Sulfonamidnuyu derivatives and pharmaceutical drug

 

(57) Abstract:

The invention relates to new sulfonamidnuyu derivatives or their pharmaceutically acceptable salts, which have the properties of inhibitor action of endothelin receptors and can find application in the treatment of diseases associated with disorders in the circulatory system, such as hypertension, ischemia, angina, spasms of the blood vessels as well as to pharmaceutical drugs based on them. Sulfonamidnuyu derivatives correspond to the General formula I, where R1means phenyl, substituted lower alkyl or lower alkoxy, substituted heterocyclyl represents pyridyl, substituted lower alkyl; R2means phenyl, substituted lower alkoxy and/or halogen;3means hydroxy, lower alkoxy or balance-NR4R5; R4means hydrogen or the residue of R6; R5means hydrogen; or R4and R5together with their associated N-atom mean N-heterocyclic residue, representing morpholine-4-yl; R6means phenyl, phenyl, substituted hydroxy or hydroxy (lower) alkyl, heterocyclyl selected from tetrazolyl or pyridyl, and hydroxy(lower)alkyl; Rameans in the Chille alkyl, heterocyclyl represents pyrimidine-2-yl; n is 0 or 1; and their pharmaceutically acceptable salts. Pharmaceutical drug that has the effect of an inhibitor of endothelin, contains one of the compounds of formula I, the conventional fillers and excipients. 2 C. and 7 C.p. f-crystals, 1 table.

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

< / BR>
where

R1means phenyl, substituted phenyl or substituted heterocyclyl;

R2means phenyl or substituted phenyl;

R3means hydroxy, (lower)alkoxy or balance-NR4R5;

R4means hydrogen or the residue of R6;

R5means hydrogen or a residue -(CH2)mR6or

R4and R5together with their associated N-atom mean N-heterocyclic residue;

R6means phenyl, substituted phenyl, cycloalkyl, heterocyclyl, (lower)alkyl, hydroxy(lower)alkyl, amino (lower)alkyl, carboxy(lower)alkyl or (lower)alkoxycarbonyl- (lower)alkyl;

Rameans hydrogen, (lower)alkyl or hydroxy;

RbZ means hydrogen, (lower)alkyl, aryl, aryl-(lower)alkyl, heterocyclyl or heterocyclyl-(lower)alkyl;

m means 0, 1 or 2; and

n means 0, 1 or 2;

and applicable to their pharmaceutical salts.

The phenyl radicals can be substituted by (lower)alkyl, (lower)alkoxy, methylenedioxy, Ethylenedioxy, (lower)alkanoyl, hydroxy, amino, mono - or di-(lower)alkylamino and/or halogen. Used in this context, the term "(lower)" means a group with 1-7 C atoms, preferably 1-4 C-atoms. Alkyl and alkoxygroup, as well as alkyl groups as fragments alkanoyl groups can be linear or branched. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec - and tert-butyl. Halogen means fluorine, chlorine, bromine and iodine, preferably from chlorine them.

Examples heterocyclyl residues are mono - or bicyclic 5 - and 6-membered heterocyclic residues with oxygen, nitrogen or sulphur as heteroatoms, such as 2 - and 3-furyl, pyrimidinyl, 2-, 3 - and 4-pyridyl, 2 - tetrazolyl-4-pyridyl, 1,2 - and 1,4-diazines, morpholino, 2 - and 3 - thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl and tetrazolyl, which can be substituted, for example, (Nissi is but mono - or di-(lower)alkylamino or halogen. Educated R4and R5N-heterocyclic residues are preferably monocyclic 6-membered heterocyclyl residues, which may contain one oxygen atom or nitrogen atom, such as morpholino, piperidino, piperazine derivatives and N4-(lower) alkylpiperazine.

Preferred residues R1are substituted by (lower) alkyl or (lower) alkoxy phenyl and monocyclic containing a nitrogen atom heterocyclyl residues, such as pyridyl, especially 2-pyridyl which may be substituted, preferably once, (lower) alkyl. Preferred residues R2represent phenyl, substituted by (lower) alkoxy and/or halogen. Preferred residues R3represent hydroxy, and-NR4R5where R4is hydrogen, a R5is phenyl or tetrazolyl. Rarepresents preferably hydrogen or hydroxy. Rbrepresents preferably hydrogen. X and Y are preferably oxygen. Z preferably represents hydrogen, n means preferably 0 or 1.

The compounds of formula Balewadi, due to the activity of endothelin, above all disorders in the circulatory system such as hypertension, ischemia, spasms of the blood vessels and angina.

