Derivatives of 3-deoxyanthocyanins, the retrieval method (variants), intermediate compounds and pharmaceutical composition

 

(57) Abstract:

The invention relates to new derivatives of 3-deoxyanthocyanins formula I, in which X denotes a radical of the formula V or a radical of the formula C; Y denotes a radical of the formula D; R1, R3, R5, R7, R8, R10, R13- the same or different, represent each a linear or branched CNS radical with 1-6 C-atoms or the radical-OSO-3; R2, R4, R6, R9, R11- the same or different, represent each a hydrogen atom, a linear or branched CNS radical with 1-6 C-atoms or the radical-OSO-3, R12means a hydroxyl radical or a radical-OSO-3however , provided that at least one of the substituents R2or R4or R6or R9or R11denotes a hydrogen atom; in the form of pharmaceutically acceptable salts and the corresponding acids. Described compounds have a very large artifactory Ha-activity and high affinity for at-W. They are well adsorbed in the digestive tract and therefore may be administered orally. Describes how to obtain the above-mentioned compounds, intermediate compounds and Pharm what relates to new derivatives of 3-deoxyanthocyanins, methods for their preparation and the pharmaceutical compositions.

Heparin is a polysaccharide group of glycosaminoglycans, known for its antikoaguliruyuschee properties. It is known [I. Bjork and U. Lindahl, "Moleculer and Cellular Biochemistry", /1982/, Dr.W.Junk Publishers-Pays-Ba] that the coagulation of blood is a complex physiological phenomenon. Some incentives, such as contact activation and tissue factors that cause sequential activation of a number of clotting factors present in the blood plasma. Whatever the nature of the stimulus, the final stage is identical: activated factor X /Xa/ activates factor II /also called prothrombin/, which in its activated form, factor IIA, also known as thrombin/ causes partial proteolysis of soluble fibrinogen and release of insoluble fibrin, which forms the basis of a blood clot.

In normal physiological conditions, the activity of coagulation factors is regulated by proteins such as antithrombin III, AT-III/ and cofactor II heparin /HC-II/, which are also present in the plasma. AT-III has an inhibitory effect on a number of clotting factors and especially on the factors Xa and IIA.

Inhibition pulirula and antithrombotic activity, since both factors take part in the last two stages of coagulation, which are independent from the source of the stimulus.

Pentasaccharide formula /a/:

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I/R = -COCH3; /2/ R = -SO3-; represents the minimum sequence of heparin required for binding to at-III. This connection /R = -SO3-/ received about a dozen years ago by a fully chemical synthesis [P. Sinaij and others, Carbohydrate Research /1984/, 132, S. 5]. Since in the literature it has been described a number of synthetic oligosaccharides obtained by completely chemical synthesis and has anti-thrombotic and anti antikoaguliruyuschee activities.

In the European patent EP-0084999 describes derivatives formed monosaccharide units of uronic acids [glucuronic or iduronovoy] and glucosamine and having interesting antithrombotic properties. In addition to hydroxyl groups as substituents, these compounds contain N-sulfate groups of the N-acetyl group and in some cases, the anomeric hydroxyl group replaced by methoxy groups.

In the European patent EP-0165134 also describes synthetic oligosaccharides possessing antithrombotic active is local or O-phosphate group. Derivatives of uronic acid and glucosamine containing in position 3 of the glucosamine units of O-sulfate group, also described in European patent application EP-0301618. These compounds have improved antithrombotic and antikoaguliruyuschee properties. In European patent application EP-0454220 describes derivatives of uronic acids and glucose, containing as substituents, O-alkyl or O-sulfate group. These latter compounds also possess antithrombotic and antikoaguliruyuschee properties.

Sulfated glycosaminoglycanes derivatives, in which the functional N-sulfate, N-acetate or hydroxyl group replaced by the CNS, aryloxy, Arakelov - or O-sulfate groups are also described in European patent application EP-0529715. These compounds have interesting antithrombotic properties. These last are also inhibitors of proliferation of smooth muscle cells.

Oligosaccharides, and especially pentasaccharide similar to the minimum sequence of heparin required for binding to AT-III, described in Angew. Chem. Int. Ed. Engl. /1993/, 32 /3/, C. 434-436. These compounds contain units /links/ glucurone acids or glucose, hidden, that replacing one or more hydroxyl radicals or O-alkyl or O-sulfatrim groups in position 3 of the hydrogen atoms in one or more sharidny units receive oligosaccharides possessing interesting biological properties. In fact, the compounds of the present invention are different from others described in the literature, synthetic heparinoids its original structures and their numerous and unexpected biological properties. Compounds of the invention are 3-deoxy-oligosaccharides, which have very high anti-factor Xa activity and high affinity for AT-III. In addition, the compounds of the invention are well adsorbed in the digestive tract. Therefore, it products, which can be administered orally.

More specifically, the object of the present invention are the compounds of formula (I):

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in which X represents the radical OS3-, a radical of the formula /A/: R - O/A/, a radical of the formula a /B/:

< / BR>
or a radical of the formula /C/:

< / BR>
Y denotes a radical of the formula /D/:

< / BR>
R denotes a linear or branched alkyl radical with 1 to 6 C-atoms;

R1, R3, R5, R7, R8, R10, Rth CNS radical with 1-6 C-atoms; or the radical-OSO3-;

R2, R4, R6, R9and R11identical or different, represent each a hydrogen atom; gidroksilnye radical, linear or branched CNS radical with 1-6 C-atoms; or the radical-OSO3-; however, provided that at least one of the substituents R2or R4or R6or R9or R11denotes a hydrogen atom;

in the form of pharmaceutically acceptable salts or the corresponding acids.

Subsequently, the term "monosaccharide unit" will be used to denote Sidney units:

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regardless of deputies, which will be connected to this unit in positions 2, 3 or 5.

As for the radicals B, C and D communication " means that in some cases, the configuration of the carbon bearing the Deputy associated with this link, may be R, as in other cases.

Compounds of the present invention are derivatives of 3-detoxication.

Therefore, it is necessary that at least one of the monosaccharide units, which is formed by compounds of the invention, are consistent with the structure 3-methoxybenzanilide.

From this is UB> or R11denotes a hydrogen atom.

The compounds of formula I in which R2denotes a hydrogen atom, are preferred products of the invention.

The preferred products of the present invention are also the compounds of formula I in which X denotes a radical of the formula a /B/ or a radical of the formula /C/.

These compounds correspond to the following formulas /Ia/ and /Ib/:

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< / BR>
in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12and R13have the same meaning as in the formula /I/

Especially preferred compounds of formula Ia/.

The compounds of formula I and preferably those of the formula /Ia/ and /Ib/, in which R1, R3, R5, R7, R8and R10and R13identical or different, represent, each, a linear or branched CNS radical with 1-6 C-atoms or-OSO3-radical; R2, R4, R6and R9identical or different, represent each a hydrogen atom or a linear or branched CNS radical with 1-6 C-atoms; R11denotes a hydrogen atom, a linear or branched CNS radical with 1SUB>6
or R9or R11denotes a hydrogen atom; R12denotes a hydroxyl radical or a radical-OSO3-, are the preferred compounds of the invention.

Mostly preferred compounds of formula I and especially those of formula /Ia/ and /Ib/, in which R2and R6denotes a hydrogen atom; R3, R11and R12denote the radical OSO3-; R13denotes a linear or branched CNS radical with 1-6 C-atoms.

Mostly preferred compounds of formula I and especially those of formula /Ia/ and /Ib/, in which CNS radical is a methoxy radical.

