The method of obtaining derivatives of imidazole or their physiologically-tolerated salts


(57) Abstract:

Usage: in the himiko-pharmaceutical promyshlennosti as antagonists of angiotensin 2. The inventive method of obtaining derivatives of imidazole f-crystals 1 or a physiologically-tolerated salts. Reagent 1: connection f-crystals 2 with certain values radicals. Reagent 2: connection f-crystals 3. The connection structure of f-crystals 1, 2, 3:

< / BR>
< / BR>
and CH2A III table 3.

The invention relates to the field of organic chemistry and relates to a method of obtaining new derivatives of imidazole.

European application EP-A-324377, EP-A, EP-A-28834 and EP-A-323841 known derivatives of imidazole, pyrrole, pyrazole or triazole and their use as antagonists of receptors of angiotensin 11.

According to this invention have the new imidazole derivatives, which are unexpectedly highly effective receptor antagonists angiotensin-11 both in vitro and in vivo.

According to the invention proposes a method of obtaining the imidazole derivatives of General formula I

where R1alkyl (C3-C7);

R2the formyl group, carboxyl, (C1-C4)-alkoxycarbonyl or hydroxymethyl;

R2'Chloe: imidazo-(1,2)-pyridyl, imidazo-(1,2-a) pirimidil, benzoxazolyl, benzo(b)-type Nile, and this residue may be substituted by one or two identical or different residues selected from the group of chlorine, tetrazolyl, carboxyl, carboxy-(C1-C4)-alkyl, (C1-C4-alkoxycarbonyl and phenyl, possibly substituted by fluorine;

r 0,1 or 2; or a physiologically-tolerated salts, characterized in that the compound of General formula II

R where R1and R2have the above values,

R2'chlorine or a group S-R3where R3has the above value, and when the substituent R2carboxyl group, it may be protected, is subjected to the interaction with the compound of the formula III

UCH2A1where a1means the above-mentioned heterocyclic residue, substituted by one or two identical or different residues selected from the range containing chlorine, cyano, carboxyl, carboxy (C1-C4) alkyl, (C1-C4) alkoxycarbonyl and phenyl, possibly substituted by fluorine, and when the Deputy AND1carboxyl group, it may be protected, U tsepliaeva group to obtain compounds of General formula Ia

R where R1the t above the value moreover, when R2carboxyl group, it can be protected, and in the case of obtaining compounds of General formula I, in which R2' shall mean a group S(O)r3where R3has the above meaning;

r is 1 or 2, the compound of formula Ia, where R2' means a group of S-R3where R3has the above meaning, is subjected to the interaction with the oxidant, or in the case of obtaining compounds of General formula I, in which the Deputy And contains tetrazolyl residue, the compound of formula Ia, where the Deputy AND2contains a cyano, subjected to interaction with collisuem agent with the subsequent removal if necessary carboxyamide group and the allocation of target compounds in free form or in the form of a physiologically tolerable salt.

Under physiologically tolerated salts of the compounds of formulas I understand their organic and inorganic salts, which are described in Remington''s Pharmaceutical Sciences, ed. 17, S. 1418 (1985). Based on the physical and chemical stability and solubility preferred acid groups, salts of sodium, potassium, calcium and ammonium; alkali groups are the preferred salts of hydrochloric acid, sulfuric acid, phosphonic acid, carbon is the second acid, fumaric acid, tartaric acid, p-toluensulfonate acid.

Reactions are conducted at temperatures from below room temperature up to the boiling temperature of the reaction mixture, mainly between +20aboutC and the boiling temperature of the reaction mixture for about 1-10 hours

Corresponding to the invention the compounds of formula I antagonistically affect angiotensin 11 receptor, therefore, can be used for treatment of dependent hypertension angiotensin 11. The application may then in heart failure, cardiotoxic, myocardial infarction, hypertrophy of the heart, atherosclerosis, nephropathy, renal failure, and vascular diseases of the brain such as transistor ischemic attacks and apoplexy.

Renin is a proteolytic enzyme from the class of aspartate that as a consequence of various stimulants (decrease, deficiency of sodium,-receptor stimulation) is allocated juxtaglomerular cells of the kidney into the blood stream. There he it from released from the liver angiotensinogen Decapeptide angiotensin 1. Last translated by the enzyme converting angiotensin (ACE) to angiotensin-II. Angiotensin plays) is iospace. In addition, it stimulates the secretion of aldosterone from the adrenal gland and increases therefore with the help slow the excretion of sodium in extracellular fluid volume, which, for its part, contributes to high blood pressure.

Actions postreceptor are to the same stimulation exchange reaction phosphoinositol (CA2+-release), activation of proteinkinase With and simplification-dependent camp hormonereceptor.

The affinity of compounds of the formula I to the receptor of angiotensin 11 can be determined when measuring 125j-angiotensin-11 or3N-angiotensin-11 displacement receptors in glomerulosa area membranes of adrenal glands of cattle. This suspendered prepared membranes in the powder at pH 7.4.

In order to prevent the decay of radioactive ligands during incubation, added Aprotinin, an inhibitor of peptidases. Additionally applied approximately 14,000 CPM indicator with specific activity 74 TVD (mmol) commercial product) and a certain amount of the receptor protein, which binds 50% of the indicator. The reaction is started by adding 50 μl of membrane suspension to a mixture of 100 μl of buffer + Aprotinin; 50 μl of buffer with angiotensin-11 or aetsa bound and free radioligand thanks filtration analysis filters WhatmannGFIC on a Skatron cell drive. Uncharacteristic of communication are destroyed during processing filters 0.3% polyethylenimine pH-10 (sigma, N 3143). In the measurement of radioactivity in gamescentercom the counter determines the strength of the displacement of the radio-receptor. IC50values, which indicate the concentration of inhibitor to displace 50% of the ligands are determined by hem. and other J. Theor.Biol. 59, 253 (1970). They are for compounds of formula (I) in the range 110-4110-9M To determine the antagonistic action of the compounds of formula (I) can be measured by their effect on angiotensin-induced-11 increase in blood pressure in anesthetized rats, Sprague-Dawley.

