New hem-difluoridated compounds, methods of their producing and their application


FIELD: medicine.

SUBSTANCE: invention relates to the new hem-difluoridated compound of the formula: where R1 represents a group, containing alkyl chain or amino group; R2 represents hydrogen atom, either free or protected functional group of alcohol; R3 represents a group CH2OH, CH2-OGP, where GP respresents protecting group such as alkyl, benzyl (Vp), trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetate (Ac); Y, Y', Y" represent independent groups OR, where R represents H, benzyl, Ac, TMS, TBDMS, TBDPS that are used for producing antitumor, antiviral, hypoglycemic and anti-flammatory medicine and compounds for immunology and cosmetology, or glyco peptide analogs of antifreeze molecules. The invention refers particularly also to the new hem-difluoridated compound of the general formula: and to the method of producing new hem-difluoridated compound of the formula: .

EFFECT: compounds possess increased effectiveness.

7 cl, 8 ex, 24 dwg

 

The present invention relates to a method of synthesis of heme-diflorasone compounds. More specifically, but not exclusively, it can be used to obtain glycoconjugate compounds and C-glycosides, mainly to obtain antitumor, antiviral, hypoglycemic, anti-inflammatory agents, or even in immunology, cosmetology, and to obtain glycopeptides analogues molecules antifreeze.

In recent years a number of studies relating to fluorinated organic molecules, has increased significantly. Such interest in such studies is explained by the understanding of the impact of fluoride on biological activity of molecules. In fact, the physiological properties of biologically active compounds change with the introduction of fluoride, and biochemists warmly welcome new ways of selective introduction of fluorine.

However, the main contribution on new important biological molecules, achieved mainly when monitorowanie and triptoreline.

However, the importance of the introduction deformationof of CF2shown in the example of compounds such as Gemcitabine® (Gemzar, Lilly) and Vinflunine® (Pierre Fabre), which are currently undergoing clinical trials as anticancer agents (figure 1).

Such interest to selective fluorination biological is soedinenii refers to the specific nature of the fluorine atoms: its electronegativity (the most electronegative element), the binding energy of C-F (484 kJ·mol-1; C-C: 348 kJ·mol-1).

As a replacement for oxygen deformationof group CF2turned out to be a particularly attractive candidate:

on the one hand, the electronegativity of oxygen (3,5) is close enough to the electronegativity of CF2(3,3);

on the other hand, in preliminary research, conducted in 1984, the replacement of oxygen in phosphate equivalent structures such as adenosine diphosphate (ADP), it was shown that CF2represents a tetrahedral equivalent of oxygen to the spatial location of both fluorine atoms, as illustrated in figure 2.

Moreover, because electronegativity is very close, electronic effects associated with replacement is minimized.

For this reason, have recently been synthesized analogues of phosphotyrosine and phosphoserine presented in figure 3.

These compounds are inhibitors fosfatnykh enzymes involved in the transmission of intracellular signals.

In addition, carefully investigated the synthesis of analogues glycoconjugate compounds. They are compounds formed by linking (conjugation) of sugar and other compounds (aglycone), such as amino (- glycoprotein, glikopeptid), lipid (glycolipid), steroid or triterpene, alkaloid, ke is he.

Indeed, the latter, including glycoprotein and glycolipid, which are components of cell membranes, are compounds that are widely involved in many biochemical processes, such as intercellular recognition or control cell growth. For this reason, glycoconjugation connection is highlighted in therapy, and they are used as anticancer or antiviral agents.

Currently, these compounds due to the presence Sidney communication (communication containing oxygen, so to speak, in the anomeric position)are unstable with respect to several enzyme systems, including protease enzymes and hydralazine enzymes.

To have components that retain their biological properties of interest such replacement oxygen Sydney due to this relationship is not destroyed under the action of the enzymatic process.

Were synthesized analogues, where the oxygen is replaced by CH2but, despite the improved stability and steric obstruction, similar to the oxygen, it was found that the group CH2well not reproduces the biological properties of the initial connection.

To improve stability glycoconjugate compounds in the biological environment are investigated and other classes to connect the clusters, where oxygen is replaced by nitrogen or sulfur, and recently deformationof group.

Conversion O/CF2looks especially suitable for playback properties of oxygen on the electronic level; both fluorine atom plays the role of both the free electron pairs of oxygen (figure 2).

Several research groups are exploring approaches to C-glycosides (compounds, where the anomeric oxygen is replaced by carbon), but to date not been an effective method that can be used for a wide range of sugars found in glycoconjugates compounds (D-glucose, D-galactose, D-galactosamine, D-glucosamine.).

More specifically, the present invention is to eliminate these disadvantages.

With this purpose it is proposed heme-diflorasone C-glycoside compound of General formula I:

where R1represents a group containing an alkyl chain, substituted by at least one amino group, amide or acid functional group,

R2represents a hydrogen atom H or a free or protected functional group of the alcohol,

R3is a group H, CH3CH2OH, CH2-OGP, where GP represents a protective group such as an alkyl, benzyl (Bn), trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tertbutylphenol (TBDPS), acetate (Ac)...,

Y, Y', Y" are independent of the group,

where Y, Y', Y" represent H, OR, N3, R NR'r", SR"'...

where R represents H, Bn, Ac, TMS, TBDMS, TBDPS,...,

R', R" represent H, alkyl, allyl, Bn, tosylate (Ts), C(O)-alkyl, C(=O)-Bn,...,

R"' represents H, alkyl, Ac.

In addition, this compound of General formula I can be obtained by the interaction of the lactone of General formula II:

where R3represents H, CH3CH2-OGP, where GP represents a protective group such as an alkyl, benzyl (Bn), trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetate (Ac)...,

Y, Y', Y" are independent of the group,

where Y, Y', Y" represent H, OR, N3, R NR'r", SR"'...

where R represents H, Bn, Ac, IMS, TBDMS, TBDPS,...,

R', R" represent H, alkyl, allyl, Bn, tosylate (Ts), C(=O)-alkyl, C(=O)-Bn,...,

R"' represents H, alkyl, Ac;

in the presence of zinc or lanthanide derivative and at least one halogenated derivative of General formula called XCF2CO2R", where X is a halogen, and R8= alkyl, aryl...

Specified lanthanide derivative can represent, for example, diode samarium SmI2.

In accordance with the alternative, in this way it is possible to use zinc, associated with t is tamozennom.

Deoxyadenosine, to move from the compounds of formula I, where R2= OH, to the compound of formula I, where R2= H, can for example be achieved through either direct or radical recovery, or even through acetate, tosylate, xanthate, oxalate derivative with subsequent radical restoration.

In accordance with one alternative implementation, more specifically, heme-dipteronia compounds may have the General formula III:

where R5and R6represent H or functionalized or defunctionalization group, such as functionalized carbon chain, bearing, among other things, amino group, amino acid functional group, aminoclonazepam functional group of the peptide chain, a protein, a carbohydrate, a steroid, or triterpen, alkaloid, a lignin, or compounds, which are of pharmacological interest.

In accordance with another variant, heme-dipteronia connections may, more specifically, to have the General formulae IVa and IVb:

where R5, R6, R7and R9represent H or functionalized or defunctionalization group, such as functionalized carbon chain, bearing, among other things, an amino group, aminokislotna the functional group, aminoclonazepam functional group of the peptide chain, a protein, a carbohydrate, a steroid or triterpene, alkaloid, a lignin, or compounds, which are of pharmacological interest.

One of the intermediate compounds obtained with the aim of obtaining the compounds of formula I may be a compound of General formula V containing ester functional group:

where R4can represent such a group as alkyl, aryl, allyl group, this group is either functionalized or not.

Such ester functional group-CO2R4can be amylene, to obtain the acid of formula VI:

The specified ester functional group-CO2R4you can also recover to a functional group of an alcohol, for example, using tetraborate sodium (NaBH4or sociallyengaged (LiAlH4) to obtain the C-glycoside compounds of General formula VII:

Compounds of General formula VII, by themselves, can oxidize to aldehydes in a variety of ways, such as how Swarna, dessa-Martin, to obtain the compounds of General formula VIII:

Compound VIII can also be obtained from the esters V chere is h tiefer and recovery.

