Di - and trivalent small molecule inhibitors of selectin, pharmaceutical composition, method of inhibiting selectin

 

(57) Abstract:

The invention relates to novel di - and trivalent small selectin inhibitors of formula II, where X is selected from the group comprising-CN, -(CH2)nCO2H, -(CH2)nCONHOH, -O(CH2)m-CO2H, -(CH2)nCOZ, -(CH2)nZ, -CH(CO2H), (CH2)mCO2H,

-OH; Y = -(CH2)f; R1, R2independently selected from the group including hydrogen, lower alkyl, halogen, -OZ, -NO2, -NH2; R3selected from the group including hydrogen, lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkyl-carboxylic acid; f = 1 - 6; n = 0 to 2; b = 0 - 2; m = 1 to 3; Z represents lower alkyl, phenyl, or their pharmaceutically acceptable salts, esters, Amida. Also disclosed are a pharmaceutical composition based on new compounds and a method of inhibiting the binding of E-selectin or P-selectin with sLexor sLea. 3 S. and 6 C.p. f-crystals, 1 table.

The technical field

The invention relates to compounds that inhibit the binding of E-selectin, P-selectin or L-selectin with sialyl-Lewisxand sialyl-Lewisaand to methods of inhibiting the binding of E-selectin, P-selectin or L-telerama, refers to pharmaceutically active compositions containing compounds that inhibit the binding of E, P or L-selectin with sialyl - Lewisxand sialyl-Lewisa.

Prior inventions

E-selectin, also known as ELAM-1 for endothelial leukocyte adhesion to the molecule-1, LECAM-2, adhesion molecules to the lectin cells is a glycoprotein, which is located on the surface of endothelial cells, cells that are arranged in series along the inner walls of the capillaries. E-selectin recognizes and binds to carbohydrate sialyl-Lewisx(sLex), which is present on the surface of some cells. E-selectin helps white blood cells (leukocytes) to learn and adhere to the capillary wall in places where the tissue surrounding the capillary, infected or damaged. E-selectin is in fact one of the three currently known selectins. The other two are L-selectin and P-selectin. P-selectin expresses in inflamed endothelium and platelets, and has a very large structural similarities with E-selectin and can also learn sialyl-Lewisx. L-selectin expresses in leukocytes and also has a large structural salami Iaand Ibat the end of the description.

When the tissue is affected by the microorganism or damaged, white blood cells, also called leukocytes, play a major role in the response to inflammation. One of the most important aspects of the response to inflammation is the adhesion of cells. Usually leukocytes circulating in the blood flow. However, when the tissue becomes infected or become damaged, leukocytes must be able to learn diseased or damaged tissue and should be able to contact the wall of the capillary around the affected tissue and diffuse through the capillary in the affected tissue. E-selectin helps two specific types of white blood cells to recognize the affected places and contact with the wall of the capillary so that these leukocytes could diffuse into the affected tissue.

There are three main types of white blood cells (leukocytes: granulocytes, monocytes and lymphocytes. Among these categories of E-selectin recognizes sLexpresented as a glycoprotein or glycolipid on the surface of monocytes and neutrophils. Neutrophils represent a subclass of granulocytes, which phagocytic and destroy small organisms, especially bacteria. Monocytes after they leave cramoisy, foreign body and physiologically aged cells.

Monocytes and neutrophils are able to find out the location where the tissue is damaged, by binding to E-selectin, which produces at the surface of endothelial cells that line (along the lines) of the capillaries when the tissue surrounding the capillary, diseased or damaged. Usually the production of E-selectin and P-selectin is increased as affected adjacent to the capillary tissue. P-selectin is present mainly in the pellet storage from which it can be rapidly mobilized to the cell surface after activated endothelium. In contrast, E-selectin requires de novo RNA and protein synthesis, and peak expresii achieved after approximately 4-6 hours after activation and reduced to the baseline level after approximately 24-48 hours. White blood cells recognize the affected area, because sLexpart present on the surface of white blood cells, bind to E-selectin and P-selectin. This binding slows the speed of circulating white blood cells in the bloodstream because it is an intermediate rolling of leukocytes along the activated endothelium until mediated integrin

Although the migration of white blood cells to the site of damage helps to fight infection and destroy the foreign substance, the accumulation of excessive numbers of white blood cells can cause widespread tissue damage. Compounds able to block this process and can therefore be used as therapeutic agents. It would therefore be useful to develop inhibitors that would prevent the binding of white blood cells with E-selectin and P-selectin. For example, some of the diseases that could be treated by inhibiting the binding of selectin with sLexinclude ARDS (respiratory distress syndrome in adults), Crohn's disease, septic shock, traumatic shock, multiple damage to the body, autoimmune diseases, asthma, inflammatory bowel disease, psoriasis, rheumatoid arthritis, reperfusion injury, which occurs after heart attacks, strokes, transplantatsii bodies. In addition, as found on some white blood cells, sLeaclose related chemical isomer sLexfound on various cancer cells, including cancer cells of the lung and colon. It is assumed that the adhesion of cells, uclue

This invention relates to compounds having the following structure of formula II:

< / BR>
where X is selected from the group consisting of-CN, -(CH2)nCO2H, -(CH2)nCONHOH, -O(CH2)mCO2H, -O(CH2)mCONHOH, -(CH2)nCONHNH2, -(CH2)nCOZ, -(CH2)nZ, -CH(CO2H)(CH2)mCO2H, -(CH2)nO(CH2)mCO2H, -CONH(CH2)mCO2H, -CH(OZ)(CO2H),

-CH(Z)(CO2H), -(CH2)nSO3H, -(CH2)nPO3D1D2, -NH(CH2)mCO2H, -CONH(CHR3)CO2H,

(1-H-tetrazolyl-5-alkyl), and-OH.

For divalent structures Y represents -(CH2)f-, -CO(CH2)fCO, -(CH2)fO(CH2)f, - CO(CH2)fO(CH2)fCO-, -(CH2)gS(O)b(CH2)fS(O)b(CH2)g-,

-CO(CH2)gS(O)b(CH2)fS(O)b(CH2)gCO-, -(CH2)fV(CH2)f-, -(CH2)fCOVCO(CH2)f-,

-CO(CH2)fCOVCO(CH2)fCO-, -CO(CH2)fV(CH2)fCO-, -CONH(CH2)fNHCO-,

-CO(CH2)fW(CH2)fCO-, -(CH2)fWS2)fWCO(CH2)f- or -(CH2) (CH2)fW(CH2)fCH2- where V is-N[(CH2)q]2N - and q is, independently, 2 to 4, and W is aryl or heteroaryl;

For trivalent structures Y is:

< / BR>
and T is selected from the group comprising -(CH2)f-, -CO(CH2)f-, -(CH2)gS(O)b(CH2)f-, and-CO(CH2)gS(O)b(CH2)f-,

where the carbonyl group is adjacent to biphenylyl link;

R1and R2independently selected from the group comprising hydrogen, alkyl, halogen, -OZ, -NO2, -(CH2)nCO2H, -NH2and-NHZ;

R3selected from the group comprising hydrogen, alkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkalicarbonate acid and alkylcarboxylic;

f is 1-16, g is 0-6, n = 0-6, m is 1-6, p is 0-6, b is 0-2, Z is alkyl, aryl or aralkyl, and D1and D2represent, independently, hydrogen or alkyl, and their pharmaceutically acceptable salts, esters, amides and prodrugs.