As the drug is Na-thiobarbital /TrapanalByk Gulden (in the dosage of 100 mg/kg intraperitoneally. Intravenous injection is carried out in the jugular area. Blood pressure is measured in A. arotis, primarily pre-treated animals tartrate pentaline. (10 mg/g intramuscularly) in such a way that achieved a lower level of blood pressure (blockade ganglia). G 11 /hypertensionCiba) is injected in a volume of 0.1 ml (100 g intravenously over 10-minute intervals. The dose is 0.5 mg/kg Connection Waginalnom.

The compounds of formula (I) are effective in the range of 0.1 to 100 mg/kg Invention also concerns pharmaceutical compositions comprising the compounds of formula I and other active substances, such as diuretics or non-steroidal anti-inflammatory active substances. The compounds of formula I can also be used as diagnostics for the renin-angiotensin-system.

The pharmaceutical preparations contain an effective amount of the active substance of the formula I and, optionally, other active substances together with inorganic or organic pharmaceuticals substance carrier. Application can be done through the nose, intravenously, subcutaneously or through the mouth. The dosage of the active substance depends on the species of warm-blooded animals, body weight, age and type of use.

The pharmaceutical preparations of this invention are obtained in the form of a solution, mixture, granules or pills.

For oral application of the active compounds are mixed with the usual additional substances additives, such as substances-carriers, stabilizers or inert diluents, and using conventional methods brought to the desired form of administration (tablets, pills, capsules, aqueous, SP is able to be applied, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, fumarate magnesium or starch, in particular maize starch. You can get as dry and wet granules. As oily substances carriers or solvents are considered, for example, vegetable or animal oils such as sunflower oil or cod-liver oil.

For subcutaneous or intravenous injection of the active compounds or their physiologically tolerated salts, preferably with the usual substances, such as solvents intermediary, emulsifiers or other auxiliaries, are transferred in the form of solutions, suspensions or emulsions. As solvents are considered, such as water, physiological solutions of sodium chloride or alcohols, e.g. ethanol, propandiol or glycerin, it is also sugar solutions such as glucose or mannitol, or a mixture of various of the above-mentioned solvents.

1. Examples for new chemical compounds.

Used in the examples, the abbreviations have the following meanings:

DMF N, N-dimethylformamide,

NBS N-bromosuccinimide,

AlBN -,-azobis-isobutyronitrile,

EI obrabotki.nehvatajet (tOAC),

DIP diisopropyl ether,

N. N. heptane.

P R I m e R 1. 1-[(2-carboxy-benzo[b]furan-5-yl)methyl]-2-butyl-4-chloro-5-hydroxy - methyl-imidazol

a) complex ethyl ester 5-methyl-benzo[b]furan-2-carboxylic acid.

12 g (0,088 mol) of 2-hydroxy-5-methyl-benzaldehyde are dissolved in 150 ml of abs. DMF. Added 14.6 g of potassium carbonate (0,105 mol), then dropwise 9.5 g (0,088 mol) of ethyl ester of Chloroacetic acid. After 3 h, diluted with reverse flow 500 ml of N2Oh, extracted 3 times with ethyl acetate, washed 4 times with water, dried with magnesium sulfate and concentrated. Chromatography on SiO2with ethyl acetate (cyclohexane (1: 5) gave 7.6 g of oil. MS (EI) 204 (M+Rf[SiO2; tOAc)cyclohexane (1:4)] 0,41.

b) complex ethyl ester 5-bromomethyl-benzo[b]furan-2-carboxylic acid.

7.6 g (37 mmol) of the compound from a) are boiled with 6.6 g of N-BS and 300 mg of AlBN 10 h in 200 ml of CCL4during reverse flow. After cooling, mixed with N2O. the Phases are separated, the organic phase dried with MgSO4and gathering. Chromatography on SiO2with t (cyclohexane (1:4) gives 5,4 g of oil. MS (EI) 282,284 (M+).

Rf[SiO2, Et OAc/cyclohexane (1:4)] 0,38

C) 1-[(2-Etoxycarbonyl-benzo[b] furan-5-yl)methyl]-2-Buti-253 310) dissolved in 20 ml of methanol and mixed with a solution of 127 mg of sodium in 5 ml of methanol. After 30 min the mixture was concentrated and dissolved in 40 ml F. 1.5 g (5.5 mmol) of the compound from b) is added and stirred for 14 h at 25aboutC. After infusion of 200 ml of N2About extracted Et, the organic phase is washed with water, dried with MgSO4and thicken. Chromatography on SiO2with Et SLA/cyclohexane (1:1) to give 0.73 g of oil.

MS (DCl) 391 (M++ H).

Rf[SiO2; Et SLA (cyclohexane) (1:2)]0,29.

d) 1-[2-carboxy-benzo-[b] -furan-5-yl)-methyl]-2-butyl-4-chloro-5-hydroxymethyl - imidazole.

0,79 g (2.5 mmol) of the compound from C) is boiled in 20 ml of ethanol with 20 ml of 2N NaOH in a reverse flow. After 2 h, dissolved in water, set pH 3.5 2N HCl and extracted with dichloromethane. After drying and thickening obtain 0.31 g of the above compound as amorphous powder.

MS(DCl) 363 (M++ H).

Rf(SiO2, Et OAc/cyclohexane (1:1)]to 0.03.

P R I m m e R 2. 1-[(2-carboxy-benzo[b]thiophene-5-yl)methyl]-2-butyl-4-chloro-5-hydro-ximation of IDAs

a) 4-Toluene-thio-acetaldehyde-diethylacetal.

