The way to obtain 2',3'-dideoxy-3'-thiacytidine or 2',3'- dideoxy-3'-thia-5-fortitudine enriched nucleoside enantiomer, a method of obtaining 1,3-oxathiolane, the method of obtaining enriched enantiomer 2 acyloxy-5-acyloxy-1, 3-oxathiolane, the enantiomers, the method of cleavage of nucleoside enantiomers

 

(57) Abstract:

The invention relates to methods and compositions for the preparation of antiviral nucleoside analogues, in particular 2',3'-dideoxy-3'-thia-citizen (VSN-189). VSN-189 or 2',3'-dideoxy-3'-thia-5-perltidy mostly in the form of isomers is produced by interaction of 1,3-oxathiolane formula I, where R is gidrozaschitnym group, R' is acyl group, with a base selected from the group comprising sililirovany cytosine or 5-ferritin in the presence of SnCl4. This way of synthesis allows for stereospeakers obtaining biologically active isomer-VSN-189 and related compounds. Moreover, the stereochemistry at position 4 of the nucleoside can be controlled to obtain the enriched enantiomer-VSN-189 and its analogues. 15 C. and 12 C. p. F.-ly, 4 Il.

The way to obtain 2',3'-dideoxy-3'-thiacytidine or 2',3'-dideoxy-3-'thia-5-fortitudine enriched nucleoside enantiomer, a method of obtaining 1,3-oxathiolane, the method of obtaining enriched enantiomer 2 acyloxy-5-acyloxy-1,3-oxathiolane, enantiomer, fashion cleavage of nucleoside enantiomers.

The present invention relates to methods and compositions for preparation against which refers to the selective synthesis of isomer VSN-189 and related compounds, and selective synthesis VSN-189 and related compounds enriched in enantiomer.

Prior art

Since 1981 he started the documentation of the disease, which became known as Acquired Immune Deficiency Syndrome /AIDS, as well as its predecessor, " AIDS-related Complex /UCS/. In 1983 was established cause of AIDS, and the virus was named as the human Immunodeficiency Virus, type 1 /HIV-1/. Usually, a person infected with the virus develop AIDS, all AIDS cases, and it always leads to death.

The disease AIDS is the final result after passing HIV-1 to its own life cycle. The life cycle of the virion begins with the attachment of the virion with the immune cell in the host, lymphocyte T-4 through binding glycoprotein on the surface of the protective shell of the virion with 4-glycoprotein linfocitos cells. One day only, the virion resets its own glycoprotein membrane, penetrates through the membrane of the host cell and exposes its RNA. The virion enzyme, reverse transcriptase, manages the process of transcription of RNA into single-stranded DNA. Viral RNA is destroyed, and the second is camping for playback cells.

From this point on human cells in the process of self-reproduction, using its RNA polymerase for transcription of the DNA is integrated into the viral RNA. Viral RNA is translated to the glycoproteins, structural proteins and viral enzymes that are linked with intact viral RNA. When a host cell ends reproductive stage, a new cell-virion, not the lymphocyte T-4, gives birth to a new process. The number of viral cells of HIV-1, thus, is growing, while the number of lymphocytes T-4 is reduced.

The typical human immune system reaction that destroys the invading virions, tested, because a large part of the life cycle of the virion goes dormant in the immune cell. Furthermore, the viral reverse transcriptase enzyme used to create new virionyx cells, is not very specific and allows for errors in transcription, resulting in continuously modified glycoproteins on the surface of viral containment. This lack of specificity reduces the effectiveness of the immune system, as antibodies that are specific generated against a single glycoprotein, can be useless against on ivalsa, while the protective immune system continues to weaken. In the end, HIV establishes immense control over the immune system of an organism that allows you to start the onset of opportunistic infections that without the introduction of antiviral drugs and/or immunomodulators leads eventually to death.

During the virus life cycle there are three critical points that were identified as "targets" for the action of antiviral drugs: (1) initial attachment of the virion to the lymphocyte T-4 or a section of macrophages; (2) transcription of viral RNA into viral DNA; (3) build new virionyx cells during reproduction.

Inhibition of virus on the second critical stage, that is in the process of transcription of viral RNA into viral DNA has led to the creation of a large number of therapeutic agents used to treat AIDS patients. This transcription should be carried out for the virion to reproduction, because the genes of the virion-encoded RNA; a host cell reads only the DNA. Introducing medications, which block reverse transcriptase from the complete education of viral DNA, you can stop the replication of HIV-1.

Nucleoside analogues such as 3'-personal fluoro-derivatives of these nucleosides are relatively effective to stop HIV replication at the stage of reverse transcriptase. Another promising transcriptase inhibitor - 2',3'-dideoxy-3'-thiacytidine (BCH-189), which contains a ring oxathiolane replace the sugar residue in nuke.

AZT has been used successfully as an anti-HIV medication, because it violated the formation of viral DNA within the host cell, lymphocyte T-4. When AZT enters the cell, cellular kinases activate it by postlarvae to AZT-triphosphate. Then AZT-triphosphate enters into competition with natural timelineview nucleosides for the receptor site on the enzyme, the reverse transcriptase of HIV. Natural nucleosides have two reactive ends: first, to attach to the previous nucleoside and the second to associate with subsequent nucleotide. The AZT molecule contains only the first reactive end; once on the site of the HIV enzyme, azide group AZT stops the formation of viral DNA, as azide cannot form a 3',5'-fosfodiesterazu connection with ribose subsequent nucleoside.