The compounds of formula I and their salts can be obtained according to the invention due to the fact that in the compound of formula II

< / BR>
where a is a translatable in the carboxyl group residue, a R1, R2X, Y, Z, Ra, Rband n have the above values, balance And transform into a carboxyl group, optionally obtained and thus the compound of the formula I, in which R3represents hydroxy, hydroxyl group, R3transform in the (lower) alkoxygroup or the group-NR4R5or pharmaceutically applicable Sol.

Examples of residues And are primarily formanova group and the remainder furan-2-yl. These residues by well-known methods by treatment with oxidizing agents can be converted into a carboxyl group, and available in the source material of the formula II group, not inert with respect to the use of oxidants, such as hydroxyl groups, it is advisable to protect. Oxidizing agent suitable for oxidizing farmerboy groups to carboxyl gr is Le, for example, benzene, in the presence of crown ether at room temperature. Clearly indicated in the formula I is hydroxyl group, and denoted by Raand/or available in R1hydroxyl groups can be protected by well-known methods in the form of an ether, such as acetal, or in the form of ketala, for example, the acetonide. Furan-2-silt group can oxidize to carboxylic groups by treatment with periodate, for example, periodate sodium, in the presence of ruthenium chloride (III) in a two-phase system containing CCl4, acetonitrile and water.

The compounds of formula II are novel and are likewise an object of the present invention. The compounds of formula II in which a represents formally the remainder can be obtained from the corresponding methyl compounds (see European patent publication EP-A-0526708) by oxidation, for example, selenium dioxide (see European patent publication EP-A-0601386).

The compounds of formula II in which a represents furan-2-sludge residue, a Y denotes oxygen or sulfur, can be derived from compounds of the formula

CH3OOCCH(R2X)COOCH3< / BR>
by condensation with 2-furnishedin to 2-furan-2-yl-(5-R2)-pyrimidine-4,6-sulfonamide salt of the formula R1SO2NHM, and then with the compound of the formula

MY'CH2(CRaRb)nCH2OB,

where Y' represents oxygen or sulphur, M represents a cation, for example, a cation of an alkali metal such as Na+or+and B is a protective group, and if necessary, denoted by Rathe hydroxyl group is present in a protected form.

Formed in this way carboxyl group can be converted by well-known methods in complex (lower) alkilany ether (R3means (lower)alkoxy) or amide (R3means-NR4R5or in pharmaceutically applicable Sol. Examples of pharmaceutically applicable salts are alkali metal salts such as sodium salt and potassium salt, and salts of alkaline earth metals such as calcium salt and magnesium salt.

The compounds of formula I have a selective inhibitory effect against endothelially receptors a and b (ETAand ETB), which is confirmed by the following series of experiments:

I. Inhibition of binding of endothelin with recombinant ETAreceptor

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

To analyze the response to the binding of the frozen membrane preparations were thawed and after centrifugation for 10 min at 25000 x g and 20oC resuspendable buffer for analysis (50 mm Tris-buffer, pH of 7.4, containing 25 mm MnCl2, 1 mm etc and 0.5% serum albumin blood of cattle). 100 μl of this membrane suspension containing 5 mg of protein were incubated with 50 μl of125I-endothelin (specific activity 2200 CI/mmol) in the buffer for analysis (25000 pulses/min to a final concentration of 20 PM) and 100 µl of buffer for analysis, sod the C or for 24 h at 4oC. Separation of free and bound membrane radio was carried out by filtration through a glass fiber filter.

II. Inhibition of binding of endothelin to membranes of human placenta (ETBreceptor) (see Life Sci. 44:1429 (1989))

The human placenta homogenized in 5 mm Tris buffer, pH of 7.4, containing 1 mm MgCl2and 250 mm sucrose). Homogenized centrifuged at 3000 x g for 15 min at a temperature of 4oC, then the residue containing plasmamembrane fraction was centrifuged at 72000 x g for 30 min and the precipitate was washed in 75 mm Tris buffer, pH of 7.4, containing 25 mm MgCl2. Then the precipitate obtained from 10 g of original tissue, suspended in 1 ml of 75 mm Tris buffer, pH of 7.4, containing 25 mm MgCl2and 250 mm sucrose, and frozen in 1 ml aliquot of sample at -20oC.

To analyze binding assays frozen membrane preparations were thawed and after centrifugation for 10 min at 25000 x g and 20oC resuspendable buffer for analysis (50 mm Tris-buffer, pH of 7.4, containing 25 mm MnCl2, 1 mm etc and 0.5% serum albumin blood of cattle). 100 μl of this membrane suspension containing 35 µg of protein, incu final concentration of 20 PM) and 100 µl of buffer for analysis, containing varying concentrations of test compounds. Incubation was carried out for 2 h at 20oC or for 24 h at 4oC. Separation of free and bound membrane radio was carried out by filtration through a glass fiber filter.

