Way optical separation pornoencaricaturas connection

 

(57) Abstract:

Usage: in medicine as a drug for the treatment of hypertension, angina, arrhythmia, asthma and disorders of cerebral circulation. The inventive product, f-crystals of ((+) (I): []2D5+ 189(C= 0,50, ethanol) ((-)I): []2D5- 189(C= 0,050, ethanol) . Reagent 1: connection F.-ly (( )) 1. Reagent 2: optically active carboxylic acid f-ly II . Process conditions: process carried out at 20 to 100°C With subsequent processing of the obtained crystalline diastereomeric salt or her MES base at 20-50°C. the Compound (+) 1 is more active than compound f-crystals of (-) 1. 3 C.p. f-crystals, 2 tab.

The invention relates to methods of optical separation pornoencaricaturas compounds, which are important intermediate product in the synthesis of optically active derivative of pianolasociety, useful in the treatment of hypertension (hypertension) and asthma.

In the form of racemic mixtures, as described in the Layout of the Japan patent N 49788/1990 and in U.S. patent N 4900752, the result derived pianolasociety formula III

O , where a is gidroksinalidicksova, and n is 0 or an integer from 1 to 3;

when R1is a hydrogen atom, R2is a hydrogen atom, a group S(Z) CH3-nXnin which Z represents an oxygen atom or a sulfur atom, and X and n are as defined above, or a group S(Z) NHCH3-nXnin which Z and n represent the same as that defined above; and when R1does not represent a hydrogen atom, R1and R2together the group (CH2)m-1C(Z), where m is an integer of 4 or 5, Z is defined above, a group (CH2)m-2NHC(Z) or group (CH2)m-2OC(Z), where Z and m are as defined above.

Compound III shows intense vasodilating and hypotensive (lowering blood pressure) activity and thus, as expected, are useful as drugs for the treatment of hypertension, angina, arrhythmia, disorders of cerebral circulation, asthma.

As described in the layout of the Japan patent N 49788/1990, compound III can be synthesized as follows. The reaction scheme 1.

[(] Reaction scheme 2 Compound I

. The reaction scheme 2, the Compound ( I)

The formula (IN)

The reaction scheme 3, the Compound ( I)

The reaction scheme 4, the Compound [( I)]

Example, as halogen atom (e.g. chlorine atom, bromine or iodine), an acetoxy group or triptoreline-group;

Y1represents a chlorine atom, a bromine atom, an iodine atom, ortho - or para-toluensulfonate group or methansulfonate group; and

m, n and X are as defined above.

The compound (A), which is a compound III in which R1represents a hydrogen atom, can be obtained by reacting pornoencaricaturas connection, which is obtained in the form of a racemic mixture (in short referred to as compound ( I), with allermuir the reagent CA(OH)-CH3-nXnin which X, Y and n are as defined above, optionally in the presence of a base (refers to the reaction scheme 1).

Connection (In), which is compound (III) in which R1represents a hydrogen atom, can be obtained by reacting the compound ( I) isocyanate With(O)NCH3-nXnor isothiocyanato XnCH3-nNC(S), in which X, Z and n are as defined above (which relate to the reaction scheme 2). The compound (C), which is compound (III) in which R1and R2together represent the group (CH2)m-1C(O), can be obtained by vzaimode such as defined above, optionally in the presence of a base, and then the cyclization of the reaction product optionally in the presence of a base (refers to the reaction scheme 3).

The compound (D), which is compound III, where R1and R2together represent the group (CH2)m-2NHC(Z), where Z and m are as defined above, can be obtained by reacting the compound ( I) with an isocyanate (O)CN(CH2)m-2Y1or isothiocyanato (S)CN(CH2)m-2Y1in which Y1and m are as defined above, and then the cyclization of the reaction product optionally in the presence of a base (relates to reaction scheme 4).

Connection (E), which is compound (III) in which R1and R2together represent a group of CH2)m-2OC(O), in which m is as defined above, can be obtained by reacting the compound ( I) with halogenerator YC(O)O(CH2)m-2Y1in which Y, Y1and m javlautsa such as defined above, optionally in the presence of a base, and then the cyclization of the reaction product optionally in the presence of a base (relates to reaction scheme 5).