Compound VIII can be obtained in the form of Polyacetal.

Posidnia the compounds of formula I, where R1= CH2-OH, you can also oxidize to aldehydes using any of the above methods.

In addition, in accordance with another embodiment of the invention, the compounds of formula I, where R1=COOH, can be used in the reaction IGO with an amine, aldehyde and isonitrile, to obtain the compounds of formula III,

where R1=-S(=O)-NR5R6.

In accordance with the latest alternative embodiment, compounds of General formula I can be obtained by the reaction of a combination of sugar derived from an amine, for example, amino acid or peptide.

Finally, a group of CF2is particularly resistant to biochemical processes of degradation and therefore makes possible the synthesis digitalisierung structures.

Pharmacophoric properties in this system are determined by the structure of the fragment conjugated with hamptonyoung a glycoside, which in turn performs the role of the media, ensuring the delivery of the active segment in the biological environment. Thus the stability of the conjugate is determined hamptonyoung connection, which does not affect the biological activity of the conjugate and, thus, does not depend on the nature of the media pharmacophoric properties.

The connection is of General formulas I-VIII, as well as their possible derivatives and pharmaceutically acceptable additive is an acid salt of a mineral or organic acid may, for example, exist in the form of tablets, capsules, drops, oral solutions or suspensions, emulsions, suppositories. In addition to pharmaceutically acceptable and non-toxic, inert fillers, such as distilled water, glucose, starch, lactose, talc, vegetable oils, ethylene glycol, ..., thus obtained compositions may also contain preservatives.

In these compositions can contain any other active ingredients.

A number of compounds of the present invention and other active ingredients in such compositions may vary according to applications, the age and weight of the patient.

Examples of preparing compounds in accordance with the present invention will hereinafter be described by non-limiting examples.

Common abbreviated names of units are defined as follows:

EQ.: equivalent

g: grams

Hz: Hertz

mg: milligram

MHz: megahertz

minutes: minutes

ml: milliliter

mmol: mm

µmol: micromoles

nmol: nanomoles

In the examples hereinafter described getting heme-diflorasone glycoconjugate compounds of the General formula I:

These compounds may be synthesized in various ways.

To reduce the number of stages during the synthesis of the heme-diflorasone glycoconjugate compounds, lactones 1 were used as electrophilic substances (figure 4). Derivative 2 was obtained from lactones 1 under the action of ethylbromoacetate 3 in the presence of zinc (Zn) or diiodide samarium

SmI2.

It should be noted that this method is General and can be applied to all classes of substituted different way glucopyranose (Y, Y', Y" = OR, N3, R NR'r", SR"...), the original lactones easily accessible in one or several stages of commercial products (for example, in a series of glucose by oxidation of commercial products at one stage).

Synthesis of intermediate C-glycoside compounds 6 and 7(figure 5 and 6).

In the example of figure 5, of 0.82 g of activated zinc (Zn) (0,82 g, 12.5 mmol, 7 EQ.) enter into a two-neck vessel with a capacity of 100 ml, in the upper part of which is a refrigerator and inlet valve. All this is placed in vacuum, and the zinc is heated with a heat gun for approximately 5 minutes, then vacuum filled with argon from the inflatable chamber.

Add 15 ml of anhydrous tetrahydrofuran (THF)and the resulting solution heated under reflux. This solution is injected mixture obtained in argon atmosphere and consisting of l is the thatnot 4 (0,960 g, 1,782 mmol, 1 EQ.), ethylbromoacetate BrCF2COOEt 5 (0,69 ml, 5,346 mmol, 3 EQ.) and anhydrous tetrahydrofuran (15 ml).

Installation of leave under heating under reflux for 2 h 30 min (after the reaction carried out thin-layer chromatography (TLC) with a mixture (3:7 ethyl acetate/cyclohexane as eluent), then added to a solution of 30 ml of 1N hydrochloric acid and dichloromethane.

The phases are separated, and the extraction is carried out with dichloromethane (3×10 ml dichloromethane sequentially added to the aqueous phase and extracted), the organic phase is collected, dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated using an evaporator under vacuum.

The separation is carried out using chromatography on a column of silica gel with a mixture of cyclohexane/ethyl acetate as eluent, at a ratio of nine to one. After concentrating the collected fractions, the product 6 is obtained in the form of a yellowish oil with a yield of 89 wt.% in a single diastereoisomer.

If instead of zinc use diode Samaria, compound 6 obtained as a partial mixture of both diastereoisomers (a mixture (2:1)), exit 62 wt.%.

Characteristics of the instrument used for the analysis of all compounds described in this application are set forth below.

Spectra1H,13C,l9F NMR write n the spectrometers BRUKER DPX DPX 300 and 600. For spectra1H and13C NMR as an internal standard tetramethylsilane was used. For spectra19F-NMR as internal standard used Trichlorofluoromethane (CFCl3). Chemical shifts are expressed in ppm (ppm), constants of spin-spin interaction J in Hertz (Hz).

Used the following abbreviations:

With - for singlet, user. for broad singlet, d for doublet, t for triplet, q for quadruplet, m for multiplet or array, DD for doublet of doublets.

Infrared spectra were registered on a Fourier transform infrared instrument PERKIN-ELMER PARAGON 500, in the liquid film on the crystal of NaCl or KBr tablet (for solid products). Frequency absorption is expressed in cm-1.

Mass spectra were obtained on a spectrophotometer JEOL AX 500 with a gun FAB JEOL (Xe, 4 kV, 10 mA).

Separation using column chromatography is carried out at a low pressure, following chromatographic techniques on silica gel Kieselgel 60 (230-400 mesh mesh, Merck).

Control is carried out using thin-layer chromatography (TLC) plates Kieselgel 60F-254-0,25 mm. The ratio of the distance traveled by the compound on the substrate, and the distance traveled by the eluent, called the coefficient of retention (Rf).

The analyses carried out to confirm the structure of the obtained product 6 is presented below:

oncologia chromatography (TLC)

Rf = 0,55, eluent: ethyl acetate/cyclohexane 3:7

These NMR:

19F-NMR (282 MHz; solvent: deuterated chloroform (CDCl3)) -117,67, d, 2JF-F=256 Hz; -120,03, d, 2JF-F=256 Hz

1H-NMR (300 MHz; solvent: deuterated chloroform (CDCl3))

1,19, t3J=7,14 Hz, 3H: - CH3(OEt); 3,52-3,70, m, 3H (H5+2H6); 3,90-3,95 m, 3H: H2+H3+H4, 4,18, kV,3J=7,14 Hz, 2H: CH2(OEt); 4,39-5,19, m, 8H: 4 CH2(OBn); 7,14-7,24 m, 20H; 4x 5 CH(Ph).

13C-NMR (75.5 MHz; solvent: deuterated chloroform(CDCl3))

14,29, CH3(OEt); 63,89, CH2(OEt); 68,68, CH2(C6); 73,06, CH; 73,82, 75,47, 75,67, 76,37: 4xCH2(OBn); 77,83, CH; 78,62, CH; 83,79, CH; 96,59, DD,2JC-F=28,17 Hz and2JC-F=26,Hz, -CF2C(OH)O-; 112,79, DD,1JC-F=263,6 Hz and1JC-F=259,GC, CF3; 137-138 CH(Ph); 163,32,DD,2JC-F=31,6 Hz and2JC-F=31,0 Hz, CFCOOEt.

IR (cm-1)

4059,6, 3478,5, 3089,5, 3064,3, 3031,6, 2923,7, 2852,0, 2257,3, 2925,7, 1875,4, 1769,3, 1663,6, 1605,9, 1586,4, 1497,3, 1454,0 1396,7, 1372,1, 1315,6, 1087,7, 1027,9, 910,6, 856,8, 802,1, 736,7, 698,1, 648,9, 605,5, 540,9, 462,7.