Table 1 presents revealed in this series of experiments the inhibitory activity of the compounds of formula I in relation to ETAand ETBreceptors, referred to as IC50i.e. as the concentration [µm] required for inhibition of 50% of the specific binding125I-endothelin.

The compounds of formula I, thanks to their ability to inhibit the binding of endothelin can be used as a means for the treatment of diseases associated with processes that promote vasoconstriction. Examples of such diseases are high blood pressure, first and foremost pulmonary hypertension and subarachnoid haemorrhage. Other indications for the use of the compounds according to the invention are coronary heart disease, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, infarction of the brain, migraine and Raynaud's syndrome. Compounds according to izobreteniya vessels, inflammation, stomach ulcers and duodenal ulcers, leg ulcers, gram-negative sepsis, shock, glomerulonephritis, renal colic, glaucoma, asthma, dialysis and the treatment and prevention of diabetic complications and complications with the introduction of cyclosporine, as well as other diseases caused by the activity of endothelin.

The compounds of formula I can be administered for oral, rectal, parenteral, e.g. intravenous, intramuscular, subcutaneous, intrathecal or transdermal; or they can be assigned to the hyoid reception or in the form of ophthalmic compositions or in the form of aerosols. Examples of application forms are capsules, tablets, administered orally suspensions or solutions, suppositories, injectable solutions, eye drops, ointments or solutions for spray.

The preferred form of administration is intravenous, intramuscular or oral administration. Dosage, which is administered an effective amount of compounds of formula 1, depends on the specific form of the active substance, the age and needs of the patient, as well as the form of the introduction. As a rule, the daily dose is from 0.1 to 100 mg/kg body weight. Drugs, Soini supplements. So, for example, tablets or granules can contain a number of binders, excipients, carriers or diluents. Liquid preparations can be represented, for example, in the form of sterile, mixed with water solutions. Capsules along with the active substance can additionally contain fillers or thickeners. In addition, can be used flavorings, as well as substances which are usually used as preservatives, stabilizers, moisture retaining means and emulsifiers, as well as salts for modifying the osmotic pressure, buffers and other additives.

The above carriers and diluents can be an organic or inorganic substances, such as water, gelatin, lactose, starch, magnesium stearate, talc, gum Arabic, polyalkylene glycols, etc., the use of all these auxiliary substances for the production of preparations is their toxicity.

The following examples serve for a more detailed explanation of the invention.

Example 1

a) a solution of 4.6 g of sodium in 150 ml of methanol was added 25 g nanometrology ether of resorcinol and 37 g of dimethyl ether of hormonology acid. The reaction mixture Perea water. The organic phase was dried with sodium sulfate and the solvent drove away. In this way received of 40.7 g of methyl ester of (RS)-(3 - methoxyphenoxy)acetoxyl acid in the form of oil, MS:(M+H)+255.

b) In a solution of sodium methylate from 450 ml of methanol and 11.3 g of sodium was added 17 g of the hydrochloride of acetamidine and 40 g of (RS)-(3 - methoxyphenoxy)acetoxyl acid. The reaction mixture was stirred for 2 h at 20oC, then concentrated and distributed between toluene and water. The aqueous phase using a 2H HCl was set at pH 4 and stirred at 0oC for 16 hours the Precipitate was filtered, washed with water and simple with ether, and dried. In this way received of 25.7 g of 6-hydroxy-5-(3-methoxyphenoxy)-2 - methyl-3H-pyrimidine-4-it is in the form of a white solid, MS: (M+H)+249.

C) In a solution of 11.9 g of 6-hydroxy-5-(3 - methoxyphenoxy)-2-methyl-3H-pyrimidine-4-she's in 150 ml of dioxane was added to 24.5 ml of base Hunga and 23.6 ml POCl3. The reaction mixture was stirred for 16 h at 120oC, then drove away excess reagent and dioxane. The remainder of double-concentrated with toluene and was distributed between chloroform and water. The organic phase is washed with NaHCO3and water, dried and concentrated. The rest of echimidine in the form of a yellowish oil, MS: (M+H)+286.

g) 9 g of 4,6-dichloro-5-(3-methoxyphenoxy)-2 - methylpyrimidine and 17 g of p-tert-butylbenzenesulfonamide potassium in 35 ml of dry dimethyl sulfoxide was heated in an argon atmosphere for 3 h to 120oC. Then DMSO drove away, the residue was distributed between ethyl acetate and 1H hydrochloric acid and the organic phase is washed until neutral state. Then the organic phase was dried, the solvent evaporated and the residue was mixed with 35 ml of methanol. In this way they obtained 11.1 g of p-tert-butyl-N-[6-chloro-5-(m - methoxyphenoxy)-2-methyl-4-pyrimidinyl]benzosulfimide, tPL170oC.

