmol in Assay-buffer (Assay) (25000 cpm. the final concentration of 20 pmol) and 100 l Assay-buffer containing varying concentrations of test compounds. Incubation carried out for 2 h at 20oC or for 24 h at 4oC. Separation of free or associated with a membrane, the radio is performed by filtration over glass fiber filter.

In table. 1 shows the inhibitory effect of the compounds of formula 1, are considered in this experience, as the IC50that is , as the concentration ( mol) required to inhibit 50% of specific links125I-endothelin (endothelin labeled125I).

II. Inhibition of endothelin-induced contractions on isolated aortic rings of rats.

From the thoracic aorta of adult rats Wistar-Kyoto carved rings with a length of 5 mm, the Endothelium was removed with a light rubbing of the inner surface. Each ring was immersed at a temperature of 37oC in an isolated bath of 10 ml Krebs-Henseleit is of n to pre-stressing 3g. After 10 min of incubation with the test compound or binder was added to the cumulated doses of endothelin-1. The activity of test compounds was determined by calculation of the ratio of the dose, i.e. a shift to the right, induced 100 mol of the test compounds (offset to higher values), EC50endothelin, and EC50(Approx. translation: EC - effective concentration) means endothelin-concentration required for half maximal contraction. The higher the dose, the test connection potentsialnye inhibits the biological activity of endothelin-1. EC50endothelin in the absence of the test compound is 0.3 nmol.

The value of the right shift EC50endothelin obtained by using compounds of formula 1, are presented in table. 2.

III. The inhibitory effect of the compounds of formula 1 vasoconstriction may occur in vivo in rats in the following experience:

Rats were shot by thiobutabarbital sodium (100 mg/kg) (i.p.) - vnutriplevralnogo. Through the femoral artery catheter was introduced for measurement of systemic arterial blood pressure and through the femoral vein catheter was introduced into the vein (Vena cava inferior) for injection of the test compounds. Umbrella Doppler superimposed around lewocki at the place of exit was formed renal ischemia. The test compounds were administered (i. a. intraarterially) for 10 min before ischemia in doses of 5 mg/kg or intravenous (i.v.) doses of 10 mg/kg In control experiments renal blood flow compared with predications value reduced by 434%

Values of measurements obtained using the two compounds of formula 1, are presented in table. 3.

The compounds of formula 1 on the basis of their ability to inhibit the binding of endothelin can be used as a tool for the treatment of diseases associated with vascular spasm. Examples of such diseases are high blood pressure, coronary artery disease, cardiac insufficiency, renal and myocardial ischemia, renal failure, dialysis, cerebral ischemia, cerebral infarction, migraine, subarachnoid haemorrhage syndrome RONO (Raynaud) and high pulmonary pressure. They can also be applied in case of atherosclerosis, the elimination of restorative by vascular dilatation induced by Balloon, inflammation, gastric ulcer and duodenal ulcer, the ulcer (Ulkis cruris), gram-negative sepsis, shock, inflammation of the renal glomeruli, renal colic, glaucoma, asthma, and for treatment and prevention of diabetic complications and the="ptx2">

The compounds of formula 1 can be used orally, rectally and in parallel, for example intravenously, intramuscularly, subcutaneously, intracapsular, transdermal; or can be applied sublingual or as ophthalmological preparations or in the form of an aerosol. Examples of applications can include capsules, tablets, used by mouth suspensions or solutions, suppositories, injectable solutions, eye drops, ointments or solutions for spraying.

The preferred form is intravenous, intramuscular or oral administration. The dosage at which accept the compounds of formula 1 in effective amounts depend on the specific active substance, from the return and the needs of the patient, and the method of application. Mainly used dosage of about 0.1-100 mg/kg of body weight per day. Preparations containing the compounds of formula 1 can contain inert or pharmacodynamic supplements. Tablets or granules can contain binders, fillers, carriers, or diluents. Liquid preparations can be represented, for example, in the form of sterile, miscible with water solutions. Capsules can in addition to the active substance optionally contain napolnitelyami as a preservative, stabilizing, moisturizing and emulsifying means, and also salts for modifying the osmotic pressure, buffer and other additives.

The above carriers and diluents may consist of organic or inorganic substances, for example, water, gelatin, lactose, starch, magnesium stearate, talc, Jummi arabicum, polyalkyleneglycol and similar substances. The whole premise is the fact that when getting drugs used excipients are non-toxic.

Example 1. a) sodium glycolate, sodium 30 g of ethylene glycol and 138 mg of sodium add 886 mg of n-tert.-butyl-N - [6-chloro - 5-(o -, methoxyphenoxy)-4-pyrimidinyl] benzosulfimide. The reaction mixture is stirred in an argon atmosphere for 4 h at 95oC. and Then distilled ethylene glycol and distribute the residue between ethyl acetate and 1 n hydrochloric acid. The organic phase is dried and the solvent is distilled off. The residue is crystallized from diisopropyl ether. Obtain 870 mg of n-tert.-butyl-N-[6-(2-hydroxyethoxy)-5- (o-methoxyphenoxy)-4-pyrimidinyl]benzosulfimide. Melting point 143-148oC.

b) 775 mg obtained above sulfonamida dissolved in 20 ml of warm ethanol. The mixture is mixed I obtain deposition add 3 ml of isopropyl ether. Get 775 mg of n-tert.-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)- 4-pyrimidinyl] benzosulfimide-sodium. Melting point > 250oC.

The source material was obtained as follows:

c) To a solution of sodium methylate from 150 ml of methanol and 4.6 g of sodium successively added dropwise 25 g guaiacol and 37 g of dimethyl ether of hormonology acid. The mixture is stirred for one hour at 45oC when you remove the moisture, then distilled methanol. The residue is dissolved in 200 ml of toluene and washed with water, 1% sodium hydroxide solution and water up until the organic phase becomes colorless. After drying and evaporation of the solvent the residue is distilled. Obtain 39.5 g of dimethyl-(o-methoxyphenoxy) malonate. Boiling point 128oC/0.05 mm RT.article.

d) To a solution of sodium methylate from 150 ml of methanol and 3.5 g of sodium while cooling on ice, add 5.5 g of the acetate of formamidine and 12.7 g of dimethyl-(o-methoxyphenoxy)malonate. The reaction mixture is stirred for one hour while removing moisture at 0-5oC, then stirred for 2 h at room temperature. Then the solvent is distilled off, dissolve the residue in 100 ml of water, the aqueous phase is extracted with toluene and removed organic phase is>e) 9.4 g obtained above pyrimidinone suspended in 20 ml of acetonitrile and mixed with 12 g collidine. Then added dropwise 5 ml of POCl3in 15 ml of acetonitrile while removing moisture. The reaction mixture is stirred for 8 hours at a temperature of the reflux condenser, and then the solvent is distilled off and the excess reagent. The residue is dissolved in methylene chloride and washed with water, saturated solution of hydrogencarbonate sodium and saturated solution hydrogencarbonate sodium and saturated sodium chloride solution. The solution is concentrated and through a short column on kieselgel contribute with methylene chloride as a means for elution. The eluate is concentrated and the residue from ethanol/hexane recrystallized. Obtain 8.5 g of 4,6-dichloro-5-(o-methoxyphenoxy) pyrimidine. The melting point of 79-80oC.

f) 0.8 g of 4,6-dichloro-(o-methoxyphenoxy)pyrimidine and 1.5 g of n-tert.-butylsulfonyl potassium in 3 ml of dry dimethyl sulfoxide is heated in an argon atmosphere for 1.5 h to 120oC. and Then distilled dimethyl sulfoxide, distribute the residue between ethyl acetate and 1 N. hydrochloric acid and the organic phase is washed until neutral. The organic phase is dried, the solvent is evaporated and the residue is mixed with 3 is dependent on the melting point 152oC.