In Westerstede connection in which Z is an oxygen atom, with a reagent of Louisana.

As described in the layout of the Japan patent N 49788/1990, the compound ( I) can be obtained as follows.

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The compound ( I) can be obtained by processing the known compound (F) with sodium hypochlorite, the recovery of the N-oxide group of the compound (C) obtained in this way, by using a reducing agent such as triethylphosphite, and then by the interaction of the thus obtained compound (H) with ammonia in an inert solvent.

However, never reported on the optical separation of the compound (I).

Furthermore, the said racemic compound III, which has asymmetric carbon atoms at positions 3 and 4 Pyrenophora cycle has two optical isomers (compound (IIIWand (IIILJ)). However, the above computation Japan patent N 49788/1990 does not describe any of these optically active derivatives of pianolasociety, nor any way of getting these optically active derivatives.

In medicine it is often observed that the optical isomers differ from each other in pharmacological activity and safety (safety). So is S="ptx2">

Found that optically active derivative of pianolasociety [corresponding to the compound (IIIW)], which is synthesized through the optically active pornoencaricaturas connection, showing the right rotation in ethanol [corresponding to the compound ( I), which will be described below], is significantly superior compared to the optically active derivative of pianolasociety [corresponding to the compound (IIILJ)], which is synthesized through enantiomer [corresponding to the compound (-)I, which will be described below] , from the point of view of drug activity, thereby determining the integrity of the invention.

Thus, the invention relates to a method for the optical separation of the compound ( I), which involves the reaction of interaction pornoencaricaturas the compounds of formula ( I)

[() 1] with optically active carboxylic acid of the formula (II).

HOO-O2H with subsequent separation of the thus obtained diastereomeric salt or its MES base.

Compound II, which is an optically active separating reagent and occurs in the form of two optical isomers of the compounds ([+] II) and ([-] II) might be synthesized organisations ( I) on the connection ([+] I) and its antipode, namely, the compound ([-] I), will be described in detail. The reaction scheme 1

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In stage a, the compound ( I) is subjected to interaction with the connection ([-] II), which is used as separating optically active reagent, and crystallized. Thus diastereomer salt ([+] I [-] II) can be easily obtained in the form of crystals.

However, it should here be noted that the obtained crystals can be solvated depending on the solvent (see examples).

Similarly diastereomer salt ([-] I [+] II) can be easily obtained by using the compounds ([+] II) as separating optically active reagent.

Thus the corresponding optical isomer of the compound ( I) can be easily obtained by choosing appropriately separating reagent.

As the solvent used in stage A, preferred are ketones, such as acetone and methyl-isobutylketone, although the present invention does not limit the choice of solvent. In this case diastereomer salt crystallizes in the form of MES.

The reaction temperature may usually range from -20 to 100aboutC, preferably from 10 the, preferably -10 to 20aboutC.

Bicrystalline thus diastereomeric salt can be recrystallized, for example from acetone, thereby obtaining crystalline diastereomer salt with high purity.

In stage B, the crystalline diastereomer salt ([+] I [-] II) or MES is subjected to reaction with a base selected from the following - sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide. Thus the target connection ([+] I), showing the right rotation in ethanol, can be easily obtained.

Similarly, the connection ([-] I) can be easily obtained from diastereomeric salt ([-] I [+] II) or its MES.

Optical purity of the compound ([+] I) can be determined by the interaction of the compounds with methyl-isocyanate, thereby obtaining the compound of urea of the formula ([ + ] (IV)

O [(+) IV] and then analyzing the obtained compound with an optically active liquid chromatography column (Chiralcel OS, manufactured by Daicel chemical industries limited).

Optical purity of the compound ([-] I) can be defined podobnym accordance with the method, described in Japan patent N 49788/1990, shows very high activity in lowering blood pressure, compared with enantiomer (compound (IIILJ)) obtained from the compound ([-] I).

It is therefore evident that the use of compound (III*) in the treatment of, for example, hypertension is more effective than the use of compound (III).

Analysis using optically active liquid chromatography column (Chiralcel OS, manufactured by Daicel chemical industries limited) proves that no racemization occurs during the receipt of the compound (IIIW) from compound ([+] I) or obtaining a compound (IIILJ) from compound ([-] I).