Mass spectrometry: FAB+ (Xe, 4kV, matrix 3-nitrobenzyl alcohol)

686(2%)=(M+Na)+, 663(4%)=M+, 661(6%), 572(3%)=(M-Bn)+, 554(3%)=(M-Bn-H20)+, 463(4%), 391(12%), 307(14%), 289(12%), 271(16%), 181(96%), 154(100%), 136(84%), 107(50%), 91(100%), 81(46%), 69(40%), 55(76%), 43(64%), 29(20%).

Then, to obtain the derivative 7 can be deoxis the plan, using different ways (direct or radical restoration, through acetate, tosylate, xanthate derivatives).

The saponification can be carried out almost quantitatively under different conditions, with the hydroxides of sodium, potassium or lithium, in an aqueous solution of ethanol or THF (Fig.6):

Into the flask containing ester 6 (0.5 g, about 1.75 mmol, 1 EQ.) in tetrahydrofuran (5 ml) or ethanol (5 ml), add an aqueous solution Litin LiOH (2M, 0?75 ml, 2 EQ.) or an aqueous solution of caustic soda NaOH (0.07 g, 1.6 mmol), and then stirring is continued for twelve hours. If you are using ethanol, the reaction mixture is evaporated, then the residue is added dichloromethane. The mixture was acidified with 1M hydrochloric acid, HCl, and then extracted several times with dichloromethane. The organic phase is collected, dried over MgSO4filter and concentrate.

The resulting product is a colorless oil, and the yield is quantitative.

These NMR:

19F-NMR (CDCl3, of 282.5 MHz)

-117,4, d (2JF-F=GC); -119,1, d (2JF-F=GC).

1H-NMR (CDCl3, 300 MHz):

3,40-3,60 m, 3H, H5 and H6; 3,90-4,00 m, 3H, H2, H3 and H4; to 4.38-4,79, m, 8H, 4 CH2(OBn); 7,05-7,22, m, 20H, H-arene.

13C-NMR (CDCl3, 75.5 MHz)

68,6 (C6); 72,2 (C5); 73,5, 75,5, 75,9, 76,4 (4 CH2(OBn)); 77,7, 78,5, with 83.6 (C2; C3 and C4); 96,0, DD,2JC-F=27,0 Hz and2JC-F=28,Hz, -CF2C1(OH)O-; to 112.4, DD,1JC-F=260,3 Hz and1JC-F=259,2 Hz, CF2; 128,1, 128,, 128,4, 128,8, 128,9 129,0 (arene. With); 137,2, 137,7, 137,9, 138,6 (arene. C, Quaternary) 163,6, DD,2JC-F=30,5Hz and2JC-F=32,8gts, CF3COOH.

The synthesis of heme-difterinogo connection of compounds 6 and 7

Interaction with amines

This reaction makes it possible to access very interesting compounds, analogues of glycopeptides.

Derivatives of compound 6 interact with various primary or secondary amines with the corresponding amides. Used amines are aliphatic, benzyl or aromatic amines and derivatives of amino acids such as lysine (Fig.7):

In an inert atmosphere in the flask containing the solution of the original product 6 (50 mg; 0,075 mmol; 1 EQ.) and Boc-lysine-OMe acetate 8 (48 mg; 0.15 mmol; 2 EQ.) in dichloroethane EDC (3 ml), add triethylamine Et3N (53 μl; the 0.375 mmol; 5 EQ.). The mixture is heated at the boil under reflux for forty-eight hours, and then the solvent evaporated.

Purification of the crude product by chromatography on a column of silica gel using a mixture of cyclohexane/ethyl acetate in a ratio of seven to three as eluent.

After concentration of the product 9 is obtained as light-yellow solid product with a yield of 84 wt.%.

These NMR:

19F-NMR (CDCl3, of 282.5 MHz)

-117,4, D., (2JF-F=GC); 121,9, d, (2JF-F=GC).

1H-NMR (CDCl3, 300 MHz)

1,18-1,60, m, 15 H, (CH3)3C, and (CH2)3; 3,06-3,19, m, 2H, CH2N; 3,52 at 3.69, m, 6 H, H5; H6 and CO2CH3; 3,84-4,18 m, 4H, H2; H3; H4 and CHN; 4,36-4,85 m, 8H, 4 CH2Bn; 5,01, d, J=8,3 Hz, 1H, NHBoc; 6,60 m, 1H, NH; 7,10-7.23 percent, m, 20N, arene. N.

13C-NMR (CDCl3, 75.5 MHz)

22,7, 28,8 ((CH2)2); 28,9 ((CH3)3C); 32,5 (CH2); 39,6 (CH2N); 52,7 (CO2CH3); 53,6 (CHN); 68,7 (C6); 73,6, 75,3, 75,8, 76,4 (4 CH2Bn); 72,1, 77,9, 78,6, 83,6 (C2, C3, C4 and C5); 96,1, DD,

2JC-F=27,4 Hz (CF2CO(OH)); 112,5, DD,1JC-F=261,GC (CF2); 127,6, 127,7, 127,8, 128,3, 128,4, 128,5 (arene. C)137,5, 137,9,138,0, 138,3 (arene. C, Quaternary); 155,6 (CO2Me); of 163.7, DD,2JC-F=27.4 Hz (CF2CONH); TO 173.3 (NHCO2tBu).

Glycosylamine derived alanine can be obtained from compound 6 (Fig) or from compound 7 (figure 9) according to three different methods.

First A method identical to the method used for compound (9), derived from lysine. The yield by weight for the compound (11) is 30% (Fig).

The second method B (Fig.9) is as follows.

In an inert atmosphere BOP (benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium hexaflurophosphate) (35 mg; 7,87·10-3mmol; 1 EQ.) and diisopropylethylamine DIEA (28 μl; 0,016 mmol; 2 EQ.) injected into the flask containing the acid 7 (50 mg; 7,87·10-3mmol; 1 EQ.) in dichloromethane is DHM (2 ml). The reaction mixture is stirred for one hour, and then add to it a solution consisting of alanine 10 (11 mg; 7,87·10-3mmol; 1 EQ.) and DIEA (14 μl; 7,87·10-3mmol; 1 EQ.) in dichloromethane (2 ml). Stirring is continued for twenty-four hours. The mixture is then washed with a 1M solution of hydrochloric acid HCl. The organic phase is dried over magnesium sulfate, filtered and evaporated.

Then the crude product is purified by preparative plate silica gel using a mixture of cyclohexane/ethyl acetate as eluent in a ratio of seven to three.

The product 11 is manufactured in the form of white crystals with a yield of 77 wt.%.

The third method C (Fig.9) is as follows:

In an inert atmosphere in the flask containing the acid 7 (50 mg; 7,87·10-3mmol; 1 EQ.) in dichloromethane (2 ml), injected BOPCl (bis-(2-oxo-3-oxazolidinyl)fatfingered) (40 mg; 7,87·10-3mmol; 1 EQ.) and diisopropylethylamine DIEA (28 μl; 0,016 mmol; 2 EQ.). Thereafter, stirring is continued for one hour, then added to the reaction mixture solution consisting of alanine derivative 10 (22 mg; 0,016 mol, 2 EQ.) and diethylamine DIEA (44 μl; is 0.023 mmol; 3 EQ.) in dichloromethane (2 ml). Stirring is continued for twenty-four hours, then the mixture was washed with 1M HCl solution. The organic phase is dried over magnesium sulfate, filtered and evaporated.

C is the crude product is purified by preparative plate silica gel using a mixture of cyclohexane/ethyl acetate in a ratio of seven to three as eluent.

The product 11 is manufactured in the form of white crystals with a yield of 44 wt.%.

These NMR:

19F-NMR (CDCl3, of 282.5 MHz)

-118,0, D., (2JF-F=GC); -122,2, D., (2JF-F=GC).

1H-NMR (CDCl3, 300 MHz)

1,26, f,3J=7,2 Hz, 3 H, CH3; 3,50-3,66 m, 3H, H5 and H6; 3,63, C, 3 H, CO2CH3; the 3.89-3.96 points, m, 3H, H2, H3 and H4; 4,40-4,81, m, 10 H, NH; and 4 CHN CH2Bn; 7,11-7,21, m, 20H, arene. H

13C-NMR (CDCl3, 75.5 MHz)

16,7 (CH3); 47,2 (CHN); 51,7 (CO2CH3); 67,3 (C6); 72,3, 73,9, 74,3, 75,0 (4CH2Bn); 70,9, 76,2, 77,1, 82,2 (C2, C3, C4 and C5); 126,6-127,4, m (arene. C); 136,5, 136,9, 137,0, 137,4 (arene. C, Quaternary); 171,0 (CO2Me).

