Substituted beta-phenyl-alpha-hydroxyl propanoic acid, synthesis method and use

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), where each R1, R2 and R3 is independently selected from a group comprising H, OH, F, Cl, Br, a methoxy group and an ethoxy group; or R1 and R2 together form -OCH2O-, and R3 is selected from a group comprising H, OH, methoxy group, ethoxy group and halogens; R4 denotes OH or o-acetoxybenzoyloxy nicotinoyloxy or iso-nicotinoyloxy; R5 denotes or , and at least one of R1, R2 and R3 is not hydrogen.

EFFECT: method for synthesis of a compound of formula (I) and use of the compound of formula (I) in preparing medicinal agents for preventing or treating cerebrovascular diseases.

17 cl, 14 tbl, 5 dwg, 12 ex

 

The area of technical applications

The present invention relates to a derivative of the substituted β-phenyl-α-hydroxypropanoic acid, the process of its synthesis and use for the manufacture of a medicinal product (drug) for the treatment and prevention of cardiovascular and cerebrovascular diseases.

History origin

Root Tribute-Canopy (Radix Salviae Militiorrhizae) is used in traditional Chinese medicine for the treatment of cardiovascular and cerebrovascular diseases, with a particular therapeutic effect. It is assumed that Selivanova acid (chemical name: β-(3,4-dihydroxyphenyl)-α-hydroxypropanoic acid) is the main active ingredient in water-soluble components of the root Tribute-Canopy. Pharmacological tests show that β-phenyl-α-hydroxyl-propanoic acid is the pharmacologically active component of propanoic acid, but its effect is not pronounced. Therefore, β-phenyl-α-hydroxypropanoic acid was modified, and the resulting derivatives may have the same or greater efficiency than the original compound, and to provide improved therapeutic effect in the treatment and prevention of cardiovascular and cerebrovascular diseases. For example, borneol can overcome Cardioceras the social barrier, while papanoida acid is not likely to pass through cardiocerebral barrier. Therefore, the structure PROPANEDIOL acid can be modified by the incorporation of the chemical structure of borneol.

Information about opening

One of the purposes of the present invention is the elimination of the derivative of β-phenyl-α-hydroxypropanoic acid and process for its synthesis, and the use of derivative substituted β-phenyl-α-hydroxypropanoic acid in the production of medical drugs for the prevention and treatment of cardiovascular and cerebrovascular diseases.

In one aspect of this opening formula (I) derived β-phenyl-α-hydroxypropanoic acid

where each of R1, R2, R3individually selected from the group consisting of H, OH, F, Cl, Br, methoxy, ethoxy, or R1and R2together form-OCH2O-, a R3is selected from the group consisting of H, OH, methoxy, ethoxy and Halogens;

R4represents OH or acyloxy;

R5is selected from the group consisting of cycloalkyl, amino and substituted amino, with the proviso that if R5amino, at least one of R1, R2and R3is not H.

In one modification of the present invention R4the present is the focus of a OH.

In another modification of the present invention R4represents urologic or substituted heterocyclic radicals, acyloxy. Preferably, R4was substituted o-acetoxybenzoic, 3 pyridinylmethyl or 4 pyridineboronic.

In a further modification of the present invention R5represents:

,,or.

Even later versions of R1and R2respectively represent IT.

Even later versions of R1and R2together form-OCH2O.

In a preferred modification, where R1and R2respectively are OH, R3=H, R4=OH andi.e. the connection of ether bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate, as shown in the formula (II).

In another preferred modification, where R1and R2together form-OCH2O-, R3=H,orand,

or, alternatively, R3=H,andor otherwise, R3=H, R4=OH andor.

In the other aspect of this discovery is described the synthesis of the compounds of formula (I), that includes the interaction of the compounds of formula (III) with the compound of the formula (IV) or hydroxide using catalyst:

where R1, R2, R3, R4and R5have the same meaning as above in formula (I).

Otherwise, the process may include the interaction of the compounds of formula (V) with the compound of the formula (VI) or hydroxide using catalyst:

where R1, R2, R3and R5have the same meaning as above in formula (I), a R4' is acyloxy.

As a catalyst it is possible to choose a concentrated H2SO4, kremnipolymer acid, phosphomolybdenum acid, p-toluensulfonate,, trichloride aluminum, zinc chloride and/or magnesium chloride. Preferably, the catalyst used t-toluensulfonate,, trichloride aluminum and/or zinc chloride. In particular, it is advantageous to use p-toluensulfonate and/or.

The molar ratio of the interaction of the compounds of formula (III) with the compound of the formula (IV) may be 1:0.8~1:1.5, preferably 1:1~1:1.5, more preferably 1:1.25 to about 1:1.5 and most preferably 1:1.5.

The molar ratio of inter is Astia the compounds of formula (V) with the compound of the formula (VI) may be 1:0.8~1:1.5, preferably 1:1~1:1.5, more preferably 1:1.25 to about 1:1.5 and most preferably 1:1.5.

Optionally, the reaction can be conducted in a solvent. The solvent can be selected from the following group: ethyl acetate, dichloromethane, tetrahydrofuran, acetone, toluene, 1,4-dioxane and N,N-dimethylformamide. Preferred solvents are tetrahydrofuran and acetone. The most preferred tetrahydrofuran. You can use a single solvent or any combination.

The temperature for the reaction is selected depending on the solvent used. Suitable temperature ranges from 0 to 150°C. the Most suitable temperature of 65°C.

The duration of the reaction may range 2-24 hours, preferably 8-12 hours and ideally 8 hours.

In one particular modification is considered the synthesis of the compounds of formula (II), which includes the interaction of β-(3,4-dihydroxyphenyl)-α-hydroxypropanoic acid with borneol using a catalyst. As the catalyst can be a catalyst of the Lewis acid, such as toluensulfonate,, trichloride aluminum and/or zinc chloride, are preferred. In the specified process the molar ratio of β-(3,4-dihydroxyphenyl)-α-hydroxypropanoic acid to borneol may be 1:1~1:1.5, the pre is respectfully 1:1.25 to about 1:1.5, most preferably 1:1.5. The reaction is carried out in a solvent which is selected from the following group: tetrahydrofuran, toluene, 1,4-dioxane or N,N-dimethylformamide, preferably tetrahydrofuran. The reaction temperature varies depending on the solvent, but generally falls within 65~150°C, preference is given to 65°C. the Duration of the interaction may be 8-12 hours, preferably 8 hours.

If the catalyst is usedit can be obtained as follows: add ammonia to a solution of ZrOCl2to achieve a pH of 9-12, to withstand, to wash out any residue of Cl-to heat in a drying Cabinet to dry, chop, then add to a solution of (NH4)2S2O8for impregnation, drain, dry, grind, and then calcined at a temperature of 500~700°C for 2-5 hours and get the result.

In a further aspect of the present invention discusses the use of the compounds for the production of medicines for the prevention and treatment of cardiovascular and cerebrovascular diseases. In particular, the use of ether bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate (compound of formula (II)in the manufacture of medical preparations DL the prevention and treatment of cardiovascular and cerebrovascular diseases.

Brief description of drawings

Figure 1 depicts the scheme of the synthesis of the compounds of formula (II) in Example 1, i.e. ether bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate.

Figure 2 shows the mass spectrum of the final products obtained in Example 1.

Figure 3 shows the infrared range of the final products obtained in Example 1.

Figure 4 shows the range of1H NMR of the final products obtained in Example 1.

Figure 5 shows the range of13C NMR of the final products obtained in Example 1.

Further, the present invention is described with images of examples of synthesis and pharmacodynamic tests. However, it should be understood that these examples are given solely for illustration and in any way does not limit the present opening.

Example 1: synthesis of (I) ether bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate

(1) Synthesis of acetylglycine.

In a three-neck flask with a capacity of 250 ml add 0.33 mol of glycine and 100 ml of distilled water, thoroughly shaken to dissolve and slowly, stirring occasionally, add one drop of 0.67 mol of acetic anhydride. The mixture was thoroughly shaken for 50 minutes, then filtered with a centrifuge. The precipitate is washed and dried, the result is a white crystal with access 86,0%.

(2) Synthesis of 2-methyl-4-(3,4-diacetoxybenzoic)oxazolone

In a three-neck flask with a capacity of 50 ml add 0.20 mol of 3,4-dihydroxybenzaldehyde, 0.24 mol acetylglycine and 0.26 mol of anhydrous sodium acetate, then add 189 ml of acetic anhydride and mixed until a homogeneous mass. The reaction lasts for 4 hours at 80°C water bath with stirring, the temperature was then raised to 100°C and continue the reaction for one hour while stirring. The resulting mixture is cooled at room temperature, and then placed in the fridge to cool it further. Then to the mixture, stirring occasionally, add 100 ml of water, and at the bottom of a precipitate in the form of a yellow crystal. Output yellow crystal after filtering, washing and drying is 75,0%.

(3) Synthesis of β-(3,4-diacetoxybiphenyl)-α-acetamidoacrylic acid

To the flask add 0.15 mol of 2-methyl-4-(3,4-diacetoxybenzoic)oxazolone, 166 ml of acetone and 166 ml of distilled water, then slowly heated to boiling and continue to heat under reflux for 3 hours. The mixture discolor with use of activated charcoal. After filtering, the filtrate is left for crystallization, and then filtered with a centrifuge, washed, dried, and the result was 72.9% crystalline powder color, natural off-white canvas.

(4) Synthesis of β-(3,4-dihydroxyphenyl) pyruvic acid

To 0.25 mol of β-(3,4-diacetoxybiphenyl)-α-acetamidoacrylate acids are added 1500 ml of 1 mol l-1of hydrochloric acid. Then the mixture is heated under reflux with stirring for 8 hours. After bleaching with activated charcoal and filtering by pressing the filtrate is evaporated to obtain a residue in the form of a crystal. The mixture is drained, filtered, washed, dried, and get loose white crystal, with yield of 48.1%.