(1) Sample test (hypotensive activity).

Compound (IIIWand (IIILJ) were each separately dissolved or suspended in 0.5% aqueous solution of methylcellulose and forcibly made orally by three male spontaneously hypertensive rats 11 weeks of age using a gastric probe.

Animals were pre-warmed in a heated box at the 50aboutC for 3-5 min, and then transferred to a restrictive cage at 37aboutWith that the Ko., Limited). In table. 1 shows the percent reduction of blood pressure after 1 h after injection of the drug. Each value represents the average from three animals subjected to the test.

In table. 2 shows the analytical data of the compounds (IIIWand (IIILJ).

P R I m e R 1. Stage A: separation diastereomeric salt (acetone of MES ([+] I [-] II) and diastereomeric salt (acetone of MES ([-] I [+] II).

In 100 g of acetone dissolve of 117.6 g (0,500 mmole) [ ] - 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N-pyrano[2,3-f] benzo-2,1,3-oxadiazole (Union ([ ] I)) and of 92.9 g (mmole 0,510) (-)-2-(4-oxygenase)-propionic acid (compound ([-] II)), and the mixture is stirred for 3 hours while cooling with ice.

Dropdown thus precipitated crystals are filtered by suction, washed with 500 ml ice acetone and dried under reduced pressure. So get to 64.6 g diastereomeric salt (acetone MES ([+] I [-] II)) in the form of light yellow crystals (yield: 27,2%, optical purity: 95.7% and the enantiomeric excess).

This diastereomer salt (acetone MES ([+] I [ - ] (II) heated to boiling under reflux in 270 g of acetone, and the Kai purity diastereomeric salt (acetone of MES ([+] I [ - ] (II) increases to 100% enantiomeric excess (yield 80%).

When measuring so pl. this substance, it slowly begins to decompose at about 102aboutC. In the non-aqueous titration with perchloric acid in acetic acid as solvent, it was confirmed that one molecule of acetone is a solvate form.

On the other hand, the filtrates are combined and the acetone removed from the filtrate. Then to the residue add 1500 ml of ethyl acetate and 1000 ml of water, 32,8 g (of 0.39 mmole) of sodium bicarbonate and 200 g of sodium chloride and the mixture is shaken.

The resulting solution was left to stand to thereby cause separation of the phases. An ethyl acetate phase was collected and to it was added 200 ml of water, 6,56 g (0,078 mmole) of sodium bicarbonate and 40 g of sodium chloride. The resulting mixture was again shaken and left to stand to thereby cause phase separation.

Thus obtained an ethyl acetate phase is dried by adding anhydrous sodium sulfate and filtered, and then it is distilled ethyl acetate. So get to 94.7 g of brown solid.

This brown solid and 73.4 g (mmole 0,403) [+]-2-(4-oxygenase)-propionic acid (compound ([+] II) are dissolved in 700 g of acetone and stirred for 3 h at ohlazhdeniya 280 ml ice acetone, and then dried under reduced pressure. So get 75,79 g diastereomeric salt ([-] I [ + ] (II) acetone MES) in the form of light yellow crystals (yield 31,9%, optical purity: 100% enantiomeres excess).

When measuring so pl. of this reaction product he slowly begins to decompose at about 102aboutC. In the non-aqueous titration with perchloric acid in acetic acid confirmed that one molecule of acetone solvated.

Stage B: separation of compounds ([+] I) ([ - ] I), Formula ([+] I)

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To 66,7 g (0,140 mmole) diastereomeric salt (acetone MES ([+] I [-] II) add 1000 ml of ethyl acetate, 700 g of water, 17.0 g (0,160 mmole) of sodium carbonate and 140 g of sodium chloride, followed by shaking and allowed to stand to thereby cause phase separation.

An ethyl acetate phase was collected and washed with 200 ml of water, 2,1 (at 0.020 mmole) of sodium carbonate and 40 g of sodium chloride.

In addition, this phase is washed with aqueous solution of sodium chloride (40 g/200 ml water). Then ethylacetate phase is dried by adding anhydrous sodium sulfate and filtered. After distillation of the ethyl acetate receive 32,85 g of compound ([+] I) (yield 96%).