Example 2. Analogously to example 1, section (a) of n-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl] benzosulfimide receive N-[6-(hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl)-n-isopropylbenzenesulfonyl with a melting point 142-143oC.

Analogously to example 1, section b), the connection is transferred to water-soluble sodium salt with about a close quantitative yield. The source material was obtained analogously to example 1, section f) by reacting 540 mg of 4,6-dichloro-5-(o-methoxyphenoxy)pyrimidine with 360 mg of n-isopropylbenzenesulfonyl potassium.

Example 3. Analogously to example 1, section (a) of N-[6-chloro-5-(o-tolyl-oxy)-4-pyrimidinyl] -n-tert. -butylsulfonyl get n-tert.-butyl-N-[6-(2-hydroxyethoxy)-5-(o-tolyloxy)-4-pyrimidinyl] -benzosulfimide. Melting point 190-192oC.

The source material was obtained as follows:

Analogously to example 1, section c) interact diethylmalonate with sodium-o-cresolate to obtain diethyl-(o-tolyloxy)malonate. Boiling point 120oC/0.05 mm RT.article.

Analogously to example 1, section (d) of the above-mentioned malonic ether to obtain 5-(o-tolyloxy)-6-hydroxy-4(3H)-pyrimidinone from methanol/hexane). In the interaction of the latter compound with n-tert.-butylsulfonyl potassium receive, finally, N-[6-chloro-5-(o -, tolyloxy)-4-pyrimidinyl]-n-tert.-butylsulfonyl.

Example 4. Analogously to example 1, section (a) of n-tert.-butyl-N-[2-chloro-5-(o-chlorophenoxy)-4-pyrimidinyl] benzosulfimide get n-tert.-N-[6-(2-hydroxyethoxy)-5-(o-chlorophenoxy)-4-pyrimidinyl] benzosulfimide with a melting point of 178-179oC (from diisopropyl ether).

The source material was obtained as follows:

Analogously to example 1, section (e) of diethylmalonate and sodium-o-chlorophenolate receive diethyl-(o-chlorophenoxy)malonate in the form of a colourless liquid, which analogously to example 1, section d) was transferred to 5-(o-chlorophenoxy)-6-hydroxy-4(3H)pyrimidinone. Of the latter compound analogously to example 1, section (e) obtain 4,6-dichloro-5-(o-chlorophenoxy)pyrimidine with a melting point of 76-77oC (from ethanol/hexane), and the last in the interaction with n-tert. -butylsulfonyl get potassium n-tert.-butyl - N-[2-chloro-5-(o-chlorophenoxy)-4-pyrimidinyl] benzosulfimide with a melting point of 186-187oC (methanol).

Example 5. Analogously to example 1, section (a) of N-[6-chloro-5-(o-chlorophenoxy)-4-pyrimidinyl-] -n-isopropamide with a melting point 174-175oC (from ethyl acetate).

Starting material is prepared analogously to example 1, section (f) of 4,6-dichloro-5-(o-chlorophenoxy)pyrimidine and n-isopropylbenzenesulfonyl potassium. Melting point 174-176oC (from methanol).

Example 6. Analogously to example 1, section (a) of n-tert.-butyl-N-[6-chloro-5-(m-methoxyphenoxy)-4-pyrimidinyl] benzosulfimide get n-tert.-butyl-N-[6-(2-hydroxyethoxy)-5-(m-methoxyphenoxy)4 - pyrimidinyl] benzosulfimide, melting point 165-167oC (from diisopropyl ether).

When interacting sulfonamida with 0.5 n KOH in ethanol potassium salt with a melting point 213-215oC.

Sodium salt get analogously to example 1, section b) melting point 265-270oC (from diisopropyl ether).

The source material was obtained as follows:

Analogously to example 1, section c) diethylmalonate interacts with sodium m-methoxypropanol to obtain diethyl-(m-methoxyphenoxy)malonate in the form of a colourless liquid. Melting point 143oC/0.05 mm RT.article.

Thus obtained malonic ester analogously to example 1, section d) was transferred to 5-(m-methoxyphenoxy)-6-hydroxy-4(3H)-pyrimidin, from kotorogoC.

In the interaction of these compounds with n-tert.-butyl-benzosulfimide-get potassium n-tert.-butyl-N-[6-chloro-5-(M-methoxyphenoxy)-4-pyrimidinyl]benzosulfimide with a melting point of 152oC (from methanol).

Example 7. Analogously to example 1, section (a) of n-tert.-butyl-N-[6-chloro-5-phenoxy-4-pyrimidinyl] benzosulfimide get n-tert.-butyl-N-[6-(2-hydroxyethoxy)-5-phenoxy-4 - pyrimidinyl] -benzosulfimide; melting point 165-167oC (from diisopropyl ether).

The source material was obtained as follows:

Diethylmalonate analogously to example 1, section c) reacts with sodium phenolate to obtain diethylpyrocarbonate; boiling point 140oC/0.05 mm RT. Art. Of the malonic ester analogously to example 1, section e) receive 5-phenoxy-6-hydroxy-4(3H)-pyrimidinone, and similarly to example 1, section (e) obtain 4,6-dichloro-5-phenoxypyridine; melting point 89-90oC (from ethanol-hexane). In the interaction of the latter with n-tert. -butyl-benzosulfimide get potassium n-tert.-butyl-N-[6-chloro-5-phenoxy-4-pyrimidinyl]benzosulfimide with a melting point 143-144oC.

Example 8. Analogously to example 1, section (a) of 4,6-Dichlorotoluene with a melting point 141-142oC.

Starting material is prepared analogously to example 1, section c), (d) and (e) by the interaction of diethylmalonate with sodium-n-methoxypropanol to obtain diethyl-n-methoxyphenylalanine, boiling point 140oC/0.05 mm RT. Art. and further interaction to obtain 5-(n-methoxyphenoxy)-6-hydroxy-4-(3H)-pyrimidinone or 4,6-dichloro-5-(n-methoxyphenoxy)-4-pyrimidine with a melting point of 107-108oC (ethanol/hexane).