In a solution of 12.5 g of sodium in 250 ml of ethanol was added dropwise 62 g of para-thiocresol in 100 ml of ethanol at 0aboutC. After the addition of 15 g of sodium iodide was added dropwise to 98.5 g bromoacetaldehyde diethylacetal and boiled for 4 h at obaut and distil.

Boiling point 118about(0.01 Torr), the yield of 92.9 g

b) 5-methylbenzo[b]thiophene.

320 g R2O5mixed with 246 ml of orthophosphoric acid and heated to 130aboutC (1 h). If 180aboutWith the type of 92.9 g of the compound from a) with a 5 mm Od by using the capillary tube below the surface of the polyphosphoric acid. The product is distilled. Get 26 grams as an oil.

MS(EI) 135 (M+)

C) 2-acetyl-5-methylbenzo[b]thiophene.

A solution of 26 g of compound b) and 13.5 g of acetylchloride in 250 ml of CH2CL2was added dropwise to a suspension of 23.4 g of AlCl3in 780 ml of CH2CL2. After 90 min, poured a dark green solution into ice-cold dilute Hcl, the organic phase is separated, dried with MgSO4and thicken. Gain of 25.5 g of the product as oil.

MS(EI) 178 (M+).

d) 5-methyl-benzo[b]thiophene-2-carboxylic acid.

11,7 g NaOH dissolved in 58 ml of N2About and mixed with 10aboutWith 14.1 g of bromine. At 0aboutTo add to 5.2 g of 2-acetyl-5-methyl-benzo[b]thiophene in 50 ml of dioxane. After 90 min set the acidic value of pH with 5N HCl and extracted with CH2CL2. After drying with Na2SO4thicken. After trituration with Et SLA sucked off. Get 3 g of kristallov. MS (El-benzo[b]-thiophene-2-carboxylic acid.

3 g of compound d) boil 2.5 N. ethanolic solution of Hcl (50 ml) for 2.5 h with reverse flow. After thickening gain of 2.27 g of oil.

MS (EI) 220 (M+)

Rf[SiO2; CH2Cl2) MeOH (100:1)] of 0.82.

(f) ethyl ester 5-bromo-methyl-benzo-[b] -thiophene-2-carboxylic acid.

Out of 2.27 g of compound e) and 1.83 g of NBS receive according to example 1b (1,77 g oil).

MS (EI) 298 + 300 (M+).

g) 1-[(2'-etoxycarbonyl-benzo[b]thiophene-5'-yl)methyl]-2-butyl-4-chloro-5-hydroc - sometimesa.

From 1.1 g of 2-butyl-4-chloro-5-hydroxymethylimidazole and 1.77 g of the compound of (f) are obtained analogously to example 1 C) 0.5 g of the above compound in the form of butter.

MS (DCI) 407 (M + H)

Rf(SiO2; t/cyclohexane (1:1) 0,2

h) 1-[(2-carboxy-benzo[b] thiophene-5-yl)methyl] -2-butyl-4-chloro-5-hydroxymethyl - imidazole.

Analogously to example 1 (d) is produced from compound of (g) 0.26 g of the above compound, melting point 195aboutC (decomposition).

P R I m e R 3. 1-[(2-carboxy-indol-5-yl)-methyl]-2-butyl-4-chloro-5-hydroxymethyl - imidazole.

a) 30 g (0,189 mol) of p-tolylhydrazine dissolved in 600 ml of 1N HCl and heated to 40-50aboutC. Add 23 g of pyruvic acid is silt ester 5-methyl-indole-2-carboxylic acid.

130 g R2ABOUT5add to 111 ml of orthophosphoric acid. After cooling, add 37 g of the compound from a) and heated to 80aboutC. After the start of the reaction the temperature rises to 130aboutC. After cooling, poured on ice water and extracted with acetic ester. The organic phase is washed with NaHCO3(1N), N2O and saturated NaCl solution, dried with Na2SO4and thicken. Product precrystallization of n-hexane (Et OAc). Get 11.7 g of product with a melting point 158aboutC.

(C) ethyl ester of 1-acetyl-5-methyl-indole-2-carboxylic acid.

11,7 connection from (b) are mixed in 100 ml of dehydrated DMF with 2.6 g of sodium hydride (50% in oil). Then add 4.5 g of acetylchloride and stirred for 3.5 hours After pouring in N2About extracted with Et SLA. The organic phase is washed three times H2About 1 and once with saturated NaCl solution, dried with MgSO4and thicken. After chromatography on SiO2get 6 g of the above compound in the form of butter.

MS (EI) 245 (M+)

Rf[SiO2; Et OAc (cyclohexane (1:4)] 0,23

d) ethyl ester of 1-acetyl-5-methyl bromide-indole-2-carboxylic acid

Analogously to example 1 b) is obtained from 6 g of the compound from example 3 (C) and 4.3 g of NBS above-mentioned(1:0)]0,21

e) 1-[(2-etoxycarbonyl-indol-5-yl)-methyl] -2-butyl-4-chloro-5-hydroxymethyl-imide - azole.

Analogously to example 1 (C) receive from 0.6 g of 2-butyl-4-chloro-5-hydroxymethyl-imidazole and 1.1 connections from example 3d) 160 mg of the above compound in the form of soap.

MS (DCI) 390 (M + N+)

Rf[SiO2; Et OAc (cyclohexane (1:1)] 0,2

f) 1-[(2-carboxy-indol-5-yl)-methyl] -2-butyl-4-chloro-5-hydroxymethylimidazole.

Analogously to example 1 (d) is obtained from 160 mg of the compound from example 3 (e), 40 mg of the above compound in the form of resin.