More specifically, this invention relates to compounds of the formula III:

< / BR>
where X represents-COOH, -(CH2)nCOOH, or-O(CH2)nCOOH and
-, -(CH2)nS(CH2)nS(CH2)n- ,- (CH2)nCO- , or -(CH2)nCOW(CH2)nWCO(CH2)nwhere W and n are such as defined above.

Particularly preferred compounds include compounds A-J (see end of text).

In addition, the present invention relates to pharmaceutical compositions comprising a compound of formula II or formula III and a pharmaceutically acceptable carrier.

This invention relates to a method of inhibiting the binding of E-selectin, P-selectin or L-selectin with sLexor sLeaincluding the stage of the introduction to the patient an effective amount of compounds having the structure of formula II or formula III, in order to inhibit the binding of E-, P - or L-selectin or P-selectin with sLexor sLeaor pharmaceutically active composition containing the compound of the formula II or III and a pharmaceutically acceptable carrier.

Compounds according to this invention can be used in methods of treatment of diseases such as ARDS, Crohn's disease, septic shock, traumatic shock, multiple damage to the body, autoimmune diseases, asthma, inflammatory diseases Chicherov, transplantatsii organs, and cancer, which consist in the introduction of the animal, if necessary, of such treatment, a therapeutically effective amount of compounds having formula II or formula III, to reduce symptoms.

A detailed description of the preferred embodiment variants of the invention

It was found that compounds having the formula (II) above, inhibit the binding of E-, P-, or L-selectin with sLexor sLea.

Used herein, the term "alkyl" means a monovalent group with a straight or branched chain of from 5-12 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, etc.

The term "lower alkyl" refers to any alkyl group having from one to six carbon atoms.

The term "halogen" refers to any atom selected from the group consisting of chlorine, fluorine, bromine, and iodine.

The term "alkoxy" means an alkyl group attached to the molecule through an oxygen atom, including, but not limited to, methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy etc.

The term "alkylamino" is propylamino etc.

The term "aryl" means a carbocyclic aromatic groups including, but not limited to, phenyl, 1-or 2-naphthyl, fluorenyl, (1,2)-dihydronaphtho, indenyl, indanyl, thienyl, benzothiazyl, cyanopyridyl etc.

The term "aralkyl" (also called arylalkyl) means aryl group associated with the alkyl group, including, but not limited to, benzyl, 1-and 2-naphthylmethyl, galamensis, alkoxybenzyl, hydroxybenzyl, aminobenzyl, nitrobenzyl, guanidines, fluorenylmethyl, phenylmethyl (benzyl), 1-phenylethyl, 2-phenyl-ethyl, 1-naphtalate etc.

The term "hydroxyalkyl" means HE's associated with the alkyl group.

The term "aminoalkyl" means a group having the structure - NRxRyassociated with the alkyl group. Group Rxand Ry, independently, selected from, for example, hydrogen, alkyl and aryl.

The term "alkyl carboxylic acid" means a carboxylic group (-CO2H) associated with the alkyl group.

The term "alkyl carboxamide" means the group having the formula-CONRxRyrelated alkyl group, where Rxand Rysuch as defined above for aminoalkyl.

Used herein, the term "pharmaceutically of pryemlemost, esters, Amida and prodrugs of the compounds of this invention which are, within the indicated (voiced) medical assessment, are suitable for use in contact with the tissues of patients without excessive toxicity, agitation, allergic reactions, etc. correspond to the reasonable value of benefit/risk, and effective for their intended use, and also relates to zwitterionic forms of the compounds of the present invention, where they are possible. The term "salt" refers to a relatively non-toxic salts of the accession of inorganic and organic acids of the compounds of the present invention. These salts can be obtained in situ during the final isolation and purification of the compounds or by the specific interaction of the purified compound in its free form with a suitable organic or inorganic acid or base, and the allocation thus obtained salt. Illustrative examples of such salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naftilan, mesilate, glucoheptonate, lactobionate, laurylsulphate salt, ALCI, magnesium, etc. and also non-toxic salts of the cations ammonium, quaternionic ammonium and amine, including, but not limited to, ammonium, Tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc., (See, for example, S. M. Berge et al., "Pharmaceutical Salts," J. Pharm.Sci., 66: 1-19 (1977), which is here referred to).

Examples of pharmaceutically acceptable non-toxic esters of the compounds of this invention include C1-C6alkyl esters where the alkyl group is a straight or unbranched chain. Acceptable esters also include C5-C7cycloalkyl esters, and arylalkyl esters, such as benzyl, but not limited to. C1-C4alkyl esters are preferred. Esters of the compounds of this invention can be obtained according to conventional methods.

Examples of compounds pharmaceutically acceptable, non-toxic amides of this invention include amides derived from ammonia, primary C1-C6alkyl amines and secondary C1-C6dialkyl amines, where the alkyl groups are straight or branched chain. In the case of secondary amines, ammonia,1-C3alkyl primary amides and C1-C2dialkyl secondary amides are preferred. Amides of the compounds of this invention can be obtained according to conventional methods.

The term "prodrug" refers to compounds that are rapidly transformed in vivo in a related compound of the above formula, for example, hydrolysis in the blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are here referred to.

This invention also relates to pharmaceutically active compositions which contain compounds according to this invention. It is also assumed that the pharmaceutically active composition may contain the compound in this invention and other compounds that inhibit or compete with E-selectin or P-selectin for binding with sLexor sLeaincluding sLexor sLeathemselves.

Pharmaceutically active compositions of this invention contain a physiological carrier and a compound of formula II or III.

The pharmaceutical compositions according to this invention may contain Xinyi, physiologically acceptable carriers, adjuvants or diluents, which are collectively called here the carriers, for parenteral injection, for oral administration in solid or liquid form, for rectal or topical application, etc.

The composition can be applied to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), nutrizionale, vnutrivaginalno, intraperitoneally, locally (powders, ointments or drops), or buccal or by inhalation (spray or in the form of aerosols for the nose).

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for transformation into sterile injectable solutions or dispersion. Examples of acceptable aqueous or nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyol (propylene glycol, polyethylene glycol, glycerin, etc.,), acceptable mixtures thereof, vegetable oils (such as olive oil or kanalowe (cannola) oil) and injectisome organic esters, such as etiloleat. The proper fluidity of moamer particles in the case of dispersions and by the use of surfactants.