Binding assays with the following amino acids such as phenylalanine, threonine, methionine, Proline, and the dipeptide, is performed with the use of BOPCl as a condensing agent, i.e. in accordance with the same method that is used when linking with alanine (figure 10).

Product 12b receive in the form of white crystals with a yield of 42 wt.% (11).

These NMR:

19F-NMR (CDCl3, of 282.5 MHz)

-117,7, D., (2JF-F=GC); -121,6, D., (2JF-F=GC).

1H-NMR (CDCl3, 300 MHz)

3,07 m, 2 H, CH2Ph; 3,44-3,67 m, 3h, H5 and H6; 3,57, C, 3 H, CO2CH3; 3,91-3,98 m, 3 H, H2, H3 and H4; 4,25-4,85 m, 10 H, NH, and 4 CHN CH2Bn; 7,00-7,14, 25 H, Aran

13C-NMR (CDCl3, 75.5 MHz)

37,5 (CH2Ph); 52,4 (CO2CH3); 53,1 (CHN); 6,3 (C6); 73,2, 75,0, 75,3, 76,0 (4 CH2Bn); 72,0, 77,0, 78,2, 83,2 (C2, C3, C4 and C5); RUB 127.3-to 129.3, m (arene. With); 135,0, 137,5, 137,9, 138,0, 138,4 (arms, Quaternary); 170,3 (CO2Me).

Product 12c receive in the form of white crystals with a yield of 28% by weight (Fig).

These NMR:

19F-NMR (CDCl3, of 282.5 MHz)

-118,3, D., (2JF-F=GC); -121,2, D., (2JF-F=GC).

1H-NMR (CDCl3, 300 MHz)

1,12, f,3J=6,4 Hz, 3H, CH3; 3,48-3,64 m, 3H, H5 and H6; 3,7, s, 3H, CO2CH3; 3,89-4,00 m, 3H, H2, H3 and H4; 4,22-4,82, m, 11H, NH; CHN,CHOH and 4 CH2Bn; 7,0-7,24 m, 20H, arene H.

13C-NMR (CDCl3, 75.5 MHz)

20,5 (CH3); 53,2 (CO2CH3); 57,8 (CHN); 68,6 (CHOH); 68,7 (C6); 73,5, 75,4, 75,8, 76,4 (4 CH2Bn); 72,2, 77,2, 78,4, 83,6 (C2, C3, C4 and C5); 128,1 are 128.9 m (arene. C); 137,8, 137,9, 138,1, 138,7 (arene. C, Quaternary); 170,5 (CO2Me).

Product 12d get with the release of 36 wt.% (Fig).

These NMR:

19F-NMR (CDCl3, of 282.5 MHz)

-117,4, D., (2JF-F=GC), -121,7, D., (2JF-F=260 Hz).

1H-NMR (CDCl3, 300 MHz)

1,89-1,99, m, 2H, CH2; 2,09, s, 3H, SCH3; 2,46, t3J=7,0 Hz, 2H, CH2S; to 3.58-of 3.77, m, 3H, H5 and H6; 3,68, s, 3H, CO2CH3; 3,96-4,03 m, 3H, H2, H3 and H4; 4,43-4,88 m, 10H, NH; and 4 CHN CH2Bn; 7,14-7,30 m, 20H, arene. H.

13C-NMR (CDCl3, 75.5 MHz)

15,7 (CH2); 29,9 (SCH3); 31,6 (CH2S); 51,8 (CO2CH3); 53,2 (CHN); 68,6 (C6); 73,6, 75,4, 75,8, 76,4 (4 CH2Bn); 72,4, 77,4, 78,5, 85,6 (C2, C3, C4 and C5); 128,1 are 128.9 m (arene. C); 137,9, 138,3, 138,5, 138,8 (arms, even artigny) ;which is 171,5 (CO2Me).

Product 12e receive in the form of white crystals with a yield of 32 wt.% (Fig).

These NMR:

19F-NMR (CDCl3, of 282.5 MHz)

-112,6, D., (2JF-F=GC); -113,7, D., (2JF-F=GC); -117,2 d (2JF-F=GC); -117,3, D.,(2JF-F=GC).

1H-NMR (CDCl3, 300 MHz)

1,52-1,89, m, 4H, (CH2)2; 3,5-3,63 m, 3H, H5 and H6; to 3.67, s, 3H, CO2CH3; 3,82-4,06 m, 5H, CH2N; H2; H3 and H4; 4,33-4,92 m, 9H, CHN and 4 CH2Bn; 7,10-7,20 m, 20H, arene. H.

Product 12f receive in the form of white crystals with a yield of 17 wt.% (Fig).

These NMR:

19F-NMR (CDCl3, of 282.5 MHz)

-117,6, D., (2JF-F=GC); -122,4, D., (2JF-F=GC).

1H-NMR (CDCl3, 300 MHz)

1,35, f,3J=7,2 Hz, 3H, CH3; 3,05 m, 2H, CH2Ph; 3,5-3,71, m, MN, H5 and H6; 3,70, s, 3H, CO2CH3; 3,89-4,01 m, 3H, H2; H3 and H4; 4.26 deaths-4,89, m, 11H, NH, 2 and 4 CHN CH2Bn; 6,05 m, 1 H, NH; 7,10-7,20, m, 25H, arene. H.

Compound 7 can also be used in the reaction IGO with an amine, such as benzylamine 18, aldehyde 19 and isonitriles, such as utilitzant 20, to obtain the compounds 13-17.

This method for the synthesis of therapeutic compounds (manno - and mucopeptide), which are inhibitors of the binding between selectin and tetrasaccharides, Sullom Lewisx(sLex).

Leukocytes play an important role in many inflammatory and immunodeficiency, the ideological phenomena. In many of these phenomena first stage represent the interaction between endothelial cells and leukocytes in the bloodstream.

Studies of molecules that are specific to the cell surface involved in these interactions showed,what leukocytes and endothelial cells have on their surface a specific lectins called selectins. They are molecules from the family of Kalnyshevsky molecules responsible for cell adhesion. sLexrepresents one of the ligands involved in binding between selectins, thereby causing adhesion of leukocytes to endothelial tissue, leading to acute forms of disease, such as rheumatoid arthritis, psoriasis, cancer.

As a consequence, the development of sLex-inhibiting small molecules represents an attractive therapeutic approach.

Synthesis of compound 13 (Fig).

All reagents were diluted with dry methanol to obtain a concentration of 1M.

A 25 ml flask was placed a solution of hexanal (of 0.081 ml; 0,675 mmol) with a solution of benzylamine 18 (0,059 ml, 0.54 mmol) and the mixture is stirred in an argon atmosphere for two hours at room temperature.

Then in the solution add utilitarianistic 20 (0,074 ml; 0,675 mmol) and a solution of heme-diflorasone D-glucose as the acid 7 (286 mg; 0.45 mmol)and the mixture is stirred in an argon atmosphere within twenty-four hours at room temperature.

Then the methanol is evaporated and purification of the product is carried out by chromatography on a column of silica gel with a gradient elution with a mixture of ethyl acetate/cyclohexane as eluent in proportions in the range from 1:9 to 2:8.

TLC

Rf = 0,18, eluent: ethyl acetate/cyclohexane (2:8).

These NMR:

19F-NMR (CDCl3)

-104,39 (d2JF-F=260,1 Hz); -104,85 (d2JF-F=257,GC); -108,61 (d2JF-F=255,8gts); -108,89 (d2JF-F=254,GC); -108,95 (d2JF-F=260,1 Hz); -112,49(d2JF-F=255,8gts); -114,35 (d2JF-F=254,GC); -116,17 (d2JF-F=257,GC).

