Derivatives of carboxylic acids

 

(57) Abstract:

The invention relates to new derivatives of carboxylic acids of General formula I containing heterocyclic ring. These compounds have biological activity, in particular, are inhibitors of the binding of endothelin to receptors, and can find use for the treatment of hypertension, myocardial infarction, renal failure and other diseases. The proposed compounds correspond to the General formula I, where R1- tetrazol, nitrile, carboxyl group, a COOR group7where R7means alkyl with 1-4 carbon atoms or a cation of an alkaline or alkaline-earth metal, group-CONHSO2R8where R8means alkyl with 1-4 carbon atoms or-COCH2SO2-R9where R9means alkyl with 1 to 4 carbon atoms; R2the hydroxy - group, amino group, mono - and dialkylamino with 1-4 carbon atoms in the alkyl part, alkyl with 1-4 carbon atoms, halogenated with 1-4 carbon atoms, alkoxygroup with 1-4 carbon atoms; X is nitrogen or the radical CR10where R10means hydrogen or alkyl with 1-5 carbon atoms or CR10together with CR3forms a 5 - or 6-membered alkylene or alkenylamine Kolchanova group may be replaced by oxygen, aminogroups or alkylamino with 1-4 carbon atoms;3- amino group, mono - or dialkylamino with 1-4 carbon atoms in the alkyl part, alkyl with 1-4 carbon atoms, alkoxygroup with 1-4 carbon atoms, or CR3together with CR10have the above meaning; R4and R5every means phenyl, unsubstituted or substituted with halogen, alkyl with 1-4 carbon atoms or alkoxyl with 1-4 carbon atoms; phenyl, each phenyl in anthopology can be related by a simple bond, methylene or ethylene group, or cycloalkyl with 3-7 carbon atoms; R6- alkyl with 1-8 carbon atoms and alkenyl with 3-6 carbon atoms, unsubstituted or substituted with halogen, cyano or alkoxyl with 1-4 carbon atoms, alkylthiol with 1-4 carbon atoms or phenyl, phenyl, unsubstituted or once or twice substituted by halogen, alkyl with 1-4 carbon atoms or alkoxyl with 1-4 carbon atoms, or cycloalkyl with 3-8 carbon atoms, unsubstituted or substituted by alkyl with 1-4 carbon atoms, five - or six-membered heterocycle containing one sulfur atom or oxygen, unsubstituted or substituted by alkyl with 1-4 carbon atoms, Z is sulfur, oxygen, sulfinil or sulfonyl. 3 Tabasco activity.

Known derivatives of 3-alkoxycarbonyl acid, which can be used as a herbicide (see application EP 0 481 512 A1, class 07 D 239/60, a 01 N 43/54, published. 22.04.1992 year).

The purpose of the invention is to develop derivatives of carboxylic acids, which is an inhibitor of binding of endothelin to its receptor.

The problem is solved proposed derivatives of carboxylic acids of General formula (I)

< / BR>
in which R1- tetrazol, a carboxyl group, a COOR group7where R7means alkyl with 1-4 carbon atoms or a cation of an alkaline or alkaline-earth metal, group-CONHSO2R8where R8means alkyl with 1-4 carbon atoms or-COCH2SO2-R9where R9means alkyl with 1-4 carbon atoms;

R2the hydroxy - group, amino group, mono - and dialkylamino with 1-4 carbon atoms in the alkyl part, alkyl with 1-4 carbon atoms, halogenated with 1-4 carbon atoms, alkoxygroup with 1-4 carbon atoms;

X is nitrogen or the radical CR10where R10means hydrogen or alkyl with 1-5 carbon atoms or CR10together with CR3forms a 5 - or 6-membered alkylene or alkenylamine ring which may be substituted by one lloreda, aminogroups or alkylamino with 1-4 carbon atoms;

R3- amino group, mono - or dialkylamino with 1-4 carbon atoms in the alkyl part, alkyl with 1-4 carbon atoms, alkoxygroup with 1-4 carbon atoms, or CR3together with CR10have the above meaning;

R4and R5every means phenyl, unsubstituted or substituted with halogen, alkyl with 1-4 carbon atoms or alkoxyl with 1-4 carbon atoms; phenyl, each phenyl in the ortho-position may be associated;

R6- alkyl with 1-8 carbon atoms and alkenyl with 3-6 carbon atoms, unsubstituted or substituted with halogen, cyano or alkoxyl with 1-4 carbon atoms, alkylthiol with 1-4 carbon atoms or phenyl, phenyl, unsubstituted or once or twice substituted by halogen, alkyl with 1-4 carbon atoms or alkoxyl with 1-4 carbon atoms, or cycloalkyl with 3-8 carbon atoms, unsubstituted or substituted by alkyl with 1-4 carbon atoms, five - or six-membered heterocycle containing one sulfur atom or oxygen, unsubstituted or substituted by alkyl with 1-4 carbon atoms;

Z is sulfur, oxygen, sulfinil or sulfonyl.

The compounds of formula I, as well as undermentioned promezhutochni substituted carbon atoms. Such compounds can be in the form of pure enantiomers or pure diastereomers, and mixtures thereof.

Obtaining the compounds according to the invention in which Z is sulfur or oxygen, is derived from epoxides of the formula IV, which get well-known manner, for example as described in J. March, Advanced Organic Chemistry, 2nd ed., 1983, C. and 750 862, which is obtained from the ketones II or olefins III:

< / BR>
Derivatives of carboxylic acids of formula VI can be obtained by the fact that the epoxides of General formula IV (e.g., R1=COOR7) enter into interaction with alcohols or thiols of the General formula V in which R6and Z have the above meaning

< / BR>
To do this, heat the compounds of General formula IV with compounds of formula V in a molar ratio of from about 1:1 to 1:7, preferably 1-3 molar equivalents, at a temperature of from 50 to 200oC, preferably from 80 to 150oC.