These compositions may also contain additives such as preserving, wetting, emulsifying, and dispersing funds. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc., in Addition, it may be desirable inclusion isotonic means, for example, sugars, sodium chloride, etc., Using tools that slow down the absorption, for example, aluminum monostearate and gelatin can be prolonged absorption of injectable pharmaceutical form.

When necessary and for more effective distribution, the compounds can be incorporated into the delivery system slow or timed actions or delivery systems targeted actions, such as polymer matrices, liposomes, and microspheres. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing means in the form of sterile water or other sterile injectable medium immediately before use.

For solid dosage forms for oral administration include capsulesthe-ester is mixed with, at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or (dry) diluents, as for example, starches, lactose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and the Arabian gum, (C) humectants, as for example, glycerol, (d) a disintegrator, such as agar-agar, calcium carbonate, potato starch or barley starch, alginic acid, certain complex silicates and sodium carbonate, (e) the dissolution retarders, such as paraffin, f) absorption accelerators, as for example, Quaternary ammonium compounds, (g) wetting means, as for example, cetyl alcohol and glycerol monostearate, (h) absorbents, such as kaolin and bentonite, and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulphate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also contain tabularasa agents.

Solid compositions of a similar type can also be used as fillers in soft and tendonopathy gelatinolytic etc.

Solid dosage forms such as tablets, coated tablets, capsules, pills and granules can be prepared with coatings and shells, such as intersolubility coatings and others well known in this field. They may contain substances that make the material opaque, and, in addition, they can provide such a composition that releases the active compound or compounds in a certain part of the intestinal tract in a slow way. Examples of compositions of the fill, which can be used are polymeric substances and waxes.

The active compounds can also be in microencapsulated form, if desired, one or more of the foregoing fillers.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in this field, such as water or other solvents, solubilizing means and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - buta is the new oil, kanalowe oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters sorbitan and fatty acids or mixtures of these substances, etc.

Besides such inert diluents, compositions can also contain additives, such as wetting means, emulsifying and suspendresume tools, sweetening substances, substances imparting taste and smell.

Suspensions, in addition to the active compounds, may contain suspendresume means, as for example, ethoxylated isostearyl alcohols, esters of polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant or mixtures of these substances, etc.

Compositions for rectal use are preferably suppositories which can be obtained by mixing the compounds of this invention with suitable, not causing irritation fillers or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore melt in the rectal or vaginal cavity and release the active which include lubrication, powders, aerosols and drug inhalation.

The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and needed preservatives, buffers or propellants when required. It is also assumed that ophthalmic formulations, eye ointments, suspensions, powders and solutions are included in the scope of this invention.

Compounds according to this invention can also be applied in the form of liposomes. As is well known in this field, liposomes is usually derived from phospholipids or other lipid substances. Liposomes are formed by mono - or multilamellar of hydrated liquid crystals that are dispersed in the aquatic environment. You can use any non-toxic physiologically acceptable and metabolisable a lipid capable of forming liposomes. The proposed composition in liposomal form can contain, in addition to the binding of selectin inhibitors of the present invention, stabilizers, preservatives, fillers, etc., the Preferred lipids are phospholipids and phosphatidyl choline (lecithins), both natural and synthetic. Methods of obtaining liposomes are well known in this field.

The actual dose levels of active adianta, which is effective to obtain the desired therapeutic response for a particular composition and method of administration. Therefore, the selected dosage depends upon the desired therapeutic effect, the route of administration, the desired duration of treatment and other factors.

The total daily dose of the compounds according to this invention, the input host in single or divided doses may be in the range from about 0.3 mg to about 50 mg per kilogram of body weight. Standard dosage can contain such an integral part of the dosing unit, which can be used to provide a daily dose. Note, however, that the exact dose level for any particular patient, regardless of whether it is a man or an animal, will depend on a number of factors, including body weight, health condition, sex, diet, time and route of administration, absorption and excretion, combination with other drugs and the severity of the particular disease to be treated.

In particular, the compounds of this invention can be used to treat a number of diseases related to inflammation and cell-cell recognition and adhesion. For example, the compounds according to this invention is psoriasis and rheumatoid arthritis, and reperfusion tissue injury that occurs after heart attacks, strokes and organ transplants, traumatic shock, multiple organ damage, autoimmune diseases, asthma, inflammatory bowel disease. In each case, if necessary, of such treatment, an effective amount of the compounds of this invention administered to a patient as such or as part of a pharmaceutically active composition. Also found that, when the need for such introduction, the patient can enter combinations of compounds. Compounds according to this invention can also be used to treat other diseases that are associated with cell-cell adhesion. Because the proposed compounds inhibit the binding of E-selectin or P-selectin with sLexor sLeaany disease that is associated with such interactions can potentially be treated by inhibition of this binding interaction.

In addition to the detection of certain white blood cells, sLeadetected in various cancer cells, including cancer cells of the lung and colon. It is also suggested that cell adhesion, including sLeamay be involved in the metastasis of necator> Many of the compounds of this invention can be synthesized following the General synthetic schemes 1-8.

In scheme 1 substituted biphenyl Pat. USA N 5444050) interacts with the acid chloride of decollate that gives duridian Preferred examples include acid chlorides linear or branched sekisei from five to 16 carbons and the aryl acid chlorides and aralkyl of decislon. These compounds can be restored using one of many methods known to experts in this field, namely by catalytic hydrogenation, for restoration of the wolf-Kijner, with metal hydrides, such as triethylsilane, or repair on Clemens. The obtained compound is converted into phenol by the action of tribromide boron in a halogenated solvent, preferably at 0oC to room temperature (CT). Glycosylation using protected mannaseo link in the presence of epirate triphoridae, with subsequent alkaline hydrolysis provides the desired compound (scheme 2).

In some cases it is desirable to build a bridge between the two rings, which later replace link mannose before attaching the ring, which is carboxylate. For example, in this scheme is then reaction Friedel-with anisole receive ketone Restore ketone one of a number of different ways, well-known experts in this field, gives compound Introduction of lithium in the ortho-position relative to metaxylem groups with subsequent conversion to boranova acid and palladium-mediated bailee connection gives Demethylation esters with subsequent glycosylation and unprotect gives the target connection

In other examples (see diagram 3) it may be appropriate to carry out the reaction of the Friedel-on connection, such as (U.S. Pat. USA N 5444050), in which the sugar is already in place. For example, can be treated with succinic anhydride in the presence of a Lewis acid such as aluminum chloride, to obtain the keto-acid Recovery ketone one of a number of methods known to experts in this field, gives the acid which is converted into the acid chloride using thionyl chloride in a halogenated solvent at a low temperature, or other suitable method. The acid chloride is subjected to interaction with one of a number of primary or secondary amines, especially diamines such as Ethylenediamine, piperazine, homopiperazine, 4,4'-trimethylene-dipiperidino, or other alkylamino, receiving a multimeric compounds such as the Restoration of amides using b what Lisa protective groups network connection required Except in amides can directly hydrolyze getting amides