The object of the present invention is also a method of obtaining compounds of formula (I), characterized in that the compound of formula (II):

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in which X' denotes chloroacetoxy, levulinate radical, a radical of the formula /A/, a radical of the formula a /B1/:

< / BR>
or a radical of the formula /C1/:

< / BR>
P1P2P3and P5identical or different, represent, each, a protective group, such as acyclic acyl radical with 1-6 C-atoms, preferably acetyl radical; aromatic achilly radical; or benzyl radical;

P4P6identical or different, represent, each, a protective group such as an alkyl radical with 1-6 C-atoms, preferably a methyl radical; or a benzyl radical;

R'1, R'5, R'8identical or different, represent, each, a linear or branched CNS radical with 1-6 C-atoms; acyclic, acyloxy radical with 1-6 C-atoms, preferably acetoxyethyl; aromatic acyloxy radical, preferably benzoyloxy radical; or ALK-2-enyloxy radical with 2 to 7 C-atoms, preferably of allyloxy radical;

R'7, R'10identical or different, are specified for R'1values; or they represent chloroacetoxy or levulinate radical;

R'2, R'6and R'9identical or different, represent each a hydrogen atom or have the meanings indicated for R'1; enter into interaction with the compound of the formula (III:

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where P7has the values specified for P4in the formula (II);

P8has the values specified for P1in the formula (II);

R'4and R'11identical or different, have the same meaning as R'2in the formula (II); and

R'3, R'12and R'13
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in which X', P1P2P3P4, R'1and R'2have the same meaning as indicated for formula (II);

P7, R'3and R'4have the same meaning as for the formula /III/;

Y' denotes a radical of the formula /D1/;

< / BR>
where P8, R'11, R'12and R'13have the same meaning as for the formula /III/;

which are then subjected to either catalytic hydrogenation, then the saponification and sulfate crystallization; or the saponification, then sulfate crystallization and then catalytic hydrogenation; or catalytic hydrogenation, then sulfate crystallization and after the saponification, to obtain the compounds of formula (I).

The above method is a preferred method of the invention. However, the compounds of formula I may be obtained by other known from the chemistry of sugars, ways, and especially by introducing into the interaction of monosaccharide containing protective groups, such as described by J. W. Gren b. Protective Groups in Organic Synthesis /Wiley, n.y. 1981/, hydroxyl radicals, and in certain cases the carboxyl radicals, if they are with other protected monosaccharide to obtain the disaccharide, which is then injected into inter is ucati protected tetrasaccharide, then secure pentasaccharide and then the protected hexasaccharide [approach "step by step"].

The protected oligosaccharides /Tetra, Penta and hexasaccharides/ then remove the protective group and in some cases they sulfation or partially remove the protective group, then sulfation and then remove the protective group, to obtain compounds of the formula /I/.

Such methods are known in carbohydrate chemistry and particularly described: G. Jaurand and others in Bioorganic and Medicinal Chemistiy Letters /1992/, 2 /N 9/ c. 897-900; J. Basten, etc. b Bioorganic and Medicinal Chemistry Letters, /1992/, 2 /N 9/ c. 901-904; J. Basten and others, in Bioorganic and Mesicinal Chemisty Letters /1992/, 2 /N 9/ c. 905-910, and M. Petitou and C. A. C. van Boeckel b "Cnemical Syntheses of heparin fragments and analogues" c. 203-210 - Progress in the Chemistry of Organic Natural Products. Ed. Springer Verlag Wien - n.y. /1992/.

The compounds of formula II, when X' represents a radical of the formula a /B1/, can be obtained by introducing into the interaction of activated through its anomeric carbon of a monosaccharide, such as, for example, the compounds of the formula /V/:

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where P5, R'5, R'6and R'7are specified in the formula a /B1/ value; with the compound of the formula /VI/:

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in which R'1, R'2P1P2and P4are specified for formula (II) value;

for recip specified for the formula /V/ value;

R'1, R'2P1P2and P4are specified for formula (II) value;

according to the method described by T. Peters and others Can. J. Chem. /1989/, 67, c. 491-496; and G. H. Veeneman and J. H. van Boom in Tetrahedron Letters, /1990/, 31, c. 275-278.

Treating this compound by known methods [R. Schmidt, Angew, Chem. Int. Ed. England /1986/, 25/3/ c. 212-235], and especially by acetolysis using benzylamine, then trichloroacetonitrile obtain compounds of formula (II) in which X' denotes a radical of the formula a /B1/.

Getting some compounds of the formula /VII/ and especially compounds for which R'2and R'6have the above for R'1values, but does not mean a hydrogen atom, described by J. Basten and others, Bioorganic and Medicinal Chemistry Letters, /1992/, 2 /N 9/ c. 905-910.

The compounds of formula /VII/ can also be obtained by introducing into the interaction of compounds of the formula /VI/ with other activated monosaccharides, for example, with compounds of the formula /V'/:

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where P5, R'5, R'6and R'7are specified for the formula /V/ value.

The compounds of formula /V'/, for which R'6is specified for R'1values and does not denote a hydrogen atom, are known compounds described in M. Petitou and C. A. A. van Boeckel program formula /V/, in which R'6denotes a hydrogen atom, can be obtained from compounds of formula /VIII/:

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where Bz denotes bentely radical.

The connection formula /VIII/ receive 3-deoxy--D-abovecaptioned [obtained by the method of T. V. Rajanbabu, described in J. Org. Chem. /1988/, 53, c. 4522-4530], which is subjected to the effects of benzoyl chloride mainly organic solvent. Thus, the compound obtained is exposed to Anantara order to obtain compounds of the formula /VIII/.

The compounds of formula /VI/, when R'2denotes a hydrogen atom, can also be obtained from compounds of formula /VIII/, which enter into interaction with 1,6: 2,3-di-D-mannopyranose, to obtain the compounds of formula IX/:

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in which Bzmeans bentely radical.

This compound is then exposed to a strong Foundation for obtaining 1,6:2,3-di anhydride-4-O-/3-deoxy-D-abovecaptionskip-a-D-mannopyranose, the compounds of the formula /X/:

< / BR>
From a compound of the formula /X/ and using classical methods [G. Jaurand and others, Bioorganic and Medicinal Chemistry Letters, /1992/, 2/ N 9/ c. 897-900; J. Basten and others, Bioorganic and Medicinal Chemistry Letters, /1992/, 2 /N 9/, S. 901-904; J. Basten and others, Bioorganic and Medicinal Chemistry Letters, /1992/, 2 /N 9/ c/1992/].

get the compounds of formula /XI/:

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in which R'1P1P2and P4have such meaning as indicated for formula (VII);

P9means levelentry or chloracetamide radical.

The connection formula /XI/ then exposed to hydrazine to obtain the compounds of formula /VI/, where R'2denotes a hydrogen atom.

Compounds of formulas /IX/, /X/ and /XI/ are new products and are also part of the invention.

The compounds of formula /VI/, for which R'2is specified for R'1values and does not denote a hydrogen atom, can be obtained similarly, using as initial products protected derivative of glucose, activated at the level of their anomeric carbon, instead of the compounds of the formula /VIII/. The compounds described in M. Petitou and C. A. C. van Boeckel in "Chemical Synthesis of heparin fragments and analogues" C. 203-210 - Progress in the Chemistry of Organic Natural Products, Ed. Springer Verlag Wien-n. y. /1992/. The same authors also describe a similar formation of compounds of formula IX/, containing in position 3 protected hydroxyl radical.