(5) Synthesis of β-(3,4-dihydroxyphenyl)-α-hydroxypropanoic acid

To to 0.17 mol of β-(3,4-dihydroxyphenyl)pyruvic acid added 112 g of zinc amalgam and 1808 ml of 1.4 mol l-1hydrochloric acid, the reaction is conducted by heating under reflux for 8 hours. After filtering, the filtrate is extracted with repeated using ethyl acetate and dried using anhydrous Na2SO4. After removal of ethyl acetate is obtained β-(3,4-dihydroxyphenyl)-α-hydroxypropanoic acid with a yield of 40.3%.

(6) Synthesis bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate ether

To the flask add 0.12 mol of β-(3,4-dihydroxyphenyl)-α-hydroxypropanoic acid and 0.18 mol borneol, then as a catalyst add 0,86 g of p-toluenesulfonic acid or 2.00 g self-madeand 500 ml of tetrahydrofuran. The reaction is carried out at a temperature of 65°C for 8 hours. After completion of the reaction the catalyst, the solvent and unreacted borneol removed and receive a viscous black substance is the which defend and using column chromatogram get a yellowish oil.

Catalystobtained as follows: prepare a solution of 1 mol l-1ZrOCl2from 0.025 molstirred in an ice water bath; slowly drop by drop add 6 mol l-1ammonia up until the pH reaches 10; infused for 12 hours, filtered with a centrifuge, washed with filtered residue of Cl-(using 0.1 mol l-1AgNO3test); nakalimot precipitate at 110°C for 10 hours, crushed; soaked in 0.5 mol l-1the solution of (NH4)2S2O8within 12 hours; filter wringer; dried; crushed and nakalimot in a muffle furnace at a temperature of 600°C for 3 hours, after which get.

(7) the Mass spectrum, the infrared range,1H NMR range and13C NMR range obtained yellowish oil

Figure 2 represents the mass spectrum of the obtained yellowish oil, which shows that 351,7 is the molecular ion peak (M+H2O) and that the molecular weight of the oil is 333,69.

Figure 3 is an infrared (KBr) range v/cm-1: 3363.61 (OH), 2953.12 (CH3), 2913.90 (CH2), 1725.51 (C=O), 1608.20, 1521.53, 1450.32 (base of benzene ring), 1281.36 (C=O ester), 111439 (C-O secondary hydroxyl), 885.71 and 805.68 (1,2,4-tetamashimba benzene ring).

Figure 4 represents the1H NMR (CD3COCD3, 500 MHz) δ: 6.57-7.64 (m, 3H, Ar-H), 4.10-4.32 (m, 1H, -CH(OH)-), 4.83 (t, 1H, -CH-), 2.79-2.92 (m, 2H, -CH2-).

Figure 5 represents the13C NMR (CDCl3, 500 MHz) δ: 174.790, 143.807, 143.056, 128.557, 121.549, 116.895, 115.488, 81.983, 71.646, 48.860, 47.881, 44.798, 39.871, 36.506, 27.918, 27.057, 19.653, 18.774, 13.501.

The above characteristic data has proved that the synthesis is obtained ether bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate.

Example 2: synthesis of (II) bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate ether

The synthesis is carried out in the same way as in Example 1, except that in a three-neck flask add 0.12 mol of β-(3,4-dihydroxyphenyl)-α-hydroxypropanoic acid and 0.15 mol of borneol, then as a catalyst add 0,86 g of p-toluenesulfonic acid and 500 ml of tetrahydrofuran, and the reaction is carried out at a temperature of 65°C for 12 hours. After the interaction, the reaction solvent is removed by vacuum distillation, and the obtained viscous substance is exposed to the vacuum of 1.3×10-3PA) using an oil pump in a boiling water bath for removal of borneol, and then add 200 ml of ethyl acetate. The resulting solution was washed with a saturated solution of NaHCO3to remove unreacted β-(3,4-dihydroxyphenyl)-α-propane sour the s and p-toluenesulfonic acid. The obtained ethyl acetate layer is evaporated under reduced pressure and the result is a sticky brown substance that defend and using column chromatogram obtained from the solution of a yellowish oil. The obtained yellowish oil has the same mass spectrum and infrared range, and that the oil in Example 1.

Example 3: synthesis of (III) bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate ether

The synthesis is carried out in the same way as in Example 1, except that in the three-neck flask, add 0.1 mol of β-(3,4-dihydroxyphenyl)-α-hydroxypropanoic acid and 0.12 mol of borneol, then as a catalyst type of 1.33 g400 ml of 1,4-dioxane, and the reaction is carried out at a temperature of 100°C for 8 hours. After the interaction of the catalystremove the straining wringer, the solvent is removed by vacuum distillation, and the obtained viscous substance is exposed to the vacuum of 1.3×10-3PA) using an oil pump in a boiling water bath for removal of borneol. The obtained brown viscous substance and defend using column chromatogram get a yellowish oil, which has the same mass spectrum and infrared range, and that the oil in Example 1.

Example 4: synthesis of (IV) bornyl β-(3,4-dihydroxyl enyl)-α-hydroxypropionate ether

The synthesis is carried out in the same way as in Example 1 with the only difference that in the three-neck flask add 0.06 mol of β-(3,4-dihydroxyphenyl)-α-hydroxypropanoic acid and 0.09 mol of borneol, then as a catalyst type of 0.60 g of trichloride aluminum and 200 ml of N,N-dimethylformamide as solvent and the reaction is carried out at a temperature of 150°C for 10 hours. After the interaction between the solvent is removed by vacuum distillation, and the obtained viscous substance is exposed to the vacuum of 1.3×10-3PA) using an oil pump in a boiling water bath for removal of borneol. The obtained brown viscous substance and defend using column chromatogram get a yellowish oil, which has the same mass spectrum and infrared range, and that the oil in Example 1.

Example 5: synthesis bornyl β-(4-chlorophenyl)-α-hydroxypropionate ether

(1) 2-Methyl-4-(4-chlorobenzylidene)oxazole get by, similar to that described in Example 1(2), except that 4-chlorobenzaldehyde is used instead of 3,4-dihydroxybenzaldehyde. The result is crystal brown with access 87,4%.

(2) Synthesis of β-(4-chlorophenyl)-α-acetamidoacrylic acid

To the flask was added 0.10 mole of 2-methyl-4-(4-chlorobenzylidene)oxazolone, 110 ml of acetone, 110 ml of water and 2 ml of concentrated hydrochloric is islote, slowly bring to the boil and then leave to heated under reflux for 3 hours. After bleaching with activated charcoal and filtering, the filtrate is left for crystallization and receive as a result of straining with the extraction, washing and drying orange crystalline powder with a yield of 81.1%of.

(3) Synthesis of β-(4-chlorophenyl) pyruvic acid

To the flask add 4.55 g of β-(4-chlorophenyl)-α-acetamidoacrylic acid, 91 ml of 1 mol l-1hydrochloric acid and 45 ml of tetrahydrofuran, the mixture is heated under reflux for 10 hours. After bleaching with activated charcoal and filtering, the filtrate is left for crystallization and receive as a result of straining with spinning, rinsing and drying off-white crystalline powder with a yield 77.3 per cent.

(4) Synthesis of β-(4-chlorophenyl)-α-hydroxypropanoic acid

To 15,00 g of β-(4-chlorophenyl)pyruvic acid added for 98.00 g Zn(Hg), 219 ml of 2.5 mol l-1hydrochloric acid and 35 ml of tetrahydrofuran is heated under reflux for 10 hours. After straining, when the mixture is still hot, the filtrate is evaporated to obtain 80 ml and left overnight. After straining with the extraction, washing, drying and recrystallization get flaky Crist is FL with access 64,0%.

(5) Synthesis bornyl β-(4-chlorophenyl)-α-hydroxypropionate ether

In a three-neck flask add 0.12 mol of β-(4-chlorophenyl)-α-hydroxypropanoic acid and 0.15 mol of borneol, then as a catalyst add 0,86 g of p-toluenesulfonic acid and 500 ml of tetrahydrofuran, conduct the reaction at a temperature of 65°C for 12 hours. After the interaction, the reaction solvent is removed by vacuum distillation, and the resulting brown viscous substance is subjected to vacuum effects (1,3×10-3PA) using an oil pump in a boiling water bath for removal of borneol, then add 200 ml of ethyl acetate to obtain a solution. The resulting solution was washed with a saturated solution of NaHCO3to remove unreacted β-(4-chlorophenyl)-α-hydroxypropanoic acid and p-toluenesulfonic acid. The organic phase is evaporated under vacuum, obtaining the resulting brown viscous substance that defend and using column chromatogram get a yellowish oil.

Infrared (KBr) range ν/cm-1: 3461.45 (HE), 2981.99 (CH3), 2935.46 (CH2), 1731.08 (C=O), 1598.03, 1492.10, 1453.90 (base of benzene ring), 1269.86 (C=O ester), 1106.22 (C-O secondary hydroxyl), 846.84 (pair-diseasemay);

1HNMR (500 MHz, CDCl3)δ: 6.57-7.64 (m, 3H, Ar-H), 4.10-4.32 (m, 1H, -CH(OH)-), 4.83 (t, 1H, -CH-), 2.79-2.92 (m, 2H, -CH2-), 1.205 (t, 3H, -CH 3).

13CNMR (500 MHz, CDCl3) δ: 13.5, 19.5, 19.5, 23.3, 30.2, 32.5, 40.8, 45.4, 49.4, 50.6, 71.3, 82.4, 128.7, 128.7, 129.1, 129.1, 131.5, 137.5, 170.8.

Example 6: synthesis bornyl β-(3-methoxy-4-hydroxyphenyl)-α-hydroxypropionate ether

(1) 2-Methyl-4-(3-methoxy-4-acetoacetanilide)oxazole get by, similar to that described in Example 1(2), except that 3-methoxy-4-hydroxybenzaldehyde is used instead of 3,4-dihydroxybenzaldehyde. The result is a yellow crystal with a yield of 73.5%.