Separately, Diaz is Ohm receive connection ([-] I). (analytical data): so pl.: 145-146about(For both compounds ([+] I) ([ - ] I)). Optical rotation:

connection ([+] I): [ ]D25+ 189about(C = =0,050, ethanol

connection ([-] I): [ ]D25- 189about(C = =0,50, ethanol) Optical purity is determined under the conditions specified in the table. 2.

Each test compound is subjected to interaction with methyl isocyanate. Mcevenue compound, thus obtained, analyzed using optically active liquid chromatography column (Chiralcel OS, manufactured by Daicel chemical industries limited).

Each of the compounds ([+] I) ([ - ] I) shows an optical purity of 100% enantiomeres excess.

NMR spectrum: each of both compounds ([+] I) ([ - ] I) shows a spectrum identical with the spectrum of compounds ([ ] I), i.e., racemic mixture.

NMR (l3) + DMSO-d6) memorial plaques:

of 1.26 (3H), 1,49 (3H), 2,80-3,30 (3H), OF 3.33 (1H), 3,76 (1H), PC 6.82 (1H) and 7,98 (1H).

P R I m m e R 2. Stage A: separation diastereomeric salt (methyl-isobutyl ketone MES ([+] I [-] II) and diastereomeric salt (methyl-isobutylketone MES ([-] I [+] II).

27.8 g of isobutyl ketone dissolved 4,70 g (20 mmol) ( )-7,8-dihydro-6,6-dijonboy acid (compound ([-] II) and the solution stirred at 21aboutC for 15 minutes

To the thus obtained solution was added 10 mg of the seed crystal (methylisobutylketone of MES [+] I [-] II). Stirring is continued for an additional 2 hours, to thereby crystallize the reaction product. Then stop stirring and the reaction mixture is left to stand in the refrigerator over night.

Drop down so the crystals are collected by suction, washed with a 7.1 grams of isobutyl ketone and dried under reduced pressure. So get 4.59 g diastereomeric salt (methylisobutylketone of MES [+] I [-] II) in the form of light yellow crystals (yield 44,4%).

When measuring so pl. of this reaction product he slowly begins to decompose at about 95aboutC. In the non-aqueous titration with perchloric acid in acetic acid confirmed that one molecule solvated mixture.

On the other hand, the filtrates are combined and added to 28.2 g of a 20% aqueous solution of sodium chloride and 1.22 g (11.5 mmol) of sodium carbonate. The resulting mixture was shaken, allowed to stand to thereby cause separation of the phases. Methylisobutylketone phase sobstory thereby cause phase separation.

To the thus obtained methylisobutylketone phase add 2,07 g (11.4 mmol) (+)-2-(4-oxygenase)-propionic acid (compound ([+] II)). After dissolution of the compound by stirring at room temperature to this solution was added 10 mg of the seed crystal (methylisobutylketone of MES ([-] I [+] 11), to thereby crystallize the reaction product. Then the reaction mixture is left to stand in the refrigerator over night.

Drop down so the crystals are filtered by suction, washed with a 7.1 g of the cooled mixture and dried under reduced pressure. So get 4,25 g diastereomeric salt (methylisobutylketone of MES ([+] I [-] II) in the form of light yellow crystals (yield 41,1%).

When measuring so pl. of this reaction product he slowly begins to decompose approximately 95aboutC. In the non-aqueous titration with perchloric acid in acetic acid confirmed that one molecule solvated mixture.

Stage B: separation of compounds ([+] I) ([ - ] I).

To 4.26 deaths g (8.23 mmol) diastereomeric salt (methylisobutylketone of MES ([+] I [ - ] (II) obtained in stage And add 53,4 the existence and leaving to stand, to thereby cause separation of the phases. An ethyl acetate phase was collected and washed with 14.2 g of water and 3.6 g of sodium chloride.

An ethyl acetate phase is dried by adding anhydrous sodium sulfate and filtered. After distillation to 48.6 g of ethyl acetate to the residue is added to 7.3 g of hexane, followed by crystallization under cooling with ice for 3 hours Then drop down crystals thus collected. Thus obtain 1.84 g of the compound ([+] I) (yield 95%).