The compounds of formula II, when X' represents a radical of the formula /C1a/:

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in which: R'5, R'can be obtained by introducing into the interaction of the compounds of formula /VI/ with the compound of the formula /XIIa/:

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in which R'5, R'6, R'8, R'9, R'10P5and P6are specified for the formula /C1/ value; to obtain the compounds of formula /XIIIa/:

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where:

R'5, R'6, R'8, R'9, R'10P5and P6are specified for the formula /C1/ value; and

- R'1, R'2P1P2and P4have you specified for the formula /II/.

The compounds of formula /XIIIa/ then treated as indicated in the case of compound /VII/, to obtain compounds of the formula II, in which X' denotes a radical of the formula /C1a/.

The compounds of formula /XIIa/ when R'9denotes a hydrogen atom, are obtained from compounds of the formula /XIV/:

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in which R'5, R'6, R'8, R'10and P6are specified for the formula /C1/ value; which is subjected to acetals, then remove the protective group and then subjected to the impact of trichloroacetonitrile. The compounds of formula /XIV/ can be obtained from compounds of the formula /X/ according to the method described for compounds of formula /XI/.

The compounds of formula /XIIa/ when R'9is specified for R'1values and does not denote a hydrogen atom, G. Derivatives of 1,6: 2,3-di-anhydrous-4-O-/--D-glyukopiranozil/a-D-mannopyranose are known products described J. Basten and others in Bioorganic and Medicinal Chemistry Letters /1992/, 2 /N 9/, S. 905-910.

The compounds of formula II, when X' represents a radical of the formula /CIb/

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in which R'5, R'6, R'8, R'9, R'10P5and P6are specified for the formula /C1/ the value can be obtained by introducing into the interaction of the compounds of formula /XIIb/:

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in which R'5, R'6, R'8, R'9, R'10P5and P6have you specified for the formula /C1/ values, with the compound of the formula /VI/ to obtain compounds of the formula /XIIIb/:

< / BR>
in which R'1, R'2, R'5, R'6, R'8, R'9, R'10P1P2P4P5and P6have you specified for the formula /Ha/ values.

The compounds of formula /XIIIb/ then treated as described for compounds of formula /Ha/, to obtain compounds of the formula II, in which X' denotes a radical of the formula /C1b/.

The connection formula /XIIb/ when R'9denotes a hydrogen atom, can be obtained from compounds of the formula /X/. This connection makes the connection FS. 37-64.

From this connection and when using the known methods described G. Jaurand and others in Bioorganic and Medicinal Chemistry Letters /1992/ 2 /N 9/, S. 897-900; J. Basten and others, in Bioorganic and Medicinal Chemistry Letters, /1992/, 2 /N 9/, S. 901-904; J. Basten and others, in Bioorganic and Medicinal Chemistry Letters /1992, 2 /N 9/, S. 905-910; and M. Petitou and C. A. A. van Boeckel "Chemical Synthesis of heparin fragment and analogues" C. 203-210 - Progress in the Chemistry of Organic Natural Products, Ed. Springer Verlag Wien-n.y. /1992/; get the compounds of formula /XVI/:

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in which R'5, R'6, R'8, R'10and P6have a specified formula /XIIb/ value.

These compounds are then subjected to acetals, then treated with benzylamine and trichloroacetonitrile, to obtain compounds of the formula /XIIb/.

The compounds of formula /XIIb/, for which R'9does not denote a hydrogen atom, but is specified for R'1values can be obtained in the same way.

Various intermediate compounds, to obtain compounds of formula /IIb/ in which R'5, R'6, R'8, R'10P5and P6are specified for the formula /S1/ value, and R'9is specified for R'1values and does not denote a hydrogen atom, are known products which are described G. Jaurand and others in Bioorganic aB>2
denotes a hydrogen atom, can be obtained from compounds of the formula /X/, which is converted into a compound of the formula /XVII/:

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The connection formulas /XVII/ subsequently either treated with ventilator sodium, then acelerou; or treated with aralkylamines, preferably by benzylbromide, ALK-2-arilgalogenide, preferably by allylbromide, then treated with ventilator sodium and after that acelerou, to obtain compounds of the formula /XVIII/:

< / BR>
in which R'1P1and P2have a specified formula /II/ value.

The compounds of formula /XVIII/ then treated in an acid environment in order to obtain compounds of the formula /XIX/:

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in which R'1P1and P2have you specified for the formula /II/.

The compounds of formula /XIX/ then subjected to selective siciliani in position 6', process levulinate anhydride, oxidize under the terms of Jones and atrificial to esters using alkylhalogenide, is subjected to reaction removal levelinglineage radical and alkylate in acidic or neutral medium, to obtain compounds of the formula II, in which X' denotes a radical of the formula /A/ and R'2denotes a hydrogen atom.

who meet specified for R'1values. Intermediate compounds necessary for obtaining these compounds are described in the literature and especially G. Basten and others in Bioorganic and Medicinal Chemistry Letters, /1992/, 2 /N9/, S. 905-910; and C. A. A. van Boeckel, etc. in J. Carbohydrate Chem. /1985/, 4, S. 293.

The compounds of formula (III when R'4denotes a hydrogen atom, can be obtained from compounds of the formula /XX/:

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in which R'3, R'11P7and P8have you specified for the formula /III/ values; and P10means levelentry or chloracetamide radical.

The compounds of formula /XX/ are acetals, then treated with benzylamine, enter into interaction with the reagent Vilsmeier, treated with alcohol in the presence of silver carbonate and then exposed to hydrazine, to obtain the target compounds of the formula III // /R'4= H/.

The compounds of formula (III when R'4is specified for R'1values represent known compounds. The compounds described in the literature J. Basten and others in Bioorganic and Medicinal Chemistry Letters, /1992/, 2 /N 9/, S. 905-910.

The above method allows to obtain compounds of the invention in the form of salts. For connection of the corresponding acid compounds of the invention in the form of the slot can then be neutralized with base to obtain the desired salt.

To obtain the salts of the compounds of formula (I), you can use any inorganic or organic base, giving compounds of the formula (I) pharmaceutically acceptable salts.

It is preferable to use sodium hydroxide, potassium, calcium or magnesium. Sodium and calcium salts of compounds of formula (I) are the preferred salts.

The compounds of formula (I) constituting the present invention have interesting pharmacological and biochemical properties. Mostly they have a high activity anti-factor Xa and high affinity for at-III.

As described above, factor Xa activates the cascade of coagulation prothrombin to thrombin, which proteolysed soluble fibrinogen with the release of insoluble fibrin, which forms the basis of a blood clot. Inhibition of factor Xa, therefore, is a privileged opportunity to achieve antikoaguliruyuschey and antithrombotic activity.

The activity of anti-factor Xa [anti-Xa] products of the invention were evaluated at pH of 8.4 according to the method described by Teien, A. N. and M. Lie in Thrombosis Research /1977/, 10 c. 399-410, and it was shown that the products of the invention have activity as anti-Xa, RA is at-III was determined by spectrofluorometry in terms described D.'th and others in Biochemistry, /1987/, 26, c. 6454-6461. The results of the experiments showed that the compounds of the invention have a very high affinity for at-III.

In addition, the overall antithrombotic activity of the products of formula I was evaluated in the rat by model venostasis and induction by thromboplastin, according to the method described in J. Reyers and others in Thrombosis Research /1980/ 18, S. 669-674. ED50compounds of the invention at least of the same order or lower than that of other known synthetic heparinoids. Compounds of the invention therefore have a particularly interesting specificity of action and antikoaguliruyuschey and antithrombotic activity.