The benefits of AZT in the clinical aspect is the duration of existence, reduced the frequency and risk of opportunistic infections and increased amounts of peripheral CD 4 lymphocytes.

When immunosor who noted a significant reduction in him, when using AZT. However, the benefits of AZT should be assessed in relation to acute adverse reactions suppress the bone marrow, vomiting, myalgia, insomnia, severe headaches, anemia, peripheral neuropathy, and seizures. Moreover, these adverse effects are observed immediately after the start of treatment, while no less than six weeks of therapy necessary to realize the benefits of using AZT.

As DDC, and D4T are potent inhibitors of HIV replication, the activity of which is comparable to AZT (D 4T) or superior to AZT (DDC). However, as DDC, and D4T turn in their 5'-triphosphates less effective than natural counterparts and are resistant to desaminase and phosphorylases. Clinically, both compounds are toxic. Currently DD1 is used in combination with AZT to treat AIDS. However, side effects DD1 include sporadic pancreatitis and peripheral neuropathy. Initial tests on the 3'-fluoro-2'-3'-dideoxythymidine show that the antiviral activity comparable to that of AZT.

Recently conducted tests on BCH-189 showed that it has anti-HIV activity similar to that of AZT and DDC, but without cellular toxicity, which causes the e number of BCH-189.

Commonly used chemical approaches for the synthesis of nucleosides or nucleoside analogues can be classified into two broad categories: (1) modification of intact nucleosides by changing their carbohydrate component, a nitrogenous base, or both, and (2) modification of carbohydrates and base or synthetic precursor at a suitable stage of the synthesis. Because the structure of BCH-189 carbon atom substituted at the sulfur atom of the carbohydrate ring, the second approach seems more feasible. The most important factor in implementing this latest strategy is to place the base side of hydrocarbon rings in the glycosylation reaction, since only the isomers possess useful biological activity.

In this technology is well known that storiespreteen the inclusion of bases in the anomeric centers of carbohydrates can be controlled by strengthening effect on neighbouring group in position 2-Deputy carbohydrate ring (Chem.Ber.114: 1234 (1981)). However, BCH-189 and its analogs do not have the 2-substituent and, therefore, cannot be used in this method until you have carried out an additional stage for the introduction of functional groups that posvol this technology is well known, "a significant number of unwanted-nucleosides are formed during the synthesis of 2'-desoxyribose" (Chem. Ber. 114:1234, 1244 (1981)). Moreover, this reference teaches that the use of simple catalysts for Friedel-Crafts like SnCl4in the synthesis of nucleosides leads to the formation of undesirable emulsions during processing of the reaction mixture, the formation of complex mixtures and isomers and stable complexes between SnCl4and more main siliconized heterocycles, such as siliconized cytosine. These complexes increase the reaction time, reduce outputs and lead to the formation of undesirable unnatural N-3-nucleosides. Thus, the prior art involves the use of trimethylsilyltriflate or trimethylsilyltriflate as a catalyst when connecting pyrimidine bases with carbohydrate ring, which allows to achieve high yield of biologically active isomers. However, the use of these catalysts for the synthesis of BCH-189 or analogues BCH-189 does not receive preferential-isomer; the result of these reactions is the ratio of the isomers of approximately 50:50.

Thus, there is a need for an efficient synthetic method for the synthesis of BC is s, -BCH-189 and related analogues.

Moreover, there is a need in the stereoselective synthesis pathway-BCH-189, enriched with enantiomer, as the other enantiomer is inactive and, therefore, represents 50% of unwanted impurities.

Disclosure of the invention

The present invention is associated with the opening of the extremely effective ways of synthesis of compounds of BCH-189 and various analogues of BCH-189 from inexpensive precursors to select the desired functionality. This way of synthesis allows the stereoselective preparation of biologically active isomer of these compounds, -BCH-189 and related compounds. Moreover, the stereochemistry at the 4'-position of the nucleoside can be controlled to obtain the enriched enantiomer-BCH-189 and its analogs.

The term "analogues of BCH-189" means a reference to nucleosides, which are formed from pyrimidine bases substituted in position 5 and which are connected with substituted 1,3-oxathiolane.

The method of the present invention includes ozonation allyl ether or ester with the formula CH2= CH-CH2-OR, in which R is a protective group such as alkyl, silyl or acyl, which leads to the formation of glycolaldehyde with the formula OCH is about-1,3-oxathiolan; the conversion of the lactone to the corresponding carboxylate in position 5 oxathiolane rings; the connection acetate with siliconized pyrimidine base in the presence of SnCl4education-isomer analogue 5'-(R-oxy)-2',3'-dideoxy-3'-thia-nucleoside; and replacement of the protective group R is hydrogen with the formation of BCH-189 or equivalent BCH-189.

The invention can be used to obtain BCH-189 or analogues BCH-189, which is enriched with enantiomer position 4' through selective recruitment of the protective group R, to allow the enzyme to carry out stereoselective choice. For example, the protective group R can be chosen so that the substituent in position 2 oxathiolanes of the lactone will butyryloxy group, and this allows for the stereoselective enzymatic hydrolysis by esterase from pig liver. In the end optically active hydrolyzed lactone can then be converted into the corresponding diacetate and connect with siliconized pyrimidine base, as mentioned above.

Accordingly, one objective of this invention is to provide an efficient method for the preparation of isomer BCH-189 and analogues BCH-189 with high yields. Moreover, the measure not racemate mixture of BCH-189 and analogues BCH-189. Another object of this invention is to develop a path synthesis for the preparation of BCH-189, enriched with enantiomer.