Compounds containing essential communication can be obtained according to scheme 4. Oxidation of complex hydroxyamino in aldehydes followed by samakonasana gives the esters are converted into the acid chlorides of the acids Linking by reaction Friedel -, recovery, demethylation, glycosylation and removing protection leads to esters

In some cases it may be desirable to obtain other compounds by sequential reactions shown in scheme 5. Thus, it is possible to subject the reaction Friedel-other halogenated anhydrides, for example, the acid chloride of 3-bromopropionic acid, to obtain Recovery Antilibanus ketone can be accomplished by one of several methods known to experts in this field, receiving a halide Reaction with 1,3-propane dithiol, or other suitable disulfide in the presence of a suitable base network connection Demethylation can be accomplished in one of several ways, especially by tribromide boron in a halogenated solvent at low temperature, which gives the phenol Phenol is subjected to interaction with protected mannopyranoside using apirat trifari ernative, the glycoside can be treated with a suitable oxidizing agent such as m-chloroperoxybenzoic acid, in an appropriate solvent, which gives sulfon. Processing water base gives the target compound

In other cases (see scheme 6), the intermediate product is subjected to reaction Friedel-with the acid chloride of decollate in halogenated solvent in the presence of aluminum chloride or other Lewis acid, getting Remove protection mannose parts using aqueous hydroxide or methoxide, then a hydroxide, gives the target compound

In figure 7, the substituted biphenyl Pat. USA N 5 444 050) is subjected to interaction with the acid chloride trehosnovnoy acid, getting Antilibanus ketone These ketones can be reduced by one of a number of different ways known to specialists in this area and are listed in scheme 1. The compounds obtained can be demetilirovanie, glucosinolate and delete them protection with required connections

In a similar way (see figure 8) is subjected to reaction Friedel-with bromohydrin bromelicola, receiving the Interaction of bracelona 1,3,5-substituted benzene by tritiya in the presence of base gives the connection Hydrolysis of the protective groups gives required is

EXAMPLE 1

1,6-Bis-[3-(3-carboxymethyl)-4-(2--D-manno - paranoiacs)phenyl] hexane

Stage 1: Adipoyl chloride (2.0 g, 10.9 mmol) dissolved in 1,2-dichloromethane (55 ml) and cooled in an ice bath. Add luminiares (5.8 g, to 43.5 mmol) and then methyl ester 3-(2-methoxyphenyl)phenylacetic acid (5.75 g of 22.4 mmol) [T. P. Kogan, B. Dupre, I. L. Scott, K. Keler, H. Dao and P. Beck, US Patent 5444050 and T. P. Kogan, B. Dupre, K. M. Keller, I. L. Scott, H. Bui, R. V. Market, P. J. Beck, J. A. Voytus, B. M. Revelle and D. Scott, J. Med.Chem, 1995, 38, 4976-4984] and the mixture is stirred at room temperature for 30 minutes, then mixed with ice water (30 ml). Organic matter is separated and the aqueous portion extracted with dichloromethane (3 x 5 ml). Organic substances combine, dried (MgSO4), then concentrated under reduced pressure. The residue is purified on a flash chromatography (SiO2, gradient elution from hexane to 3:1 hexane/acetate) to give the product (2,23 g, 33%).1H NMR (400 MHz, CDCl3): of 7.96 (DD, J=6,6, 1.9 Hz, 2H), 7,92 (d, J=1.9 Hz, 2H), 7,42 (m, 2H), 7,34 (t, J=6 Hz, 2H), 7.18 in-7,28 (m, 4H),7,00 (d, J=6.3 Hz, 2H), a 3.87 (s, 6H), of 3.69 (s, 6H), 3,68 (s, 4H), 3,01 (m, 4H), of 1.84 (m, 4H) ppm. IR (NaCl): 1741, 1677 cm-1.

Stage 2: part a: the Product from step 1 (2,23 g, 3.6 mmol) is dissolved in acetonitrile and treated with a solution of lithium hydroxide (0.8 g, 18 mmol monohydrate of lithium hydroxide and extracted with ethyl acetate. The extracts are combined, dried (MgSO4), then concentrated under reduced pressure. IR (NaCl): 1711, 1677 cm-1< / BR>
Part b: the Ketoacid of part a (1.86 g, 3.1 mmol) dissolved in dimethyl sulfoxide (15 ml) and mixed with hydrazine (1.0 ml, 31 mmol). This mixture is heated at 80oC in nitrogen atmosphere for 2.5 hours, then cooled. Add tert-piperonyl potassium (3.5 g, 31 mmol) and the mixture is again heated at 80oC overnight, then mixed with water (30 ml) and acidified with 2H HCl, and extracted with ethyl acetate. The extracts are combined, dried (MgSO4) and concentrated under reduced pressure, obtaining (1.6 g, 9%). IR (NaCl): 1713 cm-1.

Stage 3: part a: Decollato from stage 2, part b (1.6 g, 2.8 mmol) dissolved in dichloromethane (14 ml) under nitrogen atmosphere and cooled in a bath with a mixture of dry ice/2-propanol. Slowly add tribromide boron (1.4 ml, 14 mmol); the mixture is stirred at room temperature for 2 hours, then mixed with ice-water (25 ml). Organic matter is separated, washed with saturated sodium bicarbonate solution (20 ml), water (20 ml), saturated solution of sodium chloride (20 ml), then dried (MgSO4) and concentrated under reduced pressure, obtaining of 2.38 g of the crude product.

the t at the boiling temperature of phlegmy during the night, then concentrate under reduced pressure. The residue is dissolved in dichloromethane (50 ml) and treated with sodium carbonate, then filtered through a silica substrate. The filtrate is concentrated under reduced pressure and the residue is purified by means of flash chromatography (SiO2gradient elution, hexane to 3:1 hexane/ethyl acetate) to give 1,6-bis-(3-(3-carbomethoxybiphenyl)- 4-hydroxyphenyl)hexane (0.9 g, 38%).1H NMR (400 MHz, CDCl3): 6,80 is 7.50 (m, 14H), 3,70 (s, 6H), 3,68 (s, 4H), to 2.55 (DD, J=5,5, 5,5 Hz, 4H), to 1.59 (m, 4H), of 1.36 (m, 4H) ppm. IR (NaCl): 3430, 1731 cm-1.

Stage 4: 1,6-Bis-(3-(3-carbomethoxybiphenyl)-4-hydroxyphenyl) hexane (0.9 g, 1.6 mmol) dissolved in 1,2-dichloroethane (8 ml). Pentaacetate-D-mannose (1.9 g, 4.8 mmol) is added in one portion, then slowly add Efrat boron TRIFLUORIDE (2.5 ml, 19.2 mmol). The mixture is stirred under nitrogen atmosphere overnight at room temperature, then mixed with water (15 ml). Organic matter is separated and the aqueous portion extracted with dichloromethane (3 x 2 ml). The extracts combined with the first organic fraction is dried (MgSO4), then concentrated under reduced pressure. The residue is purified on a flash chromatography (SiO2, gradient elution hexane to 3: 1 hexane/ethyl acetate), obtaining 0 MHz, CDCl3): 7,31-7,37 (m, 6H), 7,19-7,24 (m, 4H), 7,09 - 7,13 (m, 4H), 5.25-inch (d, J= 0.6 Hz, 2H), 3,57-3,66 (m, 6H), 3,3-3,50 (m, 10H), of 2.54 (m, 4H), 1,58 (m, 4H), of 1.34 (m, 4H) ppm. IR (NaCl): 1752 cm-1.