d) In the solution glycolate, sodium, 35 g of ethylene glycol and 1.66 g of sodium was added 11 g of p-tert-butyl-N-[6-chloro-5-(m-methoxyphenoxy)- 2-methyl-4-pyrimidinyl]benzosulfimide. The reaction mixture was stirred in an argon atmosphere for 16 hours at a temperature of 95oC, then mixed with 100 ml of 1H hydrochloric acid and 50 ml of water and was extracted twice with 100 ml of ethyl acetate, respectively. The organic phase is washed with water, dried and evaporated. The residue was led from dichloromethane/isopropyl ether. The way it was obtained 8.8 g of p - tert-butyl-N-[6-(2-hydroxyethoxy)-2-methyl-5-(m - methoxyphenoxy)-4-pyrimidinyl] benzosulfimide-5-(m-methoxyphenoxy)-4-pyrimidinyl] benzosulfimide in 40 ml of dichloromethane was added 0.2 g of dimethylaminopyridine and 3.9 ml of acetanhydride. The reaction mixture was stirred for 3 hours at a temperature of 20oC and with a saturated solution of NaHCO3installed at pH 7. The organic phase is washed with water, dried and evaporated. The residue was purified on silica gel with chloroform. The way it was obtained 1.1 g of 2-[6-acetyl-(4-tert-butylphenyl-sulfonyl)amino] -5- (3-methoxyphenoxy)-2-methylpyrimidin-4-yloxy] ethyl ester of acetic acid in the form of a foamy substance, MS: (M+H)+572.

W) 0.2 g of 2-[6-acetyl-(4-tert - butylphenylmethyl)amino]-5-(3-methoxyphenoxy)-2-methylpyrimidin - 4-yloxy]ethyl ester of acetic acid and 0.6 g of selenium dioxide in 10 ml of dioxane was stirred in an autoclave at a temperature of 140oC for 50 h and Then the reaction mixture was filtered and the filtrate was concentrated. The residue was distributed between ethyl acetate and water. The organic phase was dried, the solvent is kept off and the residue was purified on silica gel with chloroform/methanol in a ratio of 95: 5. The way it was obtained 0.27 g of 2-[6-(4-tert-butylphenylphosphine)-2 - formyl-5-(3-methoxyphenoxy)pyrimidine-4-yloxy] ethyl ester of acetic acid in the form of a foamy substance, MS: (M+H)+544.

C) 0.27 g of 2-[6-(4-tert-butylphenylphosphine)-2-formyl-5-(3 - methoxyphenoxy) pyrimidine-4-yloxy] accalia for 16 hours at a temperature of 20oC. Then the reaction mixture was distributed between toluene and water. The organic phase was dried, evaporated and the residue was purified on silica gel with chloroform/methanol. The way it was obtained 0.09 g of 4-(2-acetoacetate)-6-(4-tert-butylphenylphosphine) -5-(3-methoxyphenoxy)pyrimidine-2-carboxylic acid in the form of a foamy substance, MS: (M-H)-558.

and 0.09 g of 4-(2 - acetoacetate)-6-(4-tert-butylphenylphosphine)-5-(3 - methoxyphenoxy)pyrimidine-2-carboxylic acid was stirred in 4 ml of methanol and 1.5 ml of water with 0.05 g of sodium carbonate for 2 hours at a temperature of 20oC. Then methanol is evaporated and the residue was distributed between chloroform and water 1H hydrochloric acid. The organic phase was dried and evaporated. The residue was purified on silica gel with chloroform/methanol/water in the ratio of 60:35:5. In this way received 0,034 g of 6-(4-tert-butylphenylphosphine)-4-(2 - hydroxyethoxy)-5-(3 - methoxyphenoxy) pyrimidine-2-carboxylic acid, MS: (M-H)-515,9.

Example 2

Analogously to example 1 from 2-chloro-5-methoxyphenol received 4-(4-tert - butylphenylphosphine)-5-(2-chloro-5-methoxyphenoxy)-6-(2 - hydroxyethoxy)pyrimidine-2-carboxylic acid, MS: (M-H)-550,2, through the following intermediate stages:

a) methyl ester of (RS)-(2-),

C) 4,6-dichloro-5-(2-chloro-5-methoxyphenoxy)-2-methylpyrimidin,

g) of p-tert-butyl-N-[6-chloro-5-(2-chloro-5-methoxyphenoxy)-2-methyl-4 - pyrimidinyl]benzosulfimide,

d) p-tert-butyl-N-[6-(2-hydroxyethoxy)-2-methyl-5-(2-chloro-5 - methoxyphenoxy)-4-pyrimidinyl]benzosulfimide,

e) 2-[6-(4-tert-butylphenylphosphine)-5-(2-chloro-5 - methoxyphenoxy)-2-methylpyrimidin-4-yloxy]ethyl ester acetic acid,

g) 2-[6-(4-tert-butylphenylphosphine)-5- (2-chloro-5-methoxyphenoxy)-2-formylpyridine-4-yloxy]ethyl ester acetic acid,

C) 4-(2-acetoacetate) -6-(4-tert - butylphenylphosphine)-5-(2-chloro-5-methoxyphenoxy)pyrimidine-2 - carboxylic acid.