In addition, the purpose of this invention is the production of intermediate substances, BCH-189 or analogues of BCH-189 can be synthesized, and corresponding to the formula 2-(R-OK-simetal)-5-acyloxy-1,3-oxathiolan, where R represents a protective group such as alkyl, silyl or acyl, as well as the method of obtaining these compounds. Moreover, the purpose of this invention to provide enriched enantiomer of 2-acetoxymethyl-5-acetoxy-1,3-oxathiolane and 2-butoxymethyl-oxo-1,3-oxathiolane, as well as the development of methods for obtaining these compounds.

Another object of this invention is the production of intermediate compounds, of which BCH-189 or analogues of BCH-189 can be synthesized following formula:

< / BR>
where R is a protective group such as alkyl, silyl or acyl;

Y can be hydrogen, methyl, halogen, alkyl, alkenyl, quinil, hydroxyalkyl, carboxyethyl, thioalkyl, selenology, phenyl, cycloalkyl, cycloalkenyl, tiari and selenourea,

as well as the development of methods for obtaining these compounds.

Moreover, this is nasirovna the following formula:

< / BR>
where R is a protective group such as alkyl, silyl or acyl;

Y can be hydrogen, methyl, halogen, alkyl, alkenyl, quinil, hydroxyalkyl, carboxyethyl, thioalkyl, selenology, phenyl, cycloalkyl, cycloalkenyl, tiari and selenourea,

as well as the development of methods for obtaining these compounds.

Fig. 1 illustrates a variation of the synthesis of BCH-189 and analogues BCH-189 according to the present invention;

Fig.2 illustrates a variation of the synthesis of BCH-189 according to the present invention;

Fig. 3 illustrates a variation of the synthesis of 5-methyl-saidinovich and timelinemax derivatives BCH-189 according to the present invention;

Fig. 4 illustrates a variation of the synthesis of BCH-189, enriched enantiomers according to the present invention.

The best variant embodiment of the invention.

BCH-189 is a compound of the following formula:

< / BR>
The process of obtaining BCH-189 and analogues BCH-189 according to this invention is shown in Fig. 1. Allyl ether or ester is subjected to ozonation with the formation of aldehyde , which reacts with thioglycolic acid with the formation of the lactone . The lactone is treated regenerating agent: for example, diisobutylaluminium-hydride (DIBAL), b is ml trade name "Red-AI"TM), and NaBH4, followed by treatment of the carboxylic anhydride, getting carboxylate - This carboxylate combined with siliconized pyrimidine base in the presence of a Lewis acid, which can catalyze the stereospecific combination, for example with SnCl4with the formation of the isomer of the substituted nucleoside 5 important relation : d - isomers of 100:0. With substituted nucleoside remove the protective group, receiving BCH-189 or similar BCH-189.

This technique can be modified to obtain BCH-189 or analogues BCH-189, enriched anantapuram in position 4', through the selection of suitable protective groups R, which makes it possible stereoselective enzymatic hydrolysis by esterase from pig liver, lipase from the pancreas of a pig or subtilisin, or other enzymes, which are hydrolized in accordance with stereoselective mechanism. The resulting optically active can be transformed into an enriched enantiomer carboxylate and subjected to combined with siliconized pyrimidine base, as noted above, when receiving the enriched enantiomer BCH-189 or analogues BCH-189.

The protective group R can be chosen in such a way as to ensure the. the moreover, the protective group can be selected, upon request, to provide an additional area of recognition for the enzyme, which is used later in the reaction of enantio-selective hydrolysis. You can use any group in this way. For example, it is possible to use alkyl, silyl and acyl protective group or groups having essentially the same properties as noted above.

Applied alkyl protective group is triphenylmethyl or alkyl group having essentially the same protective properties as triphenylmethyl group. Silyl-protective group, is used here, is a tri-substituted silyl group of the following formula:

< / BR>
where R1, R2and R3can be lower alkilani, for example, stands, ethyl, bootrom and alkyl of 5 carbon atoms or less, or phenyl, moreover, R1may be identical with R2; R1, R2and R3can be all identical.

Examples silyl-protective groups include trimethylsilyl and t-butyldiphenylsilyl, but are not limited to.

Applied acyl group is to describe the acyl protective group (as in ) or to describe the carboxy carbon atoms or less; substituted lower alkyl, where alkyl contains one, two or more simple substituents, including, but not limited to, amino, carboxyl, hydroxyl, phenyl, lower alkoxy-Deputy, for example, methoxy, ethoxy; phenyl; substituted phenyl, where the phenyl contains one, two or more simple substituents, including, but not limited to, lower alkyl, halogen, e.g. chlorine and bromine, sulfate, sulfonyloxy, carboxyl, Carbo-lower-alkoxy-Deputy, for example, carbomethoxy, carbethoxy, amino, mono - and di-lower alkylamino group, for example, methylamino, amido, hydroxy, lower alkoxy group, e.g. methoxy, ethoxy, lower alkanoyloxy group, for example, acetoxy group.

Applied here siliconized pyrimidine base is a compound of the following formula:

where X - or tri-substituted, silyloxy - or tri-substituted, silylamine-group;

Z - three-substituted silyl-group;

Y - group, described below.

Applied here, the three-substituted silyl group has the following formula:

< / BR>
where R1, R2and R3can be lower alkyl, for example, stands, ethyl, bootrom and alkyl of 5 carbon atoms or less, or phenyl. Moreover, R1can service groups include trimethylsilyl and t-butyldiphenylsilyl group, but limited by them.