(2) β-(3-Methoxy-4-acetoxyphenyl)-α-acetamidoacrylic acid is obtained by means similar to those described in Example 1(3), except that 2-methyl-4-(3-methoxy-4-acetoacetanilide)oxazole is used instead of 2-methyl-4-(3,4-diacetoxybenzoic)oxazolone. The result is a loose crystal color, natural off-white canvas with the release of 71.6 per cent.

(3) β-(3-Methoxy-4-hydroxyphenyl)pyruvic acid is obtained by means similar to those described in Example 1(4), except that instead of β-(3-methoxy-4-acetoxyphenyl)-α-acetamidoacrylic acid using β-(3,4-diacetoxybiphenyl)-α-acetamidoacrylic acid. The result is a yellowish friable crystal with access 64,2%.

(4) β-(3-Methoxy-4-hydroxyphenyl)-α-hydroxypropanoic acid is obtained by means similar to those described in Example 5(4), except that instead of β-(3-methoxy-4-hydroxyphenyl)pyruvic sour is and is used instead of β-(3,4-dihydroxyphenyl)pyruvic acid. The result is a yellowish oil or crystal with the release of 77,8%.

(5) Bornyl β-(3-methoxy-4-hydroxyphenyl)-α-hydroxypropionate ether obtained by similar to that described in Example 5(5), except that β-(3-methoxy-4-hydroxyphenyl)-α-hydroxypropanoic acid is used instead of β-(3,4-dihydroxyphenyl)-α-hydroxypropanoic acid. The result is a yellowish crystal with access to 59.8%.

Infrared (KBr) range ν/cm-1: 3363.61 (OH), 2953.12 (CH3), 2913.90 (CH2), 1725.51 (C=O), 1608.20, 1521.53, 1450.32 (base of benzene ring), 1281.36 (C=O ester), 1114.39 (C-O secondary hydroxyl), 885.71, 805.68 (1,2,4-tetamashimba benzene ring), 1237.58, 1027.61 (arylalkylamine ether).

1H NMR (400 MHz, CD3COCD3.) δ: 6.679-6.869(m, 3H, Ar-H), 4.920-4.983 (m, 1H, -CH-), 4.257-4.286 (t, 1H,-CH(OH)-), 3.819(s, 3H, -OCH3), 2.804-2.978 (m, 2H, -CH2-).

13C NMR (500 MHz, CD3COCD3) δ: 13.5, 19.5, 19.5, 23.3, 30.2, 32.5, 41.1, 45.4, 49.4, 50.6, 56.1, 71.3, 82.4, 113.1, 116.8, 121.4, 133.0, 142.9, 151.3, 170.8.

Example 7: synthesis of ester of mental β-(benzo[1,3]dioxol-5-yl)-α-(nicotinergic) propionate

(1) 2-Methyl-4-(benzo[1,3]dioxol-5-ylmethylene)oxazole get by, similar to that described in Example 1(2), except that benzo[1,3]dioxol-5-carbaldehyde is used instead of 3,4-dihydroxybenzaldehyde. The result is a yellow crystal with a yield of 76.5%.

(2) β-(Benzo[1,3]dioxol-5-yl)-α-acetamidoacrylate the acid is obtained by, similar to that described in Example 1(3), except that 2-methyl-4-(benzo[1,3]dioxol-5-ylmethylene)oxazole is used instead of 2-methyl-4-(3,4-diacetoxybenzoic)oxazolone. The result is a loose crystalline powder color, natural off-white canvas with access to 78.7%.

(3) β-(Benzo[1,3]dioxol-5-yl)pyruvic acid is obtained by means similar to those described in Example 1(4), except that β-(benzo[1,3]dioxol-5-yl)-α-acetamidoacrylic acid is used instead of β-(benzo[1,3]dioxol-5-yl)-α-acetamidoacrylic acid. The result is a loose crystal yellow with a yield of 65.4%.

(4) β-(Benzo[1,3]dioxol-5-yl)-α-hydroxypropionic acid is obtained by means similar to those described in Example 5(4), except that β-(benzo[1,3]dioxol-5-yl)pyruvic acid is used instead of β-(3,4-dihydroxyphenyl)pyruvic acid. The result is a yellowish oil or crystal with access to 78.7%.

(5) Ether of methyl β-(benzo[1,3]dioxol-5-yl)-α-hydroxypropionate is synthesized by a method similar to that described in Example 5(5), except that instead of β-(3,4-dihydroxyphenyl)-α-hydroxypropionic acid used β-(benzo[1,3]dioxol-5-yl)-α-hydroxypropionic acid. It turns a yellowish oil.

(6) Synthesis of methyl ether of β-(benzo[1,3]dioxol-5-yl)-α-(nicotinergic) propionate

In a three-neck flask 0.12 m the l ether methyl β-(benzo[1,3]dioxol-5-yl)-α-hydroxypropionate dissolved in 15 ml of acetone, then added some catalyst DCC/DMAP (2,3-dichloroethylidene/4-dimethylaminopyridine). A solution of 0.15 mol of nicotinic acid, dissolved in 5 ml of acetone, is added in drops in an ice bath. The reaction takes place in an ice bath for 2 hours, then at room temperature for 1 hour. After completion of the reaction is vacuum filtration, the reaction solvent is removed by distillation and 200 ml of ethyl acetate is added to the obtained viscous substance. The resulting solution is poured a saturated solution of NaHCO3to remove unreacted nicotinic acid and catalyst. The organic phase is concentrated under vacuum to obtain a brown viscous substance, which is further divided by column chromatography to obtain a yellow oil (ether methyl β-(benzo[1,3]dioxol-5-yl)-α-(nicotinergic)propionate with access to 45.5%.

IR (KBr) ν/cm1: 3056.56 (H-C=C), 2967.42 (CH3), 2940.54 (CH2), 1723.02 (C=O), 1597.32, 1520.17, 1462.10 (base of benzene ring), 1452.62, 1480.34, 1585 (base pyridine ring), 1268.53 (C=O ester), 1235.79, 1017.23 (arylalkylamine ether), 1125.33 (C-0 secondary hydroxyl), 884.43 and 798.62 (1,2,4-triple-substituted).

1H NMR (400 MHz, CD3COCD3) δ: 7.56-9.00 (m, 4H, pyridine-N), 6.679-6.869 (m, 3H, Ar-H), 6.06 (s, 2H, -OCH2O-), 5.10 (m, 1H, -CH(O)-, 4.920-4.983 (m, 1H, -OCH(clcy)-), 2.804-2978 (m, 2H, -CH2-).

13C NMR (500 MHz, CD3COCD3) δ: 20.7, 21.0, 21.0, 22.3, 25.7, 28.5, 33.9, 37.8, 39.6, 47.1, 72.6, 75.6, 101.2, 112.7, 115.2, 121.0, 122.1, 126.0, 132.7, 136.4, 146.0, 148.7, 150.4, 151.4, 165.9, 170.8.

Example 8: synthesis of methyl ether of β-(benzo[1,3]dioxol-5-yl)-α-(isonicotinoyl) propionate

The synthesis is carried out by a method similar to that described in Example 7, except that instead of nicotinic acid is used isonicotinoyl acid. The final product is obtained in the form of a yellowish oil output 47,83% and represents the methyl ether of β-(benzo[1,3]dioxol-5-yl)-α-(isonicotinoyl) propionate.

IR (KBr) ν/cm-1: 2966.27 (CH3), 2943.14 (CH2), 1720.82 (C=O), 1592.37, 1517.09, 1467.10 (base of benzene ring), 1452.24, 1484.56, 1598.23 (base pyridine ring), 1267.67(C=O ester), 1237.58, 1027.61 (arylalkylamine ether), 1103.14 (O secondary hydroxyl), 880.43 and 795.81 (1,2,4-triple-substituted).

1H NMR (400 MHz, CD3COCD3) δ: 7.56-9.00 (m, 4H, pyridine-H), 6.679-6.869 (m, 3H, Ar-H), 6.06 (s, 2H, -OCH2O-), 5.10 (m, 1H, -CH(O)-), 4.920-4.983 (m, 1H, -OCH(clcy)-), 2.804-2.978 (m, 2H, -CHr2).

13C NMR (500 MHz, CD3COCD3) δ: 20.7, 21.0, 21.0, 22.3, 25.7, 28.5, 33.9, 37.8, 39.6, 47.1, 72.6, 75.6, 101.2, 112.7, 115.2, 122.9, 122.9, 126.0, 132.7, 136.4, 146.0, 148.7, 150.3, 150.3, 165.9, 170.8.

Example 9: synthesis of ether bornyl β-(benzo[1,3]dioxol-5-yl)-α-(2-acetoxybenzoic)propionate

Steps (1)-(4) synthesis are identical to steps (1)to(4) in example 7.

(5) the Ether bornyl β-benzo[1,3]dioxol-5-yl)-α-hydroxyprop is ionata synthesized way, similar to that described in Example 5(5), except that instead of menthol is used borneol is obtained yellowish oil.

(6) Ether bornyl β-(benzo[1,3]dioxol-5-yl)-α-(2-acetoxybenzoic) propionate is synthesized by a method similar to that described in Example 7(6), except that instead of nicotinic acid is 2-acetoxybenzoic acid and ether bornyl β-(benzo[1,3]-dioxol-5-yl)-α-hydroxypropionate is used instead of the methyl ether of β-(benzo[1,3]dioxol-5-yl)-α-hydroxypropionate. The product is obtained in the form of oil or crystals are light yellow-brown with access 43,8%.

