(+)form 7,8-dihydro-6,6 - dimethyl-7 - hydroxy-8-amino-6n - pyrano(2,3-f) benzo-2,1,3-oxadiazole showing right rotation in ethanol

 

(57) Abstract:

Usage: in medicine, in particular in the synthesis of the drug. useful in the treatment of hypertension. The inventive product (+)form 7,8-dihydro-6,6-dimethyl-7-hydroxy-8 - amino-6N - pyrano(2,3 f)benzo - 2, 1,3-oxadiazol, the angle of rotation at 25°C +189, yield 96% so pl. 145 - 146°C. table 2.

The invention relates to optically active pornobeastiality connection, which is an important intermediate in the synthesis of optically active derivative of pianolessons - azole, useful in the treatment of hypertension (hypertension) and asthma, and to methods of optical time - division pornoencaricaturas connection in the form of a racemic modification.

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 represented by the formula (III)

O in which a represents a hydroxyl group or a group OC(O)CH3-nXnin which X represents fluorine atom, chlorine atom, bromine atom, methyl group or methoxy group, and n represents 0 or an integer of 1-3;

when R1represents a hydrogen atom, R2represents the atom vodorodic defined above, or a group(Z)NHCH3-nXnin which Z and n are as defined above; and when RIdoes not represent a hydrogen atom, R1and R2together represent the group (CH2)m-1C(Z), in which m represents an integer of 4 or 5, and Z is as defined above, the 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, cerebrovascular disease, and asthma.

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

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The reaction scheme 2

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< / BR>
The reaction scheme 3

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The reaction scheme 4

< / BR>
The reaction scheme 5

< / BR>
In the above reaction schemes, Y represents a leaving group such as halogen atom (e.g. chlorine atom, bromine or iodine), an acetoxy group or triptoreline-group;

YIrepresents a chlorine atom, a bromine atom, and is defined above.

The compound (A), which is a compound III in which RIrepresents a hydrogen atom, can be obtained by reacting pornoencaricaturas connection, which is obtained in the form of a racemic mixture (briefly referred to as compound ( 1) in the future), with allermuir reagent YC(O)CH3-nXnin which X, Y and n are as defined above, not necessarily in the presence of a base (refers to the reaction Scheme I).

Connection (In), which is compound (III) in which RIrepresents a hydrogen atom, can be obtained by reacting compound ( 1) isocyanate With(O)NCH3-nXnor isothiocyanato Hpsn3-nNC(S), in which X, Z and n are as defined above (which relate to the reaction scheme 2).

The connection, which is a compound III in which R1and R2together represent the group (CH2)m-1C(O), can be obtained by reacting compound ( 1) with allermuir the reagent CA(OH)(CH2)m-1Y1in which Y, Y1and m are as defined above, optionally in the presence of a base, and then the cyclization of the reaction product optionally in the presence of base is together represent the group (CH2)m-2NHC(Z), where Z and m are as defined above, can be obtained by reacting compound ( 1) with the isocyanate (O)CN(CH2)m-2Y1or isothiocyanato (S)CN(CH2)m-2YIin which YIand 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 the group (CH2)m-2OC(O), in which m is as defined above, can be obtained by reacting compound ( 1) with the halogen-carbonate YC(O)O(CH2)m-2Y1in which Y, Y1and m are 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 these reaction schemes, the compound III in which Z is a sulfur atom, can be obtained by sulfurimonas the corresponding compounds 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 connection is local connection F with sodium hypochlorite, the recovery of the N-oxide group of the compound G obtained in this way, by using a reducing agent such as triethyl phosphate, 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 compounds ( 1).

Furthermore, the said racemic compound III, which has asymmetric carbon atoms at positions 3 and 4 Pyrenophora cycle has two optical isomers (compounds III* III**). 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 the field of medicine is often observed that the optical isomers differ from each other in pharmacological activity and safety (safety). Therefore, it is desirable to optically separate these isomers in order to develop better medicines.