Example 3

Analogously to example 1 from 4,6-dichloro-5- (3-methoxyphenoxy)-2-methylpyrimidine received 4-(2 - hydroxyethoxy)-5-(3-methoxyphenoxy)-6-(4 - methoxyphenylacetylene) pyrimidine - 2-carboxylic acid, MS: (M-H)-490,3, through the following intermediate stages:

a) N-[6-chloro-5-(3-methoxyphenoxy)-2-methylpyrimidin-4-yl]-4 - methoxybenzenesulfonamide,

b) N-[6-(2-hydroxyethoxy)-5-(3 - methoxyphenoxy)-2-methylpyrimidin-4-yl] -4 - methoxybenzenesulfonamide,

a) 2-[6-(4-methoxyphenylacetylene) -5-(m-methoxyphenoxy)-2-methylpyrimidin-4-yloxy]ethyl ester acetic kicksyday acid,

d) 4-(2-acetoacetate)-6-(4 - methoxyphenylacetylene)-5-(m-methoxyphenoxy)pyrimidine-2 - carboxylic acid.

Example 4

a) Analogously to example 1B) from 34 g of ethyl ester of (RS)-(3-methoxyphenoxy)acetoxyl acid and 23 g of 2-furnishedin received 15.6 g of 2-furan-2-yl-5-(3 - methoxyphenoxy)pyrimidine-4,6-diol in the form of a foamy substance, MS: (M+H)+300.

b) Analogously to example 1B) from 15.5 g of 2-furan-2-yl-5-(3-methoxyphenoxy)pyrimidine-4,6-diol and 43 ml of POCl3received 15.9 g of 4,6-dichloro-2-furan-2-yl-5-(3-methoxyphenoxy)pyrimidine, tPL106oC, MS: (M+H)+338.

C) Analogously to example 1D) from 1 g of 4,6-dichloro-2-furan-2-yl-5-(3-methoxyphenoxy)pyrimidine and 1.5 g of p-tert-butylbenzenesulfonamide potassium was received of 1.34 g of 4-tert-butyl-N-[6-chloro-2-furan-2-yl-5-(3-methoxyphenoxy)pyrimidine-4 - yl]benzosulfimide, MS: (M-H)-513.

d) Analogously to example 1D) from 0.3 g of 4-tert-butyl-N-[6-chloro-2-furan-2-yl-5-(3 - methoxyphenoxy)pyrimidine-4-yl] benzosulfimide and 12 ml DL - isopropylideneglycerol was obtained 0.25 g (RS)-4-tert-butyl-N-[6- (2,2 - dimethyl[1,3]dioxolane-4-ylethoxy)-2-furan-2-yl-5-(3 - methoxyphenoxy)pyrimidine-4-yl]benzosulfimide, tPL135oC, MS: (M-H)-608.

d) In a solution of 0.25 g of (RS)-4-tert-butyl-N-[6-(2,2 - dim and 3.6 ml of acetonitrile was added a solution of 0.7 g of periodate sodium and 0.015 g of ruthenium chloride in 10 ml of water. Then the reaction mixture was stirred for 1 h at a temperature of 20oC and extracted with methylene chloride. The organic phase was dried and evaporated. The residue was purified on silica gel with chloroform. In this way received 0.04 g of (RS)-4-(4-tert-butyltrichlorosilane-6-(2,2 - dimethyl[1,3] dioxolane-4-ylethoxy) -5- (3 - methoxyphenoxy)pyrimidine-2-carboxylic acid, MS: (M-H)-586.

e) a Solution of 0,033 g of (RS)-4-(4-tert-butyltrichlorosilane-6-(2,2 - dimethyl[1,3] dioxolane-4-ylethoxy)-5-(3-methoxyphenoxy)pyrimidine - 2-carboxylic acid in 2 ml of dioxane was mixed with 1.3 ml 1H HCl and heated for 30 min to 90oC. After evaporation the residue was chromatographically using eluents chloroform-methanol-water in the ratio of 60:35:5 and in this way got to 0.007 g of (RS)-6-(4-tert - butylphenylphosphine)-4-(2,3-dihydroxypropane)-5-(3 - methoxyphenoxy)pyrimidine-2-carboxylic acid in the form of a foamy substance, MS: (M-H)-546.