Example 9. Analogously to example 1, section (a) of n-tert.-butyl-N-[6-chloro-5-(o-ethoxyphenoxy)-4-pyrimidinyl] benzosulfimide get n-tert.-butyl-N-[6-(2 - hydroxyethoxy)-5-(o-ethoxyphenoxy)-4-pyrimidinyl] benzosulfimide with a melting point 120 121oC (from diisopropyl ether).

Starting material is prepared analogously to example 1, section c), (d), (e) and (f) of dimethylcarbonate through the following intermediate stages:

dimethyl-(o-ethoxyphenoxy)malonate, boiling point 150oC/0,05 MRT. Art.

5-(o-ethoxyphenoxy)-6-hydroxy-4(3H)-pyrimidinone;

4,6-dichloro-5-(o-ethoxyphenoxy)-4-pyrimidine;

5-n-tert. -butyl-N-[6-chloro-5-(o-ethoxyphenoxy)-4-pyrimidinyl] benzosulfimide, melting point 162 163oC (from methanol).

oC (from diisopropyl ether).

Starting material is prepared analogously to example 1, section c), d) and f) through the following intermediate stages:

n-(2,2-dimethylpropyl)benzosulfimide, boiling point 105oC/0.05 mm RT.article.

2,2-dimethyl-n-(2,2-dimethylpropyl)benzosulfimide potassium;

n-(2,2-dimethylpropyl)-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl] benzosulfimide, melting point 164 165oC (from methanol).

Example 11. Analogously to example 1, section (a) of N-[6-chloro-2-methyl-5-(m-methoxyphenoxy)-4-pyrimidinyl] - n-isopropylbenzenesulfonyl (melting point 152 153oC) receive n-isopropyl-N-[6-(2-hydroxyethoxy)-2-methyl-5-(m-methoxyphenoxy)-4-pyrimidinyl]-benzosulfimide with a melting point 129 130oC (from diisopropyl ether).

The source material was obtained as follows:

Analogously to example 1, section (e) when applying the hydrochloride ndimethylacetamide instead of acetate of formamidine dimethyl-(m-methoxyphenoxy)malonate, gives 5-(m-methoxyphenoxy)-2-methyl-6-hydroxy-4(3H)-pyrimidinone.

From him analogously to example 1, section (e) obtain 4,6-dichloro-2-methyl-5-(m-methoxyphenoxy)pyrimidine, and using n-isopropylbenzenesulfonyl potassium FL 152 153oC (from methanol).

Example 12. Analogously to example 1, section (a) of N-[6-chloro-5-(o-methoxy)-2-phenyl-4-pyrimidinyl] -n-isopropylbenzenesulfonyl get N-6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-phenyl-4-pyrimidinyl] -n-isopropylbenzenesulfonyl.

The source material as in example 1, section d), (e) and (f), prepared from dimethyl-(o-methoxyphenoxy)malonate-5-(o-methoxy)-2-phenyl-6-hydroxy-4(3H)-pyrimidinone, 4,6-dichloro-2-phenyl-5-(o-methoxyphenoxy)pyrimidine (melting point 135 - 136oC) from N-[6-chloro-5-(o-methoxy)-2-phenyl-4-pyrimidinyl] -n-isopropylbenzenesulfonyl (melting point 190 -191oC) (from methanol).

Example 13. To 780 mg benzyltriphenylphosphonium chloride in 10 ml of abs. tetrahydrofuran (THF) at 20oC add 1.3 ml of 1.6 molar, utility in hexane. The reaction mixture was stirred for 15 min at -20oC, and then mixed with 280 mg of 2-[(5-formyl-6-n-toluene-sulfonamide-4-pyrimidinyl)oxy]ethyl acetate. The reaction mixture was allowed to warmed to room temperature and stirred at this temperature for 2 hours, the Tetrahydrofuran is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, the organic phase is washed with water and a saturated solution of chlorine is 2). Receive 160 mg of 2-[[5-[(E/Z)-styryl]-6-n-toluensulfonate-4-pyrimidinyl]oxy]-acetic acid ethyl ester with a melting point of 146 156oC.

The source material was obtained as follows:

5-allyl-4,6-dichloropyrimidine-n-toluensulfonate get potassium N-[6-chloro-5-[(E/Z)-propenyl]-4-pyrimidinyl] -n-toluensulfonate and out of when interacting with the ethylene glycol sodium get N-[6-(2-hydroxyethoxy)-5-[(E/Z)-propenyl] -4-pyrimidinyl] -n-toluensulfonate; melting point 130 132oC.

When interacting with acetanhydride in the presence of pyridine in tetrahydrofuran get 2-[[5-[(E/Z)-propenyl] -6-n-toluensulfonate-4-pyrimidinyl]oxy]ethyl acetate; melting point 160 163oC.

390 g of the above compound and 8 mg of osmium tetroxide is added to a mixture of 2.5 ml of water and 7 ml of dioxane and then added for 30 min at room temperature to 450 mg sodium-m-peroidic and after 2 h stirring at room temperature once 8 mg of osmium tetroxide. The reaction mixture is stirred for another 5 h and processed, and get 2-[(5-formyl-6-n-toluensulfonate-4-pyrimidinyl)oxy] acetic acid ethyl ester with a melting point of 130 144oC(after crystallization from ethyl acetate and diethyl ether).

oC.

Example 15. 80 mg of 2-[(5-phenylethyl-6-n-toluensulfonate-4-pyrimidinyl] oxy] ethyl acetate is stirred for 15 h at 20oC in 5 ml of methanol with 53 mg of potassium carbonate in powder form. Then under reduced pressure to remove methanol, dissolve the residue in ethyl acetate, the organic phase is washed with water and saturated sodium chloride solution, dried and evaporated. The remainder chromatographic over silica gel with methylene chloride/ethyl acetate (1 1) and ethyl acetate.

Receive 40 mg of N-[6-(2-hydroxyethoxy)-5-phenylethyl-4-pyrimidinyl]-n-toluensulfonate in the form of a white resin.

Example 16. Analogously to example 15 from 2-[[5-[(E/Z-styryl) -6-n-toluensulfonate]-4-pyrimidinyl]oxy]ethyl acetate to obtain N-[6-(2-hydroxyethoxy)-5-[(E/Z)-styryl]-4-pyrimidinyl] -n-toluensulfonate in the form of a white resin.

Example 17. Analogously to example 1, the section of the Ute N-[6-(2-hydroxyethoxy)-5-(2,4,6-trichlorophenoxy)-4-pyrimidinyl] -n-isopropylbenzenesulfonyl with a melting point 182 - 183oC (from methylene chloride and isopropyl ether).

The source material was prepared from 4,6-dichloro-5- (2,4,6-trichlorophenoxy)pyrimidine and n-isopropylbenzenesulfonyl; melting point 217 - 218oC (from methylene chloride and isopropyl ether).