The inventors have found that an optically active derivative of pianolasociety corresponding to compound III*, which is synthesized through the optically active pornoencaricaturas with whom, noticeable is excellent compared to the optically active derivative of pianolasociety, the corresponding compound (III**), which is synthesized through the enantiomer corresponding to the connection (-) I, which will be described below from the viewpoint of drug activity.

Brief description

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)

O [()1] in the form of the racemic mixture with an optically active carboxylic acid of the formula II

HOOO2H and then the separation of the thus obtained diastereomeric salt. In addition, the invention relates to optically active pornobeastiality connection (+) I, showing the right rotation in ethanol, corresponding to the specified connection [+] I, of the two optical isomers obtained by the above method.

Compound II, which is an optical active separating reagent and occurs in the form of two optical isomers of the compounds [+] II and [-] II can be synthesized according to the method described in the layout of the Japan patent N 83144/1986.

Now the method of optical razdeleniem reaction I

Stage AND

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Stage B

< / BR>
In stage a, the compound ( I) is subjected to interaction with 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, diastereomers Sol [-] 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 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 to 30aboutC.

Temperature Krist>/P>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 and then analyzing the obtained compound with an optically active liquid chromatography column (Chiralcel OS, manufactured by Daicel chemical industries limited).

Optical purity of compound [-] I) can be determined in a similar way.

As will be seen below in the example the IP is e Japan patent N 49788/1990, shows exceptionally high activity in lowering blood pressure, compared with the enantiomer of the compound (III**) 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 in the form of a racemic modification.

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 (III*) from compound [+] I or obtain compound (III**) from compound [-] I.

Example test (hypotensive activity).

Compounds III* III** were each separately dissolved or suspended in 0.5% aqueous solution of methylcellulose and forcibly made orally by three male spontaneously hypertensive rats II - 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 37aboutIn order to measure systolic blood pressure method is anago pressure after 1 h after injection of the drug. Each value represents the average from three animals subjected to the test.

Table.2 gives the analytical data of compound III* III**.

P R I m e R 1. (a) stage A. the Division diastereomeric salt (acetone of MES ([+] I [-] II and diastereomeric salt (acetone of MES [-] I [+] II).

In 1000 g of acetone dissolve of 117.6 g (0,500 mol) [ ]-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N-pyrano [2,3-f]benzo-2,1,3-oxadiazole (connection [ I and of 92.9 g (0,510 mole) (-)-2-(4-oxygenase)-propionic acid compound [-] I 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 then distilled 77 g of acetone. The residue is crystallized while cooling with ice for 2 hours Thus optical purity diastereomeric salt (acetonaemia 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 (0,39 mole) 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 mole) 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 (0,403 mole) [+]-2-(4-oxygenase)-propionic acid (compound ([+] II) are dissolved in 700 g of acetone and stirred for three hours while cooling with ice.

Precipitated crystals thus filtered by the mayor, receive 75,79 g diastereomeric salt ([-] I [ + ] (II) acetone MES) in the form of light yellow crystals (yield: 31,9% optical purity: 100% enantiomeric 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.

(b) stage B: separation of compounds ([+] I) ([ - ] I)

O

To 66,7 g (0,140 mole) diastereomeric salt (acetone MES ([+] I [-] II) add 1000 ml of ethyl acetate, 700 ml of water, 17.0 g (0,160 mole) 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 g (at 0.020 mole) 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 an ethyl acetate phase is dried by adding anhydrous sodium sulfate and filtered. After distillation of the ethyl acetate receive 31,85 g of compound ([+] I) (yield 96%).

Separately, diastereomer salt (acetone MES [-] I [ + ] (II) treated in a similar manner as described above. Thus obtained compound ([-] I).

Analytical data so pl. 145-146about(For both compounds ([+] I) ([ - ] I). Optical rotation is SUP>about(0,50, ethanol)

Optical purity (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 limited).

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

NMR spectrum:

Each of the two compounds ([+] I) ([ - ] I) shows the spectrum is identical with the spectrum of compounds ([ I), i.e., racemic modification.