The reaction may proceed in the presence of a diluent. For this purpose you can use any inert to the reagents solvents.

Examples of such solvents or diluents are water, aliphatic, alicyclic and aromatic hydrocarbons to the methylene chloride, chloroform, carbon tetrachloride, ethylchloride and trichloroethylene, ethers, such as diisopropyl ether, disutility ether, methyl-tert.butyl ether, propylene oxide, dioxane and tetrahydrofuran, ketones, such as acetone, methyl ethyl ketone, methylisobutylketone and methyl isobutyl ketone, NITRILES, such as acetonitrile and propionitrile, alcohols, for example methanol, ethanol, isopropanol, butanol or ethylene glycol, esters such as ethyl acetate and amylacetate, acid amides, for example dimethylformamide, dimethylacetamide and N-organic, sulfoxidov and sulfones, such as dimethyl sulfoxide and sulfolane, bases, for example pyridine, cyclic urea such as 1,3-dimethylimidazolidin-2-he and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine.

The reaction is carried out preferably in the temperature range fromoC to the boiling point of the solvent or solvent mixture.

The presence of a catalyst of the reaction is preferred. As a catalyst can be used in a strong organic and inorganic acids and Lewis acid. For example, among others, used sulphuric acid, hydrochloric acid, triperoxonane acid, p-toluene-acid, apirat traktorista the sludge, can be also obtained if compounds of the formula VI, in which R4and R5means unsubstituted or substituted phenyl, subjected to hydrogenation in the ring.

The compounds of formula VI can be obtained in the form of pure enantiomers on the basis of pure enantiomers of the formula IV by their interaction in the described manner with the compounds of the formula V.

Alternatively, enantiomerically pure compounds of the formula VI obtained if racemic or diastereomeric the compounds of formula VI is subjected to the classical splitting of the racemate with a suitable enantiomerically pure bases such as brucine, strychnine, quinine, quinidine, jinhongya, chinchinim, yohimbinum, morphine, dehydroabietylamine, ephedrine (-), (+), deoxyephedrine (+), (-), threo-2-amino-1-(p-nitrophenyl)-1,3-propane diol (+), (-), threo-2-( N,N-dimethyl-amino)-1-(p-nitrophenyl)-1,3-propane diol (+), (-), threo-2-amino-1-phenyl-1,3-propane diol (+), (-), -methyl-benzylamine(+), (-), -(1-naphthyl)ethylamine(+), (-), -(2-naphthyl)-ethylamine (+), (-), aminomethylphenol, N,N-dimethyl-1-phenethylamine, N-methyl-1-phenethylamine, 4-nitrophenylamino, pseudoephedrine, norephedrine, norpseudoephedrine, derivatives of amino acids, peptide derivatives.

The target is lots of General formula VI, in which the substituents have the above significance, is introduced into reaction with compounds of formula VII

< / BR>
in which R11means halogen or R12-SO2-, and R12can be alkyl with 1-4 carbon atoms, halogenation with 1-4 carbon atoms or phenyl. The reaction takes place preferably in one of the above-mentioned inert solvent and adding a suitable base, i.e. the base, which contributes to deprotonization intermediate product of the formula VI, in the temperature region from room temperature up to the boiling point of the solvent.

The compounds of formula VII are partly known commercial products or can be obtained in a known manner.

Foundations can serve as a hydride of an alkaline or alkaline-earth metal, such as sodium hydride, potassium hydride or calcium hydride, a carbonate of an alkali metal, for example sodium carbonate or potassium, hydroxide of alkali or alkaline earth metal, for example sodium hydroxide or potassium hydroxide, an ORGANOMETALLIC compound, for example, utility, or alkali metal amide, for example litesoplepies.

The compounds of formula I can be produced from the corresponding carboxylic sour the main form, for example gelegenheid acid or anhydride, which are then subjected to the interaction with the corresponding hydroxyl compound HOR7where R7means alkyl with 1-4 carbon atoms. This interaction is carried out in conventional solvents and often with the addition of the grounds listed above. Both these operations can be also simplified by the fact that carboxylic acids act on the hydroxyl compound in the presence of vodoteplolichil means, such as a carbodiimide.

In addition, the compounds of formula I can be obtained in such a way that originate from the salts of the corresponding carboxylic acid, i.e. compounds of the formula I, in which R1means a group COOR7where R7denotes the cation of an alkaline or alkaline-earth metal. These salts can be introduced into the reaction with many compounds of the formula R13-A, in which R13means alkyl with 1-4 carbon atoms, and a represents off a nucleophilic group, for example halogen, such as chlorine, bromine, iodine, or possibly substituted with halogen, alkyl or halogenation aryl - or alkylsulfonyl, such as toluensulfonyl and methylsulphonyl, or other equivalent outgoing group. The compounds of formula R13-A with reaktsionnosposobnykh carried out in conventional solvents and preferably with the addition of the base, and you can apply all of the above reasons.

Obtaining derivatives of carboxylic acids is illustrated by the following examples.