Example 18. Analogously to example 1, section (a) of N-[6-chloro-5-(2,4,6-trichlorophenoxy)-4-pyrimidinyl] -o-toluensulfonate and ethylene glycol sodium get N-[6-(2-hydroxyethoxy)-6-(2,4,6-trichlorophenoxy)-4-pyrimidinyl] -o-toluensulfonate with a melting point 144 145oC (from isopropyl ether).

The source material was prepared from 4,6-dichloro-5- (2,4,6-trichlorophenoxy)pyrimidine and o-toluensulfonate; melting point 107 109oC (from isopropyl ether).

Example 19. Analogously to example 1, section (a) of N-[6-chloro-5-(2,4,6-trichlorophenoxy)-4-pyrimidinyl] -2,4 - cellculture and ethylene glycol sodium get N-[6-(2-hydroxyethoxy)-5-(2,4,6-trichlorophenoxy)-4-pyrimidinyl] -2,4-killsometime with a melting point 157 158oC (propyl ether).

The source material was obtained as follows:

To a solution of 18.0 g of 2,4,6-trichlorophenol and 32.0 g of diethylmalonate in 180 ml of acetone and 20 ml of toluene added to 16.9 g of anhydrous throwaway from the precipitate and evaporated under reduced pressure. The residue is dissolved in toluene, washed with an organic solution of 5% sodium carbonate solution and then with water, dried over sodium sulfate and evaporated after filtration of the salts under reduced pressure. The residue is distilled at a pressure of 1 mm RT.article and receive a colorless oil (Klp. 171 174oC) when interacting with the acetate of formamidine and sodium methylate receive 5-(2,4,6-trichlorophenoxy)-4,6(3H, 5H) pyrimidinedione with a melting point >270oC, which is before the subsequent reaction of interaction at 80oC dried overnight under reduced pressure.

A solution of 7.6 g of 5-(2,4,6-trichlorophenoxy)-4,6-(3H,5H)pyrimidinedione, 6.6 g of tetraethylammonium, 3,3 ml collidine, of 13.7 ml PoCl3in 70 ml of CH3CN is heated at reflux for 4.5 h, the solution was evaporated under reduced pressure, the residue is treated three times by a simple ether, the combined organic solution was filtered over night, evaporated under reduced pressure and the residue from the ether and n-hexane recrystallized.

Get 4,6-dichloro-5-(2,4,6-trichlorophenoxy)-pyrimidine with a melting point 104 105oC.

From 4,6-dichloro-5-(2,4,6-trichlorophenoxy)pyrimidine 2,4-cellculture receive N-[6-chloro-5-(2,4,6-three is viewed in ether).

Example 20. In the interaction of 4,6-dichloro-5-[(2-methoxy-4-methyl)phenoxy] -pyrimidine n-tert. -butylbenzenesulfonamide, and then etilenglikolem sodium get n-tert-butyl-N-[6-(2-hydroxyethoxy)-5[(2-methoxy-n-tolyl)oxy]-4-pyrimidinyl benzosulfimide in the form of a solid substance.

The source material is prepared by the interaction of methylguanine with diethylmalonate, and then with acetate of formamidine to obtain 5-[(2-methoxy-4-methyl)phenoxy] -4,6(3H, 4H)-pyrimidinedione (melting point 234 236oC, and then by further interaction of the latter with POCl3.

Example 21. In the interaction of 4,6-dichloro-5-[(2-methoxy-4-methyl)phenoxy] -pyrimidine n-isopropylbenzenesulfonyl, and then with ethylene glycol sodium get N-[5-(2-methoxy-4-methyl)phenoxy-pyrimidinyl]-n-isopropylbenzenesulfonyl with a melting point of 135 - 136oC (from ethyl acetate).

Example 22. In the interaction of 4,6-dichloro-5-[(2-methoxy-4-methyl)phenoxy pyrimidine with o-ethylbenzylamine, and then with ethylene glycol sodium get N-[5-(2-methoxy-4-methyl)phenoxy-6-(2-hydroxyethoxy)-4-pyrimidinyl] -o-ethylbenzophenone in the form of a solid substance.

Example 23. In the interaction of 4,6-dichloro-5-(2-metal.-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzosulfimide with a melting point 123 124oC (from ether acetic acid).

Example 24. In the interaction of 4,6-dichloro-5-(2-methoxy)phenoxy-2-methylpyrimidine n-isopropylbenzenesulfonyl, and then with ethylene glycol sodium get N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl)-n-isopropylbenzenesulfonyl with a melting point 124 126oC (from acetonitrile, isopropanol and water).

Example 25. In the interaction of 4,6-dichloro-5-(2-methoxyphenoxy)-2-cryptomaterial n-isopropylbenzenesulfonyl, and then with ethylene glycol sodium get N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-(2-trifluoromethyl)-4-pyrimidinyl]-n-isopropylbenzenesulfonyl in the form of a solid substance.

Example 26. In the interaction of 4,6-dichloro-5-(2-methoxyphenoxy) -2-cryptomaterial with n-tert.-butylbenzenesulfonamide and ethylene glycol sodium get n-tert.-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-(trifluoromethyl)-4-pyrimidinyl]-benzosulfimide with a melting point of 190 192oC (from toluene).

Sodium salt: melting point 288-289oC.

Example 27. In the interaction of 5-(1,3-benzodioxol-5-yloxy)-4,6-dichloropyrimidine with n-tert.-butylbenzaldehyde, and then with ethylene glycol sodium pordage substances.

Example 28. In the interaction of 5-(1,3-Benedikta-5-yloxy)-4,6-dichloropyrimidine n - isopropylbenzenesulfonyl, and then with ethylene glycol sodium get N-[5-(1,3-benzodioxol-5-yloxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-n-isopropylacetanilide in the form of a solid substance.

Example 29. In the interaction of 5-(2-methoxyphenoxy)-4,6-dichloropyrimidine with o-methoxybenzenesulfonamide, and then with ethylene glycol sodium get N-(6-[2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl] -o-methoxybenzenesulfonamide with a melting point 164-165oC (from ether acetic acid).

Example 30. In the interaction of n-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl] benzosulfimide with monosodium salt of 1,4-butanediol get n-tert.-butyl-N-[6-(4-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzosulfimide in the form of a white foam.

Example 31. In the interaction of 4,6-dichloro-5-(2-naphthyloxy)pyrimidine n-isopropylbenzylamine, and then with a sodium salt of ethylene glycol receive N-[6-(2-hydroxyethoxy)-5-(2-naphthyloxy)-4-pyrimidinyl]-n-isopropylbenzenesulfonyl with a melting point 160-161oC (from isopropyl ether).

Example 32. In the interaction of 4,6-dichloro-roxilox)-5-(2-naphthyloxy)-4-pyrimidinyl]-n-tert.-butylbenzenesulfonamide with a melting point 197-198oC (from isopropyl ether).