Siliconized pyrimidine base can be replaced with different Y-substituents, including, but not limited to them, hydrogen, methyl, halogen, alkyl, alkenyl, quinil, hydroxyalkyl, carboxyethyl, thioalkyl, selenology, phenyl, cycloalkyl, cycloalkenyl, tiari and selenourea group in position 5 of siliconized pyrimidine bases (Y-Deputy in Fig.1) to modify properties such as the transport properties or the metabolic rate of the analog BCH-189.

Illustrative examples of the synthesis of BCH-189 or analogues BCH-189 according to the present invention shown in Fig.2 to 4 and in the following descriptions.

In Fig. 2 shows the synthesis of BCH-189, based on the allyl alcohol . Oil suspension of NaH (4.5 g, 60%, 110 mmol) is washed twice THF (tetrahydrofuran) (100 ml) and the resulting solid is suspended in THF (300 ml). The suspension is cooled to 0oC and added dropwise allyl alcohol (6.8 ml, 100 mmol) and the mixture stirred for 30 minutes at 0oC. t-butyl-divinycell-chloride (from 25.8 ml, 100,8 mmol) is added dropwise at 0oC and the reaction mixture is stirred 1 hour at 0oC. Solution "stew" water (100 ml) and extracted with diethyl ether (200 ml). United extras oC at 0.5 - 0.6 mm RT.cent.), receiving a colorless liquid (28 g, 94 mmol, 94%). (1H-NMR: 7,70-to 7.35 (10H, m, aromatic-H); to 5.93 (1H, m, H2); lower than the 5.37 (1H, d, H1) J=1,4 and 14.4 Hz; 5,07 (1H, d, H1) J=1,4 and 8.7 Hz; is 4.21 (2H, m, H3); of 1.07 (9H, s, t-Bu).

Similarily ester (15.5 g, 52,3 mmol) dissolved in CH2Cl2(400 ml) and ozoniruyut at -78oC. Upon reaching full ozonolysis added at -78oC DMS (dimethyl sulfoxide) (15 ml, 204 mmol, 3.9 EQ) and the mixture warmed to room temperature and stirred over night. The solution was washed with water (100 ml), dried over MgSO4, filtered, concentrated and distilled under vacuum (100-110oC at 0.5 - 0.6 mm RT.article) to give a colorless liquid (15.0 g, 50.3 mmol, 96%).1H-NMR: 9,74 (1H, s, H-CO); 7,70 - TO 7.35 (10H, m, aromatic H); is 4.21 (2H, s, -CH2); to 1.22 (9H, s,t-Bu)).

Silicony glycoaldehyde (15.0 g, 50.3 mmol) was dissolved in toluene (200 ml) and one portion add thioglycolic acid (3,50 ml, 50.3 mmol). The solution is distilled off over 2 hours and the water formed is removed by means of traps Dean-Stark'a. The solution is cooled to room temperature and washed with saturated solution of NaHCO3water washing water is extracted with diethyl ether (200 ml). The combined extracts washed with water (100 ml), dried napenda hardens.

Recrystallization from hexane yields a white solid (15,8 g, 84%). (1H-NMR: 7,72-7,38 (10H, m, aromatic H); of 5.53 (1H, t, H2) J = 2,7 Hz; 3,93 (1H, DD, -CH2O) J = 9,3 Hz; 3,81 (1H, d, 1H4) J = 13,8 Hz; with 3.79 (1H, DD, -CH2O); to 3.58 (1H, d, 1H4); of 1.02 (9H, s, t-Bu)).

2-(t-Butyl-diphenylsilane)-methyl-5-oxo-1,2-oxathiolan (5.0 g, 13,42 mmol) dissolved in toluene (150 ml) and the solution cooled to -78oC. a Solution of Dibal (14 ml, 1.0 M in hexano, 14 mmol) is added dropwise, while the internal temperature of the support below -70oC for all time. At the end of the addition the mixture is stirred for 30 minutes at -78oC. Add acetic anhydride (5 ml, 53 mmol) and the mixture is heated to room temperature and stirred over night. The mixture was added water (5 ml) and the resulting mixture is stirred for 1 hour at room temperature. The mixture is diluted with diethyl ether (300 ml), add MgSO4(40 g) and the mixture is intensively stirred for 1 h at room temperature. The mixture is filtered, concentrated and the residue is subjected to instant chromatography with 20% EtOAc in hexano, receiving a colorless liquid (of 3.60 g, 8,64 mmol, 64%), which is a mixture of anomers in a ratio of 6:1. (1H-NMR of the main isomer: 7,70-to 7.35 (10H, m, aromatic H); 6,63 (1H, d, 2,02 (3H, with a, CH3CO) OF 1.05 (9H, s, t-Bu);1H-NMR minor isomer: 7,70-to 7.35 (10H, m, aromatic H); 6,55 (1H, d, H5) J = 3,9 Hz; the 5.45 (1H, t, H2); 4,20-of 3.60 (2H, m, -CH2O); of 3.25 (1H, DD, 1H4) J = 3,9 and 11.4 Hz; 3,11 (1H, d, 1H4) J = 11,4 Hz; 2,04 (3H, s, CH3CO) WAS 1.04 (9H, s, t-Bu)).