IR (KBr) ν/cm-1: 2981,99 (CH3), 2935,46 (CH2), 1731,08 (C=O), 1598,03, 1492,10, 1453,90 (base benzoic rings), 1269,86 (C=O ester), 1106,22 (C-O secondary hydroxyl), 880,43 and 795,81 (1,2,4-triple-substituted), 746,84 (ortho-disubstituted).

1H NMR (400 MHz, CD3COCD3) δ: 7.18-8.00 (m, 4H, Ar-H), 6.679-6.869 (m, 3H, Ar-H), 6.06 (s, 2P, -OCH2O-), 5.10 (m, 1H, -CH(O)-), 4.920-4.983 (m, 1H, -OCH(clcy)-), 2.804-2.978 (m, 2H, -CH2-).

13C NMR (500 MHz, CD3COCD3) δ: 13.5, 19.5, 19.5, 20.3, 23.3, 30.2, 32.5, 37.8, 45.4, 49.4, 50.6, 56.1, 72.6, 82.1, 112.7, 115.2, 120.9, 121.0, 121.5, 125.5, 130.3, 132.7, 133.5, 146.0, 148.7, 153.6, 165.9, 169.0, 170.8.

Example 10: synthesis of β-(benzo[1,3]dioxol-5-yl)-α-hydroxyl-N-(3-phenyl-1-ethoxycarbonylethyl)propionamide

Steps (1)-(4) synthesis were identical to steps (1)to(4) in example 7.

(5) Synthesis of ethyl ether 2-amino-4-phenylbutyrate

In 1650 homophenylalanine was added 350 ml of anhydrous ethanol and stirring was served dry HCl gas. The gas supply was stopped after 1.5 hours, and the reaction apparatus was changed.

The reaction mixture was heated under reflux for 1.5 hours. After the reaction most ethanol was removed by distillation to precipitate a large amount of white crystal, and then of 19.2 g of white needle-like crystal was obtained after vacuum filtration, washing and drying. White crystal was dissolved in an aqueous solution, and the pH of the solution obtained was adjusted with NaOH solution. The solution was extracted with ethyl ether. Then the solvent was removed, resulting in 14,92 g colorless or yellowish liquid with a yield of 78.2%.

(6) Synthesis of β-(benzo[1,3]dioxol-5-yl)-α-hydroxyl-N-(3-phenyl-1-etoxycarbonyl-propyl)propionamide

To the flask was added 0.40 g of β-(benzo[1,3]dioxol-5-yl)-α-hydroxypropionic acid and 12 ml of CH3CN, and the flask was cooled externally with a mixture of ice and water. Was added to 0.62 g of the ester of ethyl 2-amino-4-phenylbutyrate and 0.02 g of DMAP under stirring with a magnetic stirrer. After the mixture was stirred until clarification was added 0.45 g of DCC. The reaction temperature rose natural way to room temperature with stirring, and the reaction occurred at room temperature for 5 hours. After the solvent was delete the n by vacuum distillation, was added ethyl acetate. The resulting solution in ethyl acetate was washed with a solution of NaHCO3, aqueous solution of HCl and water, then distilleria in vacuum to obtain a billet of the desired composition. After cleaning the workpiece chromatography was obtained 0.39 g of a white solid substance with access to 51.3%.

IR (KBr) ν/cm-1: 3417.26 (alcoholic hydroxyl), 3255.79 (NH), 2967.53 (CH3), 2934.21 (CH2), 1723.79 (C=O), 1669.97 (C=O amide), 1593.37, 1515.19, 1463.13 (base benzoic rings), 1239.98, 1026.76 (arylalkylamine ether), 1111.35 (C-O secondary hydroxyl), 884.45 and 792.17 (1,2,4-triple-substituted); 698.69, 750.62 (one-deputizing benzoic ring).

1H NMR (400 MHz, CD3COCD3) δ: 6.18-7.50 (m, 8H, Ar-H), 6.13 (s, 2H, -OCH2O-), 4.82 (m, 1H, -CH(NH)-), 4.55 (m, 1H, -CH(OH)-), 4.12(q, 2H, -OCH2-), 2.804-2.978 (m, 2H, -PhCH2-), 2.30-2.54 (m, 4H, -CH2CH2-), 1.31 (1, 3H, -CH3).

13C NMR (500 MHz, CD3COCD3) δ: 14.1, 30.3, 32.3, 41.7, 52.7, 61.3, 73.3, 101.2, 112.7, 115.2, 121.0, 126.1, 128.1, 128.1, 128.9, 128.9, 132.7, 138.0, 146.0, 148.7, 171.5, 172.7.

Example 11: synthesis of 2-hydroxyl-3-(benzo[1,3]dioxol-5-yl)-N-[2-hydroxyl-3-(1-naphthoxy)-propyl]propionamide

Steps (1)-(4) synthesis were identical to steps (1)to(4) in example 7.

(5) Synthesis of 1-aftelepabblewogue ether

In a three-neck flask with a round bottom 500 ml added there is a 10.03 g of 1-naphthol, 3.1 g of NaOH, 20,4 g epichlorhydrin (S/R) and 0.5 g of potassium iodide (KI), then 330 ml of ethanol. Then the flask was placed in a microwave reactor. Reacts what I did at 30°C with stirring and microwave radiation power of 300 W for 12 minutes Then the reaction mixture was removed and subjected to vacuum filtration, the filtrate was concentrated to obtain an oily substance. H2O was added to the oily substance, and the mixture was extracted with ethyl ether. Layers of ethyl ether were combined and washed with a solution of NaOH, then washed with H2O once. The layer of ethyl was dried with anhydrous magnesium sulfate and concentrated to obtain to 12.95 g of product with a yield of 93.2%in.

(6) Synthesis of 1-amino-3-(1-naphthoxy)-2-propanol

450 ml of concentrated aqueous ammonia was placed in the reaction flask (manufactured taking into account the impact of microwaves), then added 3.0 g of 1-naphthyl epoxypropyl ether, and the reaction occurred at 40°C while stirring with a magnetic stirrer and mikrovolnovom the radiation power of 300 W for 14 minutes After the reaction, the reaction mixture was concentrated until dry, then was added ethyl acetate and the pH was brought to acidic level by means of concentrated hydrochloride. After vacuum filtration was obtained 1-amino-3-(1-naphthoxy)-2-propanol hydrochloride, then it was dried to a white dry matter. Dry matter was dissolved in water when heated and the pH was adjusted to alkaline level. After cooling, a large amount of white dry matter was precipitate. The precipitate was subjected to wakuu the Noah filtration and dried, the resulting 2.0 g of dry white substance with a yield of 63%.

(7) Preparation of 2-hydroxyl-3-(benzo[1,3]dioxol-5-yl)-N-[2-hydroxyl-3-(1-naphthoxy)propyl]propionamide

of 0.43 g of 1-amino-3-(1-naphthoxy)-2-propanol was dissolved in 15 ml of acetone, then drops while stirring with a magnetic stirrer was added to 0.45, DCC and 0.10 g of DMAP, and 0.40 g of β-(benzo[1,3]dioxol-5-yl)-α-hydroxypropionic acid, dissolved in 5 ml of acetone. The reaction occurred at room temperature for 1 hour, has developed a large amount of white solids. After the reaction, the reaction mixture was subjected to vacuum filtration, the filtrate was dehydrated, and then to the final dry product was added ethyl acetate and the resulting solution was washed with a solution of NaHCO3. The ether layer was dehydrated, was a brown oily substance, which was purified by preparative liquid chromatography. There was obtained 0.27 g of a yellowish oil with a yield of 32.8 per cent.

IR (KBr) ν/cm-1: 3409.82 (alcoholic hydroxyl), 3251.72 (NH), 2969.37 (CH3), 2944.74 (CH2), 1723.49 (C=O), 1664.74 (C=O ester), 1591.77, 1519.90, 1469.21 (base benzoic rings), 1235.78, 1029.63 (arylalkylamine ether), 1101.15 (C-O secondary hydroxyl), 885.53 and 794.61 (1,2,4-triple-substituted); 3050 (base naphthalene), 798.69, 780.62 (one-deputizing naphthalene ring).

1H NMR (400 MHz, CD3COCD3) δ: 6.75-8.30 (m, 10H, Ar-H), 613 (s, 2H, -OCH2O), 3.55 (m, 2H, -CH2(NH)-), 4.55 (m, 1H, -COCH(OH)-), 4.35 (m, 1H, -CH(OH)-), 4.02 (q, 2H, -OCH2-), 2.90-3.07 (m, 2H, -PhCH2-).

13C NMR (500 MHz, CD3COCD3) δ: 41.7, 45.1, 68.5, 71.3, 73.3, 101.2, 104.3, 112.7, 115.2, 120.4, 121.0, 122.2, 125.4, 126.1, 126.6, 127.4, 127.6, 132.7, 134.5, 146.0, 148.7, 156.8, 172.7.