Example 1

Methyl ester of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid

Dissolve 5 g (19.6 mmol) of the methyl ester of 3,3-diphenyl-2,3-epoxypropanol acid in 50 ml of absolute methanol and mixed at 0oWith 0.1 ml of epirate boron TRIFLUORIDE. Stirred for 2 hours at 0oAnd the following 12 hours at room temperature. The solvent is distilled off, the residue is absorbed with ethyl acetate, washed with a solution of acid sodium carbonate and water and dried over magnesium sulfate. After removal of the solvent remains 5.5 g (88%) of light yellow oil.

Example 2

Methyl ester of 2-hydroxy-3-phenoxy-3,3-diphenylpropionic acid

Heat together 5 g (19.6 mmol) of the methyl ester of 3,3-diphenyl-2,3-epoxypropanol acid and 5.6 g (60 mmol) of phenol in air for 6 hours at 100oC. After distillation of the excess of phenol in high vacuum and chromatographic purification of the residue on silica gel using mixtures of hexane/ethyl acetate to obtain 4.9 g (77%) of light yellow oil.

Example 3

Methyl ester of 2-(4,6-dimethoxy-pyrimidine-2-yloxy)-3-meth is fenilpropionovoy acid in 40 ml of dimethylformamide and mixed with 0.3 g (12 mmol) of sodium hydride. Stirred for 1 hour and then added 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylamino. After stirring for 12 hours at room temperature gently hydrolyzing with 10 ml of water, set acetic acid to pH 5 and the solvent is distilled off in high vacuum. The remainder absorb 100 ml of ethyl acetate, washed with water, dried over magnesium sulfate and the solvent is distilled off. The residue is mixed with 10 ml of ethyl ether and the precipitate is sucked off. After drying remains of 3.48 g (82%) of white powder.

So pl. 81oC.

Example 4

2-(4,6-Dimethoxy-pyrimidine-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid

Dissolve 2,12 g (5 mmol) of 2-(4,6-dimethoxy-3,3-diphenylpropionic acid in 50 ml of dioxane, mixed with 10 ml of a 1 N. potassium alkali is added and stirred for 3 hours at 100oC. the Solution was diluted with 300 ml of water and extracted to remove unreacted complex ether ethyl acetate. Then with diluted hydrochloric acid to set the pH value of the aqueous phase equal to 1-2 and extracted with ethyl acetate. After drying over magnesium sulfate and removal of the solvent mix the residue with a mixture of ethyl ether/hexane and sucked off the remaining balance. After drying remains 1,83-methoxy-3,3-diphenylpropionic sodium

Dissolve 1.68 g (4 mmole) of 2-(4,6-dimethoxy-pyrimidine-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid in 4 ml of 1 n caustic soda and 100 ml of water. The solution is subjected to drying by freezing and receive quantitatively sodium salt introduced carboxylic acid.

Example 6

Methyl ester of 3,3-DICYCLOHEXYL-2-hydroxy-3-methoxypropionate acid

Dissolve 10 g (34.9 mmol) of methyl ester of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in 50 ml of methanol and 50 ml of glacial acetic acid, mixed with 1 ml of hydrate of oxide of ruthenium (IV) in dioxane and hydronaut hydrogen in an autoclave at 100 ATM and 100oC. the Catalyst is filtered off, the residue is condensed and mixed with ethyl ether, washed with common salt solution, the organic phase is dried and concentrated. Get the 10.1 g of the desired product in the form of butter.

Example 7

Methyl ester 2-[(4,6-dimethoxy-pyrimidine-2-yl)thio]-3-methoxy-3,3-diphenylpropionic acid

Dissolve 7,16 g (25 mmol) of methyl ester of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in 50 ml of dichloromethane, was added 3 g (30 mmol) of triethylamine was added dropwise and with stirring, 3.2 g (28 mmol) of the chloride methansulfonate. Stirred for 2 hours at room temperature, the industry is t to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxy-pyrimidine-2-thiol and 8.4 g (100 mmol) of acid sodium carbonate in 100 ml dimethylformamide. After stirring for 2 hours at ambient temperatures and following 2 hours at 60oSince then poured into 1 l of ice water and the precipitate is sucked off. After drying remains 3,19 g (29%) of white powder.

Example 8

Methyl ester of 2-hydroxy-3,3-diphenylalanine acid

Dissolve 1.5 g (5.9 mmol) of methyl ester of 3,3-diphenyl-2,3-epoxy-propionic acid in 10 ml of absolute ether, was added dropwise to a cooled to -78oWith the solution cuprate obtained from 635 mg (7 mmol) of copper cyanide (I), dissolved in 10 ml of absolute ethyl ether, and 8,14 ml (13 mmol) of a 1.6 n solution metallicy. Stirred 1 hour at -78oWith and give solution to warm to room temperature. Then diluted with 100 ml of ethyl ether and 100 ml of water, the ether phase is washed with dilute citric acid and a solution of acidic sodium carbonate and dried over magnesium sulfate. The crude product is subjected to chromatographic purification on silica gel with a mixture of cyclohexane/ethyl acetate and receive 250 mg (16%) light yellow oil.