2-(t-Butyl-diphenylsilane)-methyl-5-acetoxy-1,3-oxathiolan (0.28 g, 0.67 mmol) dissolved in 1,2-dichloroethane (20 ml) and add sililirovany cytosine (0.20 g, 0.78 mmol) in one portion at room temperature. The mixture is stirred for 10 minutes, and thereto is added a solution of SnCl4(0,80 ml, 1.0 M solution in CH2Cl2, 0.80 mmol) dropwise at room temperature. Cytosine (0.10 g, 0,39 mmol) and a solution of SnCl4(of 0.60 ml) was added in the same way an hour later. After the reaction for 2 hours the solution is concentrated and the residue tricerat by triethylamine (2 ml) and subjected to instant chromatography (first with pure EtOAc and then with 20% ethanol in EtOAc); receiving solid reddish-brown (100% in-configuration) (0.25 g, 0.54 mmol, 80%). (1H-NMR (DMSO-d6): of 7.75 (1H, d, H6) J = 7,5 Hz; the 7.65 to 7.35 (10H, m, aromatic H); 7,21 and 7,14 (2H, broad, -NH2); to 6.19 (1H, t, H5); to 5.57 (1H, d, H5); the 5.25 (1H, t, H2); of 3.97 (1H, DD, -CH2O) J = 3,9 and 11.1 Hz; a 3.87 (1H, DD, -CH2O); to 3.41 (1H, DD, 1H4) J = 4.5 and 11 is the solution of H-Bu4NF (0,50 ml, 1.0 M solution in THF, 0.50 mmol) dropwise at room temperature. The mixture is stirred for 1 hour and concentrated under vacuum. The residue away with a mixture of ethanol-triethylamine (2 ml/1 ml) and subjected to instant chromatography (first with EtOAc, then with 20% ethanol in EtOAc) to give a white solid 100% clean anomer (BCH-189; 0.11 g, 0.48 mmol, 98%), which is then recrystallized from a mixture of ethanol/CHCl3/hexane. (1H-NMR (DMSO-d6): to $ 7.91 (1H, d, H6) J=7,6 Hz; 7,76 and was 7.45 (2H, broad, -NH2); to 6.19 (1H, t, H5); 5,80 (1H, d, H5) J = 7,6 Hz; of 5.34 (1H, broad, -OH); to 5.17 (1H, t, H2); 3,74 (2H, m, -CH2O); of 3.42 (1H, DD, 1H4) J = 5,6 and 11.5 Hz; to 3.09 (1H, DD, 1H4) J = 4,5 and 11.5 Hz)).

BCH-189 and its analogs can also be synthesized by the combination of similarvideo derivative of uracil with Siliconefree derivative of uracil (1.80 g, 7,02 mmol) is combined with (1,72 g of 4.13 mmol) in 1,2-dichloroethane (50 ml) in the presence of SnCl4(5.0 ml), as described above, upon receipt of a derivative of cytosine 13. The reaction becomes complete after 5 hours. By the instantaneous chromatography, first with 40% EtOAc in hexane and then with EtOAc obtained as a white foam (1.60 g, of 3.43 mmol, 83%). (1H-NMR: 9,39 (1H, broad, NH) of 7.90 (1H, d, H6) J = 7,9 Hz; 7,75-to 7.35 (10H, m, aromatic H); 6,33 (1H, DD, HUB>4) J = 5,4 and 12.2 Hz; of 3.13 (1H, DD, 1H4) J = 3,2 and 12.2 Hz)).

A derivative of uracil can be transformed into a derivative of cytosine 13. A derivative of uracil 16 (0.20 g, 0.43 mmol) dissolved in a mixture of pyridine/dichloromethane (2 ml/10 ml) and the solution cooled to 0oC. Triperoxonane anhydride (72 μl, 0.43 mmol) is added dropwise at 0oC and the mixture is heated to room temperature and stirred for 1 hour. Additionally add triperoxonane anhydride (0,50 μl, 0.30 mmol) and the mixture is stirred for 1 hour. The TLC showed no mobility with EtOAc. The reaction mixture was then taken away by tube and transferred to a saturated ammonia solution of methanol (30 ml), and the mixture is stirred for 12 hours at room temperature. The solution is concentrated and the residue is subjected to instant chromatography, getting a reddish-brown foam (0.18 g, 0,39 mmol, 91%) which was identical with the compound obtained by the reaction of a combination of cytosine.

In Fig. 3 shows the synthesis of 5-methylcytidine and timelinemax derivatives VSN-189. Acetate 11 (0,93 g of 2.23 mmol) in 1,2-dichloroethane (50 ml) reacts with similarbank thymine derivative (1.0 g, 3,70 mmol) and a solution of SnCl4(4,0 ml), as described in the preparation of a derivative of cytosine (<) J = 4,2 Hz; to 4.01 (1H, DD, 1H5) J = 3,9 and 11.4 Hz; 3,93 (1H, DD, 1H5) J = 4,5 and 11.4 Hz; to 3.41 (1H, DD, 1H2) J = 5,4 and 11.7 Hz; totaling 3.04 (1H, DD, 1H2) J= 5,7 and 11.7 Hz; of 1.75 (3H, s, CH3); of 1.07 (9H, s, t-Bu)).