Diastereomer salt (methylisobutylketone MES ([-] I [+] II) form in the same manner as described above.

Thus obtained compound ([-] I).

Join ([+] I) ([ - ] I) show that each of them, optical purity of 100% enantiomeric excess. Featured example 1.

Synthesis of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(n-(1-oxo-5-chloro)-pentyl)-amino-6N-pyrano[2,3-f] benzo-2,1,3-oxadiazole (intermediate) Formula (+)-form

O

715 mg (3.04 from mmole) of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N-pyrano[2,3-f] benzo-2,1,3-oxadiazole (connection [+] I), 470 μl of triethylamine and 70 ml of methylene chloride is stirred at room temperature. To the resulting solution was added 430 μl (3,34 mmole) of the acid chloride of 5-haralanova acid.water sodium sulfate and filtered. After removal of the solvent receive a named connection. This reaction product is further purified in some way, but as such is subjected to the next reaction.

(b) Synthesis of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(2-oxo-piperidinyl)-6N-pyrano[2,3-f] benzo-2,1,3-oxadiazole (corresponding to compound (IIIW)) The formula (+)-form

O

In 200 ml of acetone suspended 1,08 g (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(n-(1-oxo-5-chloro)-pentyl) -amino-6N-pyrano[2,3-f]benzo-2,1,3-oxadiazole, of 8.40 g (60.8 mmol) of potassium carbonate and 1.01 g (between 6.08 mmol) of potassium iodide and the mixture is heated to boiling under reflux for 10 h under nitrogen atmosphere.

After cooling, the insoluble substances otfiltrovana and the filtrate diluted with ethyl acetate, washed with water twice and brine (saline) once and dried over anhydrous sodium sulfate.

After removal of the solvent the residue is treated on preparative silikagelevye thin-layer chromatography (manifesting solvent: ethyl acetate). Thus obtain 40 mg of the titled compound (yield 4%). Some portion of this reaction product is then crystallized from ethyl acetate, to thereby obtain light yellow crystals.

Anal is example 2.

Synthesis of (-)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(p-1-oxo-5-chloro)-pentyl-amino-6N-pyrano[2,3-f] benzo-2,1,3-oxadiazole (intermediate) Formula (-)-form

O

At room temperature, stirred 769 mg (3,27 mmole) of (-)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N-pyrano[2,3-f] benzo-2,1,3-oxadiazole (connection [-] I), 500 ál (of 3.60 mmol) of triethylamine and 70 ml of methylene chloride. To the resulting solution was added 465 μl (of 3.60 mmol) of acid chloride of 5-haralanova acid. After the reaction of interaction for 2 h, the reaction mixture was washed with water three times. Methylenchloride phase is dried over anhydrous sodium sulfate and filtered. After removal of the solvent receive a named connection.

This reaction product is further purified in some way, but as such is used in the next reaction.

(b) Synthesis of (-)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(2-oxo-1-piperidinyl)-6N-pyrano [2,3-f] benzo-2,1,3-oxadiazole (corresponding to compound (IIILJ)).

Formula (-)-form

O (-) - form

In 200 ml of acetone are suspended to 1.16 g of (-)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-p-(1 - oxo-5-chloro)-pentyl)-amino-6N - pyrano[2,3-f] benzo-2,1,3-oxadiazole, 9,04 g (of 65.4 mmol) of potassium carbonate and 1.09 g (6.54 mmol) of potassium iodide and the mixture is heated under kipyacheniya substance is filtered off and the filtrate is diluted with ethyl acetate, washed with water twice and brine once and dried over anhydrous sodium sulfate.

After removal of the solvent the residue is treated using preparative thin layer chromatography on silica gel (manifesting solvent: ethyl acetate). Thus obtain 47 mg of the titled compound (yield 5%). Some portion of this reaction product is then crystallized from ethyl acetate, to thereby obtain light yellow crystals. Analytical data: so pl. 180-182aboutC. Optical purity: 100% enantiomeric excess (see tab. 2). Featured example 3.