Example 12: pharmacodynamic analysis

1. The influence of ether bornyl β-(3,4-dihydrochloride)-α-hydroxypropionate (hereinafter referred to as "ether bornyl salvante") on the blood flow in the brain microcanopen rats by occlusion of the middle artery of the cerebrum

60 rats with multiple sclerosis with biological weighing 220±20 g were randomly divided into normal control group, model control group, the group, which was introduced Selivanova acid (intraperitoneally with 1 ml/kg), and the group that was administered the ether bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate in small, medium, and high doses, respectively (intraperitoneally 5, 15 and 35 mg/kg). Rats of the normal and model groups were introduced the same amount of physiological saline intraperitoneally. Rats were given anesthesia through intraperitoneal injection of 1% pentobarbital sodium 40 mg/kg, then put them on his back, fastened to the head and produced a cervical incision along the midline. The rat was introduced tracheotomies tube, and left them to breathe spontaneously. Right General Yar is MNA vein and common carotid artery were isolated and was introduced catgut for future use. Animals were fixed in a stereotactic apparatus, on the right temple a drill was open cranial window of size 6×8 mm, after hemostasis cerebral Dura mater was cut with scissors to expose the cerebral mild cerebral membrane. The window was covered and sealed with cement and dental cement, and the cranial window was fixed laser probe laser Doppler meter microcirculatory blood flow. Then the animals were fixed in position on one side, the right common carotid artery was raised, tied in the proximal part and carefully cut with scissors, artery was introduced nylon catgut with a diameter of 0.3 mm, the Distance between the slit artery and paropia rats was observed prior to the introduction of catgut. When nylon catgut introduced to achieve the marked position, the rate of introduction of catgut should slow down and at the same time you need to watch the cerebral microcirculatory blood flow, as reflected by the laser-Doppler meter microcirculatory blood flow. When catgut reaches the middle of the large arteries of the brain, there has been a sharp weakening of the microcirculatory blood flow. After a sharp weakening of the microcirculatory blood flow, catgut was then introduced at about 1 mm, and the distal section, and Cath is that in the artery were tightly bandaged. The excess part of the catgut was cut off. At the end of the study, it was verified that blocked if nylon catgut initial section of the middle of the large arteries of the brain, and information about animals, the artery which was not locked, have been erased. Animals from the control group of drugs were introduced. After the cranial window was prepared, the probe type J 12200 laser-Doppler probe microcirculatory blood flow was recorded at the cranial window, the probe was not moved and did not rotate during the entire study. Micro circular flow before ligation and 5, 15, 30, 45 and 60 min after ligation was recorded, and animal data in groups with drug therapy were recorded at the same points in time. Average microcirculatory blood flow observed within 1 min in each moment of time, was listed as micro circular flow of the corresponding point in time.

Table 1
Effect on cerebral microcirculatory blood flow in rats by occlusion of the middle artery of the great brain (n=10)
GroupDoseMicrocirculatory blood flow (ml)
5 min15 min30 min45 min60 min
Control/65.3±5.767.4±7.467.8±6.865.1±5.964.2±8.5
Exemplary/10.2±2.311.4±3.413.2±4.114.0±3.414.9±6.5
Selivanova
acid
1 ml/kg10.8±3.620.1±6.9**31.2±9.5**33.0±6.8**29.4±6.9**
Study drug5 mg/kg11.4±5.412.4±4.612.9±5.116.1±4.116.0±6.9
Study drug15 mg/kg9.4±3.712.8±5.620.7±3.2* 25.0±5.2**24.4±4.8**
Study drug35 mg/kg10.8±2.719.4±5.1**32.7±6.2**35.4±8.2**35.2±5.8**
Compared with the model group: *P<0.05, **P<0.01

The results of the study showed that after an average large artery of the brain was blocked, cerebral microcirculatory blood flow in the area of blood supply (frontal and parietal share a brain) quickly decreased and remained at a relatively low level. Only after the artery was blocked for 30 min, cerebral microcirculatory blood flow increased slightly, suggesting that the animals exemplary group with ischemia of the brain has adapted successfully. Meanwhile cerebral microcirculatory blood flow increased slightly over 30 and 15 minutes after administration of 15 mg/kg and 35 mg/kg ether bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate. These results indicate an increase in the arterioles and an increase in microcirculatory blood flow can have a positive effect on ischemic cerebrovascular disease, but the corresponding IU is aNISM impacts need to be studied.

2. Protective effect of ether bornyl salvante on ischemic reperfusion (I/R) damage heart

52 rats with multiple sclerosis with biological weighing 220±20 g were randomly divided into exemplary control group, the group which was administered Selivanova acid (intramuscularly 1 ml/kg)group, which was administered ether bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate in small, medium, and high doses, respectively (intramuscularly 5, 15, 35 mg/kg). Rats of the normal and model control group was introduced the same amount of saline intramuscularly. Rats of all groups of the solution was injected over the next 5 days. When the solution was put in last time, they simultaneously gave the anesthesia through the introduction of a 1.5% solution of pentobarbital sodium treatment (45 mg/kg), then in the right carotid artery was inserted catheter and connected through the transmitter to eight Registrar physiological parameters. Was made tracheal cannula, and the ventilation rate was maintained at 60 times/min Chest was opened, catgut 6/0 were used to construct the loop at a distance of 1~2 mm from the root anterior descending coronary artery and the plastic tube was inserted through the loop, then the loop was tightened. Watched the change electrocardiogra who we are. Increase or decrease in ST segment testified successful ligation. Color myocardial tissue below the catgut ligation became darker. After 30 minutes, the plastic tube was removed to resume blood flow in the coronary arteries and cause flushing of the local tissues by reperfusion. For groups subjected to ischemia for 30 min and reperfusion for 30 min, the area of myocardial infarction were recorded before the study, after ischemia for 1 min and 30 min after reperfusion for 30 min; for groups subjected to ischemia for 30 min and reperfusion for 2 h, samples of heart tissue were taken and fixed with 10% formalin with inserts of paraffin, serially divided into parts with a thickness of 4 micrometers and above each sample separately conducted immunohistochemical analyses; the rats of group simulation operations were subjected only to the introduction of catgut, but their coronary arteries did not tie.

Impact on areas of myocardial infarction caused by ischemic reperfusion damage of the heart muscle

After the rats were subjected to ischemia and reperfusion for 30 minutes, their anterior descending coronary artery were again tied, then they were killed and their hearts were rapidly removed and an injection was 0.5 ml of 1% Evans blue in the chambers of the heart through the aorta to determine ischemic and noiselike the fir areas. After the auricle and right ventricle were cut off, the heart was frozen at -20°C for 30 min, then placed in a special groove and cut along the horizontal axis for forming a slice thickness of 2 mm Slices were placed in a 1%solution of triphenyltetrazolium chloride in a buffer solution of phosphoric acid (pH 7.4) and incubated at 37°C for 30 min to distinguish between risk zones and dead zones. Then the slices were fixed with 10% formaldehyde for 24 h to enhance color staining for contrast pictures. After that myocardial tissue was divided into normal myocardi blue, ischemic myocardi light red, dead myocardi gray. Computer software for image analysis was used to calculate the percentage area of myocardial infarction (nec) based on the zone of myocardial area at risk (aar, i.e. ischemic myocardi, including the area of ischemic infarct zone and the absence of ischemic heart attack)(nec/aar), and the proportion of the area of zone of myocardial infarction on the basis of the area of mikardo (nec/lv) to denote the extent of infarction, as well as the share of hazardous mikardo based on the region of the left ventricle (aar/lv).

Table 2
Impact on areas of myocardial infarction caused by cardiac muscle I/R
GroupDoseThe number of animalsaar/lv (%)nec/lv (%)dog/aar (%)
Exemplary control/1267.10±11.4050.52±15.6564.10±13.03
Selivanova acid1 ml/kg10At 50.21±10*41.41±5.49*49.87±7.83*
Study drug5 mg/kg964.09±18.1048.45±17.1161.72±14.65
Study drug15 mg/kg1063.02±15.9848.23±15.3462.63±13.82
Study drug35 mg/kg1151.97±13.04* 40.21±12.65*50.01±9.03*
Compared with the model control group: *P<0,05.

The results showed that, compared with model control group values aar/lv, nec/lv and nec/aar group with a large dosage decreased, respectively, 22.5%, 20.4% and 22% (P<0.01), suggesting that the area of myocardial infarction caused by ischemic reperfusion injury of the myocardium, may be reduced.

Effects on protein expression of proteins Bax, Bcl-2, caspase-3, MMP-2 and PPAR-gamma.

Standard immunohistochemical methods ABC and SP were used for contrast enhancement. "Wah": anti-rabbit polyclonal antibodies (Santa Cruz Bio Inc.) solution 1:200; S: anti-rabbit polyclonal antibodies (TBD Biotechnology center Tianjin) in solution 1100; caspase-3: anti-rabbit polyclonal antibodies (Normarkers Fromont, California), in a solution of 1:200; MMP-2: antimachine monoclonal antibodies (Normarkers Fromont, California), in a solution of 1:200; PPAR-gamma: antionline polyclonal antibody (Santa Cruz Bio Inc.) solution 1:500. Specific analyses were conducted in accordance with the instructions sets ABC and SP, DAB was used for the display of colors, neutral resin was used to prepare the drug. PBS was used instead of the first antibody as a negative is about control. Cells with positive expression of the test polypeptides were brown-yellow color, with the presence of the protein of MMP-2 in the cytoplasm, Bcl-2 is expressed in the nuclear membrane and the cytoplasm, Bax - mainly in the cytoplasm and partially in the nucleus, and the caspase-3 - mainly in the nucleus and partly in the cytoplasm. The image analysis CMIAS was used for random sampling plots slices and automatic sampling plots for analysis, and statistical analysis was performed using the mean values of optical density or integral values of optical density plots obtained myocardial tissue.

Table 3
Effects on protein expression of proteins Bax, BC1-2, caspase-3, MMP-2 and PPAR-gamma (n=100)
GroupDosageThe values of optical density
BaxBcl-2Caspase-3MMP-2PPARγ
Exemplary control/0,13±0,040,14±0,03 0,37±0,110,16±0,040,17±0,02
Selivanova acid1 ml/kg0,08±0,02*0,18±0,040,21±0,12**0,12±0,050,34±0,08**
Study drug5 mg/kg0,12±0,030,15±0,030,35±0,140,14±0,050,16±0,05
Study drug15 mg/kg0,09±0,050,15±0,060,32±0,080,14±0,030,18±0,06
Study drug35 mg/kg0,07±0,03*0,21±0,04*0,20±0,07**0,11±0,03*0,18±0,10
Compared with group experimental control *P<0,05, **P<0,01.

The results showed that the expression of Bcl-2 has really changed in the affected ischemic re infuzionnomu damage to myocardial cells, suggesting that they are involved in the regulation of apoptosis. Ether bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate can reduce the expression of proteins Bax and caspase-3 and increased expression of the protein Bcl-2, assuming that the ether bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate can stimulate the self-defense mechanisms cells against damage by stimulating the expression of BC1-2 and reduction of the levels of Bax and caspase-3, to change the processes of apoptosis and necrosis of cells, caused by ischemic reperfusion injury of the myocardium, therefore, detects a protective effect on myocardial cells.