Example 5

Analogously to example 4D) of 2- [6-(4-tert-butylphenylphosphine)-2-furan-2-yl-5-(2 - methoxyphenoxy)pyrimidine-4-yloxy] ethyl ester of acetic acid was obtained 4-(2-acetoacetate)-6-(4-tert-butylphenylphosphine)-5- (2-methoxyphenoxy)pyrimidine-2-carboxylic acid, MS: (M-H)-558, and from this Ki)pyrimidine-2-carboxylic acid, MS: (M-H)-516,4.

Example 6

To a solution of 0,053 g of 6-(4-tert-butylphenylphosphine)-4-(2 - hydroxyethoxy)-5-(3-methoxyphenoxy)pyrimidine-2-carboxylic acid in 5 ml of acetonitrile was added to 0.02 ml base Hunya, 0,052 g chloride bis(2 - oxo-3-oxazolidinyl)phosphinic acid and 0.01 ml of aniline. After 3 h the reaction mixture was evaporated and distributed between acetic ether and water. The organic phase was dried, evaporated and the residue was purified on silica gel with chloroform. In this way got to 0.032 g phenylamide 6-(4-tert-butylphenylphosphine)-4-(2 - hydroxyethoxy)-5- (3-methoxyphenoxy)pyrimidine-2-carboxylic acid, tPL143oC, MS: (M-H)-591.

Example 7

Analogously to example 6 was obtained phenylamide 4-(2-hydroxyethoxy)-5-(3-methoxyphenoxy)-6- (4-methoxyphenylacetylene)pyrimidine-2-carboxylic acid, MS: (M+H)+567.

Example 8

Analogously to example 6 was obtained phenylamide 6-(4-tert-butylphenylphosphine)-5- (2-methoxyphenoxy)-4-(2-hydroxyethoxy)pyrimidine-2-carboxylic acid, MS: (M-H)-591.

Example 9 is Similar to example 6 was obtained phenylamide 4-(4-tert-butylphenylphosphine)-5- (2-chloro-5-methoxyphenoxy)-6-(2 - hydroxyethoxy)pyrimidine-2-carboxylic acid, MS: (M+H)+amino)-6-(2-hydroxyethoxy)-5-(3 - methoxyphenoxy)pyrimidine-2-carboxylic acid, MS: (M-H)-583.

Example 11

Analogously to example 4, sections C), d), e), from 4,6-dichloro-2-furan-2-yl-5-(3-methoxyphenoxy) pyrimidine was obtained:

a) [6-chloro-2-furan-2-yl-5-(3-methoxyphenoxy)pyrimidine-4 - yl] amide 5-isopropylpyridine-2-sulfonic acid,

b) [2-furan-2-yl-6-(2-hydroxyethoxy)-5-(3-methoxyphenoxy)pyrimidine-4-yl]amide 5-isopropylpyridine-2-sulfonic acid,

a) 2-[6-[acetyl-(5-isopropylpyridine-2-ylsulphonyl)amino] -2-furan-2 - yl-5-(3-methoxyphenoxy)pyrimidine-4-yloxy]ethyl ester acetic acid,

g) 4-[(2-acetoacetate)-6-(5-isopropylpyridine-2-ylsulphonyl) amino]-5-(3-methoxyphenoxy)pyrimidine-2-carboxylic acid, and then analogously to example 1 was obtained 4-(2-hydroxyethoxy)-6-(5 - isopropylpyridine-2-ylsulphonyl)-5-(3-methoxyphenoxy) pyrimidine-2-carboxylic acid, MS: (M-H)-503.

Example 12

Analogously to example 4, sections C), d), e), from 4,6-dichloro-2-furan-2-yl-5-(3-methoxyphenoxy) pyrimidine was obtained:

a) [6-chloro-2-furan-2-yl-5-(3-methoxyphenoxy)pyrimidine-4-yl] amide 5-methylpyridin-2-sulfonic acid,

b) [2-furan-2-yl-6-(2-hydroxyethoxy)-5-(3-methoxyphenoxy) pyrimidine-4-yl]amide 5-methylpyridin-2-sulfonic acid,

a) 2-[2-furan-2-yl-5-(3-methoxyphenoxy)-6- (5-methylpyridin-2-ilal is n-2-ylsulphonyl)amino]-5-(3 - methoxyphenoxy)pyrimidine-2-carboxylic acid, and then analogously to example 1 was obtained 4-(2-hydroxyethoxy)-6-(5-isopropylpyridine - 2-ylsulphonyl)-5-(3-methoxyphenoxy) pyrimidine-2 - carboxylic acid, MS: (M-H)-475.

Example 13

Analogously to example 6 can be obtained (1H-tetrazol-5-yl)amide of 4-(2-hydroxyethoxy)-5-(3-methoxyphenoxy)-6- (5-methylpyridin-2-ylsulphonyl)pyrimidine-2-carboxylic acid.