1H-NMR (CDCl3)

0,69, t, 3H, H2O,3JH19-H20=6,GC; 0,90-1,10, m, 6H, 1,15, m, 5H, H13JH1-H2=7,1 Hz; 3,41-3,74, m, 4H; 3,78-3,99, m, 4H; 4,07, kV, 2H, H2,3JH1-H2=7,1 Hz; 4,36-4,55, m, 4H; br4.61-6,97, m, 8H; 6,76, t, 0,7H, H5,3JH4-H5=5,5Hz; 6,82, t,0,3H, H5rotamer,3JH4-H5=5,3 Hz; 7,00-7,26, m, 25H, NPh.

Mass spectrometry: (direct input, FAB+):

M+Na = 959,6

M+K = 975,7

Synthesis of compound 14 (Fig):

All reagents were diluted with dry methanol to obtain a concentration of 1M.

The solution trimethylacetaldehyde (0,073 ml; 0,675 mmol) together with a solution of benzylamine 18 (0,059 ml, 0.54 mmol) is placed in a flask with a capacity of 25 ml and the mixture is stirred in an argon atmosphere for two hours at room temperature.

Then d is billaut solution ethylisothiocyanate 20 (0,074 ml; 0,675 mmol) and a solution of heme-diflorasone D-glucose as the acid 7 (286 mg; 0.45 mmol) and the mixture is stirred in an argon atmosphere within twenty-four hours at room temperature.

The methanol is evaporated and purification of the product is carried out using chromatography on a column of silica gel using gradient elution with a mixture of ethyl acetate/cyclohexane as eluent in proportions of from 1:9 to 3:7.

The resulting product is a yellow oil in the form of two diastereoisomers who share.

Analyses of the 1st diastereoisomer 14a

TLC

Rf = 0.70 and, eluent: ethyl acetate/cyclohexane (4:6).

These NMR:

19F-NMR (CDCl3)

-105,31 (d2JF-F=267,0Hz); -106,69 (d2JF-F=267,0 Hz).

1H-NMR (CDCl3)

0,99, s, 9H, H18; 1,16, m, 3H, H1,3JH1-H2=6,GC; 3,39-3,65, m, 4H; 3,90, DD, 2H, J=8,Hz; 4,00-4,15, kV, 3H, H2,3JH1-H2=6,GC; 4,37, d, 1H, J=11,GC; 4,49, t, 2H, J=I0,GC; 4,69 is equal to 4.97, m, 7H; of 5.53, s, 1H, H7; of 6.49 m, 1 H, H5; 7,08-7,27, m, 25N, HPh.

Mass spectrometry: (direct input, FAB+):

M+Na = 945,4

Analyses of the 2nd diastereoisomer 14b

TLC

Rf = 0,65, eluent: ethyl acetate/cyclohexane (4:6).

These NMR:

19F-NMR (CDCl3)

-107,15 (d2JF-F=255,GC).

1H-NMR (CDCl3)

1,02, s, 9H, H18; 1,16, m, 3H, H1,3JH1-H2 =7,0 Hz; 3,52-4,00 m, 9H; 4.09 to, kV, 2H, H2,

J3H1-H2=7,0 Hz; 4,33-4,86, m, 8H; equal to 4.97, DD, 2H, H16N16',2JH16-H16'=17.3 Hz; 5,33, c, 1H, H7; of 6.49 m, 1H, H5; 6,98-7,27, m, 25N, NPh.

Mass spectrometry: (MALDI+):

M+Na = 945,4

Synthesis of compound 15 (Fig)

All reagents were diluted with dry methanol to obtain a concentration of 1M.

A solution of 3,4,5-trimethoxybenzaldehyde 22 (0,132 g; 0,675 mmol) together with a solution of benzylamine 19 (0,059 ml, 0.54 mmol) is placed in a flask with a capacity of 25 ml and the mixture is stirred in an argon atmosphere for two hours at room temperature.

Then add a solution of ethylisothiocyanate 20 (0,074 ml; 0,675 mmol) and a solution of heme-diflorasone D-glucose as the acid 7 (286 mg; 0.45 mmol) and the mixture is stirred in an argon atmosphere within twenty-four hours at room temperature.

The methanol is evaporated and purification of the product is carried out using chromatography on a column of silica gel using gradient elution with a mixture of ethyl acetate/cyclohexane as eluent in a proportion in the range from 1:9 to 3:7.

The resulting product is a yellow oil in the form of two diastereoisomers 15a, 15b, who share.

Analyses of the 1st diastereoisomer 15a

TLC

Rf = 0,4l, eluent: ethyl acetate/cyclohexane (4:6).

These NMR:

19F-NMR(CDCl 3)

-111,63, C.

1H-NMR (CDCl3)

1,18, t, 3H, H1,3JH1-H2=7,2 Hz; 3,38, t, 1 H, J=6,GC; to 3.58, s, 9H, H17, 3,65, s, 4H; 3,93-4,14, m, 7H; 4,40-4,53, m, 3H; 4,70-4,87, m, 3H; 4,86, DD, 2H, H16N16',2JH16-H16'=16,GC; 5,33, s, 1H; 6,38, s, 1H, H7; to 6.43, t, 1 H, H5,3JH4-H5=4,5Hz; 6,90-of 7.25, m, 27H, HPh.

Mass spectrometry: (direct input, FAB+);

M+Na= 1055,7

Analyses of the 2nd diastereoisomer 15b

TLC

Rf = 0,32, eluent: ethyl acetate/cyclohexane (4:6).

These NMR:

19F-NMR (CDCl3)

-108,12 (d2JF-F=251,GC); -115,19 (d2JF-F=251,GC)

1H-NMR (CDCl3)

1,17, m, 3H, H1,3JH1-H2=7,0 Hz; 3,32-3,41, m, 1H; 3,65, s, 9H, H17; 3,70, s, 3H; 3,78-3,98, m, 5H; 4,08, kV, 4H, H2,3JH1-H2=7,Hz 0 Hz; 4,32, s, 2H; 4,60, DD, 2H, J=10,GC; 4,67, s, 2H; 4,87, s, 1H; 5,09, s, 1H; 6,30, t, 1H, H5,3JH4-H5=4,Hz; 6,52, s, 2H, H7; 6,86-7.23 percent, m, 271, HPh.

Mass spectrometry: (direct input, FAB+):

M+Na = 1055,7

Synthesis of compound 16 (Fig)

All reagents were diluted with dry methanol to obtain a concentration of 1M.

In a flask with a capacity of 25 ml was placed a solution of benzaldehyde (0,059 ml, 0.54 mmol) and the solution benzylamine 18 (0,059 ml; 0,675 mmol) and the mixture is stirred in an argon atmosphere for two hours at room temperature.

Then add a solution of ethylisothiocyanate 20 (0,074 ml; 0,675 mmol) and a solution of heme-WPPT is arrowanas D-glucose as the acid 7 (286 mg; 0.45 mmol) and the mixture is stirred in an argon atmosphere within twenty-four hours at room temperature.

The methanol is evaporated and purification of the product is carried out using chromatography on a column of silica gel using gradient elution with a mixture of ethyl acetate/cyclohexane as eluent in a proportion in the range from 1:9 to 3:7.

The product is obtained in the form of two diastereoisomers 16a, 16b, who share.

Analyses of the 1st diastereoisomer 16a

TLC

Rf = 0,26, eluent: ethyl acetate/cyclohexane (3:7).

These NMR:

19F-NMR (CDCl3)

-111,66, s, 2F.

1H-NMR (CDCl3)

1,15, m, 3H, H1,3JH1-H2=7,0 Hz; 3,52-3,79, m, 3H; 3,83, DD, 1H, J=4,5Hz; 3,90-4,01 m, 4H, 4,07, kV, 2H, H2, J=7,0 Hz; 4,36-to 4.52, m, 4H; 4,68-4,82, m, 5H; 4,94, DD, 2H, H16,2JH16-H16'=15,8gts; 5,20, s, 1H, H7; 6,29, t, 1H, H5,3JH4-H5=4,5Hz; of 6.96-7.23 percent, m, N, HPh.