Example 9

2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid

Suspended 91,11 g (0.5 mole) of benzophenone and 45,92 g of 0.85 mol) of sodium methylate in 150 ml of methyl tert.butyl ether (MTB) with whom the slots so to the internal temperature rose to 40oC, and then again cooled with a bath to -10oC. and Then stirred for another hour without cooling when its own temperature. After adding 250 ml of water and short mixing of the separated aqueous phase. MTB-phase washed with 250 ml of the diluted solution of sodium chloride. After replacing the solvent of methanol (250 ml) was added a solution of 1 g of p-toluenesulfonic acid in 10 ml of methanol at room temperature. Stirred for an hour at proper temperature and then refluxed. When the distillation of methanol was added dropwise to 400 g of a 10% caustic soda and then add 60 ml of water. The methanol is distilled off up until the sump temperature reaches 97oC. After cooling to 55oWith mixed with 190 ml of MTB and acidified with 77 ml of concentrated hydrochloric acid to pH 2. After cooling to room temperature to separate the aqueous phase and concentrating the organic phase by distillation 60 ml of MTB. The addition of 500 ml of heptane and slow cooling to room temperature vykristallizovyvalas product. Crystalline solid product is sucked off, washed with heptane and dried in a vacuum drying Cabinet at 40oC to constant weight.

Whoopeeeee acid (splitting of the racemate with L-polymatroid ether

To 240 g of a 57% aqueous methanolic solution of the hydrochloride of L-prolongational ether (0,826 mol) was added dropwise at room temperature 148, 8 persons g of a 30% methanolic solution of methanolate sodium (0,826 mol), 2,4 l MTB and 225 g (0,826 mole) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid. After distillation 2680 ml of a mixture methanol-MTB and the simultaneous addition of 2.4 liters MTB slowly cooled to room temperature, the crystals (R-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid x L-prominetly ether) is sucked off and the solid is washed with 150 ml of MTB. The filtrate is concentrated by distillation 1.5 l MTB and mixed with 1.0 l of water. At room temperature, concentrated hydrochloric acid to establish a pH value of 1.2, after stirring and separation of the phases, separating the aqueous phase and extracted with 0.4 l of MTB. The combined organic phases are extracted with 0.4 l of water. After removal of MTB the residue is dissolved by boiling in 650 ml of toluene and after priming and slow cooling vykristallizovyvalas product. After filtration, washing with toluene and drying in a vacuum drying Cabinet get to 78.7 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35 %, considering the racemate).

Separation on chiral phase HPLC: 100%.

HPLC)-1-(4-nitrophenyl)ethylamine)

Mix 100 grams (0,368 mole) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in 750 ml of acetone and 750 ml of MTB by boiling under reflux with 30.5 g (0,184 mol) of (S)-1-(4-nitrophenyl)ethylamine, tatrallyay, refluxed one hour and slowly cooled to solidification to room temperature. Crystals (S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid x (S)-1-(4-nitrophenyl)ethylamine) is filtered off and washed with MTB. After the suspension of the residue in 500 ml of water and 350 ml of MTB set at room temperature, concentrated hydrochloric acid, the pH value of 1.2, after stirring and separation of the phases, separating the aqueous phase and extracted with 150 ml of MTB. The combined organic phases are extracted with 100 ml of water. After distillation, 370 ml of MTB mixed while heating under reflux with 390 ml of n-heptane and cooled slowly to room temperature to crystallize the product. After filtration, washing with n-heptane and drying in a vacuum drying Cabinet get 35,0 g S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35%, considering the racemate).

Separation on chiral phase HPLC: 100%.

HPLC: 99.8 per cent.

Example 12

Benzyl ester of 3-methoxy-2-(4-methoxy-6,7-XI-3,3-diphenyl-2-hydroxypropionic acid in 150 ml of dimethylformamide and mixed with 13,7 g (99 mmol) of potassium carbonate. The suspension is stirred for 30 minutes at room temperature. Then added dropwise over 5 minutes to 10.7 ml (90 mmol) of benzylbromide and continue to stir for another hour, while the temperature rises to 32oC. To this mixture are added successively to 24.84 g (180 mmol) of potassium carbonate and to 20.52 g (90 mmol) of 2-methanesulfonyl-4-methoxy-6,7-dihydro-5H-cyclopentenopyridine and stirred for 3 hours at 80oC.

For processing dilute the contents of the flask 600 ml of water, carefully acidified with concentrated hydrochloric acid and add 250 ml of acetic ether. Falls of 31.4 g of acid product, which is filtered off. From the mother liquor allocate ester phase, the aqueous phase is again extracted with ethyl acetate and thicken the combined organic phase. Oily residue (19 g) clean chromatography (cyclohexane/ethyl acetate = 9/1) and get another 10.5 g of the acidic product.

Total yield: 41,9 g (with 82.2 mmol) of 91%.

So pl.: 143-147oC.

Mass spectrum: MN+=511.

Example 13

3-Methoxy-2-(4-methoxy-(6,7-dihydro-5H-cyclopentadienide-2-yloxy)-3,3-diphenylpropionic acid

Dissolve 40 g (78,4 mmol) of benzyl ester of 3-methoxy-2-(4-methoxy-6,7-dihydro-5H-cyclopentadienide is on charcoal (10%) and treated with hydrogen prior to the termination of the gas absorption. The catalyst is filtered off, the solution evaporated and the residue recrystallized from ethyl ether.

Example 14

Ethyl ester 2S-3,3-diphenyl-oxiran-2-carboxylic acid

Dissolve to 2.57 g (10.2 mmol) of ethyl ester of 3,3-diphenyl-acrylic acid and 464 mg of 4-phenylpyridine-N-oxide in 24 ml of methylene chloride and mixed with 432 mg (6,5 mol.%) chloride (5,5)-(+)-N,N-bis(3,5-di-tert.-butylaniline)-1,2-cyclohexanediamine (III). Under ice cooling was added 6.4 ml of a 12% solution of sodium hypochlorite, stirred for 30 minutes under ice cooling and overnight at room temperature. The reaction solution was diluted with water to 200 ml), extracted with ethyl ether, dried and evaporated. Obtain 2.85 g of colorless oil. After purification by HPLC (cyclohexane: ethyl acetate = 9:1) obtain 1.12 g of oil with a ratio of enantiomers of about 8:1 in favor of the S-configuration.