The results obtained during the various pharmacological studies carried out with the products of the invention have shown that they are very well absorbed and their half-lives large. This allows us to foresee, during their use in therapy, the possibility of a single daily injection.

These studies also showed that the products of formula (I), forming the subject of the present invention, are absorbed by the digestive tract, and the entered number is not prohibited for use in therapy of the human is x well parenteral, as oral.

The compounds of formula (I) in very low toxicity; their toxicity is compatible with their use as medicaments.

Compounds of the invention can also find use in the treatment of proliferation of smooth muscle cells, because they have been shown to exhibit inhibitory effect, in a noticeable extent greater than that of heparin, in the growth of smooth muscle cells.

Compounds of the invention are also effective against angiogenesis and is suitable for the treatment of certain infections caused by retroviruses.

In addition, the compounds of the invention also provide a protective and regenerative effect on the nerve fibers.

Compounds of the invention are very stable, therefore, is thus particularly suitable as the beginning of the current medicines.

The invention also extends to pharmaceutical compositions containing as an active start compound of formula (I) or one of its pharmaceutically acceptable salts, in some cases in Association with one or more relevant and inert excipients.

The thus obtained pharmaceutical composition ol the TCI or gelatin capsules with the medicine. Solutions for injection are preferred pharmaceutical forms.

Pharmaceutical compositions containing as an active beginning at least one compound of formula (I) or one of its salts, especially suitable for treatment as a preventative or therapeutic agent, diseases of blood vessels, such as atherosclerosis and arteriosclerosis; States hypercoagulability observed, for example due to surgery, tumor growth or coagulation disorders caused by viral, bacterial or enzymatic activators.

The dosage may vary within wide limits depending on the age, weight and health of the patient, nature and severity of the disease, as well as the route of administration. This dosage includes the introduction of one or more doses of about 0.5 kg to 1000 mg per day, preferably 1-100 mg / day, for example, about 20 mg / day, intramuscularly or subcutaneously, with the introduction carried out periodically or at regular intervals, or a daily dose of about 200-1000 mg per day orally.

These doses are, of course, can be selected for each patient depending on the observed results and the program.

The invention is illustrated by the following examples.

Get

Obtain I

Ethyl-2,4,6-tri-O-benzoyl-3-deoxy-1-thio-D-abovecaptioned [connection formula /VIII/].

Stage A: 1,2,4,6-Tetra-O-benzoyl-3-deoxy-D-abovecaptioned 66 mol of 3-deoxy-1,2: 5,6-di-O-isopropylidene-D-removecolumns [T. V. Rajanbabu, J. Org.Chem. /1988/, 53, S. 4522-4530] in the form of a solution in a mixture of water with ethanol in the presence of an acidic resin Dowe heated for 4 hours at 60oC to obtain 3-deoxy-D-abovecaptioned. Is evaporated to dryness, then dried, viparita in the presence of pyridine.

Thus the resulting syrup is dissolved in 150 ml of pyridine and add 356 mmol of benzoyl chloride. Left under stirring for 3 hours at room temperature. Is evaporated to dryness, diluted with dichloromethane, washed with water and crystallized from ethyl acetate to obtain 7,66 g 1,2,4,6-Tetra-O-benzoyl-3-deoxy-D-abovecaptioned. Output = 30%. So pl. 164oC. []2D0= +1o/c = 1,33, CH2Cl2/.

Stage B:

4,51 mmol obtained in the previous stage of the compounds dissolved in anhydrous toluene in an argon atmosphere at 20oC, then add 9,03 mmol of ethanthiol. Add 4,since the washing water is evaporated to dryness and the obtained residue in the form of syrup purified on a column of silica. Thus obtain 1.64 g of a mixture of anomers and ethyl-2,4,6-tri-O-benzoyl-3-deoxy-1-thio-D-abovecaptioned. This compound is used without other purification. Yield = 70%.

Obtaining II

Ethyl-2,4,6-tri-O-benzyl-3-deoxy-1-thio-D-abovecaptioned [compound of the formula /V/].

of 5.82 mmol received in the receiving I compounds dissolved in a mixture of methanol with dichloromethane /1:1 by volume/. Add 0.90 mmol of sodium methylate. The reaction mixture is left under stirring for 3 hours at 20oC, then neutralized with acidic resin Dowex /AG 50 WX 2/. Filtered and evaporated to dryness. The residue is dissolved in 18 ml of anhydrous dimethylformamide, and then, at 0oC add to 19.7 mmol of sodium hydride and 17.0 mmol of benzylbromide. Left under stirring for 2 hours, then add to 34.1 mmol of methanol. The reaction solvent is evaporated and purified on a column of silica, getting 2,12 g of the desired product as a mixture of anomers. Yield: 76%.

The acquisition of the third

1,6:2,3-Di-anhydrous-4-O-/2,4,6-tri-O-benzoyl-3-deoxy-D-abovecaptionskip/--D-mannopyranose [compound of formula IX/].

According to the method described by G. H. Veeneman and J. H. Boom in Tetrahedron Letters /1990/, 31, S. 275-278, at -20oC, 8,53 AI molecular sieves and 21.3 mmol N-iodosuccinimide, then added dropwise 1.7 mmol 0.04 M solution triftoratsetata. Leave the reaction medium under stirring for 2.5 hours, filtered and purified on a column of silica, receiving of 3.07 g of 1,6:2,3-di-anhydrous-4-O-/2,4-tri-O-benzoyl-3-deoxy-D-abovecaptionskip/a-D-mannopyranose. Crystallized from a mixture of ethyl acetate with hexane /90:10 by volume/. Yield = 65%. So pl. = 153oC. //2D0= -12o/c=1,10, CH2Cl2/.

Receiving IV

1,6:2,3-Di-anhydrous-4-O-/3-deoxy-D-abovecaptionskip/ --D-mannopyranose [compound of the formula /X/].

1,6:2,3-Di-anhydrous-4-O-/2,4,6-tri-O-benzoyl-3-deoxy-D-abovecaptionskip/--D-mannopyranose are dibenzoylmethane using sodium methylate, getting 1,6:2,3-di-anhydrous-4-O-/3-deoxy-D-abovecaptionskip/--D-mannopyranose. Yield = 95%. //2D0= -46o/c = 1,02, CH3OH/.

Getting V

3-O-Acetyl-1,6-anhydrous-2-O-benzyl-4-O-/benzyl-2-O-acetyl-3-deoxy--D-glucopyranose [connection formula /VI/] .

This compound is obtained from 1,6:2,3-di-anhydrous-4-O-/3-deoxy-D-abovecaptionskip/a-D-mannopyranose, compounds described in obtaining IV, using methods similar to those already described M. Petitou and C. A. A. van Boeckel in "Che:2,3-di-anhydrous-4-O-/3-deoxy-4,6-O-isopropylidene--D-abovecaptionskip /a-D-mannopyranose, the reaction ventilator sodium,

acetylation, remove isopropylidene radical with acetic acid, similarobama, reaction with levulinate anhydride, the oxidation conditions Jones, etherification to complex ester with benzylbromide, and then treatment with hydrazine.

The various stages are listed below:

Stage A:

< / BR>
To a solution of 1,6:2,3-di-anhydrous-4-O-/3-deoxy-D-abovecaptionskip-a-D-mannopyranose in dimethylformamide /5 mmol in 35 ml/ argon atmosphere was added dropwise 1.5 mmol p-toluenesulfonic acid also can be used campanulaceae/ and 250 mmol of 2,2-dimethoxypropane. Left under stirring for 2.5 hours, then add 1.8 mmol of triethylamine. Diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, obtaining 1,6: 2,3-di-anhydrous-4-O-/3-deoxy-4,6-O-isopropylidene -- D-abovecaptionskip/ a-D-mannopyranose. This connection is used in the next stage without performing purification. Yield = 81%.