13C-NMR (CDCl3):

14,2, C1; 41,6, C4; 52,0, 61,6, C2; 66,2, 68,5, 71,7, 73,5, 75,1, 75,4, 75,9, 77,5, 78,6, 83,5, 96,9, t10,2JC10-F=27,GC; 114,3, t, C9,1JCF=262,GC; 126,9, 127,2, 127,7, 127,8, 127,9, 128,0, 128,1, 128,2, 128,3, 128,4, 128,5, 128,5, 128,6, 128,8, 130,0, 133,0, 136,3, 137,8, 138,0, 128,6, 165,1, t8,2JC8-F=26,4 Hz; 168,3; 169,7.

Mass spectrometry: (MALDI+):

M+Na = 965,5

M+K = 981,5

Analyses of the 2nd diastereoisomer 16b

TLC

Rf = 0,71, eluent ethyl acetate/cyclohexane (5:5).

These NMR:

19F-NMR (CDCl3)

-107,71(d2JF-F=253,1 Hz); -115,09 (d2JF-F=253,1 Hz).

1H-NMR (CDCl3)

1,16, m, 3H, H1,3JH1-H2=7,0 Hz, 3,35 is 3.40, m, 1H; 3,51-3,70, m, 4H; 3,84-4,00, m, 5H; 4,08, kV, 2H, H2,3JH1-H2=7,0 Hz; 4,23, s, 1H; 4,62, DD, 2H, J=9,GC; 4,67, s, 1H; 4,81, d, 1H, J=3,8gts; 4,98, s, 1H; 5,08, d, 1H, H16or H16'N16',2JH16-H16'=18,0 Hz; between 6.08, t, 1H, H5,3JH4-H5=4,Hz; 6,76-6,85, m, 1H; 6,95-7,29, m, N, HPh.

Mass spectrometry: (MALDI+):

M+Na = 965,4

M+K = 981,3

Synthesis of compound 17 (Fig)

First diastereoisomer ethyl ether (2-{benzyl-[2,2-debtor-2-(3(R),4(S)-Tris-benzyloxy-6(R)-benzoyloxymethyl-2(R)-hydroxyethylamino-2-yl)acetyl)amino}-2-phenylacetylamino)acetic acid 16a (0,139 g, 0.147 mmol) was placed in a flask with a capacity of 25 ml together with 6.6 ml of methanol and a pinch of 10% palladium on charcoal (Pd/C) with a spatula. After establishing a vacuum is connected inflatable chamber with hydrogen and stirring is continued overnight at room temperature.

The solution is filtered on celite, then evaporated, getting the product 17 in the form of white crystals.

These NMR:

19F-NMR (CD3OD)

-108,37 (d2JF-F=261,GC); -109,29 (d2JF-F=256,8gts), -111,04 (d2JF-F=261,GC); -115,44 (d2JF-F=256,8gts); -120,50, C.

1H-NMR (CD3OD)

1,19,t, 3H, H1,3JH1-H2=7,1 Hz; 3,39-3,52, m, 1H; 3,59-3,98, m, 7H; 4,04-4,19,m, 2H; 4,28, DD, 1H,2J=17,GC; 5,22, DD, 1H, H16H16'N16',2JH16-H16'=17,GC; 5,67, s, 1H, H7; 6,69-7,40 m, 10H, HPh

Mass spectrometry: (direct input, FAB+):

M+Na = 605,0

In a series of glucose describes how to obtain the amide 21 (Fig. 22).

In the flask with a capacity of 50 ml in an argon atmosphere ester 6 (rate of 0.193 g, 0,291 mmol, 1 EQ.) dissolved in anhydrous dichloromethane (5 ml). Add pair-methoxybenzylamine 22 (0,057 ml, 0,436 mmol, 1.5 EQ.) and the mixture is left under stirring overnight. Then the solution is evaporated in vacuum.

Cleaning is carried out by chromatography on a column of silica gel using a mixture of cyclohexane/ethyl acetate in a ratio of nine to one as eluent.

After concentration of the product 21 is received in the form of a white solid, yield 56 wt.% weight.

The analyses carried out to confirm the structure of the obtained product 21 below:

TLC

Rf = 0.52 in, eluent: ethyl acetate/cyclohexane (3:7).

These NMR:

19F-NMR (282 MHz; solvent: deuterated chloroform (CDCl3)): -117,38, d, JF-F=GC; -121,90, d, JF-F=GC

1H-NMR (300 MHz; solvent: deuterated chloroform (CDCl3))

3,3-5, m, 16H (cycle+4×OBn); 3,66, s, 3H: - CH3(OMe); 6.73 x, d, J=8,4 Hz, 2H: 2CH (PMB); 7,07, d, J=8,4 Hz, 2H: 2CH (PMB); 7,14-7,24 m, 20H: 4x5 CH (Ph).

13C-NMR (75.5 MHz; solvent: deuterated chloroform (CDCl3)):

43,35, CH2(PMB); 55,68, CH3(OMe), 68,68, CH2(C6); 73,06, CH; 73,82, 75,47, 75,67, 76,37: 4×CH2(OBn); 77,83, CH; 78,62, CH; 83,79, CH; 96,59, DD, JWith the-F=28,Hz and JWith the-F=26,Hz, -CF2CH(OH)O-; 112,79, DD, JC-F=263,Hz and JC-F=259,GC, CF2; 114,60, 2 CH(RMV); 137-138 CH(Ph+PMB); 159,71, With Quaternary (C-OMe PBM); 163,32, DD, JC-F=31,Hz and JWith the-F=31,0 Hz, CF2CONH.

The reduction of the ester functional group

Conversion of the ester functional group defloration C-glycosides in other functional groups can be obtained in a wide range of glycoconjugates. Was investigated the reactivity of such α-ester group functions deformational group and mainly its recovery.

Ester functional group of the compound 2 (or 6) is restored to a functional group of alcohol use tetraborate sodium (NaBH4or sociallyengaged (LiAlH4) to obtain compound 23 (Fig). Then the functional group of the alcohol, this compound is oxidized to aldehyde functional group to obtain compound 24 in various ways, such as how Swarna, dessa-Martin.

It should be noted that the immediate recovery of the alcohol to the aldehyde using diisobutylaluminium the IDA (DIBAH) in neotenic connections.

Recovery of ester 25 to alcohol 26 (Fig. 23).

Ester 25 (30 mg; 45 nmol; 1 EQ.), tetraborate sodium NaBH4(5 mg; 134 nmol; 3 EQ.) and 5 ml of ethanol (EtOH) is placed in a flask with a capacity of 25 ml

The solution is kept under stirring at room temperature overnight, and then evaporated to dryness in a vacuum.

A white precipitate is re-dissolved in 10 ml of water and 10 ml of dichloromethane.

The phases are separated, the aqueous phase is extracted with dichloromethane (2×10 ml), the organic phase is collected, dried over anhydrous magnesium sulfate and evaporated in vacuum, receiving 24 mg of alcohol 26 (38 nmol), exit 86 wt.%.

The analyses carried out to confirm the structure of the obtained product 26 below:

TLC

Rf = 0,44, eluent: ethyl acetate/cyclohexane (8:2).

These NMR:

19F-NMR (282 MHz; solvent: deuterated chloroform (CDCl3))

-110,68, EBM,2JF-F=259,7 Hz, JF-Nnot measured; -117,8 DM,2JF-F=259,7 Hz, JF-Nnot measured

1H-NMR (300 MHz; solvent: deuterated chloroform (CDCl3))

0,00,, 6N (2 CH3TBDMS); 0,84, c, 9H (3 CH3TBDMS), 3,39-4,96, m, 15 NM; 7.23 percent-7,33 m, 15H(3x5CH Ph)

13C-NMR (75.5 MHz; solvent: deuterated chloroform (CDCl3)) -DEPT 135

5.04 and -5,09, 2CH3(TBDMS), 26,25, 3CH3(TBDMS); 62,37, CH2(C6); 64,16, CH2, t,2JC-F=31 Hz (CF2CH2O); 73,23, 74,87 and

75,64, 3×CH2(OBn); 73,45, 74,80, 79,52 and 84,81, 4×CH (C2 and C5); 78,15, CH, DD,2JC-F=26 and 29 Hz; 128,1 are 128.9, 3×5 CH (OBn).