MS (DCl) 362 (M + H+);

Rf[SiO2; CH2Cl2(MeOH) (2:1)] 0,27

The compounds of examples 4 to 11 are synthesized analogously to example 1. These compounds have the following General formula:


MS Example (DCl; A-CH2< / BR>
M + H)

4 413

5 423

6 379

7 407

8 409

9 371

10 439

11 440

3-(5-Methyl-indol-1-yl)-propionitrile (see example 9).

To 4 ml of hydrocity of trimethylantimony and 10 ml of Acrylonitrile in 100 ml of dioxane is added with stirring 13 g (0.1 mol) of 5-methylindole) are studied. Then heated for 2 hours to 80aboutC, then allowed to stand for 3 days at room temperature. Highly diluted acetic acid is added then the>SO4and concentrated in vacuo. The precipitate was chromatographically on SiO2with DIP as eluent.

Rf(DIP) 0,3

Conditions for the esterification of radical And in examples 5, 6 and 7 of 20 g of 5-methyl-2,3-dicarboxy-benzo[b] thiophene (example 5) is boiled for 6 h in 400 ml of absolute methanol containing 3% sulfuric acid, in a reverse flow. After cooling to room temperature, poured on ice. The precipitate is filtered off and H2The o-phase is extracted 3 times with ether, and after drying, thicken with Na2SO4and the ether is formed in the form of butter.

P R I m e R 10 (a) Alternative for the saponification of ethyl ester of example 10 to the compound obtained in example 10.

180 mg (0.38 mmol) of ethyl ester in 2 ml of ethanol is mixed with 0.5 ml of aqueous 1N NaOH and stirred for 20 to 60 h at 25aboutC. Then concentrated, and the residue purified on SiO2with CH2CL2/Meon 8/2 as a carrier fluid, and acid is formed in the form of amorphous powder.

P R I m e R 12. 1-[(3-carboxy-2-phenylimidazo[1,2-a]pyridine-6-yl)methyl] -2-butyl-4-chloro-5-F. Orme

a) 2-butyl-4-chloro-5-formyl-imidazole.

To 20 g (0,106 mol) of 2-butyl-4-chloro-5-hydroxymethyl-imidazole in 350 ml of glacial acetic acid added at 10-15aboutWith slow and with 2N KOH (20aboutAt the time of adding the base). Next extracted with 4 times 50 ml of CH2CL2and washed the combined organic extracts 3 times each time with 30 ml of saturated aqueous Panso3solution, dried with Na2SO4and thicken, and the above-mentioned compound is formed in the form of a colourless solid (18 g). So pl. 90aboutC.

b) 1-[(3-etoxycarbonyl-2-phenylimidazo[1,2-a] pyridine-6-yl)methyl]-2-butyl-4 - chloro-5-formyl-imidazole.

0.2 g (1.07 mmol) of 2-butyl-4-chloro-5-formyl-imidazole, 0,38 g (1.07 mmol) of 6-methyl bromide-3-etoxycarbonyl-2-phenylimidazo) 1,2-(pyridine, 0.15 g2CO3) (1.07 mmol) of 0.5 powdered molecular sieves was stirred 5 h at 60aboutWith in 5 ml of DMF. Next, add 100 ml of IT and washed 3 times with water. After drying with Na2SO4concentrated, and the residue chromatographic on SiO2c/H 1/1 as eluent.

MS(DCI) 465 (M++ N);

Rf[SiO2; EE/H (1:1)] 0,18.

C) Obtaining bromatologia compounds from b) and saponification of the above-mentioned compound (b) is carried out analogously to example 1 or 10A.

Example 13 carried out analogously to example 12. These compounds have the following General formula

H2C-(CH2) 18 405

19 449

20 455 F

21 455 F

For example 15: getting heterocyclic basic substance.

a) ethyl ester of pyruvic acid.

To 10 g (0.061 mol) of phenylpyruvic acid, 8.6 g (0,073 mol) of diisopropylethylamine in 200 ml of dichloromethane type of 13.9 g (0,073 mol) of triethylorthoformate. After 4 h at RT, the organic phase is washed 2 times with 10% citric acid solution and 2 times with saturated sodium bicarbonate solution. After drying with MgSO4thicken. After chromatography on SiO2c/H 1/5 as eluent get 7 grams of butter.

Rf(IT/N 1/5) 0,3

b) 2-ethyl ester bromopropionate acid.

7 g (being 0.036 mol) of ethyl ester of pyruvic acid (a), 50 ml of carbon tetrachloride is mixed with 5aboutWith 2.6 ml of bromine. Then heated to boiling for 1 h, concentrated and dissolved the residue in 100 ml. ITS phase is washed 2 times with 10% solution of Na2SO4and 1 time with H2O and dried with MgSO4. Removal of solvent in vacuo gives 9 g of compound in the form of butter.

MS(DCI) 271 (M + H)

c) 2-etoxycarbonyl-3-phenyl-6-methyl-imidazo[3,2-a]pyridine

3 g of 2-pompinovideogratis ethyl ester (b) and 1.2 g of 2-aminoanisole phase is washed 1 time with saturated solution of Na2CO3and then dried with MgSO4. After thickening chromatographic on SiO4with IT/N 1/1 as eluent.

Yield: 1.7 g

MS (DCI) 281;

Rf(IT/H 1/1) 0,2

P R I m e R 22. 1-[2-(tetrazol-5-yl)-3-chloro-benzo[d]thiophene-6-yl methyl] -2-n-butyl-4-chloro-5-Ki-drok

a) 3-chloro-6-methyl-benzo(a)thiophene-2-carboncycle amide.

To 30 ml (12.3 mmol) of the chloride of 3-chloro-6-methyl-benzo(a)thiophene-2-carboxylic acid.

(J. Org. Chem. 41, 3399, (1976) dimethoxyethane was added dropwise at 0aboutWith 100 ml of 4 N NH3in the DMA. After 30 min, concentrated and crystallized from ethanol, and is formed 14.5 g of the above compound.