Example 33. In the interaction of 4,6-dichloro-5-(o-methoxyphenoxy)-2-propylpyrimidine n-isopropylbenzylamine, and then with ethylene glycol sodium get N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy) -2-propyl-4-pyrimidinyl)-n-isopropylbenzenesulfonyl in the form of a solid substance.

Example 34. In the interaction of 4,6-dichloro-5-(o-methoxyphenoxy)-2-propylpyrimidine with n-tert. -butylbenzaldehyde, and then with ethylene glycol sodium get n-tert. -butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-propyl-4-pyrimidinyl]-benzosulfimide in the form of a solid substance.

Example 35. In the interaction of 4,6-dichloro-5-(o-methoxy)phenoxy-2-methylpyrimidine with trifter-n-toluensulfonate, and then with ethylene glycol sodium get a,,,,-Cryptor-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl] -n-toluensulfonate with a melting point of 144-145oC (from ether acetic acid).

Example 36. In the interaction of 4,6-dichloro-5-(o-methoxy)-phenoxy-2-methylpyrimidine n-chlorophenylsulfonyl, and then with ethylene glycol sodium get n-chloro-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl] benzosulfimide with a melting point 134-135oC (from ether acetic acid).

Example 38. In the interaction of 4,6-dichloro-5-(o-methoxy)phenoxy-2-methylpyrimidine with o-ethylbenzylamine, and then with ethylene glycol sodium get on-ethyl-N-[6-(2-hydroxyethoxy) -5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzosulfimide in the form of a white foam.

Example 39. In the interaction of 4,6-dichloro-5-(o-methoxy)phenoxy-2-methylpyrimidine with n-toluene-sulfonamide, and then with ethylene glycol sodium get N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl] -n-toluensulfonate in the form of a white foam.

Example 40. In the interaction of 4,6-dichloro-5-(o-methoxy)phenoxy-2-methylpyrimidine with 2 matriculation, and then with ethylene glycol sodium get N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-methyl-processing analogous to example 1, section e).

After crystallization from n-hexane receive 1 g of the derivative of a pyrimidine with a melting point 89-90oC.

d) Analogously to example 1, section (f) is subjected to interaction 580 mg of 4,6-dichloro-5-[(o-methylthio)phenoxy] per-pyrimidinyl)benzosulfimide. After crystallization from MeOH obtain 480 mg of white crystals; melting point 154-155oC.

Example 43. a) Analogously to example 1, section a) 350 mg of n-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-phenyl-4-pyrimidinyl)benzosulfimide transferred to n-tert.-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-phenyl-4-pyrimidinyl] benzosulfimide. Obtain 330 mg of white crystals after crystallization from diisopropyl ether; melting point 160-161oC.

b) 225 mg of this compound was dissolved in Etoh. To the solution was added a stoichiometric amount of KOH in MeOH. After that, the mixture solvent is distilled off and to the residue add diisopropyl ether, thus obtain n-tert. -butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-phenyl-4-pyrimidinyl)benzosulfimide potassium;

MC-588[(M+K)+]

Example 44. Analogously to example 1, section (a) of N-[2-amino-6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl] -n-tert. -butylbenzenesulfonamide receive N-[2-amino-6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-4-pyrimidinyl] -n-tert.-butylbenzenesulfonamide in the form of white crystals with a melting point of 168oC (from diisopropyl ether).

The source material was obtained as follows:

a) To a solution of 2.3 g yeah guanidine. The suspension is stirred for 3 h at room temperature in argon. After that, distilled methanol and the residue is dissolved in H2O. After the standard described processing, the connection precipitated, was added dropwise while acetic acid up until the pH of the solution will reach 4.5. Get 6.4g product raw 1.35 g which are suspended in 10 ml of dioxane. Then added 1.4 g of N-ethyldiethanolamine, 2 ml of POCl3and 1 g of triethylmethylammonium. The mixture is boiled at reflux with thorough stirring in argon atmosphere. After 30 min the mixture solvent is distilled off, the residue is dissolved in ethyl acetate and shaken out with H2O and a saturated solution of NaHCO3.

Chromatographic to clean kieselgel (CH2Cl2- ethyl acetate, 9:1 vol. as fluid funds). Get 2-amino-4,6-dichloro-5-(o-methoxyphenoxy)pyrimidine as a colorless solid; melting point 190oC.

When interacting 0.5 g of the above-described dichloroethylene and 0.75 g of n-tert.-butylbenzenesulfonamide sodium in 2 ml of dimethyl sulfoxide at 90oC get N-[2-amino-6-chloro-5-(o-methoxyphenoxy) -4-pyrimidinyl] -n-tert. -butylbenzenesulfonamide with temperaturel-N-[6-chloro-2-methyl-5-[o-(methylthio) phenoxy] pyrimidinyl]-benzosulfimide, glycolate sodium in ethylene glycol to obtain n-tert.butyl-N-[6-(2-hydroxyethoxy)-2-methyl-5-[o-(methylthio)-phenoxy]-4-pyrimidinyl] benzosulfimide with a melting point 166-167oC.

in) 225 mg of this compound when adding a stoichiometric amount of an aqueous solution of NaOH was transferred to salt sulfonamida; then diluted with methanol, thus obtaining a homogeneous solution. To this solution was added 100 mg NaJO4dissolved in 2 ml of H2O, and stirred the mixture at room temperature for 8 hours, the mixture is evaporated to dryness. The residue is distributed between ethyl acetate and an aqueous solution of 0.1 n H2SO4. After evaporation of the organic phase from diisopropyl ether crystallized n-tert.-butyl-N-[6-(2-hydroxyethoxy)-2-methyl-5-[o-(R, S-methylsulfinyl) phenoxy]-4-pyrimidinyl] benzosulfimide. Receive 150 mg of white crystals. MS: m/e 520 (M+H)+< / BR>
The source material was obtained as follows:

In the interaction of 5.4 g of dimethyl o-(methylthio)-proksimalnami acid and 2.1 g of the hydrochloride of acetamidine get 6-hydroxy-2 methyl-5-[o-(methylthio)phenoxy] -4(3H)-pyrimidine and translate it into 4,6 dichloro-2-methyl-5-[o-(methylthio)phenoxy]pyrimidine with a melting point 132-133oC.

When interacting 0.9 g of the above-described dichloroethylene with 1.3 g of n-tert. -butylbenzenesulfonamide get potassium n-tert.-butyl-N-[6-chloro-2-methyl-5-[o-(methylthio) the dryer is example 1 from 4-tert.-butyl-N-[6-chloro-5-(3-chloro-5-methoxy-phenoxy)-2-methylpyrimidin-4-yl] -benzosulfimide receive a 4-tert. -butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy) -2-methylpyrimidin-4-yl] -benzosulfimide. 500 mg educt obtain 430 mg of white crystals. Melting point 141-141,5oC (isopropylamino).