Synthesis of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-propionamido-6N - pyrano-[2,3-f] benzo-2,1,3-oxadiazole (corresponding to compound (IIIW)). Formula (+)-form

O

At room temperature, stirred 1.29 g (5,48 mmol) of (+)-7,8-dihydro-6,2-dimethyl-7-hydroxy-8-amino-6N-pyrano-[2,3-f] benzo-2,1,3-oxadiazole (connection [+] I), 690 mg (6.8 mmol) of triethylamine and 40 ml of methylene chloride, adding to a mixture of 610 mg (6.6 mmol) of Propionaldehyde (acid chloride propionic acid). The mixture is stirred at room temperature for 4 h, the Reaction mixture is extracted with 600 ml of ethyl acetate and 300 ml of water. The organic phase is collected and vysushivaya solvent mixture, containing 10 g of ethyl acetate and 5 g of hexane, allowed to stand in the refrigerator overnight, and then filtered by suction. The resulting crystals are washed with 3 ml of a mixture of ethyl acetate/hexane (2:1) twice and dried under reduced pressure, to thereby obtain the titled compound in the form of a colorless substance. Analytical data: so pl. 170-180aboutC. Optical purity: 100% E. T. (see tab. 2). Featured example 4.

Synthesis of (-)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-propionamido-6N-pyrano-[2,3-f] benzo-2,1,3-oxadiazole (corresponding to compound (IIILJ) Formula (-)-form

O

At room temperature, stirred 52 mg (0.22 mmole) of (-)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(n-(1-oxo-5-chloro)-pentyl)-amino-6N-feast ANO-[2,3-f] benzo-2,1,3-oxadiazole (connection) (-) 1), 34 μl (0.24 mmole) of triethylamine and 5 ml of methylene chloride, adding to a mixture of 21 μl (0.24 mmole) of propionyl chloride. The mixture is stirred at room temperature for 6 hours

After completion of the reaction, the reaction mixture was washed with water three times and dried over anhydrous magnesium sulfate. After removal of the solvent the residue is recrystallized from ethanol, to thereby obtain 15 mg of the named net connection (output is LASS="ptx2">

Synthesis of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-methylurea-6N-pyrano-[2,3-f] benzo-2,1,3-oxadiazole (corresponding to the compound ( + ) - (IV)

Formula (+) - form

O

At room temperature, stirred 300 mg (1,29 mmole) of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-amino-6N-pyrano-[2,3-f] benzo-2,1,3 - oxadiazole (connection (+) and (I) and 15 ml of methylene chloride. To the resulting solution was added 120 mg (2,10 mmole) of methyl isocyanate. The mixture is stirred at room temperature (20aboutC) for 5 hours

The reaction mixture was crystallized in the refrigerator and the crystals precipitated thereby was filtered. Thus obtain 214 mg of the titled compound as colorless crystals (yield 58%). Analytical data: so pl. 165-167aboutC. Optical purity: 100% E. I. (see tab. 2). Featured example 6.

Synthesis of (-)-7,8-dihydro-6,6-dimethyl-7-hydroxy-methylurea-6N-pyrano-[2,3-f] benzo-2,1,3-oxadiazole (corresponding to the compound (2) (IV). Formula (-)-form

O

At room temperature, stirred 300 mg (1,28 mmole) of (-)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N-pyrano-[2,3-f] benzo - 2,1,3-oxadiazole (compound (2) (1) and 20 ml of methylene chloride. To the resulting solution was added 120 mg (2,10 mmole) of methyl isocyanate. The mixture was stirred at e and drop down so the crystals are filtered off. Thus obtain 195 mg of the titled compound as colorless crystals (yield 52%). Analytical data: so pl. 165-167aboutC. Opticheskie purity: 100% E. I. (see tab. 2). Featured example 7.

Synthesis of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6N-pyrano-[2,3-f] benzo - 2,1,3-oxadiazole-3-oxide (compound (G)). Formula

O

At room temperature, stirred to 4.41 g (18.9 mmol) of 6-amino-3,4-dihydro-2,2-dimethyl-3,4-epoxy-7-nitro-2H-Ben - zo[b]-pyrano (compound (F)), 1.29 g (32 mmol) of hydroaxe sodium, 400 ml of ethanol and 40 ml of water, slowly adding dropwise into the mixture of 32.2 g (26 mmol) of 6% aqueous solution of sodium hypochlorite. Then the resulting mixture was stirred for 1H.