MS(DCI) 226 (M + H)

Rf(EE/H 1/1 0,3

So pl. 193aboutC.

b) 3-chloro-2-cyano-6-methyl-benzo[b]thiophene

3 g (13.3 mmol) of the above compound (a) in 40 ml of pyridine is mixed at 0aboutWith 6.2 g (53.2 mmol) of thionyl chloride. After 2 h, poured into cold, like ice 4n HCl and extracted 3 times with each 50 ml with HER. The combined organic phases are dried with MgSO4and gathering. Chromatography on SiO2c/H 1/2 gives the above-mentioned compound (1.5 g).

MS (DCI) 208 (M+H)

Rf(EE/H 1/1) 0,75

C) 1-[(2-tetrazol-5-yl)-3-chloro-benzo-[b]-thiophene-6-yl-methyl]-2-N. butyl-4-chloro-5 - guide-oximeter-imidazo the connection 22V analogously to example 1 (b,c) and 0.42 g (2.0 mmol) trimethylol-azide in 50 ml of toluene was heated for 24 h to a boil. Then agglomerated and the residue was treated with 20 ml of HER, then at room temperature was added 0.6 ml F4and 15 ml of a saturated solution of KF. After 12 h was added again 20 ml and divided phase. The organic phase was dried with MgSO4and the danger.

Chromatography on SiO2with dichloromethane (methanol 5) 1 received the above-mentioned connection.

Rf/CH2Cl2/MeOH 5/1) 0,4

MS (FAB) 437 M + H)

P R I m e R 23. 1-[(2-phenyl-3-carboxy-imidazo[1,2-a]pyrimidine-7-yl)methyl]-2-n-butyl-4-methyl thio-acid

a) ethyl ester of 2-amino-2-cyano-acetic acid

To 35 g (0,246 mol) of 2-ethyl oxime ether 1-cyanoglucosides acid in 350 ml of water and 280 ml of saturated sodium bicarbonate solution added at room temperature portions (15 min) 119 g dithionite sodium. After then heated 1 h 35aboutC; then saturated with NaCl and extracted 5 times with dichloromethane. After drying with calcium chloride the organic phase is condensed. Get to 11.8 g of oil above target connection.

Rf(CH2Cl2)CH3OH 9/1) 0,6

b) ethyl ester of 2-cyano-2-N. butyl-Carbonia-amino-acetic acid.

To 3.6 g (28,09 mmol) of compound 23 b in 50 ml of dry CH2CL2and 2.3 ml (28,09 mmol) of pyrid the 1 h then stirred at room temperature. The organic phase is then washed 3 times with N2Oh, 1 time with saturated solution of NaCl, dried with calcium chloride and thickens. Crystallization of the DIP gives 1.7 g of the mentioned target compound.

Rf(CH2Cl2/CH3OH 9/1) 0,35

So pl. 87aboutC.

(C) ethyl ester of 3-amino-2-n butylcarbamoyl-methylthioribose acid.

To 2.9 g (13,67 mmol) of compound 23 (b) and to 0.19 ml (about 1.36 mmol) of triethylamine in 60 ml of absolute ethanol is added at room temperature, 2 ml (27,26 mmol) condensed mercaptan. After 3 days add again 0.5 ml of methylmercaptan. Over the next 24 h at room temperature again spryskivaetsya 0.5 ml of methylemercaptane and to 0.19 ml of triethylamine and stirred for a further 24 h at room temperature. After that, the solvent is removed, and the residue crystallized from DIP, and is formed of 2.4 g of the specified target compounds.

Rf(CH2Cl2/EE 4/1) 0,3

So PL 120aboutC.

d) ethyl ester 2-N. butyl-4-methylthio-imidazole-5-carboxylic acid

To 4,27 g (20.0 mmol) of pentachloride phosphorus in 20 ml l2was added dropwise at -78aboutWith 2,44 (20 mmol) of 4-dimethylaminopyridine in 12 ml of CH2CL2. After 5 min precipiate and diluted with 30 ml of CH2CL2. After 2 h while cooling with ice, add 300 ml of 1 N sodium bicarbonate solution and stirred for 1 h Then the phases are separated, the aqueous phase is extracted 3 times with HER, and the combined organic phases are dried with calcium chloride. Chromatography on SiO2with CH2CL2(IT/9/1) gives 1.4 g of the above compound in the form of butter.

Rf/CH2Cl2/EE 9/1/ 0,6

MS/DCI 243 /M++ H/

Other measures process for the specified target compound 23 is carried out analogously to examples 12b and 10A.

Rf/EE/MeOH 5/1/ 0,2

MS/FAB/ 466 /M + H/

P R I m e R 24 1-[(2-phenyl-3-carboxy-imidazo[1,2-a]-pyrimidine-7-yl)-methyl]-2 - N. butyl-4-methylsulfonyl-imidazole-5 - carboxylic acid.

a) ethyl ester of 1-[(2-phenyl-3-carboxyethyl-imidazo [1,2-a]-pyrimidine-7-yl)methyl]-2-n-butyl-4-methylsulfonyl-imida - evil-5-carboxylic acid.

To 80 mg (0.15 mmol) of ethyl ester 1-[(2-phenyl-3-carboxyethyl-imidazo [1,2-a] pyrimidine-7-yl)-methyl] -2-N. butyl-4-methyltin-imidazole-5-carboxylic acid in 5 ml of dichloromethane added 52 grams (0.15 mmol) of 50% metallocarboranes acid at RT. After 1 h the mixture was washed 1 time with saturated solution of Na2CO3and 1 time with water. The organic phase is condensed, the residue UB>/EE/H 1/1/ 0,15

MS/FAB/ 538 /M+H) 45

b) the Specified target connection 24 get analogously to example 10A.