Example 47. A solution consisting of 0.11 g of sodium and 3.0 ml of ethylene glycol are heated together with 0,265 g of 4-tert.-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-thiophene-2-yl-pyrimidine-4-yl] -benzosulfimide to 110oC, after 4 h, cooled, poured on ice and mixed with IM-tartaric acid to pH 3. The resulting suspension is extracted with ether acetic acid, the organic extracts are combined, washed with water, dried with sodium sulfate and concentrated under reduced pressure. The remainder chromatographic over kieselgel with CH2Cl2ether acetic acid in the ratio 9:1 and get 4-tert.-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(thiophene-2-yl)-pyrimidine-4-yl]-benzosulfimide in the form of a white foam. MC M+555.

The source material was obtained as follows:

a) a Solution comprising of 5.17 g Na in 200 ml of abs. methanol, mixed with to 21.15 g of diethyl-(o-methoxyphenylalanine) and 16.2 g of thiophene-2-karboksimetilirovaniya, and the suspension is stirred at room temperature over night and the dock is filtered, thoroughly washed with water and dried in high vacuum at 80oC. 5-(o-methoxy-phenoxy)-2-(2-thienyl)-4,6-dihydroxy-pyrimidine with a melting point > 250oC (decomposition) is used for the next stage without further purification.

b) a Suspension consisting of 4.6 g of 5-(o-methoxyphenoxy)-2-(2-thienyl)4,6-dihydroxy-pyrimidine, with 4.7 ml of N,N-aminobutiramida-N-ethylamine and 6.4 g of PCl5boil for 20 h at reflux. Then the mixture under reduced pressure, evaporated, the residue was poured on ice and extracted with ether acetic acid. The combined extracts are washed with water, dried and evaporated in vacuum. The remainder chromatographic on kieselgel with toluene and get 4,6-dichloro-5-(2-methoxy-phenoxy)-2-thiophene-2-yl-pyrimidine, melting point 118 120oC.

C) a Solution consisting of 0,353 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-thiophene-2-yl-pyrimidine in 5 ml of DMSO is heated with 0,376 g of p-tert.-butylbenzenesulfonamide for 30 min at 150oC. the Solution is slightly thickened in a high vacuum, poured an oily residue on ice, mixed with acid (pH 3) and extracted with suspension with ether acetic acid. The organic extracts are combined, washed with water, dried over sodium sulfate and concentrated is Oseni 9:1 and get 4-tert.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-thiophene-2-yl-pyrimidine-4-yl]-benzosulfimide in the form of a white foam.

Example 48. Analogously to example 47 4-tert.butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(thiophene-3-yl)-pyrimidine-4-yl] -benzosulfimide and ethylene glycol-Na get 4-tert. -butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2- (thiophene-3-yl)-pyrimidine-4-yl] -benzosulfimide, melting point 152 - 153oC (from toluene).

Receive a 4-tert. -butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(thiophene-3-yl)-pyrimidine-4-yl] -benzolsulfonate (foam) on the basis of thiophene-3-carboxamide-hydrochloride on rat.-5-(2-methoxy-phenoxy)-2-thiophene-3-yl-3,4,5:6-tetrahydro-pyrimidine-4,6-dione (solid with so pl. > 250oC) and 4.6-sodium dichloro-5-(2-methoxy-phenoxy)-2-thiophene-3-yl-pyrimidine (so pl. 98 - 99oC).

Example 49. Analogously to example 47 4-tert.-butyl-N-[6-chloro-2-(furan-2-yl)-5-(2-methoxy-phenoxy)-pyrimidine-4-yl] -benzosulfimide and ethylene glycol-Na get 4-tert. -butyl-N - [2-(furan-2-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)- pyrimidine-4-yl] -benzosulfimide in the form of an amorphous solid.

Receive a 4-tert.-butyl-N-[6-chloro-2-(furan-2-yl)-5-(2-methoxy-phenoxy)-pyrimidine-4-yl] -benzosulfimide (foam) on the basis of furan-2-carboxamide-hydrochloride on rat.-2-(furan-2-yl)-5-(2-methoxy-phenoxy)-pyrimidine-4,6-dione (solid with the pace. RASPA the Roux 47 from 4-tert.-butyl-N-[6-chloro-2-furan-3-yl-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-benzosulfimide and ethylene glycol-Na get 4-tert. -butyl-N-[2-furan-3-yl-6-(2-hydroxy-ethoxy)-2-(2-methoxy-phenoxy) -pyrimidine-4-yl]-benzosulfimide in the form of a solid substance with so pl. 120 122oC (from toluene/n-hexane).

Receive a 4-tert. -butyl-N-[6-chloro-2-furan-3-yl-5-(2-methoxyphenoxy)-pyrimidine-4-yl] -benzosulfimide (foam) on the basis of furan-3-carboxamide-hydrochloride over the rat. -2- (furan-3-yl)-5-(2-methoxy-phenoxy)-4,6-dioxo-1,4,5,6-tetrahydro-pyrimidine (solid with so pl. exceeding 300oC with decomposition), and 4,6-dichloro-2-(furan-3-yl)-5-(2-methoxy-phenoxy)-pyrimidine.

Example 51. Analogously to example 47 4-tert.-butyl-N-[6 - chloro-5-(2-methoxy-phenoxy)-2-(pyridin-2-yl)-pyrimidine-4-yl] -benzosulfimide and ethylene glycol-Na get 4-tert.butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyridin-2-yl)-pyrimidine-4-yl] -benzosulfimide in the form of a solid substance with so pl. exceeding 250oC (from ether acetic acid).

Receive a 4-tert. -butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyridin-2-yl)-pyrimidine-4-yl] -benzosulfimide with so pl. 197 198oC from isopropylamino) based on pyridine-2-carboxamide-hydrochloride over 5-(2-methoxy-phenoxy)-2-pyridin-2-yl)-pyrimidine-4,6-diola and 4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-2-yl)-pyrimidine, T. pl. 122 - 123oC.

Pulmonaria and ethylene glycol-Na get 4-tert. -butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine-4-yl] -benzosulfimide in the form of a solid substance with so pl. 166 167oC (from ether acetone).

Receive a 4-tert. butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2- (pyridin-4-yl)-pyrimidine-4-yl] -benzosulfimide-potassium (1:1) with so pl. 193-196oC of H2O based on pyridine-4-carboxamide-hydrochloride over 5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine-4,6-diola and 4,6-dichloro-5(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine with so pl. 173-176oC.

Example 53. Analogously to example 47 4-tert.butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyridin-3-yl)-pyrimidine-4-yl] -benzosulfimide and ethylene glycol-Na get 4-tert. butyl - N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-3-yl)-pyrimidine-4-yl] benzosulfimide-K in the form of foam. MC (M+H)+551,2.

Receive a 4-tert. butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyridin-3-yl)-pyrimidine-4-yl] -benzosulfimide based on pyridine-3-carboxamide-hydrochloride over the rat. -5-(2-methoxy-phenoxy)-2-pyrimidine-3-yl-tetrahydro-IH-pyrimidine-4,6-dione and 4,6-dichloro-5-(2-methoxy-phenoxy)-2-(pyridin-3-yl)-pyrimidine (so pl. 164-165oC.)