Derivative of thymine 18 (0.20 g, 0.42 mmol) dissolved in a mixture of pyridine/dichloromethane (2 ml/10 ml) and the solution cooled to 0oC. is added triperoxonane anhydride (100 μl, of 0.60 mmol) dropwise at 0oC, and the mixture is put aside with constant stirring, allowing it to warm to room temperature. Upon reaching room temperature, it is stirred for 1 hour. By TLC shows the absence of mobility with EtOAc. Then the reaction mixture through the tube was transferred to a saturated ammonia solution of methanol (20 ml) and the mixture is stirred for 12 hours at room temperature. The solution is concentrated and the residue is subjected to instant chromatography, getting a reddish-brown foam (0.18 g, 0.38 mmol, 90%). (1H-NMR: 7,07-7,30 (12H, m, 10, aromatic H, 1NH and H6); 6,0 (1H, broad, 1NH); 6,34 (1H, t, H1) J = 4,5 Hz; the 5.25 (1H, t, H4) J = 3,6 Hz; 4,08 (1H, DD, 1H5) J = 3,6 and 11.4 Hz; of 3.96 (1H, DD, 1H5) J = 3,6 and 11.4 Hz; to 3.52 (1H, DD, 1H2) J = 5,4 and 12.3 Hz; to 3.09 (1H, DD, 1H2) J = 3,9 and 12.3 Hz; 1,72 (3H, s, CH3); of 1.07 (9H, s, t-Bu)).

Silloway ether 19 (0.18 g, 0.38 mmol) dissolved in THF (20 ml) and remediat 1 hour and concentrated under vacuum. The residue is taken using a mixture of ethanol/triethylamine (2 ml/1 ml) and subjected to instant chromatography (first with EtOAc, then with 20% ethanol in EtOAc) to give a white solid (0.09 g, of 0.37 mmol, 97%), which is then recrystallized from a mixture of ethanol/CHCl3/hexane, receiving 82 mg of pure compound (89%). (1H-NMR: (d6-DMSO): of 7.70 (1H, s, H6); of 7.48 and 7.10 (2H, broad, NH2); to 6.19 (1H, t, H1) J = 6,5 Hz; 5,31 (1H, t, OH); 5,16 (1H, t, 1H4) J = 5,4 Hz; and 3.72 (2H, m, 2H5) to 3.36 (1H, DD, 1H2) J = 6,5 and 14.0 Hz; 3,05 (1H, DD, 1H2) J = 6,5 and 14.0 Hz; of 1.85 (3H, s, CH3)).

Silloway ether (0,70 g of 1.46 mmol) was dissolved in THF (50 ml) and a solution of H-Bu4NF (2 ml, 1.0 M solution in THF, 2 mmol) is added dropwise at room temperature. The mixture is stirred for 1 hour and concentrated under vacuum. The residue away with a mixture of ethanol/triethylamine (2 ml/1 ml) and subjected to instant chromatography, obtaining a white solid 21 (0.33 g, 1.35 mmol. 92%). (1H-NMR: (d6-acetone): 9,98 (1H, broad, NH); 7,76 (1H, d, H6) J = 1,2 Hz; and 6.25 (1H, t, H4) J = 5,7 Hz; of 5.24 (1H, t, H1) J = 4,2 Hz; 4,39 (1H, t, OH), J = 5,7 Hz; of 3.85 (1H, DD, 2H5) J = 4,2 and 5.7 Hz; to 3.41 (1H, DD, 1H2) J = 5,7 and 12.0 Hz; 3,19 (1H, DD, 1H2) J = 5,4 and 12.0 Hz; of 1.80 (3H, s, CH3)).

In Fig. 4 presents a synthesis of the enriched enantiomer BCH-189 and its analogovaya added dimethyl sulfide (20 ml, 270 mmol, 1.8 EQ) at -78oC, the mixture is heated to room temperature and stirred over night. The solution was washed with water (100 ml), dried over MgSO4, filtered, concentrated and distilled under vacuum (70-80oC at 0.5-0.6 mm Od) to give a colorless liquid (17.0 g, 131 mmol, 88%). (1H-NMR: 9,59 (1H, s, H-CO) of 4.66 (2H, s, -CH2O); to 2.42 (2H, t, CH2CO) J = 7,2 Hz; 1,71 (2H, sextet, -CH2); to 0.97 (3H, t, CH3) J = 7,2 Hz; (IR (net): 2990, 2960, 2900, 1750, 1740, 1460, 1420, 1390, 1280, 1190, 1110, 1060, 1020, 990, 880, 760).

Butylisoxazole (15.0 g, 115 mmol) dissolved in toluene (200 ml) and mixed with thioglycolic acid (8.0 ml, 115 mmol). The solution is distilled for 5 hours, and the formed water is removed by means of traps Dean-Stark'a. The solution is cooled to room temperature and transferred into a separating funnel with a volume of 500 ml. and Then the solution was washed with a saturated solution of NaHCO3. The aqueous washings extracted with diethyl ether (200 ml of 2) for the recovery of any of the crude product from the aqueous layer. The ether extracts are added to the toluene layer and the resulting mixture washed with water (100 ml of 2), dried over MgSO4, filtered, concentrated and distilled under vacuum (70-80oC at 0.5-0.6 mm Od) to give a colorless oil (19 g, 93 mmol, 81%). (1H-NMR: 5,65 ( Hz; of 3.64 (1H, d, -CH2S); of 2.34 (2H, t, -CH2CO) J = 7,2 Hz; of 1.66 (2H, sextet, -CH2); of 0.95 (3H, t, CH3) J = 7,2 Hz; (IR (net): 2980, 2960, 2900, 1780, 1740, 1460, 1410, 1390, 1350, 1300, 1290, 1260, 1220, 1170, 1110, 1080, 1070, 1000, 950, 910, 830, 820, 800, 760).