Stage B:

< / BR>
To 5.0 mmol received on stage And join add 25 mmol of benzilate sodium /1M solution in benzyl alcohol/. Within 30 minutes, heated at 110oC. Cool, neutralize the om. The residue is purified on a column of silica, using as an eluting means a mixture of toluene with acetone /3:1 by volume/. The target product is obtained in the form of syrup. Yield = 81%.

Stage

< / BR>
the 4.90 mmol obtained in stage B compounds are dissolved in 22 ml of dichloromethane, cooled to 0oC, and add 19.6 mmol of acetic anhydride, a 1.96 mmol 4-dimethylaminopyridine and 9,81 mmol of triethylamine. At room temperature and within 45 minutes the reaction mixture is stirred. Add methanol and kept under stirring for 30 minutes. Then the reaction medium is diluted with dichloromethane, washed with aqueous solution of KHSO4then water, dried over anhydrous sodium sulfate, evaporated to dryness, obtaining the target product in the form of syrup. Then purified on a column of silica, using as an eluting means a mixture of toluene with acetone /9:1 by volume)/.

Yield = 85%.

Stage D

< / BR>
4,11 mmol obtained in the previous stage of the compounds dissolved in 2.2 ml of 1,1-dichloroethane and add 123 ml of an aqueous solution of acetic acid /70%/. Left under stirring for 35 minutes at 50oC. Concentrate, add toluene and evaporated, poluchasa mixture of cyclohexane with acetone /1:1 by volume/. Yield = 90%.

Stage D:

< / BR>
3.61 mmol obtained in stage G of compound dissolved in 3.3 ml of dichloromethane and added to 1.42 mmol 4-dimethylaminopyridine, was 10.82 mmol of triethylamine and 5.41 mmol of tert.-butultimately-silyl-chloride. Left under stirring for about 1 hour at 20oC, then add 43 ml of anhydrous dichloromethane and 10.8 mmol levelingage anhydride. Left under stirring for 2 hours, then add 150 ml of dichloromethane, washed first with aqueous solution of KHSO4then aqueous solution of NaHSO4, dried over anhydrous sodium sulfate, filtered and evaporated down to obtain a brown syrup. The product is used as is in the subsequent stage.

Stage E:

< / BR>
of 2.51 g obtained in the previous stage of the syrup is dissolved in 26 ml of acetone, cooled to 0oC, then add of 9.56 mmol of chromium trioxide and 4.2 ml of a 3.5 M solution of sulfuric acid. Left under stirring at room temperature for 4 hours. Then add 250 ml of dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated down to obtain a brown syrup.

Stage G:

Obtain 3-O-acetyl-1,6-Angi is obtained in the preceding stage, dissolved in 22 ml of anhydrous dimethylformamide in an argon atmosphere add 7.22 mmol of potassium bicarbonate and 10,83 mmol of benzylbromide. Left under stirring for 3 hours, then add 0.5 ml of methanol and kept under stirring for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated down to obtain a brown syrup. The total output stages D, E, W = 81%.

Stage C:

< / BR>
3.61 mmol 3-O-acetyl-1,6-anhydrous-2-O-benzyl-4-O-/benzyl-2-O-acetyl-3-deoxy-4-O-levulinic--D-glucopyranose, the compounds obtained in stage G, dissolved in 13 ml of pyridine. Cooled to 0oC and add to 18.1 mmol of hydrazine [1M solution in a mixture of pyridine with acetic acid /3: 2 by volume/]. The reaction mixture is left under stirring for 15 minutes at room temperature. Concentrate, add dichloromethane, washed with aqueous solution of KHSO4, then with water and then aqueous solution of NaHCO3and again with water. Dried over sodium sulfate, filtered and evaporated to dryness, obtaining a brown syrup. 3-O-Acetyl-1,6-anhydrous-2-O-benzyl-4-O-/benzyl-2-O-acetyl-3-deoxy--D-glucopyranose purified on a column of silica, using as solvent a mixture of cyclohexane with acetone /2:1 by volume)/.

Output = l-3-deoxy-4-O-levulinic--D-removecomponentlistener/-/1--->4/-3,6-di-O-acetyl-2-O-benzyl-D - glyukopiranozil/-trichloroacetimidate [connection formula /XIIa/].

This compound is obtained from 3-O-acetyl-1,6-anhydrous-2-O-benzyl-4-O-/benzyl-2-O-acetyl-3-deoxy-4-O-levulinic--D-glucopyranose, compounds described in obtaining V, according to known methods, namely acetolysis, removal of the anomeric protective groups and get imidate. The various stages are given below:

< / BR>
To 1,02 mmol received in the receiving V product type 102 mmol of acetic anhydride and 10.2 mmol of trifurcated. The mixture is left under stirring and argon atmosphere for 2 hours. Then evaporated until get brown syrup and purified on a column of silica, using as an eluting means a mixture of cyclohexane to ethyl acetate /2:3 by volume/.

Stage B:

< / BR>
of 1.52 mmol obtained in the previous stage of the compounds dissolved in dichloromethane and added to 57.9 mmol of benzylamine. Left under stirring for 4 hours at room temperature, then left at -20oC during the night. Add diethyl ether and washed with aqueous 1N. hydrochloric acid solution. Extracted with dichloromethane, dried over anhydrous sodium sulfate and evaporated down to obtain a brown syrup. Purified on a column of silica, use the use 0,246 mmol disaccharide, obtained in the previous stage, in the form of a solution in dichloromethane. In argon atmosphere, add 0,39 mmol of potassium carbonate and of 1.23 mmol of trichloroacetonitrile. Left under stirring for 16 hours, filtered and evaporated to dryness. O-/Benzyl-2-O-acetyl-3-deoxy-4-O-levulinic--D-removecomponentlistener/-/1--->4/-3,6-di-O-acetyl-2-O-benzyl-D-glyukopiranozil/-trichloroacetimidate obtained as a mixture of anomers. Yield = 62% /common/.

Receiving VII

1,6: 2,3-Di-anhydrous-4-O-/3-deoxy---abovecaptionskip/-- D-mannopyranose [connection formula /XV/ is a mixture of gluco and IDO].

Stage A

1,6:2,3-Di-anhydrous-4-O-/3-deoxy-6-IDO-D-abovecaptionskip/--D-mannopyranose.

To a solution of 1,6: 2,3-di-anhydrous-4-O-/3-deoxy-D-RIBO-hexopyranosyl/a-D-mannopyranose /22,81 mmol/ 400 ml of a mixture of dichloromethane to acetonitrile add 68,43 mmol of triphenylphosphine, 68,43 mmol of imidazole and 29,65 mmol of iodine. Left under stirring at 70oC for 4 hours. The solution is evaporated and the thus obtained syrup is purified on a column of silica, using as solvent a mixture of dichloromethane with acetone /10: 1 by volume/. Thus obtained 1,6:2,3-di-anhydrous-4-O-/3-deoxy-6-IDO---D-abovecaptionskip/--D-mannopyranose dissolved in 150 ml of methanol and add 42 mmol of sodium methylate solution in methanol /1M/. The mixture is heated for 9 hours at 80oC, cooled and purified on a column of Sephadex LH-20, elwira a mixture of dichloromethane with methanol /1:1 by volume/. Thus obtained 1,6:2,3-di-anhydrous-4-O-/3-deoxy-5,6-Exo-methylene-D-abovecaptionskip/--D-mannopyranose. 13.3 mmol of this compound are dissolved in 100 ml of tetrahydrofuran and 20oC was added dropwise to 54.4 mmol of DIBORANE in the form of a solution in tetrahydrofuran. Leave for 2 hours under stirring, then add 65,28 mmol of ethanol. Left under stirring for 1 hour, then add 24 ml of 3M sodium hydroxide solution and 24 ml of 30% hydrogen peroxide solution. Heated to 50oC, neutralized with acidic resin Dowex /AC 50WX4/ and evaporated to dryness, obtaining 1,6: 2,3-di-anhydrous-4-O-/3-deoxy-D-abovecaptionskip/--D-mannopyranose in the form of a mixture of Glyco - and dodecahedron. /1:6,25/.