NMR (CDCl3+ DMCO-d6) memorial plaques

of 1.26 (3H), 1,49 (3H), 2,80-3,30 (5H), TO 3.33 (1H), 3,78 (1H), PC 6.82 (1H) and 7,98 (1H).

P R I m m e R 2. (a) 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-dimethyl-7-hydroxy-8-amino-6N-pyrano[2,3-a] benzo-2,1,3-oxadiazole (connection ([ I)) and 3.70 g (20.3 mmol) (-)-2-(4-oxygenase)-propionic acid (compound ([-] II) and the solution stirred at 21aboutC for 15 minutes

To p [+] 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 (methyl-isobutylketone of MES [+] I [-] II) in the form of light yellow crystals (yield: 44.4 per cent).

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 as solvent 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 is collected and shaken again with 9.4 g of a 20% aqueous solution of sodium chloride. Then leave to stand, to thereby Vizsla) (+)-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 (methyl-isobutylketone of MES [-] I [+] II) in order to 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 (methyl-isobutylketone of MES [+] I [-] II) in the form of light yellow crystals (yield: 41.1 per cent).

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 as solvent confirmed that one molecule of methyl-isobutylketone solvated.

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

To 4.26 deaths g (8.23 mmol) diastereomeric salt (methyl-isobutylketone of MES ([+] I [ - ] (II) obtained in the above stage And add at 53.4 g of ethyl acetate, and 42.7 g of water, 0,873 g (8.23 mmol) of sodium carbonate and 10.7 g of sodium chloride, for which the following is 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 (methyl-isobutylketone MES [-] I, [+] II) should be treated in the same manner as described above. Thus obtained compound ([-] I).

Connect [+] I and [-] I show (each of) the optical purity of 100% enantiomeric excess.

Featured example 1. (a) Synthesis of (+)-7,8-dihydro-6,6 - dimethyl-7-hydroxy-8-(n-(I-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. After reaction for 2 h, the reaction mixture was washed with water three times. Methylenchloride phase is dried over anhydrous sulfa is not clear in any way, but as such is subjected to the next reaction.

(b) Synthesis of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(2-oxo - piperidyl)-6N-pyrano [2,3-f] benzo-2,1,3-oxadiazole corresponding to compound III*

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 9 h in nitrogen atmosphere.

After cooling, the insoluble matter is filtered off and the filtrate is diluted with ethyl acetate, washed with water twice and brine (saturated salt solution) 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 above compound (yield: 4%). Some portion of this reaction product is then crystallized from ethyl acetate, to thereby obtain light yellow crystals.

[Analytic] T. pl. 180-182aboutC.

Optical purity 100% enantiomeric excess shown in the table.2.

Recommended is diazole (intermediate)

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-chloro-valerianic 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 (corre - opment of the compound III**

O

In 200 ml of acetone are suspended to 1.16 g of (-)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(n-(1 - oxo-5-chloro)-pentyl) -amino-6N-pyrano-[2,3-t]-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 to boiling under reflux for nine hours under nitrogen atmosphere.

After cooling, the insoluble matter is filtered off and the filtrate is diluted with ethyl acetate, washed with NASA distillation 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.

[Analytic] T. pl. 180-182aboutC.

Optical purity 100% enantiomeric excess shown in the table.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 (corresponds to the compound III*

O

At room temperature, stirred 1.29 g (5,48 mmol) of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N-pyrano- [2,3-f] benzo-2,1,3-oxadiazole (connection [+] 1), 690 mg (6.8 mmol) of triethylamine and 40 ml of methylene chloride, adding to a mixture of 610 mg (6.6 mmol) propionyl chloride (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 dried over anhydrous sodium sulfate. The filtrate and the residue obtained after distillation of the solvent is crystallized from a solvent mixture containing 10 g of ethyl acetate and 5 g of hexane, allowed to stand in the refrigerator overnight, and then filtered by odasi the ri reduced pressure, in order to obtain the above-named compound in the form of a colorless substance.