The solution esterase from pig liver (90 μl) are added to a buffer solution (pH 7, 100 ml) at room temperature, and the mixture is intensively stirred for 5 minutes. Butyrate (2.8 g, 13.7 mmol) is added in one portion to a solution of the enzyme/buffer, and the mixture is vigorously stirred at room temperature for 2 hours. The reaction mixture was poured into a separating funnel. The reaction flask was washed with ether (10 ml) and the washings combined with the reaction mixture in the funnel. The combined mixture is extracted with hexane three times (100 ml 3). Three hexane extracts are combined and dried over MgSO4, filtered and concentrated, obtaining optically active butyrate (1.12 g, of 5.48 mmol, 40%). The excess enantiomer determined by NMR using a derivative of Tris[3-heptafluoropropyl-hydroxymethylene)-(+)-camphorato]europium (III) as a reagent for chemical shift; by this method the enrichment of one enantiomer was approximately 40%. Remaining from the reaction of the aqueous layer was subjected to continuous extraction with CH2Cl2during the aslo (1.24 g), which, according to NMR analysis, consists predominantly of 2-hydroxymethyl-oxo-1,3-oxathiolane with a small amount of butyric acid and butyrate 24.

The lactone 25 of 0.85 g of 4.16 mmol) dissolved in toluene (30 ml) and the solution cooled to -78oC. a Solution of Dibal-H (9 ml, 1.0 M in hexano, 9 mmol) is added dropwise, while the internal temperature of the support below -70oC during the addition. At the end of the addition the mixture is stirred for 0.5 hours at -78oC. Acetic anhydride (5 ml, 53 mmol) is added to the mixture with continuous stirring and left overnight to reach room temperature. To the reaction mixture was added water (5 ml) and the resulting mixture is stirred for 1 hour. Then make MgSO4(40 g) and the mixture vigorously stirred at room temperature for 1 hour. The mixture is filtered, concentrated and the residue is subjected to instant chromatography with 20% EtOAc in hexano, receiving colorless liquid 26 (0,41 g of 1.86 mmol, 45%), which is a mixture of anomers at position C-4.

2-Acetoxymethyl-5-acetoxy-1,3-oxathiolan (0.40 g, 1.82 mmol) dissolved in 1,2-dichloroethane (40 ml) and to it was added sililirovany cytosine 12 (0,70, to 2.74 mmol) in one portion at room temperature. The mixture Pol), dropwise, at room temperature. Additionally, a solution of SnCl4(1.0 ml) is added over 1 hour. The reaction is controlled by TLC. Upon completion of combination reaction solution is concentrated and the residue tricerat by triethylamine (2 ml) and subjected to instant chromatography (first in pure EtOAc and then with 20% ethanol in EtOAc) to give a reddish brown solid 27 (0,42 g, 1.55 mmol, 86%). (1H-NMR: 7,73 (1H, d, H6) J = 7,5 Hz; 6,33 (1H, t, H4) J = 4,8 Hz; 5,80 (1H, d5) J = 7,5 Hz; to 4.52 (1H, DD, 1H5) J = 5,7 and 12.3; 4,37 (1H, DD, 1H5) J = 3.3V and 12.3 Hz; of 3.54 (1H, DD, H2) J = 5,4 and 12.0 Hz; 3,10 (1H, DD, 1H3); 2,11 (3H, s, CH3)).

5'-Acetate BCH-189 (140 mg, 0.52 mmol) was dissolved in anhydrous methanol (10 ml) and to it add methoxyl sodium (110 mg, 2.0 mmol) in one portion. The mixture is stirred at room temperature until complete hydrolysis. The hydrolysis takes approximately 1 hour, and the reaction is controlled by TLC. Upon completion the reaction mixture is concentrated, and the residue taken with ethanol (2 ml). Alcohol solution is subjected to column chromatography, first using ethyl acetate and then 20% ethanol in EtOAc, getting a white foam (110 mn, 92%), the NMR spectrum of which is identical with the spectrum of standard BCH-189, 14.

1. The way to obtain 2',3'-didet what about the conduct of the interaction of 1,3-oxathiolane General formula

< / BR>
where R is hidroxizina group;

R' is acyl group,

with a base selected from the group comprising sililirovany cytosine or 5-ferritin in the presence of SnCl4.

2. The method according to p. 1, characterized in that hydroxyamino group is a silyl group.

3. The method according to p. 1, characterized in that the base is cytosine.

4. The method according to p. 1, characterized in that the base is 5-fertilizin General formula

< / BR>
where X is trialkylsilanes;

Y is hydrogen, methyl, fluorine;

Z - trialkylsilyl group.

5. Enriched with enantiomer nucleoside of the General formula

< / BR>
R is hydrogen, alkyl, silyl, acyl;

Y is hydrogen.

6. Enriched with enantiomer nucleoside of the General formula

< / BR>
R is hydrogen or acyl;

Y is hydrogen.

7. The method of obtaining 1,3-oxathiolane General formula

< / BR>
where R is hidroxizina group;

R' is acyl group,

characterized in that the conducting phase: (a) ozonirovaniya compounds of General formula CH2CHCH2OR, where R has the above significance, with the formation of glycoaldehyde General formula OHC CH2OR, where R is hidroxizina group; C) adding thioglycolic what rucenim target 1,3-oxathiolane.

8. The method according to p. 7, characterized in that the recovery of the lactone carried out by adding a reducing agent followed by the addition of carboxylic acid anhydride.