1H-NMR (deiter. chloroform):

= 1,0 (t, 3H); 3.9 to (m, 3H); to 7.3 (m, 10H).

Example 15

2-Methylsulfanyl-6,7-dihydro-5H-cyclopentadienide-4-ol

To 29,6 g (528 mmol) of potassium alkali in 396 ml of methanol are added sequentially 46,9 g (330 mmol) of methyl ether, Cyclopentanone-2-carboxylic acid and 53.5 g (192 mmole) sulfate 5-methylisothiazoline and peavley water. The precipitated crystals are filtered and dried. Get 20 g of crystals.

Example 16

4-Chloro-2-methylsulphonyl-6,7-dihydro-5H-cyclopentadienide

To 20 g (110 mmol) of 2-methylsulfanyl-6,7-dihydro-5H-cyclopentenopyridine add 255 ml of phosphorus oxychloride and stirred for 3 hours at 80oC. phosphorus oxychloride is distilled off, the residue is decomposed with ice and sucked off the precipitated crystals. Gain of 18.5 g of a brownish solid.

Example 17

4-Methoxy-2-methylsulfanyl-67-dihydro-5H-cyclopentadienide

Dissolve 18,05 g (90 mmol) of 4-chloro-2-methylsulfanyl-6,7-dihydro-5H-cyclopentadienide in 200 ml of methanol. At 45oWith added dropwise 16.7 g of sodium methylate (30% solution in methanol) and stirred for 2 hours. The reaction solution is evaporated, absorbed in ethyl acetate, acidified with diluted hydrochloric acid and an ethyl acetate extract is evaporated. Remains of 15.6 g of oil.

1H-NMR (dimethylsulfoxide):

= 2,1 (quintet, 2H); 2,5 (s, 3H); 2,8 (dt, 4H); a 3.9 (s, 3H) h/million

Example 18

2-Methylsulphonyl-4-methoxy-6,7-dihydro-5H-cyclopentadienide

Dissolve 15 g (76.2 mmol) of 4-methoxy-2-methylsulfanyl-6,7-dihydro-5H-cyclopentadienide in 160 ml of a mixture of glacial acetic acid/m is the thief of hydrogen peroxide. Then diluted with 500 ml of water and 100 ml of methylene chloride, the organic phase is separated, dried and evaporated. Remains of 14 g of oil, which vykristallizovyvalas of ethyl ether.

1H-NMR (deiter. chloroform):

= 2,2 (quintet, 2H); 3,0 (dt, 4H); 3,3 (s, 3H); to 4.1 (s, 3H) h/million

Example 19

1-Benzazolyl-3-(4,6-dimethoxypyrimidine-2-yloxy)-4-methoxy-4,4-diphenyl-butane-2-he

Dissolve 0,37 g (2.4 mmole) of phenylmethanesulfonyl in 10 ml of dry tetrahydrofuran, are then added dropwise at -70oWith 2 equivalent of utility (2,94 ml of 1.6 molar solution in hexane). After one hour at -70oWith added dropwise to 1 g (2.4 mmole) of the methyl ester of 2-(4,6-dimethoxypyrimidine-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid, dissolved in 5 ml of tetrahydrofuran. The reaction mixture is stirred for 1 hour at -70oC, 1 hour at -10oC and then warmed to room temperature. Processing was added dropwise for about 10 ml of saturated ammonium chloride solution and thoroughly extracted with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After drying and concentration purify the resulting residue by chromatography on silica gel (n-heptane/ethyl acetate 15% --> 30%) and then the amorphous powder.

Example 20

3,3-Diphenyl-oxiran-2-carbonitril

Suspended 3.1 g (54.0 per mmole) of sodium methylate in 20 ml of dry tetrahydrofuran, are then added dropwise at -10oWith a mixture of 5 g (27.4 mmol) of benzophenone and 4.2 g (54,9 mmole) of chloroacetonitrile.

The reaction mixture continued to stir for 2 hours at -10oWith, then poured on water and repeatedly extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, concentrated and the resulting residue purified by chromatography on silica gel (n-heptane/ethyl acetate).

Yield: 1.2 g (20%).

1H-NMR ( deiter. chloroform):

= 3,9 (s, 1H); of 7.4-7.5 (m, 10 H) h/million

Example 21

2-Hydroxy-3-methoxy-3,3-diphenyl-propionitrile

Dissolve 6.5 g (29.4 mmol) of 3,3-diphenyl-oxiran-propionitrile in 60 ml of methanol and mixed at 0oWith 2 ml of nortryptaline with ethyl ether. The reaction mixture is again stirred for 1 hour at 0oWith, then continue to stir at room temperature overnight. To handle diluted with diethyl ether, washed with saturated sodium chloride solution, the organic phase is dried over sodium sulfate and concentrated. As the residual gain of 7.3 g of white amorphous powder, BR>
= 2,95 (CL, HE); 3.15 in (s, 3H); 5,3 (s, 1H); 7.3 to 7.5 (m, 10 H) h/million

Example 22

2-(4,6-Dimethoxy-pyrimidine 2-yloxy) 3 - methoxy-3,3-diphenyl-propionitrile

Dissolve to 7.3 g (28.8 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic in 90 ml of dimethylformamide and mixed with 4 g (28.8 mmol) of potassium carbonate and 6.3 g (28.8 mmol) of 2-methanesulfonyl-4,6-dimethoxy-pyrimidine. The mixture is stirred for about 12 hours at room temperature, then poured into water and extracted with ethyl acetate. The combined organic phase is again washed with water, dried and concentrated. The resulting residue is purified then on silica gel (n-heptane/ethyl acetate).