After completion of the reaction was added 1 l of an aqueous solution of common salt and the mixture is extracted with ethyl acetate three times. An ethyl acetate phases are combined, washed with brine and dried over anhydrous sodium sulfate.

After removal of the solvent the residue is treated for purification using column chromatography on silica gel (manifesting solvent: ethyl acetate/hexane 1:2 by volume). So get of 4.00 g of the named compound as yellow crystals (yield 92%). Analytical data: so pl. 144-145aboutC. Recom is tion (H)).

O

At 60aboutWith a mix of 1.00 g (4,27 mmole) 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6N-pyrano-[2,3-f] benzo-2,1,3 - oxadiazol-3-oxide (compound (G) and 6 ml of benzene, adding dropwise within 15 min to 0.80 ml(4,70 mmole) of triethylphosphite.

Then the resulting mixture is stirred for 3 hours

After removal of the solvent the residue was subjected to purification using chromatography on silikagelevye column (showing solvent: ethyl acetate/hexane 1:1 by volume). So get of 0.82 g of the titled compound (yield 88%).

Some of this substance is recrystallized from hexane, to thereby obtain yellow crystals. Analytical data: so pl. 97-99aboutC. Recommended example 9.

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N-pyrano-[2,3-f] benzo-2,1,3-oxadiazole (connection [+] I). Formula

O

In 25 ml of 16.7% ammonia solution in ethanol dissolve 0,82 g (3.8 mmole) of 7,8-dihydro-6,8-dimethyl-7,8-epoxy-6N-pyrano- [2,3-f] benzo-2,1,3-oxadiazole (compound (H)), and then the mixture was allowed to react in a thick-walled glass tube under pressure at 60aboutWith in 48 hours

The reaction solvent is distilled off and the residue is subjected to chromatography on silikagelevye to the data connection in the form of a brown solid (yield 87%).

Some of this substance is recrystallized from ethanol, to thereby obtain pure titled compound as colorless crystals. Analytical data: so pl. 159-162aboutC.

NMR (l3+ DMSO-d6) memorial plaques:

of 1.26 (3H), 1,49 (3H), 2,80-3,30 (3H), OF 3.33 (1H), 3,78 (1H), PC 6.82 (1H) and 7,98 (1H).

Mass spectrum: 133 (50%), 163 (100%) and 235 (M+, 3%).

1. WAY OPTICAL SEPARATION PORNOENCARICATURAS CONNECTION 1. Way optical separation pornoencaricaturas the compounds of formula (I)

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characterized in that carry out the reaction of interaction of the compounds of formula I with an optically active carboxylic acid of the formula II:

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with the subsequent processing of the obtained crystalline diastereomeric salt or its MES base.

2. The method according to p. 1, characterized in that the compound of the formula ()1 is subjected to interaction with the compound of the formula (-)II and the resulting crystalline diastereomer salt of formula (+)I, (-)II or MES is treated with a base and get the connection formula (+)I.

3. The method according to p. 2, characterized in that the process is carried out at - 20 ... +100oC.

4. The method according to p. 2, characterized in that the Sol diastereomers

 

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The invention relates to methods for producing compounds of formula I HOOCwhere Y is-CO-, or-CH2-;

Y is a bond or-O-;

p = 1-16; and

Z is-H or-G-Q, where G is a simple bond or-CH= CH-;

and Q is phenyl, substituted C1-C3the alkoxy group

The invention relates to new derivatives of 4-promenaden, namely derivatives of the formula

where I R1= -OH

R2= --CH3R3= - OH

II R1= -H; R2= -C1; R3= -OH

III R1= -O--CH3; R2= -H;

R3= -Nhaving antiallergic activity, which can be used in medicine

The invention relates to medicine and can be used in pediatric patients for the treatment of complex grits I degree

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: medicine.