Stage 5: Glycoside from step 4 (1.5 g, 1.2 mmol) dissolved in acetonitrile (6 ml) and treated with a solution of the monohydrate lithium hydroxide (1.0 g, 24 mmol) in water (10 ml). The mixture is stirred at room temperature overnight, then acidified to pH 2 with concentrated hydrochloric acid. The mixture is concentrated under reduced pressure and the residue purified using HPLC (reversed phase, gradient elution 5-50% acetonitrile in water control at 254 nm) to give 1,6-bis-[3-(3-carboxymethyl)-4-(2- -D - mannopyranoside)phenyl]hexane, (0.35 g, 33%) as a white solid, so pl. 115-117oC;1H NMR (400 MHz, DMSO-d6): 7,31-7,37 (m, 6H), 7,19-7,24 (m, 4H), 7,09-7,13 (m, 4H), 5.25-inch (d, J=0.6 Hz, 2H), 3,57-3,66 (m, 6H), 3,3-3,50 (m, 10H), of 2.54 (m, 4H), 1,58 (m, 4H), of 1.34 (m, 4H) ppm. IR (Kbr): 3420, 1711 cm-1.

EXAMPLE 2

1,6-Bis-[3-(3-carboxymethyl)-4-(2- -D - mannopyranoside) phenyl] hexane, disodium salt (alternativnyj way)

Stage 1: Adipocere (16,8 ml, 112 mmol) and methyl ester of 3-(2-methoxyphenyl)phenylacetic acid (60,9 g, 225 mmol) dissolved in dichloromethane (300 ml) and cooled at 0oC. the ice. The product is extracted with EtOAc (1 l), washed with water (500 ml), us.NaHCO3(50 ml) and us.NaCl (50 ml). The solution is dried over Na2SO4, filtered through a plug of magnesium sulfate, concentrated, and then recrystallized from a mixture of ether/ethyl acetate, receiving, or 64.7 g, 89%).

Stage 2: Bis-ketone (15 g, and 23.1 mmol) is dissolved in a hot mixture of EtOAc: EtOH (4: 1, 100 ml). The resulting solution is cooled, add triperoxonane acid (1 ml) and Pearlman catalyst (0.75 g). The mixture is shaken in an atmosphere of hydrogen (3,515 kg/cm250 psi) for 18 h and filtered through a substrate celite. The solution was washed with saturated NaHCO3, water and saturated salt solution, dried (Na2SO4), filtered through MgSO4and concentrate. The toluene is distilled off from the product to remove EtOAc, and the residue is dried under high vacuum, obtaining 1,6-bis-[3-(3-carbomethoxybiphenyl)-4-methoxyphenyl]hexane, quantitatively.

Stage 3: Bis-methyl ester (25.6 g, 41 mmol) dissolved in dichloromethane (165 ml) and cooled to 0oC. Slowly add tribromide boron in dichloromethane (33 ml), then put aside the cooling bath and the reaction mixture was stirred at room temperature for 20 minutes, the Reaction mixture was cooled in an ice bath, the input current of nitrogen replacing reginout EtOAc. Organic matter was separated, washed with water, brine, dried (MgSO4) and concentrated under reduced pressure, obtaining 1,6-bis-[3-(3-carbomethoxybiphenyl)-4-hydroxy-phenyl] hexane (24, 2 g, 100%).

Stage 4: To a cooled with ice to a solution of bis-phenol (25,37 g, and 42.7 mmol) and Tetra-pivaloyl - a-D - mannopyranosyl fluoride (66,4 g, 128 mmol) [I. L. Scott and T. P. Kogan, US Patent application filed May 20, 1996, entitled "High Yield Stereospecific Mannosylation"] in dichloromethane (427 ml) is added dropwise BF3OEt2(47,3 ml, 384 mmol) and cooled with ice, the mixture is stirred for 1 h the Mixture is diluted with EtOAc and washed with water (2x), sodium hydroxide (2M), water, and us. sodium chloride, dried over magnesium sulfate and concentrate under reduced pressure. Purification by chromatography (silica, elute with hexane/EtOAc gradient of 30:1 to 6:1) to give 1,6 - bis-[3-(3-carbomethoxybiphenyl)-4-(Tetra-pivaloyl - a-D - Manoj-nanosilica)phenyl] hexane (59,8 g, 89%).

Stage 5: part a: To a solution of bis-glycoside in THF (24 ml) is added methanol (24.4 mmol) and then cooled with ice their solution of sodium methoxide (from sodium, 0.5 g, 22 mmol) in methanol (24,4 ml) and the mixture is stirred at RT over night. The precipitate is collected by filtration and washed with a small volume of THF/methanol (2:1"ptx2">

Part B: the Residue is stirred in water (27 ml) at RT for 30 min then brought to pH 14 and is supported at pH 14 using the minimum amount of sodium hydroxide (2M), with stirring. After 4 hours completes the removal of protection by using HPLC with reversed phase. The solution is neutralized pre-washed ion exchange resin (Dowex 50, h form) and filtered through celite. Then the solution lyophilized getting 1,6-bis-[3-(3-carboxymethyl)-4-(2- - D-mannopyranosyl-hydroxy)phenyl]hexane, disodium salt in the form of slightly hygroscopic white powder (6.0 g, 90%), so pl. 243-245oC;1H NMR (400 MHz, D2O) to 7.64 (s, 2H), 7,58 (d, J=7.7 Hz, 2H), 7,49 (t, J=7.5 Hz, 2H), 7,37 (d, J=8,4 Hz, 2H), 7,19 (d, J=7,3 Hz, 2H), 7,12 (s, 2H), 7,07 (d, J=8.0 Hz, 2H), to 5.66 (s, 2H), 4,27 (s, 2H), 4,00-4,20 (m, 4H), Android 4.04 (DD, J=12.1 and 3,3 Hz, 2H), 3,80-to 3.92 (m, 6H), and 3.72 (d, J=9,2 Hz, 2H), 2,52 (m, 4H), 1,60 (W, 4H), 1.39 in (W, 4H);13With NMR (100 MHz, D2O) 180,9, 151,5, 138,4, 137,5, 137,4, 132,5, 130,9, 129,1, 129,0, 128,9, 127,3, 117,2, 100,2, 74,2, 70,9, 66,6, 60,9, 45,5, 32,3, 31,6, 29,5; Found: 57,54%C, 5,98%H, 5,12 Na; Rasch. for C46H52O16Na2O3H2O: 57,50%, Between 6.08%H, 4,78 Na.