Getting VIII

3-O-Acetyl-1,6-anhydrous-2-O-benzyl-4-O-/benzyl-2-O-acetyl-3-deoxy-4-O-levulinic--D-glucopyranose [connection formula /XVI/].

3-O-Acetyl-1,6-anhydrous-2-O-benzyl-4-O-/benzyl-2-O-acetyl-3-deoxy-4-O-levulinic-D-glucopyranose produced from compound described in obtaining VII, using classical methods [G. Jaurand and other Bioorganic and Medicinal Chemistry Letters /1992/, 2 /N 9/ c. Menno: receiving two corresponding 4'-6' - isopropylidene; purification and separation on a column of silica Glyco - and IDO-isomers; the reaction with ventilator sodium; acetylation; removing isopropylidene radical, selective similarobama; reaction with levulinate anhydride; oxidation under the terms of Jones, and etherification to complex ester with benzylbromide. Yield = 45%.

The various stages are given below:

Stage A:

< / BR>
3.6 mmol of 1,6:2,3-Di-anhydrous-4-O-/3-deoxy-D-abovecaptionskip/a-D-mannopyranose is dissolved in 25 ml of dimethylformamide and add 21,64 mmol of dimethoxypropane vs. 3.96 mmol p-toluenesulfonic acid also can be used campanulaceae/. Left under stirring for 1.5 hours and enter 5,94 mmol of triethylamine. Concentrate up to the receipt of syrup and purified on a column of silica, using as an eluting means a mixture of toluene with ethyl acetate /2:3 by volume/. Yield = 70%.

Stage B:

< / BR>
To for 6.81 mmol obtained in stage a connection type 29.7 mmol of benzilate sodium in the form of a solution in benzyl alcohol /1M/. Heated at 110oC with stirring for 1 hour. Then diluted with 200 ml dichloromethane, and then neutralized by which the PMC with silicon dioxide, using as eluting means a mixture of dichloromethane with acetone /10:1 by volume/. Yield = 85%.

Stage:

< / BR>
USD 5.76 mmol obtained in stage B compounds dissolved in dichloromethane and added to 3.92 mmol 4-dimethylaminopyridine, 72,27 mmol of triethylamine and 65.7 mmol of acetic anhydride. Left under stirring at room temperature for 2.5 hours, then add 100 ml of dichloromethane, washed with aqueous 10% solution of KHSO4, dried over anhydrous sodium sulfate, then filtered. Concentrate and purify the thus obtained syrup on a column of silica, using as an eluting means a mixture of dichloromethane with acetone /10:1 by volume/. //20D/= -102o/c = 1,37, CH2Cl2.

Stage G:

< / BR>
To 5,74 mmol obtained in stage In connection add 25 ml of aqueous 70% solution of acetic acid. Heated at 80oC for 6 hours. Concentrate by evaporation in the presence of toluene, receiving a yellow powder.

Stage D:

< / BR>
< / BR>
Reduction to the reaction scheme:

DMAP = 4-dimethylaminopyridine; tBOMSCl = tert.-butyl-dimethylsilane; BnBr = benzylbromide; LevO2= levulinic is= tert.-butyl-dimethyl-silyl radical.

Using obtained in the previous stage of the product, by doing as described in obtaining V, stages D, E and F receive 3-O-acetyl-1,6-anhydrous-2-O-benzyl-4-O-/benzyl-2-O-acetyl-3-deoxy-4-O-levulinic--D-glucopyranose. Total yield: 59%.

Obtaining IX

Methyl-3,6-di-O-acetyl-2-O-benzyl-4-O-/benzyl-2-O-acetyl-3-deoxy--D-glucopyranoside [compound of formula (III].

Received in the receiving VIII disaccharide are acetals, treated with benzylamine, enter into interaction with the reagent Vilsmeier, then with methanol in the presence of silver carbonate. Then the obtained compound is treated with hydrazine, receiving methyl-3,6-di-O-acetyl-2-O-benzyl-4-O-/benzyl-2-O-acetyl-3-deoxy-D-glucopyranosid.

The various stages are given below:

Stage AND

< / BR>
To 1,02 mmol received in the receiving VII of the disaccharide add 102 mmol of acetic anhydride and 10.2 mmol triperoxonane acid, heated at 50oC for 2 hours in argon atmosphere. Then evaporated until get brown syrup and purified as described in obtaining VI, stage And getting the target product. Yield = 92%.

Stage B:

< / BR>
of 1.52 mmol obtained in stage a compound is dissolved in anhydrous diethyl what the product is. Yield = 70%.

Stage:

< / BR>
Prepare the reagent Vilsmeier, mixing, at 0oC, of 2.15 mmol of bromine 2,15 mmol of triphenylphosphine in 5 ml of dimethylformamide. The precipitated white color filter in an argon atmosphere and added, maintaining the same temperature, 0,269 mmol obtained in stage B of the product in the form of a solution in 15 ml of anhydrous dichloromethane. Leave the reaction mixture under stirring for 2 days at room temperature. Then diluted with dichloromethane, washed with water, cooled to 0oC until pH 6, dried over anhydrous sodium sulfate and concentrated down to obtain a syrup. Purified on a column of silica, using a mixture of dichloromethane with diethyl ether /5:1 by volume/. Yield = 77%.

Stage G:

< / BR>
and 0.46 ml of methanol, 0.34 mmol of silver carbonate and 150 mg of calcium sulfate in 3 ml of dichloromethane is mixed for 1 hour in an argon atmosphere at 0oC. 0,227 mmol obtained in stage compounds dissolved in 8 ml dichloromethane. This solution was added dropwise to the reaction mixture and left under stirring for 20 hours at 20oC. Protect from light. Then diluted with dichloromethane, filtered and concentrated, obtaining methyl-3,6-di with silicon dioxide, using as eluting means a mixture of dichloromethane with diethyl ether /5:1 by volume/. Yield = 75%. //20D/= +27o/c = 1,18, CH2Cl2/.

Stage D:

< / BR>
0.276 mmol obtained in the preceding stage, dissolved in 2 ml) cooled to 0oC pyridine and add to 1.38 ml of a 1M solution of hydrazine hydrate is added in a mixture of pyridine with acetic acid /3:2 by volume/. Then the reaction mixture was concentrated, add methylene chloride, washed with aqueous solution of KHSO4, dried over anhydrous sodium sulfate, filtered and concentrated down to obtain a syrup. Purified on a column of silica, using a mixture of dichloromethane with diethyl ether /3:1 by volume/. Yield = 87%.

//2D0= +10o/c = 0.99, and CH2Cl2/.