9. The method according to PP.7 and 8, characterized in that the reducing agent is selected from the group consisting of diisobutylaluminium-hydride or NaBH4.

10. The method according to p. 7, characterized in that hidroxizina group selected from the group comprising alkyl, silyl or acyl.

11. The method of obtaining enriched enantiomer of 2-acyloxymethyl-5-acyloxy-1,3-oxathiolane, characterized in that the hold stages: a) mixing stereospetsifichno enzyme with a lactone of General formula

< / BR>
where R is hidroxizina group,

with the formation of 2-hydroxymethyl-5-oxo-1,3-oxathiolane enriched enantiomer; C) recovery and acylation of the specified 2-hydroxymethyl-5-oxo-1,3-oxathiolane enriched enantiomer, with the formation of 2-acyloxymethyl-5-acyloxy-1,3-oxathiolane enriched enantiomer.

12. The method according to p. 11, characterized in that the recovery and acylation enriched enantiomer of 2-hydroxymethyl-5-oxo-1,3-oxathiolane carried out by adding a reducing agent followed by the addition of carboxyanhydride.

is gerida or NaBH4.

14. The method according to p. 12, characterized in that stereospecificity enzyme selected from the group consisting of esterase from pig liver.

15. The method according to p. 12, characterized in that hidroxizina group selected from the group consisting of alkyl, Srila or acyl.

16. The (-) enantiomer isomer of 2',3'-dideoxy-3'-thiacytidine.

17. The (-) enantiomer isomer of 2',3'-dideoxy-3'-thiacytidine in substantially pure form.

18. The (-) enantiomer isomer of 2',3'-dideoxy-3'-thiacytidine substantially free of (+) -enantiomer isomer of 2',3'-dideoxy-3'-thiacytidine.

19. 2',3'-Dideoxy-3'-thiacytidine (-VSN-189) substantially in the form of a single optical isomer.

20. -2',3'-Dideoxy-3'-thia-5-perltidy.

21. Enantiomerexperiences -2',3'-dideoxy-3'-thia-5-perltidy.

22. Enantiomerically-VSN-189.

23. The (-) enantiomer isomer of 2',3'-dideoxy-3'-thia-5-fertilizin.

24. The (-) enantiomer isomer of 2',3'-dideoxy-3'-thia-5-fortitudine, in substantially pure form.

25. The (-) enantiomer isomer of 2',3'-dideoxy-3'-thia-5-fortitudine substantially free of (+)-enantiomer isomer of 2',3'-dideoxy-3'-thia-5-fortitudine.

26. 2',3'-Dideoxy-3'-thia is the nucleoside of the formula

< / BR>
where Y is hydrogen, fluorine;

R - acyl,

wherein the nucleoside is treated with an enzyme selected from the group comprising esterase from pig liver.

28. The method according to p. 27, wherein Y is hydrogen.

29. The method according to p. 27, wherein the enzyme is an esterase from pig liver.

30. The method according to p. 27, wherein Y is fluorine.

 

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d-arabinofuranosyl)-n-purine, method for their preparation and use and pharmaceutical composition" target="_blank">

The invention relates to mono-, di - or tri-esters of 2-amino-6-(C1-C5-alkoxy)-9-(-D-arabinofuranosyl)-N-purine General formula (I)

< / BR>
where arabinofuranosyl residue substituted for 2'-, 3'- or 5'-positions, and esters formed by carboxylic acids, in which decarbonising part selected from n-propyl, tert-butyl, n-butyl, methoxymethyl, benzyl, phenoxymethyl, phenyl, methanesulfonyl and succinyl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, chemical technology.

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EFFECT: improved preparing methods.

27 cl, 3 dwg, 16 ex

FIELD: medicine.

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EFFECT: enhanced effectiveness in overcoming pharmacological resistance; accelerated schizo-affective syndrome relief.

FIELD: medicine.

SUBSTANCE: method involves applying eradicative anti-helicobacterial therapy comprising Omeprazol administration at a dose of 20 mg twice a day and Ximedone at a dose of 500 mg twice a day in 12 days long course.

EFFECT: enhanced effectiveness of eradication; reduced adverse side effects risk.

FIELD: organic chemistry, medicine, pharmacy, pharmacotherapy.

SUBSTANCE: method involves administration in mammal the effective dose of 6-hydroxy-8-[4[4-(2-pyrimidinyl)piperazinyl]butyl]-8-azaspiro[4,5]-7,9-dione or its pharmaceutically acceptable salt of acid addition or its hydrate. Method expands arsenal of medicinal agents used for suppression of fear sensation.

EFFECT: valuable properties of agent.

3 tbl, 6 dwg, 4 ex

FIELD: medicine, narcology.

SUBSTANCE: invention relates to hepatoprotective and anti-encephalopathic agent used for reducing alcoholic intoxication. Invention comprises components based on succinic, fumaric, glutamic acids and, additionally, at least one vitamin of B group. Agent can comprise additionally vegetable extracts or their mixture, L-carnitine, glycine, L-arginine, taurine and/or their mixture, methylsulfonylmethane, dihydroquercitin, dimethylsulfoxide or their mixture, nicotinamide or nicotinic acid or their mixture, energy source and sweetening agent. Also, invention proposes a method for reducing alcoholic intoxication, prophylaxis and removing withdrawal syndrome, liver protection, among them, in non-alcoholic intoxication and protection against encephalopathy. Invention provides described effects without qualifying medical control.

EFFECT: valuable medicinal properties of agent.

16 cl, 3 tbl

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

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