Rf/CH2Cl2/MeOH 5/1/ 0,2

MS/FAB/ 482 /M + H/

P R I m e R 25. 1-[(2-phenyl-3-carboxy-imidazo [1,2-a]pyrimidine-7-yl)-methyl]-2-N. butyl-4-methylsulphonyl-imidazol-5-CT - oil acid.

To 120 mg (0.23 mmol) of ethyl ester 1-[(2-phenyl-3-carboxyethyl-imidazo [1,2-a] -pyrimidine-7-yl)-methyl] -2H. butyl-4-methyl-thio-imidazole-5-carboxylic acid in 10 ml of dichloromethane was added when RT 158 mg (0.46 mmol) of 50% metallocarboranes acid. The subsequent course of the reaction and separation analogous to example 24A.

Rf(EE) 0,6

MS (FAB) 554 (M + H)

(b) saponification of the specified target compounds carried out analogously to example 10A).

Rf(CH2Cl2/MeOH 5/1) 0-2

MS (FAB) 498 (M + H)

The connection 26 and 27 were obtained analogously to examples 24 and 25.

Examples 28 33 carried out analogously to example 22.

Getting 2-phenyl-3-amido-7-methyl-imidazo [1,2-a] pyrimidine (example 28): 500 mg (1.78 mmol) of 2-phenyl-3-carbethoxy-7-methyl-imidazo[1,2-a]pyridine, 213 microlitres (to 5.35 mmol) of formamide and 120 mg of the tertiary butyl potassium is heated in 10 ml of DMF for 1 h to 100aboutC. Then poured into H2About pH 8-9 install the CH222 437 Cl CH2-OH N 23 466-S-CH3CO2H 24 482-SOCH3CO2H 25 498-SO2CH3CO2H 26 455 SOCH3CO2H 27 471-SO2CH3CO2H 28 517-S-CH3CO2Et F 29 488-S-CH3CO2H 30 497-S-CH3CO2Et 31 463-SCH3CO2H 32 523-SO2CH3CO2Et 33 495-SO2CH3CO2H 34

1-[2-(4-Methoxycarbonyl)-benzoxazolyl)-methyl] -2-N. butyl-4-chloro-5-formyl-imidazol

a) methyl ester of 2-methyl bromide-benzoxazol-4-carboxylic acid.

453 mg (2,37 mmol) of 2-methyl-benzoxazol-4-carboncillo methyl ester (obtained according to N. Heterocyclic Chem. 27, 335, 1990) are dissolved in 40 ml of chlorobenzene, 421 mg (2,37 mmol) of NBS and 20 mg of benzoyl peroxide added, and the mixture is heated for 2 hours in a reverse flow. The mixture is concentrated, the residue dissolved in ethyl acetate, shaken with a saturated solution of NaHCO310% of NaS2O3and a saturated solution of NaCl and dried over Na2SO4. Concentration and chromatography on SiO2N. heptane/ethyl acetate (2:1) to give 128 mg of the target compound.

So pl. 110-113aboutWITH

MS (CI) 271 (M+H)

b) 1-[2-(4-methoxycarbonyl)-benzoxazolyl)methyl]2-N. butyl-4-chloro-formyl-them-Yes angry.

To a suspension of 176 ml (0,944 mmol) 2-H. Boo is mg (0,944 mmol) of the compound from a) in 1 ml of absolute DMF, and the suspension obtained is stirred 1 h at room temperature. Condensed to dryness, the residue dissolved in ethyl acetate, washed with water and saturated NaCl solution, dried and condensed. Chromatography on SiO2c CH2Cl2/ethyl acetate (9:1) to give 103 mg of the desired compound.

MS (CI) 376 (M + H)

P R I m e R 35. 1-[(2-(5-methoxycarbonyl)-benzoxazolyl)-methyl]-2-N. butyl-4-chlorine - ro-5-formyl-imidazole.

a) methyl ester of 2-methyl bromide-benzoxazol-5-carboxylic acid

Target the specified connection is obtained from the methyl ester of 2-methyl-benzoxazol-5-carboxylic acid analogously to example 14a.

MS (CI) 271 (M + H)

b) 1-[(2-(5-methoxycarbonyl)-benzoxazolyl)methyl]-2-N. butyl-4-chloro-5-formyl-they IDAs

This compound is obtained from the compound obtained in (a) and 2-N-butyl-4-chloro-formyl-imidazole by the method according to example 34 (b).

MS (CL) 376 (M + H)

II. Testing the biological activity

Binding in vitro receptor of angiotensin 11 (al1).

The principle of operation.

This test is used to determine the affinity of the tested compounds to the receptor of angiotensin 11 (ANG-11-subspecies-1 (al1by measuring its inhibitory effect on the binding of simple generous garden light is their membranes.

Receive 1 g of the liver of male rats Sprague Dawley (150-200 g) and homogenized in 40 ml of 50 mm Tris-Hcl buffer, rn,4, Brinkmann transmitter station (4x10 with pulses). The homogenate was centrifuged at 25000 g for 15 minutes Get the flake that resuspended in 40 ml of Tris-Hcl buffer concentration of 50 mm, pH 7.4 and centrifuged again. This washing procedure was repeated twice. Finally flakes are suspended in 400 ml (2.5 mg wet weight of the original fabric (ml) incubation buffer and stored on ice until use.

The test procedure.