[Analytic] T. pl. 179-180aboutC.

Optical purity: 100% E. I. are given in table.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-oxa - diazole (compound III**).

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-pyrano-[2,3-f] benzo-2,1,3-oxa - diazole (compound (-) I), 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 six 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 above pure compound (yield: 23%).

[Analytic] T. pl. 179-180aboutC.

Optical purity: 100% E. I. are given in table.2.

Featured example 5. Synthesis of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-methylurea-6N-pyrano-[2,3-f] benzo-2,1,3-oxadi-mmole) of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6N-pyrano- [2,3-f] benzo-2,1,3-oxadiazole (connection ( + ) (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 (20about(C) within 3 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. are given in table.2.

Featured example 6. 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).

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 (-) 1) and 20 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 pull-down crystals thus filtered. Thus obtain 195 mg of the above compound as colorless crystals (yield: 52%).

Analytical data: so pl. 165-167aboutC.


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]--Piran (compound (F)), 1.29 g (32 mmol) of sodium hydroxide, 400 ml of ethanol and 40 ml of water, slowly adding dropwise into the mixture and 32.3 g (26 mmol) of 6% aqueous solution of sodium hypochlorite. Then the resulting mixture was stirred for 1 h

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 saturated saline and dried over anhydrous sodium sulfate.

After removal of the solvent the residue is treated for purification using kolacny chromatography on silica gel (manifesting solvent: ethyl acetate/hexane 1: 2 by volume). So get of 4.00 g of the above compound as yellow crystals (yield: 92%).

Analytical data: so pl. 144-145aboutWITH

Featured example 8. Synthesis of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6N-pyrano-[2,3-f] benzo-2,1,3-oxadiazole (compound 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, doba is over 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 above compound (yield: 88%).

Some of this substance is recrystallized from hexane, to thereby obtain yellow crystals.

Analytical data: so pl. 97-99aboutWITH

Featured example 9. Synthesis of 7,8-dihydro-6,6-dimethyl-7 - hydroxy-8-amino-6N-pyrano-[2,3-f] benzo-2,1,3-oxadiazole (compound 1)

O

In 25 ml of 16.7% ammonia solution in ethanol dissolve 0,82 g (3.8 mmole) of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6N-pyrano-[2,3-f] benzo-2,1,3-oxadiazole (compound N), 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 column (showing solvent: a mixture of ethyl acetate and methanol 5: 1 by volume) to thereby gain of 0.77 g of the above compound as a brown solid (yield: 87%).

Some of this substance is recrystallized from ethanol, to thereby obtain a net name is">

NMR (DCl3+ DMCO-d6) memorial plaques of 1.26 (3H), 1,49 (3H), 2,80-3,30 (5H), TO 3.33 (1H), 3,78 (1H), PC 6.82 (1H) and 7,98 (1H).

Mass spectrum:

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

(+) Form 7,8-dihydro-6,6 - dimethyl-7-hydroxy-8 - amino-6N-pyrano (2,3-f)benzo-2,1,3-oxadiazole formula

< / BR>
showing the right rotation in ethanol.

 

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SUBSTANCE: invention refers to chemical-pharmaceutical industry, particularly a method for making the oxymorphone derivative naltrexone being an opiate antagonist by naltrexone processing by diazomethane in the presence of palladium acetate.

EFFECT: method eliminates using hardly accessible and expensive parent compounds, and it is characterised by ease of implementation.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention declares a compound of structural formula (I) or its pharmaceutically acceptable salt, solvate or hydrate wherein: X is phenol opiate wherein a hydrogen atom of a hydroxyl phenol group of substituted by a covalent bond with -C(O)-Y-(C(R1)(R2))n-N-C(R3)(R4);Y is -NR5-, R5 is (C1-6)alkyl; n is equal to 2 or 3, each of R1 and R2 is independently hydrogen, alkyl or substituted alkyl; R3 is hydrogen or methyl; R4 is a residue of L-amino acid or a residue of their N-acyl derivatives, as well as Hydromorphone 3-(N-methyl-N-(2-N'-acetylarginine amino)ethyl carbamate, or their pharmaceutically acceptable salt. What is also specified is a method for preparing the compound of formula (I) or its pharmaceutically acceptable salt.