Protein MMP-2 is associated with And/R injury of the heart muscle that results from the collapse of troponin I, which in turn directly leads to apoptosis of the cells. Specific inhibitor of MMP-2 can improve cardiac function in rats with ischemic reperfusion injury of the myocardium, and the test results showed that the ether bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate can result in a decrease of the protein of MMP-2, which may be another mechanism to ensure protection of the myocardium from s/R damage in the introduction of ether bornyl β-(3,4-dihydroxyphenyl)-α-hydroxypropionate.

3. Influence barnesboro salvanatura ether on blood pressure and left ventricular function of anesthesiaand the x rats

Rats were shot by intra-abdominal injection of 20%urethane 5 ml/kg and fixed; the neck skin of the rats was dissected, front neck muscles are separated, the trachea was opened and the tracheal cannula was introduced; common carotid artery was separated, cardiac probe was introduced through the common carotid artery into the left ventricle, intraventricular pressure was measured by pressure sensor (T-200) multi-channel polygraph RM-600 and DC amplifier (AP-601G) multichannel polygraph RM-600, then the signals of the left ventricular pressure were put into a differential amplifier (ED-601G) multichannel polygraph RM-600, to measure the maximum value increasing and decreasing left ventricular pressure (dp/dtmax-dp/dtmax); the right femoral artery was separated, arterial blood pressure was measured using a cannula; measuring electrode ECG recorder was connected to measure the electrocardiogram type I. All data were entered into the system of collecting and processing data PowerLab/8Sp through a multichannel polygraph (RM-600 and measured, analyzed, and processed by the system PowerLab/8Sp.

The abdominal cavity was opened at 1.5 cm below the xiphoid process of the bone to separate the duodenum, a small incision was made in the duodenum in side the e from the blood vessels of the eye scissors, the probe was introduced and the incision was fixed with sutures to use drugs. After the operation, and a 30-minute waiting period normal data were measured once, the monitored parameters were stable.

The tested drugs were duodenal applied through the catheter, and the indicators were tracked through 5, 15, 30, 60, 90 and 120 minutes after application. The coefficients change scores were calculated by the following formulas, and the use of statistical analysis between groups.

3.1. Effect on heart rate shot rats.

The test results showed that a dose of 4.5 mg/kg, 9 mg/kg and 18 mg/kg barnesboro salvanatura ether had no significant effect on heart rate shot rats, no significant difference was found in comparison with the group of absolute control, while the hydrochloride verapamil significantly reduced heart rate and a significant difference can be observed compared with the model group (P<0.05 or P<0.01) (table 4).

3.2. Effect on mean arterial, systolic and diastolic blood pressure shot rats.

In the group with a dose of 18 mg/kg barnesboro salvanatura ether, mean arterial, systolic and diastolic blood pressure shot rats significantly decreased after the applications of the drug, and there was a significant difference (P<0.05 or P<0.01) compared with the group of absolute control at time 15, 60, 90 and 120 minutes; in the group with a dose of 9 mg/kg barnesboro salvanatura ether mean arterial, systolic and diastolic blood pressure shot rats found a decreasing trend, and also showed significant differences (P<0.05 or P<0.01) compared with the group of absolute control at time 15 and 60 minutes; in the group with dose with 4.5 mg/kg barnesboro salvanatura ether mean arterial, systolic and diastolic blood pressure shot rats found no significant change and no significant differences from the group's absolute control; whereas hydrochloride verapamil could significantly reduce mean arterial, systolic and diastolic blood pressure shot rats, and observed significant differences (P<0.01) from group experimental control at time 5, 15, 30, 60, 90 and 120 minutes (Tables 5, 6 and 7).

3.3. The effect on the pressure inside the left ventricle shot rats.

In the group with a dose of 18 mg/kg barnesboro salvanatura the air pressure inside the left ventricle shot rats decreased significantly after the use of drugs, and there was a significant difference (P<0.05 or P<0.01) from group AB is autogo control at time 15, 30, 60, 90 and 120 minutes; in the group with a dose of 9 mg/kg barnesboro salvanatura the air pressure inside the left ventricle shot rats found a decreasing trend, and also showed significant differences (P<0.05 or P<0.01) from group absolute control at time 60 minutes; in the group with a dose of 4.5 mg/kg barnesboro salvanatura the air pressure inside the left ventricle shot rats did not change significantly after the use of drugs, and no significant differences from the group's absolute control; whereas hydrochloride verapamil significantly reduced the pressure inside the left ventricle shot rats and showed significant differences (P<0.01) from group experimental control (table 8).

3.4. Impact on the performance of dp/dt and-dp/dt shot rats.

In the group with a dose of 18 mg/kg barnesboro salvanatura broadcast rate dp/dt shot rats was significantly reduced after application of the drug, and showed significant differences (P<0.05 or P<0.01) from group absolute control at time 15, 30, 60, 90 and 120 minutes; in the group with a dose of 9 mg/kg barnesboro salvanatura broadcast rate dp/dt shot rats found a tendency to decrease, and there was a significant difference (P<0.05 or P<0.01) from the group of absolute control in moments of time the Yeni 60 and 120 minutes; in the group with a dose of 4.5 mg/kg barnesboro salvanatura broadcast rate dp/dt shot rats did not change significantly after the use of drugs, and no significant differences from the control group, selected blindly; whereas hydrochloride verapamil significantly reduced the rate dp/dt shot rats and showed significant differences (P<0.01) from the model control group.

In groups with dosage barnesboro salvanatura ether 9 mg/kg and 18 mg/kg figure-dp/dt at shot rats found a tendency to decrease, and at 60 and 120 minutes was observed a significant difference (P<0.05 or P<0.01) from the parameters of the control group, selected blindly; after the introduction of the drug in the group with dosage barnesboro salvanatura ether 4.5 mg/kg figure-dp/dt at shot rats did not change significantly differ from the parameters of the control group, selected blindly, was not observed; while the use of the hydrochloride verapamil significantly reduced the rate dp/dt at shot rats; there was a significant difference (P<0.01) from the parameters of the model control group (Tables 9, 10).

The test results showed that the use of barnesboro salvanatura ether are able to reduce the pressure inside the left ventricle, the metrics dp/dt and-dp/d. This suggested that bornology saliently ether has the effect of reducing the negative performance of the contractility of the heart, and negative cardiac performance may be the reason for the decrease in mean arterial pressure, systolic pressure and diastolic pressure in shot rats.

At the same time, the test results showed that the rate dp/dtmaxdecreased, but heart rate did not change significantly, i.e. the direct correlation between dp/dtmaxcardiac rhythm was not observed. This phenomenon requires further research.

4. Protective effect barnesboro salvanatura ether in acute myocardial ischemia in rats.

60 of male rats were randomly selected for group simulation operations (0.5% Poloxamer, 10 ml/kg), model control group (0.5% Poloxamer, 10 ml/kg), groups using verpamil (dose 10 mg/kg, tablet verapamil) and groups using barnesboro salvanatura ether (10 mg/kg, 20 mg/kg and 40 mg/kg). After 30 minutes after the rats of these groups were intragastrically introduced drugs, has been made a standard 2-channel electrocardiogram (before simulation) and the measured height of the ST segment-T. After that, the rats of group simulate the operation was made blocks the coronary artery without the financing, and rats of the other groups was produced by ligation of the coronary artery in accordance with the following method to simulate myocardial ischemia. Then rats were euthanized, fixed in the supine position on the back and recorded readings electrocardiogram (before simulation). The skin on the left side of the thoracic rat was aseptically cut, the fourth intercostal muscle was separated and the heart was removed by pressing on the right side of the thorax; left anterior descending artery was tied at a distance of 2-3 mm from the beginning of the left coronary artery and between the arterial cone and the left ear auricle; then the heart was immediately placed back into the chest cavity and the incision was sewn up. To prevent infection, the seam was smeared with penicillin. After the operation was immediately recorded postischemic ECG (min 0 after simulation) and the measured height of the ST segment-t 24 hours after surgery the animals underwent anesthesia through perianalnoe injection of 20% urethane 5 ml/kg, then again was recorded ECG (24 h after modeling) and the measured height of the ST segment-t From the abdominal aorta was taken the sample of blood, separated serum and measured the activity of lactate dehydrogenase (LDH), creatine kinase (CK)isoenzyme of creatine kinase (CK-MB), superoxide dismutase (SOD) and the content of alonelove of dialdehyde (The MDA). Heart was removed from his chest and washed with saline, the atrium was removed, the ventricle was cut into 3~4 pieces and the pieces were placed in 0.25% NBT solution and left for 10 minutes in a bath with a water temperature of 37°C; damaged by myocardial infarction was cut and weighed and counted the percentage of the weight of the damaged myocardial infarction cardiac muscles of the whole ventricle (Tables 11-14).

The results showed that all groups, which was used bornology saliently ether, decreased the proportion of heart attack the heart muscle in the entire ventricle, and a relatively strong effect was observed in the groups with medium and high dose (P<0.05 or P<0.01); in all groups with different dosages of the activity of lactate dehydrogenase (LDH), creatine kinase (CK)isoenzyme of creatine kinase (CK-MB) decreased after 24 hours; in rats with acute myocardial ischemia increased superoxide dismutase (SOD), particularly in rats of groups with a large dosage (P<0.05); in the groups with medium and high dosage tended to decrease in the content of serum MDA, but significant differences from the exemplary performance of the control group was not observed. When conducting ECG 24 hours after ligation of the coronary artery has been an increase in ST segment-T, especially among groups with high-dose (P<0.05). The results showed that application of barnesboro salvanatura ether can reduce the area of myocardial infarction in rats and to have a protective effect on acute myocardial ischemia in rats.