Yield: 6.9 g of white amorphous powder.

Mass spectrum (method of fast atom bombardment): (M+H+).

1H-NMR (deiter. chloroform):

= 3.3V (s, 3H); 4,95 (C, 6N), to 5.85 (s, 1H); 6,3 (s, 1H); 7.3 to 7.5 (t, 10H) h/million

Example 23

5-[2-(4,6-Dimethoxy-pyrimidine-2-yloxy)-3-methoxy-3,3-diphenyl)-propyl] -1H-tetrazol

Dissolve 0.5 g (1.3 mmole) of the nitrile obtained above compound in 10 ml of toluene, sequentially added 85 mg (1.3 mmole) of sodium azide and 460 mg (1.4 mmole) of tributyltinchloride and then the mixture is heated to about 40 hours under reflux. After cooling, diluted with ethylacetate magnesium and thickening remains 1.0 g of a yellow oil, which is purified on silica gel (n-heptane/ethyl acetate). After concentration of the fractions are given 60 mg derived 1H-tetrazole and 110 mg of the derivative of 1-methyl-tetrazole, both as white amorphous solids.

5-[2-(4.6-Dimethoxy-pyrimidine-2-yloxy)-3-methoxy-3.3-diphenyl)-propyl]-1 H-tetrazol

Mass spectrum (electrospray ionization): 435 (M+H+).

1H-NMR (deiter. chloroform):

= of 3.28 (s, 3H); 3,85 (s, 6N); of 5.75 (s, 1H); 7,25-7,40 (m, 10H); to 7.50 (s, 1H) h/million

5-[2-(4,6-Dimethoxy-pyrimidine-2-yloxy)-3-methoxy-3,3-diphenyl)-propyl] -1-methyltetrazol

Mass spectrum (electrospray ionization): 471 ( M+N+).

1H-NMR (deiter. chloroform):

= 3,00 (s, 3H); at 3.35 (s, 3H); of 3.80 (s, 6N); of 5.75 (s, 1H); 7,30-7,40 (m, 11N).

Example 24

2-(4,6-Dimethoxy-pyrimidine-2-yloxy)-3-methylsulfinyl-3,3-diphenyl-propionic acid

Make 1.2 g (2.9 mmol) of 2-(4,6-dimethoxy-pyrimidine-2-yloxy)-3-methyl-effect-free remedy 3,3-diphenyl-propionic acid in 15 ml of glacial acetic acid at 0oWith and added dropwise 294 μl of 30% hydrogen peroxide. Stirred over night at room temperature, poured in water, extracted with dichloromethane and washed with solutions of sodium thiosulfate and sodium chloride. After drying produce 1 g of enyl-propionic acid

Contribute 0.6 g (1,45 mole) of 2-(4,6-dimethoxy-pyrimidine-2-yloxy)-3-methyl-effect-free remedy 3,3-diphenyl-propionic acid in 15 ml of glacial acetic acid at room temperature and added dropwise 294 μl of 30% hydrogen peroxide. Stirred over night at room temperature, then heated for another 3 hours at 50oWith, poured in water, extracted with dichloromethane and washed with solutions of sodium thiosulfate and sodium chloride. After drying allocate 400 mg white solid.

Similarly receive are shown in tables 1, 2 connections.

The connection according to the present invention opens up new possibilities for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina, acute renal failure, renal failure, vasospasm of the cerebral cortex, cerebral ischemia, subarachnoid hemorrhage, migraine headaches, asthma, atherosclerosis, endotoxic shock caused by endocrinol organ failure, intravascular coagulation, re-stenosis after angioplasty, benign hyperplasia of the prostate, ischemic and poisoning kidney failure or hypertension.

Good activity of the compounds shown by the use of cloned cells Chinese hamster ovary (CHO), exprimarea ETA-receptor and membrane of Guinea-pig cerebellum with>60% ETBreceptors compared with ETA-receptors.

Getting preparation of membranes

Cells CHO, exprimarea ETAthe receptor were cultured in medium F12with 10% fetal calf serum, 1% glutamine, 100 u/ml penicillin and 0.2% streptomycin (Flexible BRL, Gaithersburg, MD, USA). After 48 hours the cells are washed with phosphate buffered saline (SFR) and incubated 5 minutes in SFR containing 0.05% trypsin. After that neutralize environment F12and the cells centrifuged at 300 g acceleration. For lysis sludge wash buffer (5 mm Tris-HCl, pH to 7.4 with 10% glycerol) and then incubated at a cell concentration of 10-7/ml lisanova buffer for 30 minutes at 4oC. Membrane centrifuged at acceleration of 20,000 g for 10 minutes and the precipitate is placed in liquid nitrogen. The cerebellum Guinea pigs homogenized in a Potter homogenizer-Elvejhem and drug allocate using differential centrifugation for 10 minutes at an acceleration of 1000 g and re-centrifuging the supernatant for 10 minutes at acceleration of 20,000 g.