Example 14

Analogously to example 4 can be obtained (R,S)-6-(2,3-dihydroxypropane)-5-(3-methoxyphenoxy)-4- (5-methylpyridin-2-ylsulphonyl)pyrimidine-2-carboxylic acid.

Example 15

Analogously to example 6 can be obtained (1H-tetrazol-5-yl)amide 6-(4-tert-butylphenylphosphine) -4-(2,3-dihydroxypropane)-5-(3-methoxyphenoxy)pyrimidine-2 - carboxylic acid.

Example 16

Analogously to example 6 was obtained 4-tert-butyl-N-[6- (2-hydroxyethoxy)-5-(3-methoxyphenoxy)-2-(morpholine-4 - ylcarbonyl)pyrimidine-4-yl] benzosulfimide, MS: (M-H)-585.

Example 17

Analogously to example 6 was obtained pyridin-3-alamid 4-(4 - tert-butylphenylphosphine)-6-(2-hydroxyethoxy)-5-(3 - methoxyphenoxy)pyrimidine-2-carboxylic acid, MS: (M-H)-592.

Example 18

Analogously to example 6 was obtained (3-hydroxyphenyl)amide 4- (4-UP>-607.

Example 19

Analogously to example 6 was obtained (2-hydroxymethylene)amide 4-(4-tert-butylphenylphosphine)-6- (2-hydroxyethoxy)-5-(3-methoxyphenoxy)pyrimidine-2-carboxylic acid, MS: (M+H)+623.

Example 20

Analogously to example 6 was obtained (3-hydroxymethylene)amide 4-(4-tert-butylphenylphosphine)-6-(2-hydroxyethoxy)-5-(3 - methoxyphenoxy)pyrimidine-2-carboxylic acid, MS: (M-H)-621.

Example 21

Analogously to example 6 was obtained pyridin-3-alamid (RS)-4-(4-tert-butylphenylphosphine)-6- (2,3-dihydroxypropane)-5-(3-methoxyphenoxy)pyrimidine-2-carboxylic acid, MS: (M-H)-622.

Example 22

Analogously to example 6 was obtained (3-hydroxyphenyl)amide (RS)-4-(4-tert-butylphenylphosphine)-6-(2,3 - dihydroxypropane)-5-(3-methoxyphenoxy)pyrimidine-2-carboxylic acid, MS: (M-H)-637.

Example 23

0.2 g of 6-(4-tert-butylphenylphosphine)-4-(2-hydroxyethoxy)-5- (3-methoxyphenoxy)pyrimidine-2-carboxylic acid was stirred in 5 ml of dimethylacetamide with 0.04 g of sodium hydride and 0.07 g of 2-chloropyrimidine for 3 hours at a temperature of 20oC, then neutralized with saturated solution of NH4Cl. Then the reaction mixture was washed with ethyl acetate. Water Iparioli and the residue was purified on silica gel with chloroform/methanol/water in the ratio of 60:35:5. The way it was obtained 0.16 g of 4-(4-tert-butylphenylphosphine)-5-(3 - methoxyphenoxy)-6-(2-pyrimidine-2-roxilox)pyrimidine-2 - carboxylic acid, MS: (M+H)+596.

An example of a

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

Ingredients 1 tablet

The compound of formula 1 of 10.0-100.0 mg

Lactose - 125,0 mg

Corn starch is 75.0 mg

Talc - 4.0 mg

Magnesium stearate 1.0 mg

Example B

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

Ingredients 1 capsule

The compound of formula 1 25.0 mg

Lactose - 150,0 mg

Corn starch - 20.0 mg

Talc - 5.0 mg

The example IN

Injectable solutions may have the following composition:

The compound of formula 1 - 3.0 mg

Gelatin - 150,0 mg

Phenol - 4,7 mg

Water for injection solutions from 1.0 ml

Example D

3.5 ml of megliola 812 and 0.08 g of benzyl alcohol are suspended 500 mg of the compounds of formula I. This suspension fill the canister with a metering valve. Then through the valve in the canister serves under pressure of 5.0 g of freon 12. By shaking the freon is dissolved in a mixture of miglyol/benzyl alcohol. This aerosol Bidny derivatives of the formula I

< / BR>
where R1means phenyl, substituted lower alkyl or lower alkoxy, substituted heterocyclyl represents pyridyl, substituted lower alkyl;

R2means phenyl, substituted lower alkoxy and/or halogen;

R3means hydroxy, lower alkoxy or balance-NR4R5;

R4means hydrogen or the residue of R6;

R5means hydrogen; or R4and R5together with their associated N-atom mean N-heterocyclic residue, representing morpholine-4-yl;

R6means phenyl, phenyl substituted by hydroxy or hydroxy (lower) alkyl, heterocyclyl selected from tetrazolyl or pyridyl, and hydroxy (lower) aklil;

Randmeans hydrogen or hydroxy;

Rbmeans hydrogen;

X is oxygen;

Y represents oxygen;

Z denotes hydrogen, lower alkyl, heterocyclyl represents pyrimidine-2-yl;

n means 0 or 1;

and their pharmaceutically acceptable salts.