1. Connection

where each R1, R2and R3independently selected from the group consisting of H, HE, F, Cl, Br, metoxygroup and ethoxypropan; or R1and R2together form-och2O-, and R3is selected from the group consisting of H, HE, metoxygroup, ethoxypropan and Halogens;
R4is a HE or, acetoxybenzoic, nicotinuric or out-nicotinergic;
R5represents a
or,
and at least one of R1, R2and R3is not hydrogen.

2. The compound according to claim 1, where R4is a HE.

3. The compound according to claim 1, where R4is a HE or, acetoxybenzoic, nicotinuric or out-nicotinergic.

4. The compound according to claim 1, where R1and R2individually HE is.

5. The compound according to claim 1, where R1and R2together form-och2Oh.

6. The compound according to claim 4, the de R 3represents H, R4is a HE, and R5represents a

7. The compound according to claim 5, where R3represents H, R4represents a
or,.

8. The compound according to claim 5, where R3represents H, R4represents a
, R5represents.

9. The method of synthesis of compounds of formula (I) according to claim 1, which includes the interaction of the compounds of formulas (III) and (IV) or its hydrate in the presence of a catalyst

R1, R2, R3, R4and R5have the same meaning as in the formula (I).

10. The method according to claim 9 where the catalyst is concentrated H2SO4, kremneva.liliya acid, posteromarginal acid, p-toluensulfonate, S2O8/ZrO2, aluminum trichloride, zinc chloride and/or magnesium chloride.

11. The method according to claim 9, where the reaction takes place in a solvent.

12. The method according to claim 11, where the solvent is ethyl acetate tetrahydrofuran, acetone, toluol, 1,4-dioxane or N,N-dimethylformamide or any combination.

13. The method of synthesis of compounds of formula (I) according to claim 1, which includes interaction is the major compounds of formulas (V) and (VI) or its hydrate in the presence of a catalyst

R1, R2, R3and R5have the same meaning as in the formula (I), and R4' is an on-acetoxybenzoic, nicotinuric or out-nicotinergic.

14. The method according to item 13, where the catalyst is DCC/DMAP.

15. The method according to item 13, in which the solvent used is acetone.

16. The use of compounds according to claim 1 to obtain drugs for prevention or treatment of cerebral vascular diseases.

17. The application of article 16, where the connection is



 

Same patents:

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: medicine.

SUBSTANCE: present invention presents new compounds which are modulators of cannabinoid receptors, particularly modulators of cannabinoid receptors 1 (CB1) or cannabinoid receptors 2 (CB2), and an application thereof for treating diseases, conditions and/or disorders regulated by a cannabinoid receptor (such as painful sensations, neurodegenerative disorders, ingestion disorders, weight loss or weight control and obesity), as well as based pharmaceutical compositions. New compounds are characterised by graphic formulas

in which radicals and groups have the values specified in the patent claim.

EFFECT: higher efficiency of applying the composition.

55 cl, 13 tbl, 3 dwg, 802 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 3,4-substituted pyrrolidine derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is an acyl selected from values given paragraph 1 of the formula of invention; R2 is unsubstituted C1-C4-alkyl or C3-C7-cycloalkyl; R3 is a fragment selected from a group of fragments of formulae: (a), (b),

(c) and (f), where any of the fragments of formulae given above (a), (b) and (f), the star (*) indicates a bond of the corresponding fragment R3 with the molecule residue in formula I; Ra denotes N-C1-C4-alkylaminocarbonyl, N-phenylaminocarbonyl, N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl- C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(C3-C7-cycloalkyl-C1-C4-alkyl)aminocarbonyl, N,N-di-(C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl)aminocarbonyl or hydrogen; Rb and Rc are independently selected from a group comprising unsubstituted C1-C4-alkyl, unsubstituted monocyclic aryl, unsubstituted monocyclic heterocyclyl, unsubstituted or substituted monocyclic C3-C7-cycloalkyl, unsubstituted aryl- C1-C4-alkyl, usubstituted monocyclic C3-C7-cycloalkyl- C1-C4-alkyl, hydrogen or acyl, where the acyl is selected from values given in paragraph 1 of the formula of invention; or Rb and Rc together may form a 6-member nitrogen-containing ring which may be unsubstituted or disubstituted with =O; Rd in the fragment of formula (c) denotes a phenyl or phenyl-C1-C4-alkyl; Re denotes hydrogen or C1-C4-alkyl; and m equals 2; each of R4 and R5 denotes hydrogen; and T denotes methylene. The invention also relates to the pharmaceutical composition based on the compound of formula I and a method of treating hypertension using the compound of formula I.

EFFECT: novel pyrrolidine derivatives having renin inhibiting activity are obtained.

7 cl, 19 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to hot or sweet flavourants in form of a synthetic amide compound or edible salt thereof in amount ranging from approximately 0.001 parts per million to approximately 100 parts per million. The amide compound has formula

where A is a phenyl or a 5- or 6-member heteroaryl ring selected from a group comprising pyridine, pyrazine, pyrazole, thiazole, furan, thiophene, benzofuran and benzothiophene; m equals 1, 2 or 3, each R1 is independently selected from hydroxyl, fluorine, chlorine, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy and isopropoxy, or alternatively two R1 are bonded to form a saturated C1-C3 alkylenedioxy ring on the phenyl; and R2 is a C3-C10 branched alkyl. The amide compound also has formula

in which substitutes A, B, R50, R60, R70, R80, n and m assume values given in the formula of invention. The amide compound is also a specific chemical compound.

EFFECT: obtaining hot and sweet taste modifiers and boosters for food and medicinal products.

39 cl, 7 tbl, 180 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula 2: and to its pharmaceutically acceptable salts and their mixtures, where values of R, M, Q, Z, W, D radicals are described in i.1 of the invention formula. Invention also relates to pharmaceutical compositions, which possess inhibiting activity with respect to Btk, based on formula 2 compounds.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions which can be applied in medicine for treatment of patients with diseases associated with inhibiting Btk activity and/or B-cell activity.

55 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds which are methyl-3-azabicyclo[3.3.0]octane-7-carboxylate, N-methyl-3-azabicyclo[3.3.1]nonane-7-carboxamide, N-propyl-3-azabicyclo[3.3.1]nonane-7-carboxamide, or pharmaceutically acceptable salts thereof. The invention also relates to compounds selected from a group, a pharmaceutical composition, methods of treating or preventing central nervous system disorders, as well as use of compounds in any of claims 1-4.

EFFECT: obtaining novel biologically active compounds having activity on neural nicotinic acetylcholine receptor.

11 cl, 14 ex, 7 tbl, 2 dwg

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or pharmaceutically acceptable salts thereof, where Q is CH or N; R2 is C1-C4 alkyl or C3-C4-cycloalkyl; Y is R5-O; where R5 is propynyl; X is selected from a group consisting of aryl, heteroaryl, C1-C5-alkyloxy, heterocycloalkyl, arylamino, heteroarylamino, heteroaryl-C1-C4-alkylamino, aryloxy, aryl-C1-C2-alkyloxy or C3-C6-cycloalkyl-C1-C4-alkyloxy, each of which is optionally substituted with 1-3 times; the optional substitute(s) for X is(are) independently selected from a group comprising halogen, cyano, trifluoromethyl, nitro, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkyloxy-C1-C4-alkoxy, -SMe, SO2-C1-C2-alkyl, -NMe2, - C(O)O-C1-C5-alkyl, -SCF3, -SO2-NH2, -SO2-C2-alkyl-OH, -CONH2, -COMe, - CONH-C1-C4-alkyl, -CONMe2, -NHCOMe, -CH2COOEt, -OCH2COOEt, -CH2- cyclopropyl, and each R3 and R4 is H; where aryl denotes phenyl or naphthyl; heteroaryl denotes monocyclic or bicyclic hydrocarbon containing 5-10 ring atoms, one or more of which are heteroatoms selected from O, N or S; heterocyclyl denotes piperidinyl or benzodioxolyl; or a compound or pharmaceutically acceptable salt thereof, selected from a group comprising (4-dimethylaminophenyl)-[4-(4-cyclopropylphenyl)-6-propargyloxyquinazolin-2-yl]methanone, (3-sulphamoylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, [3-(2-hydroxyethanesulphonyl)phenyl]amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, (3-methylsulphanylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, (3-methanesulphonylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, and (5-ethanesulphonyl-2-hydroxyphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4- dihydroquinazoline -2-carboxylic acid. The invention also relates to a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel benzoquinazoline derivatives, which are useful in treating bone disorders, are obtained.

6 cl, 128 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopenta[b]benzofuranyl derivatives of formula wherein substitutes R1, R2, R3, R4, R5, R6 and R7 and n are specified in the patent clam. These compounds exhibit properties of NF-kB-activity and/or AP-1 inhibitor/modulator. Also, the inventive subject matter are methods for preparing intermediate compounds thereof, a pharmaceutical composition containing them, administration thereof for prevention and/or treatment of inflammatory and autoimmune diseases, neurodegenerative diseases and hyperproliferative diseases caused by NF-kB- and/or AP-1-activity, and a method for prevention and/or treatment of said diseases.

EFFECT: preparation of new cyclopenta[b]benzofuranyl derivatives.

21 cl, 3 tbl, 151 ex

The invention relates to new compounds to metabolites ecteinascidin, namely ETM-305, ETM-204 and ETM-775, having the following structural formula:

These compounds are strong antitumor agents

FIELD: chemistry.

SUBSTANCE: invention relates to pharmaceutical production and a rosmarinic acid synthesis method. The method for synthesis of rosmarinic acid from plant material involves extraction with water and purification. Zosteraceae sea grass is extracted with water for 6-8 hours at room temperature while adding edible acid to pH 2.5-3.0. After extraction, the obtained solution is filtered and the grass is pressed to obtain an extra extract. The extracts are combined and purified on a membrane microfilter and then on a chromatographic column with polychrome-1. The end product is eluated with 5-7% aqueous solution of ethyl alcohol, concentrated and lyophilised.