EXAMPLE 3

1,4-Bis-[3-(3-carboxymethyl)-4-(2- -D - mannopyranoside)phenyl] butane

Stage 1: 4-(4-Methoxyphenyl)butyric acid (2.0 g, of 10.3 mmol) is treated with thionyl chloride (20 ml). The reaction centricut under reduced pressure, getting 4-(4-methoxyphenyl)butyryl chloride (2.3 g) as a yellow oil, used without further purification. IR (NaCl): 1795, 1510, 1244 cm-1.

The crude acid chloride acid (2,07 g, 9.7 mmol) and anisole (1.26 g, 11.6 mmol) dissolved in 1,2-dichloroethane (32 ml) and cooled in an ice bath. The mixture is treated with aluminum chloride (3.9 g, of 29.1 mmol) in portions, stirred for 5 minutes, then mixed with ice water (50 ml). The mixture is extracted with dichloromethane (3 x 10 ml) and the extracts combined, washed with saturated sodium chloride (100 ml), dried (MgSO4), then concentrated under reduced pressure. The residue was washed with a jet of 10:1 mixture of hexane/ethyl acetate over silica gel, then concentrated, obtaining 1,4-bis-(4-methoxyphenyl)butane-1-he (2,49 g, 82%).1H NMR (400 MHz, CDCl3): of 7.90 (d, J= 8,8 Hz, 2H), 7,11 (d, J=8,4 Hz, 2H), 6,91 (d, J=8,8 Hz, 2H), 6,83 (d, J=8,4 Hz, 2H), 3,86 (s, 3H), of 3.78 (s, 3H), 2,90 (t, J=7,3 Hz, 2H), 2,65 (t, J=7.7 Hz, 2H), 2,02 (m, 2H) ppm. IR(NaCl): 1674, 1602, 1244 cm-1.

Stage 2: Ketone (2,49 g, 8,8 mmol) dissolved in dichloromethane (30 ml) and treated triperoxonane acid (2.7 ml of 35.2 mmol), triethylsilane (2.8 ml, 17.6 mmol), then efratom triphoridae (4,4 ml of 35.2 mmol). The mixture is stirred at room temperature for 2 hours, then cooled to denaut, washed with saturated sodium chloride (100 ml) and dried (MgSO4), then concentrated under reduced pressure. The residue was washed with a jet of 10:1 mixture of hexane/ethyl acetate over silica gel and concentrated, obtaining 1,4 - bis-(4-methoxyphenyl) butane (2.0 g, 85%) as a clear oil.1H NMR (400 MHz, CDCl3): 7,07 (d, J=8,4 Hz, 4H), for 6.81 (d, J= 8,4 Hz, 4H), of 3.78 (s, 6H), of 2.56 (m, 4H), to 1.61 (m, 4H) ppm. IR (NaCl): 1605, 1248 cm-1.

Stage 3: 1,4-Bis-(4-methoxyphenyl)butane (1.78 g, 6.6 mmol) and TMEDA (4,0 ml of 26.5 mmol) is mixed with anhydrous ether (30 ml) and cooled in an ice bath. Add n-utility (10,5 ml of 2.5 M solution of 26.5 mmol), the mixture is heated to room temperature and stirred for 1 h, the Reaction mixture was cooled to 0 C and treated with trimethylboron (3.0 ml, of 26.5 mmol). The mixture is stirred at room temperature overnight, quenched 2H HCl (to pH 2) and stirred for one hour. The organic phase is separated and the aqueous portion extracted with ethyl acetate (3 x 5 ml). The extracts combined with the first organic fraction and dried (MgSO4), then concentrated under reduced pressure, getting Bronevoy acid (3.0 g), which is used without further purification. IR (NaCl): 1603, 1490, 1416, 1328, 1234 cm-1.

Untreated Bronevoy acid and methyl 3-butrecently potassium phosphate (10.7 g, a 50.5 mmol) and chloride bis(triphenylphosphine)-palladium (II) (100 mg, 0,17 mmol). The mixture Tegaserod again, then heated at the boiling temperature of phlegmy for 2 hours, cooled to room temperature and mixed with water (100 ml). The mixture is extracted with dichloromethane (3 x 10 ml) and the extracts combined, washed with water (50 ml), saturated sodium chloride (50 ml), dried (MgSO4) and concentrate under reduced pressure. The residue is purified on a flash chromatography (SiO2, gradient elution, 8:1 hexane/ethyl acetate to 4:1 hexane/ethyl acetate) to give 1,4-bis- [3-(3-carbomethoxybiphenyl)-(4-methoxy) phenyl] butane (1,14 g, 24%) as a clear oil.1H NMR (400 MHz, CDCl3): 7,41 - 7,44 (m, 4H), 7,34 (t, J=7.7 Hz, 2H), 7,21-of 7.60 (m, 2H), 7,08-7,13 (m, 4H), 6.87 in (d, J=8.0 Hz, 2H), of 3.77 (s, 6H), 3,68 (s, 6H), 3,66 (s, 4H), 2,61 (m, 4H), to 1.67 (m, 4H) ppm. IR (NaCl): 1737, 1606, 1239 cm-1.

Stage 4: 1,4-Bis-[3-(3-carbomethoxybiphenyl)-(4-methoxy) phenyl]butane (0.9 g, 1.6 mmol) dissolved in dichloromethane (3.0 ml), cooled in a bath of dry ice and treated with tribromide boron (1.2 ml, 12.8 mmol). The mixture was stirred at - 78oC for three hours, then placed in a freezer at -10oC during the night. The reaction is quenched with ice water (10 ml) and extracted with dichloromethane (3 x 5 ml). Organic substances of reduced pressure. The residue is purified on a flash chromatography (SiO2with 5:1 hexane/ethyl acetate) to give 1,4-bis-[3-(3-carbomethoxybiphenyl)- 4-hydroxyphenyl] butane (0.4 g, 47%).1H NMR (400 MHz, CDCl3): 7,42 (d, J=7,4 Hz, 2H), 7,35-7,38 (m, 4H), 7,27-to 7.32 (m, 2H), 7,02-7,05 (m, 4H), 6.87 in (d, J=8.0 Hz, 2H), 5,12 (s, 2H), 3,70 (s, 6H), 3,68 (s, 4H), at 2.59 (m, 4H), of 1.65 (m, 4H) ppm. IR (NaCl): 3439, 1732, 1606, 1263 cm-1.