2. Connection on p. 1, in which R1represents phenyl, substituted lower alkyl or lower alkoxy.

3. Connection PP. 1 and 2, in which R1represents pyridyl, z is i.i.d. lower alkoxy and/or halogen.

5. Connection PP.1-4, where R3represents hydroxy or-NR4R5.

6. Connection on p. 2, representing

6-(4-tert-butylphenylphosphine)-4-(2-hydroxyethoxy)-5-(3-methoxyphenoxy)pyrimidine-2-carboxylic acid,

4-(4-tert-butylphenylphosphine)-5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)pyrimidine-2-carboxylic acid,

4-(2-hydroxyethoxy)-5-(3-methoxyphenoxy)-6-(4-methoxyphenylacetylene)pyrimidine-2-carboxylic acid,

(RS)-6-(4-tert-butylphenylphosphine)-4-(2,3-dihydroxypropane)-5-(3-methoxyphenoxy)pyrimidine-2-carboxylic acid,

6-(4-tert-butylphenylphosphine)-4-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidine-2-carboxylic acid,

phenylamide 6-(4-tert-butylphenylphosphine)-4-(2-hydroxyethoxy)-5-(3-methoxyphenoxy)pyrimidine-2-carboxylic acid,

phenylamide 4-(2-hydroxyethoxy)-5-(3-methoxyphenoxy)-6-(4-methoxyphenylacetylene)pyrimidine-2-carboxylic acid,

phenylamide 6-(4-tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-4-(2-hydroxyethoxy)pyrimidine-2-carboxylic acid,

phenylamide 4-(4-tert-butylphenylphosphine)-5-(2-chloro-5-methoxyphenoxy)-6-(2-hydroxyethoxy)pyrimidine-2-carboxylic acid,

(1H, t is Oh acid.

7. Connection on p. 3, a 4-(2-hydroxyethoxy)-6-(5-isopropylpyridine-2-ylsulphonyl)-5-(3-methoxyphenoxy)pyrimidine-2-carboxylic acid.

8. Connection PP.1-7, designed to obtain a pharmaceutical composition having the effect of an inhibitor of endothelin receptors.

9. Pharmaceutical drug that has the effect of an inhibitor of endothelin containing one of the compounds according to paragraphs.1-7 and the usual fillers and excipients.

 

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The invention relates to novel di - and trivalent small selectin inhibitors of formula II, where X is selected from the group comprising-CN, -(CH2)nCO2H, -(CH2)nCONHOH, -O(CH2)m-CO2H, -(CH2)nCOZ, -(CH2)nZ, -CH(CO2H), (CH2)mCO2H,

-OH; Y = -(CH2)f; R1, R2independently selected from the group including hydrogen, lower alkyl, halogen, -OZ, -NO2, -NH2; R3selected from the group including hydrogen, lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkyl-carboxylic acid; f = 1 - 6; n = 0 to 2; b = 0 - 2; m = 1 to 3; Z represents lower alkyl, phenyl, or their pharmaceutically acceptable salts, esters, Amida

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The invention relates to new N-substituted piperidinylmethyl f-ly I, their N-oxide forms, isomers, and salts, where R1- halogen, C1-6alkylsulfonamides And divalent radical-CH2-CH2; -CH2-CH2-CH2- or-CH=CH-; R2is hydrogen or C1-6alkyloxy; L is a radical of formula-Alk-R4, -Alk-OR5, -Alk-NR6R7; Alk-C1-12alcander; R4is hydrogen, cyano, C1-6alkylsulphonyl,1-6allyloxycarbonyl, etc

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The invention relates to benzofuran formula I

< / BR>
where R1denotes NH2, 1-piperazinil or 4-R3-piperazinil;

R2denotes H, Cl, Br, OH or OA;

R3denotes benzyl or itself known protective for the amine function group;

X denotes a CN, COON, COOA, COOPh, COOCH2Ph, COOPy, CONR4R5or CO-Het;

R4and R5each independently of one another denotes H, A or benzyl;

A denotes alkyl with 1-4 C-atoms;

Ph denotes phenyl;

Het represents imidazol-1-yl, triazole-1-yl or tetrazol-1-yl; and

Py denotes a pyridyl;

and their salts

The invention relates to new pyrimidine compounds or their salts with pharmaceutically acceptable acids and pharmaceutical compositions based on them
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