EFFECT: method is simple and ensures high output and purity of rosmarinic acid.

2 cl, 3 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: method is realised by reacting C2-C4alkyl ether with pentaerythritol in the presence of a combination of reesterification catalysts consisting of (a) at least one base catalyst selected from a group consisting of compounds of a group Ia alkali metal or a compound of a group IIa alkali-earth metal, (b) at least one compound of a metal which can behave like a Lewis acid, where at least one compound of the metal which behave like a Lewis acid is different from the base catalyst and is selected from a group consisting of zinc octanoate, zinc acetate, hydrate of zinc acetylacetonate, zinc stearate, zinc p-toluene sulphonate, zinc naphthanate, zinc diethylthiocarbamate, manganese (II) acetate, manganese (II) acetylacetonate, manganese (III) acetylacetonate, gallium acetate, lanthanum acetate, hydrate of lanthanum acetylacetonate, aluminium phanate, aluminium isopropoxide, aluminium acetylacetonate, titanium tetrabutoxide, titanium oxide acetylacetonate, isopropoxide bis(acetylacetonate)titanium, zirconium (IV) acetylacetonate and a transition metal compound, and where the reaction is carried out via a first step in which there is only a base catalyst in the reaction mixture, followed by a second step which begins with addition of the said Lewis acid catalyst to the reaction mixture, when the amount of disubstituted intermediate product in the reaction mixture is reduced to less than 20% of the area from HELC analysis data.

EFFECT: design of an improved method of reesterification to produce tetrakis [3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyloxymethyl]methane.

9 cl, 48 ex

FIELD: chemistry.

SUBSTANCE: invention relates to improved method of preparing solid particles used as phenolic antioxidants and including in, in fact, crystal form compound of formula: in which one of R1 and R2 independently on each other represent hydrogen atom or C1-C4alkyl, and the other one represents C3-C4alkyl; x represents zero (direct bond) or number from one to three; and Y represents C8-C22alkoxy or groups of incomplete formulas

or in which one of R1' and R2' independently on each other represent hydrogen atom or C1-C4alkyl, and the other one represents C3-C4alkyl; x represents zero (direct bond) or number from one to three; y represents number from two to ten; and z represents number from two to six, in which homogeneous water dispersion is prepared, which includes compound (I) or mixture of such compounds, where R1, R2, R1' R2', Y, x, y and z have values given above, by addition of incomplete ether of fatty acid polyoxyethylene sorbitan and inoculating crystals, and obtained crystals are separated from dispersion and process is carried out until solid particles are obtained. Invention also relates to novel crystal forms pentaerythrite tetrakis-[3-(3,5-ditret-butyl-4-hydroxyphenyl)propionate], (µ-form) of pentaerythrite tetrakis 3-(3,5-ditret-butyl-4-hydroxyphenyl)propionate], crystal form of N,N'-hexane-1,6-diyl-bis-[3-(3,5-ditret-butyl-4-hydroxyphenyl propionamide)], crystal form of N,N'-hexane-1,6-diyl-bis-[3-(3,5-ditret-butyl-4-hydroxyphenyl propionamide)] and crystal modification (β-form) of N,N'-hexane-4,6-diylbis-[3-(3,5-ditret-butyl-4- hydroxyphenyl propionamide)].

EFFECT: elaboration of improved method of preparing solid particles used as phenolic antioxidants.

10 cl, 2 ex

FIELD: biochemistry and enzymology.

SUBSTANCE: preparation of amorphous HMG-KoA reductase inhibitor with specified particle size comprises dissolving HMG-KoA reductase inhibitor in hydroxyl-containing solvent and removing solvent via freeze drying.

EFFECT: provided preparation of amorphous HMG-KoA reductase inhibitor using procedure, which can be implemented in industrial scale.

4 cl, 2 dwg, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel ester compounds represented by the formula (1): wherein values for R1, R2, A, X, R3, R4, Alk1, Alk2, l, m, D, R8 and R9 are determined in the invention claim. Also, invention relates to inhibitor of matrix metalloproteinase (MTP), a pharmaceutical composition able to inhibit activity of MTP selectively, agents used in treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes mellitus or hypertension wherein the pharmaceutical composition is prepared in capsulated formulation, and to a biphenyl compound of the formula (100) given in the invention description.

EFFECT: valuable medicinal properties of compounds.

53 cl, 78 tbl, 17 ex

FIELD: industrial organic synthesis.

SUBSTANCE: invention relates to improved process of producing compounds of general formula I: (I), which are preferably used as antioxidants. In formula I, R1 and R2 . independently of each other, represent C1-C8-alkyl, cyclopentyl, and cyclohexyl, m is 1, 2, or, 3 (preferably 2), n is integer from 1 to 4, and R3 represents n-valent linear or branched C4-C30-alkyl chain optionally interrupted with oxygen atom. Process consists in reaction of compounds having general formula II: (II), in which R represents C1-C3-alkyl, with compounds depicted by general formula R3(OH)n (III), where R3 and n are such as defined above. Reaction is carried out at substantially neutral pH in presence of at least one, dissolved or suspended in reaction mixture, carboxylic acid alkali metal salt, provided that carboxylic acid in question is at least partially volatile under reaction conditions. Preferred salts are alkali metal formate and alkali metal acetate.

EFFECT: enabled conduction of reaction in absence of carrier and in substantially neutral medium and thus a number of drawbacks of the prior technical level is avoided.

16 cl, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing β-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid methyl ester that represents an intermediate compound used in synthesis of highly effective thermo- and photo-stabilizing agents. Method involves interaction of 2,6-di-tert.-butylphenol with methylacrylate in the mole ratio = 1.0:(1.0-1.1) at temperature 90-145°C in the presence of catalytic complex comprising a mixture of sodium 2,6-di-tert.-butylphenolate and 2,6-di-tert.-butylphenol and wherein catalytic complex comprising sodium alkylbenzyl sulfonate and oxyethylated sodium alkylphenolate is used additionally in the following ratio of components, wt.-%: sodium 2,6-di-tert.-butylphenolate, 0.5-4.4; sodium alkylbenzyl sulfonate, 0.005-0.06; oxyethylated sodium alkylphenolate, 0.005-0.09; 2,6-di-tert.-butylphenol, the balance. Indicated alkaline components of catalytic complex are used in the amount 0.5-4.5 mole% of the amount of 2,6-di-tert.-butylphenol as measured for sum of sodium 2,6-di-tert.-butylphenolate, sodium alkylbenzyl sulfonate and oxyethylated sodium alkylphenolate. Method shows low amount of by-side substances formed, improved quality of the end product and retention of high yield, and allows reducing amount of alkaline catalyst also.

EFFECT: improved preparing method.

1 tbl, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing β-(4-hydroxy-3,5-di-tert.-butylphenyl)propionic acid esters that are used in polymeric industry as stabilizing agents. Method is carried out by the re-esterification reaction of β-(4-hydroxy-3,5-di-tert.-butylphenyl)propionic acid methyl ester with polyhydric alcohols at enhanced temperatures (130-190°C) in the inert gas flow in the presence of catalyst comprising the following components, wt.-%: sodium 4-(β-methylcarboxyethyl)-2,6-di-tert.-butylphenolate, 30.0-45.5, and sodium aluminate, 54.5-70.0. Indicated compounds of alkaline metal are used in the amount 0.7-6.0 mole% of the amount of β-hydroxy-3,5-di-tert.-butylphenol)propionic acid methyl ester. Invention provides enhancing yield and improving color index, reducing cost of the process and reducing amount of by-side products formed.

EFFECT: improved preparing method.

2 cl, 1 tbl, 10 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing β-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid esters that are used in industry of polymers as stabilizing agents. Method involves carrying out the process of the ester interchange reaction of β-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid methyl ester with polyhydric alcohols in inert gas flow at enhanced temperatures (130-190°C in the presence of the following components, wt.-%: 2,6-di-tert.-butylphenolate sodium, 1.5-3.6; 4-(β-methylcaboxyethyl)-2,6-di-tert.-butylphenolate sodium, 4.0-8.6; sodium acrylate, 2.1-6.4; 2,6-di-tert.-butylphenol, the balance. Indicated compounds of alkaline metal are used in the amount 0.4-5.1 wt.-% of the amount of β-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid methyl ester as measure for the sum of 4-(β-methylcarboxyethyl)-2,6-di-tert.-butylphenolate sodium, alkaline metal 2,6-di-tert.-butylphenolate and sodium acrylate. Invention provides increasing yield of the end product and its enhanced quality.

EFFECT: improved preparing method.

2 cl, 1 tbl, 10 ex

FIELD: pharmaceutical chemistry, in particular crystal form of pravastatine sodium salt.

SUBSTANCE: invention relates to new crystal form of pravastatine sodium salt known under chemical name of 1,2,6,7,8,8a-hexahydro-b,d,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobubutoxy)-haphtaleneheptane acid monosodium salt, obtained by a) preparation of solution containing pravastatine and sodium cations in lower aliphatic C1-C4-alcohol; b) addition ethylacetate to said solution; c) cooling of obtained alcohol/ethylacetate mixture; and d) crystallization. Characteristics of new crystal form of pravastatine sodium salt such as crystallogram and melting point (170-1740C) also are disclosed. The subject invention also pertains to method for pravastatine production as well as pharmaceutical composition containing the same. Pravastatine, its derivatives and analogs are well-known HMG-CoA reductase inhibitors and are useful as anticholesterenemic agents in treatment of hypercholesterenemia and hyperlypemia.

EFFECT: crystal form of pravastatine sodium salt and pharmaceutical composition with improved therapeutic action.

29 cl, 5 ex, 4 dwg

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