Getting X

O-/2,4,6-Tri-O-benzyl-3-deoxy-D-abovecaptionskip-/1--->4/-/O-benzyl-2-O-acetyl-3-deoxy--D-glucopyranose /get V/ dissolved in 2.03 mmol dichloromethane at 20oC type molecular sieve, then 5,07 mmol triftoratsetata silver and of 1.52 mmol of bromine. Left under stirring for 45 minutes and then the reaction mixture is filtered, washed with water, evaporated to dryness. is cetyl-2,4-di-O-benzyl-3-deoxy-D-abovecaptionskip/-/1--->4/-O-/benzyl-2-O-acetyl-3-deoxy-D-abovecaptionskip/-/1--->4/-O-/3-deoxy-2-O-sulfo--D-abovecaptionskip/-/1--->4/-O-/benzyl-2-O-acetyl-3-deoxy-D-abovecaptionskip/-/1--->4/-O-/2-O-acetyl-3-deoxy--D-glyukopiranozil/-/1--->4/-O-/2-O-acetyl-3-deoxy--D-glucopyranosid. This compound is dissolved in 0,96 ml of ethanol, cooled to 0oC, then add to 0.30 ml of 5M sodium hydroxide. Left under stirring at 0oC for 5 hours, purified on a column of Sephadex G-25, using as an eluting means water. Is evaporated to dryness, obtaining methyl-O-/3-deoxy--D-abovecaptionskip/-/1--->4/-O-/-3-deoxy--D-glyukopiranozil/1/1--->4/-O-/3-deoxy--D-glucopyranosid.

This compound is dissolved in 5 ml of dimethylformamide, is evaporated to dryness, then again, in an atmosphere of argon, dissolved in 2.6 ml of anhydrous dimethylformamide. Add 302 mg of a complex of a sulfur trioxide - triethylamine and 20 hours at 55oC mix. The reaction mixture is cooled, add 491 mg of sodium bicarbonate in aqueous solution and left under stirring for 3 hours. Purified on a column of Sephadex G-25, using as solvent water, then lyophilized, receiving methyl-O-/3-deoxy-2,4-6-tri-O-sulfo--D-abovecaptionskip/-/1--->4/-O-/3-deoxy-2-O-sulfo-/2D0= +25o/s = 0,52, H2O/ - part 1.

//2D0= +33o= 0,64, H2O/ -part 2.

Range of proton nuclear magnetic resonance: /500 MHz, solvent D2O/ H; "": 5,16 M. D., J1""-2""=3.3V U.

Example 2.

Methyl-O-/3-deoxy-2,4,6-tri-O-sulfo--D-abovecaptionskip/-/1--->4/-O-/3-deoxy-2-O-sulfo--D-abovecaptionskip/-/1--->4/-O-/benzyl-2-O-acetyl-3-deoxy-- L-lyxo-hexopyranoside/--D-glucopyranoside according to the method described in example 1. Methyl-3,6-di-O-acetyl-2-O-benzyl-4-O-/benzyl-2-O-methyl-3-deoxy--D-glucopyranoside obtained from 1,6: 2,3-di-anhydrous-4-O/3-deoxy-D-abovecaptionskip/a-D-mannopyranose according to the method similar to those described in the receiving VII, VIII and IX. //2D0= +25o= 0,48; H2O/.

Range of proton nuclear magnetic resonance /500 MHz, solvent D2O/ a: H 1 : 4,82 m D., J =1-2:4,2 Hz; H' 1: 5,08 m D., J1'-2'=1.0 Hz; H '1: 5,27 m D., J1"-2"=3,7 Hz; H"'1:4,76 m D., J1"'-2"'=7,7 Hz; H"":5,15 M. D., J1""-2"" =3.5 Hz.

Example 3.

Methyl-O-/3-deoxy-2,4-di-O-methyl-6-O-D-abovecaptionskip /1/--->4/-O-/3-deoxy-2-O-sulfo--D-removecomponentlistener/-/1--->4/-O-/2,3,6-tri-O-sulfo--D-abovecaptionskip/-/1--->4/-O-/benzyl-2-O-acetyl-3-deoxy-a-D-glucopyranoside according to the method described in example 1. O-/6-O-Benzyl-2,4-di-O-methyl-3-deoxy-D-abovecaptionskip-/-/1--->4/-O/-/benzyl-2-O-acetyl-3-deoxy--D-abovecaptioned and 3-O-acetyl-1,6-anhydrous-2-O-benzyl-4-O-B>D
0= +24o/C = 0,6, H2O/.

Range of proton nuclear magnetic resonance /500 MHz, solvent D2O: H1 : 4,77 M. D., J1-2=5.0 Hz; H'1:5,22 M. D., J1'-2'=2,2 Hz; 5,24 M. D. J1"-2"= 3,7 Hz, H"'1: 4,76 m D., J1"'-2"' =7.5 Hz; H"":5,10 M. D., J1""-2""=3,6 Hz.

Example 4.

Methyl--O-/3-deoxy-4-O-methyl-2,6-di-O-sulfo--D-abovecaptionskip/-/1--->4/-O-/3-deoxy-2-O-sulfo--D-abovecaptionskip/-/1--->4/-O-/benzyl-2-O-acetyl-3-deoxy-/2D0=+22o= 0,54, H2O/.

Range of proton nuclear magnetic resonance /500 MHz, solvent D2O/: H1:4,78 M. D. J1-2 = 5,1 Hz; H'1:5,22 M. D., J1'-2' = 2,6 Hz; H '1:5,27 m D., J1"-2" = 3,9 Hz; H"' 1:4,75 m D., J1"'-2"' = 7,9 Hz; H"":5,11 M. D., J1""-2""=3.5 Hz.

Example 5.

Methyl-O-/3-deoxy-2,4,6-tri-O-sulfo--D-abovecaptionskip/-/1--->4/-O-/3-deoxy-2-O-methyl-a-D-glucopyranoside and O/6-O-acetyl-2,4-di-O-benzyl-3-deoxy-D-abovecaptionskip/-/1--->4/-O-/benzyl-2-O-methyl-3-deoxy--D-removecomponentlistener--D-glucopyranose and compounds described in obtaining II, according to the method described in the obtained X and XI.

//2D0= +20o/c = 0,39 : H2O/.

Range of proton nuclear magnetic resonance /500 MHz, solvent D2O/ a: H 1 : a 4.83 M. D., J 1-2=3.0 Hz, H' 1: 5,11 M. D., J 1' - ="ptx2">

Methyl-O-/3-deoxy-2,4,6-tri-O-sulfo--D-abovecaptionskip/-/1--->4/-O-/3-deoxy-2-O-methyl-D-abovecaptionskip/-/1--->4/-O-/benzyl-2-O-methyl-3-deoxy-/2D0= +30 /c = 0,40, H2O/.

Range of proton nuclear magnetic resonance /500 MHz, solvent D2O/ a: H 1 : 4,77 M. D., J 1-2=5.0 Hz, H'1: 5,20 M. D., J 1' - 2' = 2,5 Hz; H '1: 5,27 M. D., J 1" - 2" = 4.0 Hz; H"'1 : 4,67 M. D., J 1"' - 2"' = 8,0 Hz; H"" : 5,14 M. D., J 1"" - 2"" = 3.5 Hz.

Example 7.

Methyl-O-/3-deoxy-2,4,6-tri-O-sulfo--D-abovecaptionskip/-/1--->4/-O-/3-deoxy-2-O-methyl-D-abovecaptionskip/-/1--->4/-O-/benzyl-2-O-methyl-3-deoxy-D-glucopyranoside. This is the last connection receive according to the method described by M. Petitou and C. A. A. van Boeckel in "Chemical Synthesis of heparin fragments and analogues" c. 203-210. - Progress in the Chemistry of Organic Natural Products, Ed. Springer Verlag Wien - n.y., 1992. //2D0= +46o/c = 0,58, H2O/.