Evaluation of the stability hamptonyoung glycopeptides of the present invention.

Obtained in accordance with the present invention dipteronia analogues of the following derivatives were subjected to with the aim of determining the stability of CH2communication in a biologically active environment, and then were evaluated for their inhibitory capacity.

The evaluation found that experiencing two derivatives are not subjected to decay even after 5 days and the original material remained unchanged.

The test was performed in accordance with the following method.

A solution of tert-butyl methyl ether glikopeptid:galactose-phenylalanine-valine (17,72 mg; 0.3 mmol) in water (500 μl) was added to phosphate buffer (0,07 M; pH 7, 4 ml)containing alpha-galactosidase (5 links) and beta-galactosidase (6.25 units) at 37°C. the Reaction was monitored using19F NMR. The first definition was done after 24 hours, then 48, 72, 96 and 120 hours. No changes in fluoride communication was not observed in the results19F NMR and, therefore, no degradation has not occurred.

Experimental data of the IP is the same material and extracted tert-butyl ether galactose-phenylalanine-valine connections are presented below:

NMR19F(CD2OD, 282.5 MHz)

-119,3 (d, JF-F=261 Hz); -121,0 (d, JF-F=261 Hz); -121.3 (d, JF-F=261 Hz); -122,4 (d, JF-F=261 Hz).

NMR1H(CD3OD, 300 MHz)

0,97 (d, 6.7, 6H, 2SN3); 1.5 (s, 9H, 3CN3); 2,09-of 2.16 (m, 1H, CH); 1.9 (m, 2H, CH2); 3,0-3,1 (dd, 8,05 and a 14.1 Hz; 1H, hN2); 3.2 and 3.3 (dd, 5,4 and a 14.1 Hz, 1H, PhCH2); 3.5 to 3.8 (m, 4H); 4,1-4,2 (m, 2H, CHNH (Val)); 4.3 (d, 1H); 4.8 (m, 1H, CH(Phe), H2); to 7.2 (m, 5H,Har.

A similar experiment was also conducted and a derivative of glucose. However, the resulting test data showed the same stability after 5 days on alpha - and beta-field of glycosidase inhibition.

Experimental data confirmed the known from the prior art is the fact that the introduction of fluorine atom enhances communication and thus demonstrated the possibility of obtaining stable polypeptides when linking them with polymer molecules.

1. Hem-diflorasone compound of the formula:

where R1represents a group containing an alkyl chain, substituted by at least one amino group, an acid functional group or amide group;
R2represents a hydrogen atom or a free or protected functional group of alcohol;
R3represents a group CH2OH, CH2-OGP, where GP represents the t of a protective group, such as an alkyl, benzyl (Bn), trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetate (AC);
Y, Y', Y" are independent of the group OR, where R represents H, benzyl, Ac, TMS, TBDMS, TBDPS.

2. Hem-diflorasone compound of General formula:

where R5and R6represent H or a carbon chain bearing aminoclonazepam group, CO2CH3, amino group, amino acid group, benzyl group, phenyl group, 4-metoksifenilny group, 3,4,5-trimethoxyphenyl group, HE, S-methyl group, or
R5and R6together with the nitrogen atom to which they are attached, form a 5-membered saturated ring, substituted CO2CH3in position 2, the peptide chain protein;
R2represents a hydrogen atom or a free or protected functional group of alcohol;
R3represents a group CH2HE, CH2-OGP, where GP represents a protective group such as an alkyl, benzyl (Bn), trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetate (AC);
Y, Y', Y" are independent of the group OR, where R represents H or benzyl, MSS, TMS, TBDMS, TBDPS.

3. A method of obtaining a heme-difterinogo the compounds of formula:

where R1isone acid functional group, amide group, or C(=O)NR5R6;
R2represents a hydrogen atom H or a free or protected functional group of alcohol;
R3is a group H, CH3CH2OH, CH2-OGP, where GP represents a protective group such as an alkyl, benzyl (Bn), trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetate (AC);
Y, Y', Y" are independent of the group OR, where R represents H, benzyl, Ac, TMS, TBDMS, TBDPS;
R5and R6represent H or a carbon chain bearing aminoclonazepam group, CO2CH3, amino group, amino acid group, benzyl group, phenyl group, 4-metoksifenilny group, 3,4,5-trimethoxyphenyl group, HE, S-methyl group, or R5and R6together with the nitrogen atom to which they are attached, form a 5-membered saturated ring, substituted WITH2CH3in position 2, a peptide chain, a protein, including the interaction of the lactone of the formula:

with a halogenated derivative of General formula called XCF2CO2R8where X represents halogen, and R8represents alkyl, aryl, in the presence of zinc or lanthanide derived from the allocation of the specified product and optional saponification of the specified product to the acid and the latter is the fact that the reaction IGO specified product, acid and/or deoxygenating product or acid with an amine, aldehyde and isonitrile.

4. The method according to claim 3, characterized in that the derivative of sugar get in one or several stages from the corresponding commercially available sugar.

5. The method according to claim 4, characterized in that the specified interaction should deoxyadenosine.

6. The method according to claim 4, wherein R8the group includes ester functional group, which is reduced to alcohol.

7. The method according to claim 4, wherein R8the group includes an ester functional group, which is either restored to the alcohol and then oxidized to aldehyde or polyacetale, either directly restored to the aldehyde.



 

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7 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: composition is obtained by mixing of (a) first polyurethane with end silane groups obtained by interreaction of: (i) monofunctional compounds with (ii) isocyanate component containing two isocyanate groups and following interreaction of reaction product of components (i) and (ii) with (iii) compound containing group reactive toward isocyanate and one or more reactive silane groups whereat at least 10 mole % of component (iii) is compound of formula (I): with formation of moisture-crosslinked alcoxysilane functional polyesterurethane; and (b) second polyurethane with end silane groups obtained by interreaction of: (i) linear, branched or cyclic alkylmonofunctional alcohol containing 1-20 of carbon atoms, amine and/or thiol with (ii) isocyanate component containing two isocyanate groups and with product of the interreaction of components (i) and (ii) with compound (iii) containing group reactive toward isocyanate and one or more reactive silane groups corresponding to formula (I).

EFFECT: coating films applied to the substrate possess excellent tensile strength and tensile elongation which provides reducing of film cracking, blistering and peeling.

17 cl, 4 ex

FIELD: transportation.

SUBSTANCE: invention is related to composite materials used for increase of friction coefficient between wheels of transport means and working surface, and may find application in motor, aviation, construction and other industries. Composite material is described, which provides for motion of transport vehicle on slippery snow or ice surface made of composition that contains wood chips in amount of 40-97 wt %, water solution of sodium chloride or calcium chloride or potassium chloride in amount of 1-30 wt %, 1-30 wt % of soot and 1-25 wt % of wollastonite, besides, average size of soot and wollastonite particles makes from 1 mcm to 250 mcm. Method is also described for production of composite material, which provides for motion of transport vehicle on slippery snow or ice surface. Method includes preparation of aqueous solution of sodium or potassium or calcium chloride, mixing of wood chips, soot and wollastonite in solution of sodium or calcium or potassium chloride, separation of suspension by filtration, drying of produced mixture at temperature of 80-150°C and packing of dried product.

EFFECT: improved friction properties between wheel of transport vehicle and slippery surface, elimination of slipping and wheel skidding on ice.

3 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: making of compositional ferroabrasive powder includes mixing of the wet ferromagnetic powder component (iron powder) with dried at temperature 80-120°C adhesive structure-forming component - powder of nanocrystall aluminium hydroxide γ-AlOOH. Then abrasive powder component (diamond powder) and binding component are added. The mixture is agitated up to obtaining of homogenous structure and heated up to temperature of composition dehydratation - 290-350°C. Ferroabarsive compositional powder with desired particle size is formed by its rubbing through corresponding calibrated sieves. Ferroabrasive composite powder components have the following volume ratio: ferromagnetic component - 30-65%, adhesive -forming component - 30-40%, abrasive component up to 15%, binding component - the rest.