Example 64. A suspension consisting of 525 mg 4-tert.butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyridin-2-yl)-pyrimidine-reaut to reflux. After 2 min, cooled under reduced pressure, evaporated and the residue precrystallizer of the ester of acetic acid. The result is 2-[4-(4-tert.-butyl-phenylcarbonylamino)-6-chloro-5-(2-methoxy-phenoxy)-pyrimidine-2-yl] -pyridine-1-oxide with so pl. 201-202oC (decomposition).

Example 55. To a solution consisting of 46 mg Na in pure ethylene glycol added 216 mg of 2-(4-4-tert.-butyl-phenylcarbonylamino)-[6-chloro-5-(2-methoxy-phenoxy)-pyrimidine-2-yl] -pyridine-1-oxide and slowly the resulting solution is heated overnight at a temperature of 80oC. Then the solution was poured on aqueous acetic acid, the precipitate with ether acetic acid is extracted, triturated with ether and filtered. The result is 2-[4-(4-tert. -butyl-phenylcarbonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidine-2-yl] -pyridine-1-oxide in the form of an amorphous mass, which at 40oC dried in high vacuum. MC (M + H)+567,4.

Example 56. Analogously to example 54 4-tert.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidinyl-4-yl] -benzosulfimide and peracetic acid to obtain 4-[4-(4-tert. -butyl-phenyl-sulfonylamino)-6-chloro-5-(2-methoxy-phenoxy)-pyrimidine-2-yl]-pyridine-1-oxide, so pl. 247-249oC (CH2Cl+567,4; (M+Na)+589,4.

Example 58. Analogously to example 47 4-tert.-butyl-N-[6-chloro-2-ethyl-5-(2-methoxy-phenoxy)-2-pyrimidine-4-yl] -benzosulfimide and ethylene glycol-Na get 4-tert. -butyl-N-[2-ethyl-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-benzosulfimide in the form of foam.

Receive a 4-tert.-butyl-N-[6-chloro-2-ethyl-5-(2-methoxy-phenoxy)-pyrimidine-4-yl] -benzosulfimide based on propionohydroxamic over the rat.-2-ethyl-5-(2-methoxy-phenoxy)-1H-pyrimidine-4,6-dione (so pl. 265oC in the decay) and 4,6-dichloro-2-ethyl-5-(2-methoxy-phenoxy)-pyrimidine (so pl. 70 - 71oC).

Example 59. Analogously to example 47 4-tert.-butyl-N-[6-chloro-2-isopropyl-5-(2-methoxy-phenoxy)-pyrimidine-4-yl] - benzosulfimide and ethylene glycol-Na get 4-tert.-butyl-N-[6-(2-hydroxy-ethoxy)-2-isopropyl-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-benzosulfimide in the form of a solid substance.

Receive a 4-tert.-butyl-N-[6-chloro-2-isopropyl-5-(2-methoxyphenoxy)-pyrimidine-4-yl] -benzosulfimide based on isopropylidene-hydrochloride over the rat. -2-isopropyl-5-(2-methoxy-phenoxy)-1,4,5,6-tetrahydro-pyrimidine-4,6-dione and 4,6-dichloro-2-isopropyl-5-(2-methoxy-phenoxy)-pyrimidine (so pl. 70

72oC).

Example 60. Similarly Ghaut 4-chloro-N-[3-[5-fluoro-2-methoxy-phenoxy)-6-(2-hydroxyethoxy)-pyrimidine-4-yl]-benzosulfimide, so pl. 152 154oC (CH3CN and Isopropylamine).

Get 4-chloro-N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine-4-yl] -benzosulfimide (so pl. 169-171oC) from 4,6-dichloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine and 4-chlorobenzenesulfonamide-K.

Example 61. Analogously to example 47 N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine-4-yl] -4-trifluoromethyl-benzosulfimide, etilenglikolya sodium get N-[5-(5-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidine-4-yl] -4-trifluoromethyl-benzosulfimide, so pl. 154-155oC (isopropylamino).

Receive N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy) -pyrimidine-4-yl] -4-trifluoromethyl-benzosulfimide (so pl. 185 186oC) from 4,6-dichloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine and 4-trifluoromethyl-benzosulfimide-K.

Example 62. Analogously to example 47, but at the reaction temperature of 100oC, from 4-tert. -butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyrimidine-2-yl)-pyrimidine-4-yl] -benzosulfimide, etilenglikolya sodium glycol receive a 4-tert.-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyrimidine-2-yl)-pyrimidine-4-yl]benzosulfimide in the form of solids. Sodium salt: so pl. 195 198oC.

Receive a 4-tert.-butyl-N-[6-chloro-5-(2-methoxy-Hairdryer the rat.-5-(2-methoxy-phenoxy)-2-pyrimidine-2-yl-tetrahydro-pyrimidine-4,6-dione and 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine.

Example 63. Analogously to example 47 4-tert.-butyl-N-[6-chloro-5-(3-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl] -benzosulfimide and Na-etilenglikolya ethylene glycol receive a 4-tert.-butyl-N-[6-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl] -benzosulfimide in the form of a solid substance.

Receive a 4-tert.-butyl-N-[6-chloro-5-(3-methoxy-phenoxy) -2,2'-bipyrimidin-4-yl]-benzosulfimide based on the rat.-5-(3-methoxy-phenoxy)-2-(pyrimidine-2-yl)-1,4,5,6-tetrahydro-pyrimidine-4,6-dione over 4,6-dichloro-5-(3-methoxy-phenoxy)-2,2'-bipyrimidine.

Example 64.

Analogously to example 47 4-tert.-butyl-N-[6-chloro-5-(4-fluoro-2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzosulfimide and Na-etilenglikolya ethylene glycol receive a 4-tert.-butyl N-5-(4-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)2,2'-bipyrimidin-4-yl-benzosulfimide with so pl. 161 163oC.

Receive a 4-tert. butyl-N-[6-chloro-5-(4-fluoro-2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl] -benzosulfimide (so pl. 225 227oC) from 4-fluoro-2-methoxy-proksimalnami acid - diethylether over 5-(4-fluoro-2-methoxy-phenoxy)-2,2'-pyrimidine-4,6-diola (temp.decay > 131oC) and 4,6-dichloro-5-(4-fluoro-2-methoxy-phenoxy)-2,2'-bipyrimidine (so pl. 179 - 180oC).

Example 65. Similarly, glycolate ethylene glycol receive a 4-tert.-butyl-N-[5-(4-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-methyl-pyrimidine-4-yl]-benzosulfimide with so pl. 141 142oC (CH2Cl2-isopropylamino).