SUBSTANCE: before applying substitute hormonal therapy (SHT) on should evaluate antithrombogenic activity of vascular wall in women. For this purpose one should determine quantitative values of ADP-induced aggregation of thrombocytes, activity of antithrombin III in blood and fibrinolytic blood activity both before and after "cuff"-test. Then one should detect the indices calculated as the ratio of mentioned values both before and after carrying out the mentioned test. If mentioned indices are decreased against the norm by 20-40% women should be prescribed to undergo SHT at additional introduction of aspirin and supradin. The method provides prophylaxis of cardio-vascular diseases in this category of female patients due to correcting affected functional activity of vascular endothelium.

EFFECT: higher efficiency of prophylaxis.

1 cl, 1 ex, 4 tbl

FIELD: medicine, natural compounds.

SUBSTANCE: larch wood is saturated with water and extraction with ethyl acetate is carried out. Prepared extract is treated with hot water and this process is combined with distilling off a solvent. Then water-insoluble resin impurities are separated and crude product is isolated by crystallization and recrystallized. Invention provides simplifying the process.

EFFECT: improved preparing method.

2 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to compositions used for treatment and/or prophylaxis of chlamydium infections caused by C. pheumoniae. Pharmaceutical composition used for treatment and/or prophylaxis of chlamydium infection caused by C. pneumoniae comprises the taken phenolic compound, or extract, or fraction, or incomplete fraction comprising the taken phenolic compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction obtained from plants and comprising indicated compound or corresponding synthetic compound on C. pneumoniae represents the definite percent of inhibition for formation of inclusions. The composition useful for health eliciting an anti-chlamydium effect with respect to C. pneumoniae comprises the taken phenolic compound or extract, or fraction, or incomplete fraction containing indicated compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent for inhibition in formation of inclusions. Also, invention relates to applying the composition useful for health in preparing foodstuffs or as supplements for nutrition for every day. Also, invention relates to applying phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound or mixture of indicated compounds obtained from plants in manufacturing a medicinal agent used for treatment and/or prophylaxis of chlamydium infections caused by C. pneumoniae. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent in inhibition in formation of inclusions. Compositions promote to effective prophylaxis and treatment of chlamydium infections caused by C. pneumoniae.

EFFECT: valuable medicinal properties of compounds.

21 cl, 1 dwg, 1 tbl, 6 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new compounds of coumarone class, namely, to 6-nitro-2-iminocoumarin 3-carboxylic acid 4-toluidide silver salt of the formula (1): that elicits an antibacterial effect and can be used in medicine. Invention provides preparing a new compound eliciting an antibacterial effect with respect to S. aureus, E. coli, and C. albicans with mononuclear cells values 0.25; 0.5 and 7.8 mcg/ml, respectively, and with acute toxicity value LD50 for these compounds 2 460 ± 230 mg/kg.

EFFECT: valuable properties of compound.

1 cl, 1 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with phospholipid complexes of proanthocyanidine A2 and pharmaceutical compositions upon their basis as antiatherosclerotic agents, those for preventing and treating myocardial and cerebral infarction. Phospholipids of the above-mentioned complex should be preferably chosen out of lecithins, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl serine. The innovation provides the preparation to treat the above-mentioned diseases due to decreasing the quantity and burden of atheromatous plaque, decreased obstruction of carotid arteries and decreased thickness of vascular walls.

EFFECT: higher efficiency of prophylaxis and therapy.

9 cl, 11 dwg, 6 ex, 2 tbl

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to treatment of patients suffering from diseases associated with pathologic activity of matrix proteases. Treatment involves administration of compounds depicted by general formula (I).

EFFECT: increased treatment efficiency.

136 cl, 448 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to new intermediate compounds used for synthesis of derivatives of 3-hydroxy-4-aryl-5-oxopyrazoline exerting herbicide effect. Invention describes compounds of the formula (IV)and (IVa): wherein R4 and R5 form in common the group: -C-R14(R15)-C-R16(R17)-O-C-R18(R19)-C-R20(R21)-(Z2) wherein each among R14, R15, R16, R17, R18, R19, R20 and R21 represents independently of one another hydrogen atom or (C1-C4)-alkyl. Invention provides preparing new intermediate compounds that are useful for preparing the end product eliciting valuable herbicide properties.

EFFECT: improved preparing method.

24 tbl, 14 ex

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