Range of proton nuclear magnetic resonance /500 MHz, solvent D2O/ a: H 1 : 5,10 M. D., J 1-2=3.0 Hz, H'1: 5,10 M. D., J 1' - 2' = 5.0 Hz; H '1: 5,48 m D., J 1" - 2" = 3,60 Hz; H'1 = 4,68 M. D., J 1"' - 2"' = 7.5 Hz; H"" : 5,16 M. D., J 1"" - 2"" = 3,6 Hz.

Example 8.

Methyl-O-/3-deoxy-2,4-di-tri-O-sulfo--D-removecomponentlistener/-/1--->4/-O-/2,3,6-tri-O-sulfo--D-removecomponentlistener/-/1--->4/-3,6-di-O-acetyl-2-O-benzyl-D-glucopyranose /get V/. Entering into the interaction of these two compounds under the conditions described in example 1, stage A, get a connection:

< / BR>
Yield = 64%.

The thus obtained product is subjected to acetals according to the method described in obtaining VI, stage A, then the impact of benzylamine under the conditions described in stage B of obtaining VI to free anomeric hydroxyl. The corresponding imidate then get through interaction with trichloroacetonitrile in the presence of potassium carbonate according to the method described in obtaining VI, stage Century.

Entering into cooperation with this latest product with methyl-3,6-di-O-acetyl-2-O-benzyl-4-O-/benzyl-2-O-acetyl-3-deoxy--D-glucopyranoside /receiving IX/ poluchautsya-O-/3-deoxy-2,4-di-O-sulfo--D-removecomponentlistener/-/1--->4/-O-/2,3,6-tri-O-sulfo-

in which X denotes a radical of the formula IN the

< / BR>
or a radical of the formula

< / BR>
Y denotes a radical of the formula D

< / BR>
R1, R3, R5, R7, R8, R10, R13identical or different, represent each a linear or branched CNS radical with 1-6 C-atoms or the radical - OSO3-;

R2, R4, R6, R9, R11identical or different, denote-;

R12is a hydroxyl radical or a radical-OSO3-provided that at least one of the substituents R2or R4or R6or R9or R11denotes a hydrogen atom,

in the form of pharmaceutically acceptable salts and the corresponding acids.

2. The compound of formula I on p. 1 corresponding to the formula Ia

< / BR>
in which R1, R2, R3, R4, R5, R6, R7, R11, R12and R13have the meanings specified in paragraph 1 for formula I.

3. The compounds of formula I on p. 1 corresponding to the formula Ib

< / BR>
in which R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, R12and R13have the values listed in paragraph 1, for formula I.

4. The compounds of formula I under item 1, in which R2denotes a hydrogen atom.

5. The compound of formula I under item 1, in which R2and R6represent a hydrogen atom, R3, R11and R12denote the radical OSO3-, R13denotes a linear or branched CNS radical with 1-6 C-atoms.

6. The compound of formula I on p. 1, representing methyl-O-/3-deoxy-2,4,6-tri-O-sulfo--D-rebekkamaria/3-deoxy-2-O-sulfo--L-oxohexanoate -/-/1-->4/-2,3,6-tri-O-sulfo--D-glucopyranoside or its pharmaceutically acceptable salt with a base.

7. The compound of formula I on p. 1, representing methyl-O-/3-deoxy-2,4-di-O-methyl-6-O-sulfo--D-abovecaptionskip/-/1-->4/-O-/3-deoxy-2-O-sulfo--D-abovecaptionskip/-/1-->4/-O-/3-deoxy-2-O-sulfo--D-glyukopiranozil/-/1-->4/-O-/3-deoxy-2-O-sulfo--D-glucopyranoside or its pharmaceutically acceptable salt with a base.

9. The method of obtaining derivatives of 3-deoxyanthocyanins formula I consists in the fact that the compound of formula II

< / BR>
in which X' denotes chloroacetoxy, levelindicator, a radical of the formula IN1< / BR>
< / BR>
or a radical of the formula C1< / BR>
< / BR>
R'1means acyclic acyloxyacyl with 1-6 C-atoms, preferably acetoxyacetyl,

P1, R2identical or different, represent each a protective group selected from acyclic acyl radical with 1-6 C-atoms, preferably acetyl radical or benzyl radical,

P4means benzyl radical;

P3and R5the same or different, represent each a protective group, such as acyclic acyl radical with 1-6 C-atoms, preferably acetyl radical, an aromatic acyl radical, preferably bentely radical, ALK-2-analnyj radiou group, such as an alkyl radical with 1-6 C-atoms, preferably a methyl radical, or a benzyl radical,

R'5, R'6identical or different, represent each a linear or branched CNS radical with 1-6 C-atoms, acyclic acyloxyacyl with 1-6 C-atoms, preferably acetoxyacetyl, aromatic acyloxyacyl, preferably benzoyloxymethyl, or ALK-2-unilaterial with 2 to 7 C-atoms, preferably allyl oxyradical,

R'7, R'10identical or different, are specified for R'1values or do they mean chloroacetanilides or levelindicator,

R'2, R'6, R'9identical or different, represent each a hydrogen atom or have specified for R'1values, enter into interaction with the compound of the formula III

< / BR>
in which R7is specified for P4in the formula II values;

P8is specified for P1in the formula II values,

R'4and R'11identical or different, are specified for R'2in the formula II values,

R'3, R'12and R'13identical or different, are specified for R'1in the formula II values,

obtaining the compounds of formula IV

P7, R'3and R'4have a specified formula III is,

Y' denotes a radical of the formula D1< / BR>
< / BR>
in which R8, R'11, R'12and R'13have a specified formula III is,

which is then subjected to either catalytic hydrogenation, then the saponification and sulfate crystallization, or the saponification, then sulfate crystallization and then catalytic hydrogenation or catalytic hydrogenation, then sulfate crystallization and after the saponification, to obtain the compounds of formula I.

10. The method of obtaining compounds of formula I on p. 1, namely, that the monosaccharide containing a protective group of hydroxyl radicals and possibly carboxylation, if any, enter into interaction with other protected monosaccharide with the formation of the disaccharide, which is then injected into interaction with the following protected monosaccharide with the formation of protected trisaccharide, from which you can get protected tetrasaccharide, then secure pentasaccharide and then secure hexasaccharide and then Tetra-, Penta - or hexasaccharides remove the protective group and, if necessary, sulfation first or they partially remove the protective PP.1-8, characterized in that they possess antithrombotic and antikoaguliruyuschey activity.

12. Pharmaceutical composition having anti-thrombotic and anti antikoaguliruyuschey activity, containing the active ingredient and pharmaceutically acceptable additives, characterized in that the active substance it contains derivatives of 3-deoxyanthocyanins General formula I according to any one of paragraphs.1-8 in an effective amount.

13. 1,6:2,3-Di-anhydrous-4-O-deoxy --D-abovecaptionskip --D-mannopyranose or 3-deoxy-2,4,6-tri-O-benzoyl-a-D-abovecaptionskip derivative of the formula IX

< / BR>
in which M stands for hydrogen or benzoyl.

14. The compound of the formula X

< / BR>
in which R'1denotes an acyclic acyloxyacyl with 1-6 C-atoms, preferably acetoxyethyl;

P1, R2identical or different, represent each a protective group chosen among acyclic acyl radical with 1-6 C-atoms, preferably acetyl radical or a benzyl radical;

P4denotes a benzyl radical;

P9means levelentry radical.

 

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