Stage 5: 1,4-Bis-[3-(3-carbomethoxybiphenyl)-4 - hydroxyphenyl]butane (0.4 g, of 0.74 mmol) and pentaacetate-D-mannose (0,72 g of 1.85 mmol) dissolved in dichloroethane (4.0 ml) and treated with efratom boron TRIFLUORIDE (1.1 ml, 8.9 mmol). The mixture is stirred at room temperature overnight, then quenched with water (10 ml) and extracted with dichloromethane (3 x 4 ml). Organic substances combine, washed with water (15 ml), saturated sodium chloride (20 ml), dried (MgSO4) and concentrate under reduced pressure. The residue is purified on a flash chromatography (SiO2, 2: 1 hexane/ethyl acetate) to give 1,4-bis-[3-(3-carbomethoxybiphenyl)-4-(2,3,4,6-Tetra - acetyl-D-mannopyranoside)phenyl] butane (0.88 g, 99%) as a foam.1H NMR (400 MHz, CDCl3): 7,38-7,44 (m, 6H), 7,25-7,29 (m, 2H), 7,17 (CL, 2H), 7,07-7,11 (m, 4H), of 5.40 (s, 2H), 5,20-and 5.30 (m, 6H), is 4.15 (DD, J= 12,3, 4,8 Hz, 2H), 3,93 (DD, J= 12,4, 2,2 Hz, 2H), 3,76-3,82 (m, 2H), and 3.72 (s, 4H), 3,68 (s, 6H), 2.63 in (m, 4H), to 2.13 (s, 6H), for 2.01 (s, 6H), from 2.00 (s, 6H), of 1.97 (s, 6H), to 1.67 (m, 4 is srabatyvayut solution, hydrate, lithium hydroxide (0,46 g, 11 mmol in 2 ml water) and the mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the residue is acidified to pH 2 with concentrated hydrochloric acid. Part of the mixture purified HPLC with reversed phase (C18water/acetonitrile gradient 20-80% of for 45 minutes, monitor at 254 nm) to give 1,4-bis-[3-(3-carboxymethyl)-4- -D-mannopyranosyl - hydroxy)phenyl] butane (230 mg) as a white solid, so pl.: 195-197oC.1H NMR (400 MHz, DMSO-d6): 7,31-7,39 (m, 6H), 7,20-7,25 (m, 4H), 7,10-to 7.15 (m, 4H), of 5.25 (s, 2H), 4,88 (sm, J=4.0 Hz, 2H), 4,76 (CL, 2H), 4,60 (CL, 2H), 4,45 (PC, J=5,9 Hz, 2H), 3,55-3,68 (m, 5H), 3,62 (s, 4H), 3,40-to 3.50 (m, 7H), 2,60 (m, 4H), of 1.62 (m, 4H) ppm. IR (KBr): 3333, 3229, 1729, 1224 cm-1; Found: 61,30%C, 6,15%H: Rasch. for C44H50O160,4 TFA(TGA): 61,32%, 5,79.%H.

EXAMPLE 4

N, N'-Bis-[4-(3-(3-carboxymethyl)-4- -D-mannopyranoside)phenyl] butane-1-oil]-4,4'-trimethylenediamine

Stage 1: Anhydride internai acid (2.0 g, to 19.9 mmol) and aluminium chloride (17,7 g, 132 mmol) is mixed with 1,2 - dichloroethane (45 ml) and cooled in an ice bath. The mixture is treated with a solution of the ethyl ester of 3-(2-(2,3,4,6-Tetra - pivaloyl - a-D-mannopyranoside)phenylacetic acid (10.0 g, 13,2 mmol) in dichloroethane (10 ml) and the mixture is stirred for nashledanou water (100 ml) and stirred for 15 minutes. Organic matter is isolated and the aqueous portion extracted with dichloromethane (3 x 5 ml). Organic substances combine, dried (MgSO4), then concentrated under reduced pressure, obtaining (13.5 g), which is used without further purification. IR (NaCl): 1738, 1685, 1228 cm-1.

Stage 2: Acid (13.5 g, of 19.7 mmol) dissolved in dichloromethane (65 ml) and treated with efratom triphoridae (15.3 ml, 122 mmol), then triperoxonane acid (9.4 g, 122 mmol). The mixture is then treated with triethylsilane (9.4 ml, to 59.1 mmol) and stirred at room temperature overnight. The reaction mixture is mixed with water (200 ml) and the organic matter is separated. The aqueous portion is extracted with dichloromethane (3 x 10 ml) and the extracts combined with the first organic portion is dried (MgSO4), then concentrated under reduced pressure, obtaining 4-(3-(3-carbomethoxybiphenyl)-4- (2,3,4,6-Tetra-pivaloyl - a-D-mannopyranoside) butyric acid (1,49 g, 97%) as a clear oil. IR (NaCl): 1737, 1132 cm-1.

Stage 3: the Acid (16.0 g, to 23.8 mmol) is mixed with thionyl chloride (50 ml) and the mixture is stirred at room temperature for 36 hours, then concentrated under reduced pressure, obtaining the acid chloride of acid (16.3 g, 99%), which COI is (0.4 g, 1.9 mmol) in dichloromethane (5 ml) are added to a solution of carboxylic acid (2.8 g, 3,26 mmol) in dichloromethane (5 ml) at 0oC. Triethylamine (and 0.61 ml, 4.4 mmol) and 4-dimethylaminopyridine (35 mg, 10 mole.%) added and the mixture is stirred at room temperature for 1 hour, then mixed with water (20 ml). Organic matter is washed with saturated sodium chloride (20 ml), dried (MgSO4) and concentrate under reduced pressure. The residue is purified on a flash chromatography (SiO2, 2: 1 ethyl acetate-hexane) to give bis-amide (1.1 g, 18%). -1H NMR (400 MHz, CDCl3): 7,40 was 7.45 (m, 4H), 6,98-7,30 (m, 10H), 5.25 to 5,42 (m, 6H), 4.09 to 4,19 (m, 4H), 3,50-of 3.96 (m, 8H), 2,62 - 2,69 (m, 4H), 2,28-of 2.36 (m, 4H), 1,90-2,02 (m, 4H), 1.60-to around 1.74 (m, 6H), 1,35 of 1.50 (m, 2H), 1,24 (s, 18H), to 1.15 (s, 18H), 1,11 (s, 36H), 1,08 of 1.28 (m, 26H), IR (NaCI): 1739 cm-1.

Stage 5: Bis-amide (1.0 g, 0.54 mmol) dissolved in THF (3 ml) and treated with an aqueous sodium hydroxide (0.40 g, 10 mmol, in 3 ml of water). The mixture is stirred at room temperature overnight. THF is removed under reduced pressure and the residue is acidified to pH 2 with concentrated hydrochloric acid and purified HPLC with reversed phase, receiving N,N'-bis-[4-(3-(3-carboxymethyl) -4- -D-mannopyranoside)phenyl] butane-1-oil]-4,4'- trimethylenediamine (17) (30 mg, 5%) as a white solid PR=11 Hz, 2H), 4,05 (CL, 8H), of 3.77 (sm, J=11 Hz, 2H), 3,50 - 3,70 (m, 8H), 3,40-to 3.52 (m, 5H), 3,31 is 3.40 (m, 2H), 2,92 (PC, J=14 Hz, 2H), 2,55-2,62 (m, 4H), 2,42 of $ 2.53 (m, 3H), 2,27-of 2.34 (m, 4H), 1,73-to 1.82 (m, 4H). 1,57-to 1.67 (m, 4H), of 1.36 to 1.47 (m, 2H), 1,22-of 1.33 (m, 2H), 1.11-1,20 (m, 4H), 0,80-1,02 (m, 4H). IR (KBr): 3415, 1713, 1609 cm-1. MS (THE BELARUSIAN LIBRARY ASSOCIATION): 1150 (M++ Na). Analysis: calculated for C61H78N2O181,4 TFU: 59,54%, from 6.22%H, 2,18%N. Found: 59,65%, 6,56%H, 2,23%n