Test linking rezept buffer (50 mm Tris-HCl, a pH of 7.4 with 5 mm MnCl2, 40 μg/ml bacitracin and 0.2% bovine zavorotnova albumin) at a concentration of 50 µg of protein for Ispytateley download and incubated at 25oC with 25 PM [125J]-ET1(test ETA-a receptor) or with 25 PM [125J]-RZ3(test ETB-receptor) in the presence or in the absence of the test substance. The nonspecific binding determined with 10-7M ET1. After 30 minutes free and bound radioligand separated by filtering through a filter with glass fiber (Whatman, England) in a collection of cells (firm Skadron, on the outskirts of Drammen, Norway) and the filter washed with ice-buffer Tris-HCl with a pH of 7.4, containing 0.2% bovine serum albumin. The radioactivity collected with the filter residue is determined quantitatively using a liquid scintillation counter Packard 2200 CA.

Functional test system in vitro to search for antagonists of the endothelin receptor (subtype A)

This system is a functional cell based test for the endothelin receptor. Certain cells when they are stimulated by endothelin 1 (ET1show the increase in intracellular calcium concentration. This increase can be measured in intact cells, blasty, have been identified endogenous endothelin receptor (subtype A), load as follows fluorescent dye Fura-2-EN:

after treatment with trypsin, the cells re-suspended in buffer A (120 mm sodium chloride, 5 mm potassium chloride, 1.5 mm magnesium chloride, 1 mm calcium chloride, 25 mm HEPES, 10 mm glucose, pH of 7.4) to a density of 2 106/ml and incubated at 37oC in the dark with Fura-2-EN (2 μm), pluronics F-127 (0.04%) 0,2% dimethylsulfoxide. After that, the cells washed twice with buffer A and re-suspended to a density of 2 106/ml. Continuously record at 30oC signal of the fluorescence of cells with a density of 2 106/ml at a ratio of extinction to the issue of equal 380 : 510. To cells add test compound and after incubation with ET1within 3 minutes determine the maximum change in fluorescence. The response of cells to ET1without adding the test compound serves as a control means 100%.

The test of ET antagonists in vivo

Male SD rats weighing 250-300 g narcoticyou amobarbital administered artificial respiration, vagotomized and remove the spinal cord. Insert catheters into the Arteria carotis and Vena jugularis. Control animals vnutrivennoi time. 5 minutes before the introduction of ET1the test animals injected investigated the connection (1 ml/kg). To determine ET-antagonistic properties compare the pressure increase in the test animals and the control animals.

The death of mice due to sudden cardiac arrest, induced by endothelin-1

The test principle is the inhibition caused by endothelin sudden cardiac death in mice, probably due to the narrowing of arteries by pretreatment with antagonists of the endothelin receptor. After intravenous injection of 10 nmol/kg of endothelin in an amount of 5 ml/kg body weight of the animal dies within a few minutes.

Lethal dose of endothelin-1 define a small group of animals. If the test compound is administered intravenously, usually after 5 minutes should lethal injection of endothelin-1 in the comparative group of animals. Other ways of introducing this pre-introduction connections longer, sometimes up to several hours.

Register for survival and effective dose which protects 50% of the animals within 24 hours and more from sudden cardiac arrest caused by endothelin (ED 50).

NGF is seat reservation voltage 2 g and relaxation for one hour in a solution of Krebs-Henseleit at 37oC and pH 7.3-7.5 to first remove the K+-contracture. After washing the build curve doses activity of endothelin to the maximum value. Potential antagonists of endothelin put on other drugs from the same aorta 15 minutes before the starting values on the curve doses activity of endothelin. Effects of endothelin count % K+-contracture. In the case of active endothelin antagonists is the right shift of the curve doses of activity.

According to the above experience for linking to the ET - a receptor were obtained are summarized in table 3 data on the inhibition of the proposed compounds binding of endothelin to its receptor.

Derivatives of carboxylic acids of the formula I

< / BR>
in which R1- tetrazol, a carboxyl group, a COOR group7where R7means alkyl with 1-4 carbon atoms or a cation of an alkaline or alkaline-earth metal, group-CONHSO2R8where R8means alkyl with 1-4 carbon atoms or-COCH2SO2-R9where R9means alkyl with 1-4 carbon atoms;

R2the hydroxy - group, amino group, mono - and dialkylamino with 1-4 carbon atoms in the alkyl part, alkyl with 1-4 carbon atoms, halogenated with 1-4 atoms in the d or alkyl with 1-5 carbon atoms or CR10together with CR3forms a 5 - or 6-membered alkylene or alkenylamine ring which may be substituted by one or two alkyl groups with 1-4 carbon atoms and in which one methylene group may be replaced by oxygen, aminogroups or alkylamino with 1-4 carbon atoms;

R3- amino group, mono - or dialkylamino with 1-4 carbon atoms in the alkyl part, alkyl with 1-4 carbon atoms, alkoxygroup with 1-4 carbon atoms, or CR3together with CR10have the above meaning;

R4and R5every means phenyl, unsubstituted or substituted with halogen, alkyl with 1-4 carbon atoms or alkoxyl with 1-4 carbon atoms; phenyl, each phenyl in anthopology can be related by a simple bond, methylene or ethylene group, or cycloalkyl with 3-7 carbon atoms;

R6- alkyl with 1-8 carbon atoms and alkenyl with 3-6 carbon atoms, unsubstituted or substituted with halogen, cyano-group, or alkoxyl with 1-4 carbon atoms, alkylthiol with 1-4 carbon atoms or phenyl, phenyl, unsubstituted or once or twice substituted by halogen, alkyl with 1-4 carbon atoms or alkoxyl with 1-4 carbon atoms, or cycloalkyl with ICL, containing one sulfur atom or oxygen, unsubstituted or substituted by alkyl with 1-4 carbon atoms;

Z is sulfur, oxygen, sulfinil or sulfonyl.