EFFECT: what is declared is a pharmaceutical composition controlling phenol opiate release and a method of pain management in a patient in need thereof involving the introduction of an effective amount of the composition.

19 cl, 20 ex, 12 tbl

FIELD: biotechnologies.

SUBSTANCE: conjugate represents benzoate-hydrocodone that has the following structure: benzoate-hydrocodone (Bz-HC). Invention also pertains to the application of pharmaceutical compound for obtaining the drug for curing the patient with illness, disease or condition mediated by opioid binding to the opioid receptors of the patient.

EFFECT: improvement of medical treatment efficiency or prevention of drug abuse, drug withdrawal symptoms or pain relief.

10 cl, 11 ex, 4 tbl, 20 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to therapeutic or preventive means in case of disease(s) of biliary tracts, which are caused or are aggravated by sphincter of Oddi contraction. As effective component, claimed means contains compound, presented by general formula

.

In formula (I) double line, which contains from dotted line and solid line, represents double bond or single bond, R1 represents C4-C7-cycloalkylalkyl, R2 represents linear or branched C1-C5-alkyl, and B represents - CH=CH-.

EFFECT: invention also relates to compound of formula (I) and to method of treatment or prevention in case of disease(s) of biliary tracts, which are caused or intensified by sphincter of Oddi contraction.

6 cl, 1 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to a prodrug composition for treating diseases, disorders or conditions mediated by opioid binding to opioid receptors, containing a conjugate representing 3,6-diaspirin-hydromorphone in a pharmaceutically effective amount, and a biologically acceptable carrier. The invention also refers to a method of treating a patient suffering a disease, disorder or condition mediated by opioid binding to opioid receptors.

EFFECT: composition manifests improved bioavailability, lesser variability in an oral pharmacokinetic profile, lower peak plasma concentration and a lower probability of overdosage as compared to unconjugated hydromorphone.

12 cl, 21 dwg, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula KC-(II), use thereof in treating or preventing pain, method for production thereof, pharmaceutical compositions based thereon, single dose containing same, method for production thereof, method of identifying a compound of formula KC-(II), method of reducing potential abuse of composition containing a compound of formula KC-(II). In general formula KC-(II), Ra is hydrogen or hydroxyl; R5 is selected from (1-6C)alkyl and (1-6C) alkyl, substituted with (1-6C)alkxoycarbonyl group; each R1 is independently selected from hydrogen and (1-6C)alkyl; each R2 is independently selected from hydrogen, (1-6C)alkyl, and-C(O) NR21R22, where R21 and R22 are independently selected from a group consisting of hydrogen, (1-6C)alkyl and (1-6C)alkyl, substituted -C(O)OR60, where R60 is hydrogen; n equals a whole number from 2 to 4; R3 is hydrogen; R4 is , where each R6 is independently selected from hydrogen and (1-6C)alkyl, substituted guanidyl group or an amino group; W is -NR8-; R8 is hydrogen; p equals 1 or 2; and R7 is selected from acyl and acyl substituted with -COOH or-NHCOCH3.

EFFECT: novel pharmaceutical compositions.

18 cl, 20 dwg, 25 tbl, 41 ex

FIELD: pharmaceutics.

SUBSTANCE: invention relates to prodrugs of opioid active substance, which provide controlled release of active substance by enzymatic decomposition with further intramolecular cyclization. Invention also relates to compositions, containing prodrugs, and methods for using them.

EFFECT: composition can optionally include trypsin inhibitor, which interacts with enzyme, which is mediator in release of active substance from prodrugs in order to attenuate enzymatic splitting of prodrug.

16 cl, 17 dwg, 15 tbl, 49 ex

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