All incubated samples (total volume of 200 ál were prepared three times. As the incubation buffer was used 20 mm Tris-Hcl buffer 20 mm, pH 7.4, containing 135 mm NaCl, 10 mm KCl, 5 mm glucose, 10 mm MgCl2, 0.3 mm PMSF, 0.1 mm Bacitracine and 1 g/l lysozyme; 50 μl of radioligand and 50 μl solution of the test substance (or standard) is applied with a pipette on the walls 96-murine of the blade; the reaction is started by adding 100 μl of the suspension membrane on each wall. The blade is then covered with tape and incubated at room temperature on a rocking plate for 60 minutes

Experiments to determine the values of the IC50that was compared, was performed with a single concentration of radioligand (wanie was measured by adding 10 Microm nonprotein ANG-11 antagonist DUP 753 to the set of samples. The reaction was stopped by rapid vacuum filtration through glass fiber filters (Whatman GF/B) on the device Scatnon with 96 cells of blades and intensively washed with 50 mm Tris-Hcl. Measured residual associated with the membrane of the radioactivity on the filter (after the extraction of the individual discs of the filter in Minicentrifuge capsules and add 3 ml of liquid scintillation mixture) in a liquid scintillation counter Taurus (ICN).

The calculation results.

Was calculated the following parameters:

total binding (OS) linking radiolabeling ANG 11 in the absence of inhibitor.

link (S) linking radiolabeling ANG 11 in the presence of the test compound or standard.

nonspecific binding (NSS)binding in the presence of high concentrations of antagonist (10 Microm DUP-753),

specific binding (SS) With-NSS.

The value of the IC and for connections, displacing radiolabeling ANG 11 of its receptor, calculated using Biosoft Ligand PC-Software.

To assess compliance invention, the criterion of "positive effect" below provides data on the activity of the compounds according to the invention with a similar structure.

For comparison were taken following the 4-N-phthalimidomethyl)-imidazol

the value of the IC50: 8.0 x 10-6mol (see table 20 on page 278 ff).

Example 183 from EP 253 310: 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-aminobiphenyl)-methyl]-imidazole

the value of the IC50: 6.3 x 10-6mol

b) the compound according to the invention according to example 22; 2-butyl-4-chloro-5-hydroxymethyl-1-[2-(5-tetrazolyl)-3-chlorobenzo[b]-thio - Hairdryer-6-yl-methyl]-imidazole

the value of the IC501.8 x 10-6the mole.

Thus, the experimental data confirm that the introduction of various heterocyclic residues in the molecule of the compounds according to the invention leads to a noticeable improvement of their pharmacological properties.

Example IC50[M] in the liver of rats

13 2,8

14 3,2

15 1,1


17 16,2



20 7,9


22 1,8

23 0,78



26 7,0

27 1,0

28 2,5

29 0,41

30 0,8

31 0,01

32 5,3

33 0,6


35 8,6

The method of obtaining the imidazole derivatives of General formula I

< / BR>
where R1C3-C7-alkyl;

R2formyl, carboxy, C1-C4-alkoxycarbonyl or hydroxymethylene group;

R12chlorine or a group S(O)rR3where R3- C1-C6-alkyl; Z is 0, 1 or 2;

)pyrimidyl, benzoxazolyl substituted by one or two identical residues selected from the range containing chlorine, tetrazolyl, carboxyl, carboxy, C1-C4-alkyl, C1-C4-alkoxycarbonyl and phenyl, possibly substituted by fluorine,

or their physiologically-tolerated salts, characterized in that the imidazole derivative of General formula II

< / BR>
where R1and R2have the specified values;

R12chlorine or group SR3where R3has the specified value,

moreover, when the substituent R2carboxyl group, it may be protected,

subjected to interaction with the compound of General formula III


where A1-the specified heterocyclic residue, substituted by one or two identical or different residues selected from the range containing chlorine, cyano, carboxyl, carboxy, C1-C4-alkyl, C1-C4-alkoxycarbonyl and phenyl, possibly substituted by fluorine,

and when the Deputy A1carboxyl group, it may be protected;

U tsepliaeva group,

obtaining compounds of General formula Ia

< / BR>
where R1, R2and A1have the specified value is carboxyl group, it may be protected,

in the case of obtaining compounds of General formula I, in which R12group S(O)zR3where R3has the specified value, r is 1 or 2, the compound of formula Ia, where R12mean group SR3where R3has a specified value, is subjected to the interaction with the oxidant, or in the case of obtaining compounds of General formula I, in which A Deputy contains tetrazolyl residue, the compound of formula Ia, where A Deputy contains a cyano, subjected to interaction with collisuem agent with the subsequent removal if necessary carboxyamide group and the allocation of target compounds in free form or in the form of a physiologically tolerable salt.


Same patents:

The invention relates to new derivatives carbapenem General formula

where a is a pyrolidine ring;

R1represents a hydrogen atom or methyl;

R2represents a hydrogen atom;

R3represents a hydrogen atom or ion with a negative charge Q represents a group of the formula (I)

-(CH2)pZ+where p is zero or an integer 1 or 2;

Z+means pyridyl, pyrrolidinyl or genocidal, each substituted with one or two1-C4-alkyl groups, and contains a Quaternary nitrogen atom, or a group of formula (2)

-(CH2)p-R6where p is an integer 2;

Ra, Rband Rceach is1-C4-alkyl, or Q and R2together with the nitrogen atom to which they are attached, form a group of formula (3)

-Nwhere m and n are each 2 or 3

R6and R7each represents alkyl with 1-4 carbon atoms or alkyl with 1-4 carbon atoms, substituted Deputy selected from the group comprising hydroxy-, carboxy-, карбам�at2/19962/007.dwl/2059639-7t.gif" ALIGN="ABSMIDDLE">where Rd, Reand Rdeach means hydrogen or C1-C4-alkyl;

R6is1-C4-alkyl, or their salts or esters

The invention relates to new triazine derivative or triazolone series, namely: to heterocyclic compounds of General formula

(I) where R1represents a hydrogen atom, l is 0 or 1; ring a represents hexahydropyridine, tetrahydropyrrole, hexahydroazepin, dihydrothiazolo, tetrahydrooxazolo, tetrahydrothiophene or dihydropyridines; Y represents a substituted lower alkyl or aryl, or unsubstituted alkylenes group containing from 1 to 3 carbon atoms; Q represents a group of the formula