Priority signs:

14.10.1994 for the compounds of formula I, where R1- carboxyl group, a COOR group7where R7means alkyl with 1-4 carbon atoms or a cation of an alkaline or alkaline-earth metal, group-CONHSO2R8where R8means alkyl with 1-4 carbon atoms or-COCH2SO2-R9where R9means alkyl with 1-4 carbon atoms; R2is alkyl with 1-4 carbon atoms, halogenated with 1-4 carbon atoms, alkoxygroup with 1-4 carbon atoms; X is nitrogen or the radical CR10where R10means hydrogen or alkyl with 1-5 carbon atoms or CR10together with CR3forms a 5 - or 6-membered alkylene or alkenylamine ring which may be substituted by one or two alkyl groups with 1-4 carbon atoms and in which one methylene group may be replaced by oxygen, aminogroups or alkylamino with 1-4 carbon atoms;3is alkyl with 1-4 carbon atoms, alkoxygroup with 1-4 carbon atoms, or CR3together with CR10have the above meaning; R4and R5the -4 carbon atoms; phenyl, each phenyl in anthopology can be related by a simple bond, methylene or ethylene group, or cycloalkyl with 3-7 carbon atoms; R6- alkyl with 1-8 carbon atoms and alkenyl with 3-6 carbon atoms, unsubstituted or substituted with halogen, cyano or alkoxyl with 1-4 carbon atoms, alkylthiol with 1-4 carbon atoms or phenyl, phenyl, unsubstituted or once or twice substituted by halogen, alkyl with 1-4 carbon atoms or alkoxyl with 1-4 carbon atoms, or cycloalkyl with 3-8 carbon atoms, unsubstituted or substituted by alkyl with 1-4 carbon atoms, five - or six-membered heterocycle containing one sulfur atom or oxygen, unsubstituted or substituted by alkyl with 1-4 carbon atoms; Z is sulfur, oxygen;< / BR>
07.09.1995 - for compounds of formula I, where R1- tetrazol; R2the hydroxy - group, amino group, mono - and dialkylamino with 1-4 carbon atoms in the alkyl part; R3- amino group, mono - or dialkylamino with 1-4 carbon atoms in the alkyl part; Z - sulfinil or sulfonyl.

 

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The invention relates to 3-oxo-propanenitrile derived condensed pyrazole, method of production thereof and to pharmaceutical compositions containing them

The invention relates to a derivative of bis-benzo - or benzopyrano-piperidine, piperidylidene and piperazine, which are particularly useful as antagonists of platelet-activating factor and antihistamine, and their pharmaceutical compositions, methods of use of these derivatives and to the method of production thereof

The invention relates to new 1-(biphenyl-4-yl)methyl-1H-1, 2,4-triazole compounds and 1-(biphenyl-4-yl)methyl-4H-1,2,4-triazole compounds, and each of them has as a substituent in the 2'-position (2,4-dioxopyrimidine-5-ilidene)methyl or (2,4-dioxotetrahydrofuran-5-ilidene)methyl, and their salts

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

The invention relates to a method for producing compounds of formula (I) consists in the fact that the compound of formula (IX):

< / BR>
in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):

< / BR>
in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):

< / BR>
in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):

< / BR>
in which R9' matter referred to in paragraph 1 for R9where possible reaction ф�g/rupat4/200110/01/2174513-36t.gif" ALIGN="ABSMIDDLE">< / BR>
in which R1', R2', R4' and R9' have the above meanings and, if necessary, or interact product of formula (I2) with the compound of the formula (XV):

O=C=N-R6' (XV)

in which R6' matter referred to in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group, to obtain a product of formula (I3):

< / BR>
in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):

< / BR>
in which R1', R4'Hal and R3" have the above values, the compound obtained is subjected to the reaction of the exchange of the halogen-metal, then the processing of the compound of formula (IVa') (IVb'), (IVc'), (IVd') or (IVe') defined above, to obtain a product of formula (I7):

< / BR>
in which R1', R4', R2and R3" have the above meanings; then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

C) transforming functions of ester function acyl,

d) transforming Sinopoli in an acid function,

e) conversion of the acid function to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

a) transforming radical

< / BR>
in radical

< / BR>
p) conversion of the acid function in function

< / BR>
q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic cisisomer, enantiomers and diastereoisomers

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

The invention relates to derivatives of N-sulfanilimide formula I, where R1and R2denote hydrogen, halogen, C1-4alkyl, C1-4alkoxycarbonyl or phenyl which can be substituted one to three times, equal or different residues from the group comprising halogen, C1-4alkyl, trifluoromethyl; R3- halogen, cyano, trifluoromethyl; R4- 4-isoxazolyl, pyrazolyl, which may be substituted with halogen, C1-4the alkyl, amino group, cycloalkyl, as well as their acid-salt additive

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,

where Y represents oxygen or sulfur; R6, R7, R8independently of one another denote alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenyl with 1 to 4 carbon atoms, dialkylamino, phenyl which may be substituted by nitro, stands, trifluoromethyl; 1-pyrrolidinyl, 1-piperidinyl; or thienyl, pyrazolyl, isoxazolyl, each of these residues can be substituted by chlorine, amine, stands, methoxy, trifluoromethyl, methoxycarbonyl; X represents halogen, and their acid additive salt

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The invention relates to pharmaceutical industry and in order to maltol (3-hydroxy-2-methyl--pyrone) from the needles of Siberian fir (Abies sibirica L.)
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