Receive a 4-tert.-butyl-N-[6-chloro-5-(4-fluoro-2-methoxy-phenoxy)-2-methyl-pyrimidine-4-yl]-benzosulfimide (so pl. 164 165oC) from 4-fluoro-2-methoxy-proksimalnami acid-diethylether over the rat.-5-(4-fluoro-2-methoxy-phenoxy)-2-methyl-1,4,5,6-tetrahydro-pyrimidine-4,6-dione and 4,6-dichloro-5-(4-fluoro-2-methoxy-phenoxy)-2-methyl-pyrimidine (so pl. 129 - 130oC).

Example 66. Analogously to example 47 4-tert.-butyl-N-[6-chloro-5-(4-fluoro-2-methoxy-phenoxy)-pyrimidine-4-yl]-benzosulfimide and Na-etilenglikolya ethylene glycol receive a 4-tert.-butyl-N-[5-(4-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-pyrimidine-4-yl] -benzosulfimide, so pl. 143 144oC (CH2Cl2-isopropylamino).

Receive a 4-tert. -butyl-N-[6-chloro-5-(4-fluoro-2-methoxy-phenoxy)-pyrimidine-4-yl] -benzosulfimide (so pl. 146 147oC) from 4-fluoro-2-methoxy-proksimalnami acid-diethylether over the rat. -5-(4-fluoro-2-methoxy-phenoxy)-1,4,5,6-tetrahydro-pyrimidine-4,6-dione and 4,6-dichloro-5-(4-fluoro-2-methoxy-phenoxy)-pyrimidine with so pl. 100 101oC.

Example 67. Analogously to example 47 N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine-4-yl]-4-isopropyl-benzosulfimide and Na-etilenglikolya ethylene glycol, polacoC (isopropylamino).

Example 68. Analogously to example 47 N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine-4-yl]-4-tert.-butyl-benzosulfimide and Na-etilenglikolya in etilenglikole receive N-[5-(5-fluoro-2-methoxy-phenoxy)-6-(2-hydroxy-ethoxy-pyrimidine-4-yl] -4-tert. -butyl-benzosulfimide, so pl. 126 127oC (isopropylamino).

Receive N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine-4-yl] -4-isopropyl-benzosulfimide, so pl. 138-139oC, starting from 5-fluoro-2-methoxy-phenoxy)-malonic acid-diethylether over the rat.-5-(5-fluoro-2-methoxy-phenoxy)-tetrahydro-pyrimidin-4,6-dione, 4,6-dichloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine (so pl. 98-100oC) and N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine-4-yl]-4-tert.-butyl-benzosulfimide (so pl. 163-164oC).

Example 69. Analogously to example 47 4-tert.-butyl-N-[6-chloro-5-(2-fluoro-6-methoxy-phenoxy)-pyrimidine-4-yl]-benzosulfimide and Na-etilenglikolya ethylene glycol receive a 4-tert. -butyl-N-[5-(2-fluoro-6-methoxy)-6-(2-hydroxy-ethoxy)-pyrimidine-4-yl]-benzosulfimide, so pl. 158-159oC (CH2Cl2-isopropylamino).

Receive a 4-tert. -butyl-N-[6-chloro-5-(2-fluoro-6-methoxy-phenoxy)-pyrimidine-4-yl] -benzosulfimide (so pl. 181-182oC) from 2-(2-fluoro-6-melodiler-5-(2-fluoro-6-methoxy-phenoxy)-pyrimidine (so pl. 78-79oC).

Example 70. Analogously to example 47 4-tert.-butyl-N-[6-chloro-5-(3-methoxy-phenoxy)-2-(thiophene-2-yl)-pyrimidine-4-yl] -benzosulfimide and Na-etilenglikolya ethylene glycol receive a 4-tert.-butyl-N-[6-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-2-(thiophene-2-yl)-pyrimidine-4-yl]-benzosulfimide, so pl. 159-161oC (toluene/n-hexane).

Receive a 4-tert.butyl-N-[6-chloro-5-(3-methoxy-phenoxy)-2-(thiophene-2-yl)-pyrimidine-4-yl] -benzosulfimide (so pl. 206-207oC) based on the rat.-5-(3-methoxy-phenoxy)-2-(thiophene-2-yl)-3,4,5,6-tetrahydropyrimidin-4,6-dione over 4,6-dichloro-5-(3-methoxy-phenoxy)-2-thiophene-2-yl)-pyrimidine (so pl. 120-121oC).

Example A. the Tablets containing the following components, can be obtained by standard methods:

Components 1 tablet

The compound of formula 1 10,0 100,0 mg

lactose 125,0 mg

corn starch 75,0 mg

talc 4.0 mg

magnesium stearate 1.0 mg

Example Century. Capsules containing the following components,can be obtained by standard methods:

Components 1 capsule

the compound of formula 1 25.0 mg

lactose 150,0 mg

corn starch 20.0 mg

talc 5.0 mg

Example C. injectable Solutions can have the following composition:

soedinenii. 3.5 ml of miglyol 812 and 0.08 benzyl alcohol suspended 500 mg of the compounds of formula 1. This suspension contribute in a container with a metering valve. Through the valve under pressure in the vessel is injected 5.0 g of freon 12. When shaken, the freon is dissolved in a mixture of miglioranzi alcohol. This vessel with spray contains approximately 100 single doses,which can be applied separately.

1. Benzosulfimide pyrimidine derivatives of General formula

< / BR>
where R1hydrogen, lower alkyl, lower alkyloxy;

R2hydrogen;

R3hydrogen, halogen, lower alkyl, trifluoromethyl, lower alkoxygroup;

R2and R3together methylendioxy;

R4hydrogen, lower alkyl, trifluoromethyl, phenyl, furyl, pyrimidinyl, pyridyl, pyridyl-N-oxide;

R5hydrogen, lower alkanoyl;

R6R9hydrogen, halogen, lower alkyl, lower alkyloxy-lowest allylthiourea or methylsulfinyl;

R7together with R6or R8butadienyl or-och2O-;

Z-O-, vinile;

X and Y are-O-;

n 2, 3, or 4

or their salts.

2. Pharmaceutical composition for treatment of diseases associated with the activity of endothelin containing activeit benzosulfimide pyrimidine derivatives of General formula

< / BR>
where R1hydrogen, lower alkyl, lower alkoxygroup;

R2hydrogen;

R3hydrogen, halogen, lower alkyl, trifluoromethyl, lower alkoxygroup;

R2and R3together methylendioxy;

R4hydrogen, lower alkyl, trifluoromethyl, phenyl, furyl, pyrimidinyl, pyridyl, pyridyl-N-oxide;

R5hydrogen, lower alkanoyl;

R6R9hydrogen, halogen, lower alkyl, lower alkoxygroup lowest allylthiourea or methylsulphonyl;

R7together with R6and R8butadienyl or-och2O-;

Z-O-, vinile;

X and Y are-O-;

n 2, 3, or 4

or their salts in an amount of 0.1 to 100.0 mg/kg dose.

 

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