EFFECT: quality improvement of processed surfaces alongside with increase of material removal intensity, increase of abrasive processing speed, decrease of the working zone temperature.

7 cl, 1 tbl, 1 ex

FIELD: electrical engineering.

SUBSTANCE: invention relates to electrical engineering, particularly to the method of producing sealer-lubricant that comprises selecting diblock copolymer from the group of styrene-ethylene/butylene or styrene-ethylene, propylene and combination thereof. It also includes and combining diblock copolymer with mineral oil at temperature lower than that of glass transition of styrene zones. Proposed method can comprise also filtration of styrene-rubber diblock copolymer to produce particles sized to less than 1 mm.

EFFECT: sealer with higher creep resistance at 70 to 80°C.

6 cl, 3 dwg, 6 tbl, 7 ex

FIELD: heating.

SUBSTANCE: technical effect consists in enhancement of the ice resistance to destructive loads associated with hockey playing, improvement of the ice plasticity and the ice surface slip properties. In accordance with the method proposed on initially provides for freezing on a lower adhesive layer at least 1 mm thick with admixture of a composite in an amount no more than 50 ppm which is represented by water suspension of polytetrafluorethylene and/or a tetrafluorethylene-hexafluorpropylene copolymer and/or perfluordecaline. One provides for cyclically freezing on layers of varied chemical composition. Within one cycle one successively applies several clear (containing no admixtures) ice layers and several modified layers containing admixtures of ammonia in an amount from 1 ppm to 100 ppm and water suspension of polytetrafluorethylene and/or a tetrafluorethylene-hexafluorpropylene copolymer and/or perfluordecaline in an amount from 0.1 ppm to 50 ppm. The aggregate thickness of modified layers within a single cycle is no more than 2 mm. The aggregate thickness of clear ice layers within a single cycle is no less than 5 mm. After application of the lower layers on the hockey ground underlayer one provides for freezing on upper modified layers containing admixtures of ammonia in an amount from 1 ppm to 100 ppm and water suspension of polytetrafluorethylene and/or a tetrafluorethylene-hexafluorpropylene copolymer and/or perfluordecaline in an amount of approximately 50 ppm.

EFFECT: enhancement of the ice resistance to destructive loads associated with hockey playing, improvement of the ice plasticity and the ice surface slip properties.

5 cl, 1 dwg, 6 ex

FIELD: heating.

SUBSTANCE: proposed method of arranging a multilayered ice cover for curling envisages formation of an ice underlayer characterised by enhanced hardness and similar to monocrystal ice in terms of structure and slip properties. Initially one provides for freezing on a lower adhesive layer at least 1 mm thick with admixture of a composite in an amount no more than 50 ppm which is represented by water suspension of polytetrafluorethylene and/or a tetrafluorethylene-hexafluorpropylene copolymer and/or perfluordecaline. Then follows the underlayer formation by way of successively freezing on several clear (containing no admixtures) ice layers each no more than 1 mm. After that one provides for freezing pebble embossments onto the underlayer using water with a temperature no less than 60° C; the pebbles contain admixtures of ammonia in an amount from 0.1 ppm to 100 ppm and water suspension of polytetrafluorethylene and/or a tetrafluorethylene-hexafluorpropylene copolymer and/or perfluordecaline in an amount from 50 ppm to 100 ppm.

EFFECT: extended service life of the ice cover structure produced.

3 cl, 1 dwg

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a continuous method for synthesis of sulfamate derivatives of fructopyranose of the general formula (I): wherein R1, R2, R3, R4, R5, R6 and X have values given in the invention description. Invention relates to synthesis of thiopyramate with using glyme as organic solvent in both steps of the continuous process of synthesis.

EFFECT: improved method of synthesis.

17 cl, 8 tbl, 6 ex

The invention relates to the field of organic chemistry and can find application in biology and medicine
The invention relates to a method for producing sodium salt of 2,3;4,6-di-O-isopropylidene-2-keto-L-gulonovoy acid by electrochemical oxidation of 2,3: 4,6-di-O-isopropylidene--L-carbofuran on metal anodes in the presence of Nickel sulfate in an aqueous solution of sodium hydroxide under heating, and the process is carried out in the presence of sodium sulfate or potassium sulfate, or sodium phosphate, taken at a concentration of 3 to 20% at the current density of 6 to 8 A/DM2

The invention relates to compounds that are used as medicines, which have antiendotoxin activity, in particular analogs of lipid A

FIELD: chemistry.

SUBSTANCE: claimed invention relates to derivatives of α-C-phenyl-N-Tret-butylnitrone of general formula (I) , where X represents lactobionamide group, quarternary ammonium group or group ; m represents 1, 2 or 3; y represents 0 or 1; Y represents group -CH2-; m' represents 1; X' represents alkyl chain C4-C14, if necessary substituted with one or several fluorine atoms; Y' represents group selected from functional amide group (-NHC(O)-), urethane group (-OC(O)NH-) or thioester bridge (-S-).

EFFECT: invention also relates to application of claimed compounds for obtaining medication for treatment of pathologies induced by oxidative stress and formation of compounds with free oxygen radicals and to application of formula (I) compounds for obtaining cosmetic composition for prevention and treatment of ageing effects.

9 cl, 4 tbl, 11 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to method of isolation of 1-O-2-(3,4-dimethoxybenzyl)-3-carboxy-4-(3-methoxy-4-oxyphenyl)-butyl-β-D-galactopiranose of general formula (1) , which lies in exhaustive constant extraction of air-dry seeds of Scotch cottonthistle Onopordum acanthium L. with chloroform during 2 days in Soxlet apparatus, isolation from extract by means of triple procession with n-hexane with further exposure at 10°C during 7 days and further filtration.

EFFECT: new efficient method of isolation of 1-O-2-(3,4-dimethoxybenzyl)-3-carboxy-4-(3-methoxy-4-oxyphenyl)-butyl-β-D-galactopiranose.

1 cl, 1 ex

FIELD: organic chemistry, microbiology, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of caloporoside of the formula (I): wherein R1, R2 and R3 mean independently of one another hydrogen atom (H) or acyl residues with 1-10 carbon (C)-atoms; R4 means hydrogen atom (H) or -C(O)(CH2)n-COOH wherein n = 1-7 under condition that not all R1, R2, R3 and R4 mean hydrogen atom (H), and their physiologically acceptable salts also. Also, invention relates to a method for synthesis of compound of the formula (I) or its physiologically acceptable salts. Method involves fermentation of the strain Gloeoporus dichrous (Fr:Fr) Bres. ST001714, DSM 13784 under aerobic conditions at temperature 18-35°C and pH = 5-8, isolation of one or some derivatives of caloporoside that can be conversed, if necessary, to physiologically acceptable salts, and to using compound of the formula (I) as CDK-inhibitor in treatment of cancer or another diseases associated with pathological damage of cells proliferation, and to a medicinal agent based on thereof and to a method for its preparing.

EFFECT: improved preparing method, valuable medicinal properties of derivatives.

14 cl, 5 tbl, 8 ex

The invention relates to derivatives of sugars General formula (1), where n= 1-6, balance (2) - charigny radical containing leaf non sugar associated in position C-1 carbon, mannose or fucose or N-acetylglucosamine; Y is a bridging group, which represents an aliphatic hydrocarbon with the number of carbon atoms in the chain from 1 to 6, covalently associated with sharedmem radical in position-1 carbon through simple essential connection or through a group-C(O)and associated with metallocene through ester bonds or through a group-NH-C(O)-; Srma - metallocene

FIELD: chemistry.

SUBSTANCE: in method of obtaining (mercaptoorganyl)alkoxysilanes sulfide of corresponding alkali metal is subjected to interaction with mixture of (halogenorganyl)alkoxysilane and (halogenorganyl)halogensilane in alcohol under conditions excluding access of air, and at higher pressure.

EFFECT: elaboration of method of obtaining compound which allows to exclude application of gaseous and toxic initial compounds and ensuring high output of target product.

9 cl, 10 ex

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