N(II) where R2represents a hydrogen atom, a hydroxyl group or aryl group which may be substituted with halogen; R5represents a hydrogen atom; and R3and R4can have the same or different values, each represents a hydrogen atom, halogen atom or morpholinyl, or Q represents a group of the formula

N(III) where Ar1and Ar2may have about the Ohm halogen or alkyl group, or their acid additive salt

The invention relates to novel 3,5-dihydroimidazo[2,1-b] hinzelin-2 (1H)-it is a derivative of the formula I


(I) where R is a hydrogen atom, a C1-6-alkyl, phenyl, possibly substituted by 1-3 substituents, independently from each other selected from halogen atoms, hydroxy - C1-6-alkyloxy-FROM1-6is an alkyl or triptorelin groups, pyridinyl, or thienyl, unsubstituted or substituted with halogen or1-6by alkyl;

R1the atom of hydrogen or C1-6-alkyl;

R2a hydrogen atom, a C1-6-alkyl, hydroxy-C1-6alkyl or phenyl, or R1and R2together can form WITH1-5-alcander;

X is the radical of the formula

0 (a)

N-O-R3(b) or


R3a hydrogen atom, three (C1-6-alkyl)-silyl or1-6-alkyl which may be substituted by COOH, SOOS1-4-alkyl, СОNR5R6or SOON2-CONR7R8;

R4COOH, COOC1-4-alkyl, СОNR5R6, COOCH2CONR7R8or1-6-alkyl which may be substituted by COOH, SOOS1-4-alkyl, CONR5R6or COOCH2CONR7R8;

RIS-C1-4-alkyl, C1-4-algological - Nile-C1-4-alkyl;

R6a hydrogen atom, a C1-5-alkyl, hydroxy-C1-4-alkyl or C3-7-cycloalkyl, or R5and R6together with the nitrogen atom to which they are bound, can form pyrrolidinyl, morpholinyl or piperazinil, which can be substituted at the nitrogen atom WITH1-4-alkyl or hydroxy-C1-4-alkyl;

R7and R8independently from each other mean a hydrogen atom, a C1-4-alkyl or hydroxy-C1-4-alkyl, and their pharmaceutically acceptable salts and stereoisomers

The invention relates to new derivatives of glutamic acid with any abscopal valuable properties on the enzyme, using folic acid and its metabolites as substrates and finds application in medicine, as well as the way they are received

The invention relates to a series of new derivatives griseolus acid and provides the means of obtaining these compounds, and methods and compositions for their use

The invention relates to an improved process for the preparation 2,4,6,8-tetraacetyl-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (tetraazatricyclo), which finds use as an intermediate in the synthesis of explosives [1] soft acetylides agent and activator disinfectant, bleaching and washing agents [2-5]

A method of obtaining 2,4,6,8-tetraacetyl-2,4,6,8-tetraazabicyclo[3.3.0]OK - tan-3,7-dione, which is that 120 g of glycoluril in 2 l of acetic anhydride in the presence of 100 g of sodium acetate is heated at 140aboutWith under reflux for 4 h, then cooled and filtered receive 233 g (88%) of tetraazatricyclo

The invention relates to a series pyrazolo[4,3-d]pyrimidine-7-ones, which are potent and selective inhibitors of cyclic guanosine-3',5'-monophosphatase (cGMP PDE), which is useful in various fields of therapy, including the treatment of various cardiovascular diseases, in particular hypertension, heart failure and atherosclerosis

The invention relates to polycyclic compounds, their pharmaceutical compositions and methods of their use in human diseases associated with impaired memory processes, diseases of the nervous system and/or depression, such as, but not limited to, degenerative changes in the nervous system

The invention relates to new mevalonate with pyrazolopyrimidine ring, processes for their preparation, pharmaceutical compositions containing them and their pharmaceutical use, especially as antihyperlipidemic, hypolipoproteinemia and antiatherosclerotic agents, and to intermediate products useful for their preparation and methods of producing such intermediates

The invention relates to a number of optical active derivatives of endoventricular who possess excellent antiarrhythmic activity, and also provides a stereospecific method of producing the compounds, and methods and compositions which are not used

The invention relates to new derivatives of benzo(b)naphthiridine General formula

R(I) where R1hydrogen, alkyl or hydroxyl radical;

R2hydrogen, linear or branched C1-C4-alkyl, foralkyl, cycloalkyl, alkyloxyalkyl or alkylamino radical;

R3WITH1-C4-alkyl, and R4and R5different and mean hydrogen or C1-C4-alkyl;

or R3hydrogen or alkyl, or cycloalkyl and R4and R5individually, each means hydrogen;

R6hydrogen or fluorine;

n is 1 or 2, or their salts, possess antibacterial property

The invention relates to heterocyclic carbon compounds with medicinal and bioactive properties, to their preparation and use

The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

-Alk - Z1- C(=X) - Z2- R7(b-3), or

-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

The invention relates to organic chemistry, specifically to new chemical compounds, of General formula:

< / BR>
in particular 1,3-bis(2'-hydroxy-3'-morpholinopropan)-6-methyluracil(a); 1,3-bis(2'-hydroxy-3'-piperidinoethyl)-6-stands-rallu (b); 3-bis(2'-hydroxy-3'-morpholinopropan)-5-hydroxy-6-methyluracil (); 1,3-bis(2'-hydroxy-3'-piperidinoethyl)- 5-hydroxy-6-methyluracil (g); 1,3-bis(2'-hydroxy-3'-morpholinopropan)-5-(2'-hydro - XI-3'-morpholinoethoxy)-6 - methyluracil (d) and 1,3-bis(2'-hydroxy-3'-piperidinoethyl)-5-(2'-hydroxy-3'-piperidino - poxy)- 6-methyluracil (E), showing immunotropic and anti-inflammatory activity