Example 5

Di-6-[3-(3-carboxymethyl)-4-(2- -D-mannopyranoside) phenyl] hexylester

Stage 1: Oxalicacid (1.65 ml, 2M in dichloromethane, 3,30 mmol) is added to anhydrous dichloromethane (10 ml) at -78oC. dropwise over several minutes add dimethylsulfoxide (of 0.56 ml, 7,26 mmol) and the resulting solution was stirred for 10 minutes. Added dropwise ethyl 6-hydroxyhexanoate (0,50 ml of 3.07 mmol) and after thirty minutes dropwise added triethylamine (2.10 ml, 15.1 mmol). The cooling bath is removed and after 15 minutes, add water (10 ml). The mixture is stirred for 10 minutes, the layers separated and the aqueous layer was extracted with dichloromethane. The organic layers are combined and dried (MgSO4), then the solvent is removed in vacuo. Chromatography on silica gel (2:1 hexane : ethyl acetate) to give the purified product (0,44 g, 91%).1H NMR (400 MHz, CDCl3): of 9.75 (1H), 4,10 (2H), a 2.45 (2H), 2,30 (2H), 1,65 (4H), 1, is astonaut in anhydrous dichloromethane (6 ml) at 0oC and add a solution of 5-carbomethoxybiphenyl (0,44 g, 2,78 mmol) in dichloromethane (3 ml). The cooling bath is put aside and the reaction mixture was stirred at room temperature for 80 minutes. The solvent is removed in vacuo and the residue purified by chromatography on silica gel (6:1 hexane : ethyl acetate) to give the product (0.31 g, 74%).1H NMR (400 MHz, CDCl3): 4,10 (4H), 3,37 (4H), 2,28 (4H), TO 1.60 (8H), OF 1.36 (4H), 1,24 (6H).

Stage 3: Di-5-carbomethoxybiphenyl (0.16 g, of 0.53 mmol) dissolved in methanol (1 ml) and add 1H sodium hydroxide solution (of 1.05 ml, 1.05 mmol). The resulting solution was stirred at room temperature for 3 hours. The methanol is removed under reduced pressure and the remaining solution was acidified (conc. HCl) and extracted with two portions of diethyl ether. The extracts are combined, dried (MgSO4) and concentrate under reduced pressure. The residue is re-concentrated twice from acetonitrile, receiving the product as a white solid (0.16 g, quantitatively).1H NMR (400 MHz, CDCl3): 3,40 (4H), A 2.36 (4H), TO 1.60 (8H), OF 1.42 (4H).

Stage 4: Di-5-carboxypentyl (0.15 g, of 0.53 mmol) and DMF (1 drop) was dissolved in anhydrous dichloromethane (2.5 ml) and the resulting solution was cooled to 0oC. Slowly add a solution oxacillinase bath is removed and continue stirring for 20 minutes at room temperature. The solution is cooled to 0oC and add a solution of ethyl ester of 3-(2-methoxyphenyl) phenyl-acetic acid (0,29 g, 1.07 mmol) in dichloromethane (1 ml). Aluminium chloride added in three portions (0.17 g, 0.17 g, 0.08 g, a total of 3.15 mmol) at intervals of one minute. The solution is stirred for five minutes, then poured on ice and extracted with two portions of ethyl acetate. The organic layers are combined and washed with water, saturated sodium bicarbonate solution, a saturated solution of sodium chloride. The resulting solution was dried (MgSO4) and concentrate under reduced pressure. Chromatography on silica gel (gradient from 4:1 to 1:1 hexane : ethyl acetate) gives the product as a yellow oil (0.34 g, 85%).1H NMR (400 MHz, CDCl3): TO $ 7.91 (4H), 7,41 (6H), 7,28 (2H), 6,99 (2H), 4,14 (4H), 3,86 (6H), 3,66 (4H), 3,40 (4H), TO 2.94 (4H), OF 2.16 (4H), A 1.75 (4H), TO 1.59 (4H), USD 1.43 (4H), 1.26 IN (6H).

Stage 5: Di-6-[3-(3-carbomethoxybiphenyl)-4-methoxyphenyl] -6 - oxohexanoate (0.34 g, 0.45 mmol) dissolved in anhydrous dichloromethane (2.5 ml) and the resulting solution was cooled to 0oC. Add triperoxonane acid (0,23 ml, 3.0 mmol), then triethylsilane (0,29 ml, 1.8 mmol) and athirat boron TRIFLUORIDE (0.33 ml, 2.7 mmol). The cooling bath removed and the reaction mixture stirred for 1 h at room temp is Oh. The organic layer is dried (MgSO4) and concentrate under reduced pressure. Chromatography on silica gel (6:1 hexane:ethyl acetate) gives the product as a clear oil (0,23 g, 71%).1H NMR (400 MHz, CDCl3): 7,42 (4H), 7,35 (2H), 7,25 (2H), TO 7.09 (4H), 6.87 IN (2H), 4,16 (4H), OF 3.77 (6H), THE 3.65 (4H), 3,37 (4H), 2.57 M (4H), 1.57 IN (10H) TO 1.35 (8H), 1,25 (6H).

Stage 6: Di-6-[3-(3-carbomethoxybiphenyl)-4-methoxyphenyl] hexylester (0,23 g, 0.32 mmol) dissolved in dry dichloromethane (1.6 ml) and the solution cooled to 0oC. is added dropwise a solution of tribromide (1M in dichloromethane, 1,40 ml of 1.40 mmol) and the cooling bath removed. Twenty minutes later the solution is again cooled to 0oC and added dropwise absolute ethanol (1 ml). The reaction mixture was then poured on ice and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried (MgSO4), then concentrated under reduced pressure. Chromatography on silica gel (2: 1 to 1:1 hexane : ethyl acetate) to give the product (0.11 g, 50%).1H NMR (400 MHz, CDCl3): 7,42 (8H),? 7.04 BABY MORTALITY (4H), TO 6.88 (2H), 5,14 (2H), 4,16 (4H), TO 3.67 (4H), TO 3.38 (4H), 2.57 M (4H), OF 1.85 (4H), OF 1.62 (6H), OF 1.40 (6H), OF 1.27 (6H).

Stage 7: 2,3,4,6-Tetra-pivaloyl - a-D-mannopyranosyl fluoride (0.52 g, 1.00 mmol) and di-6-[3-(3-carbomethoxybiphenyl)-4 - hydroxyphenyl]hexylester (0,23 g, 0.33 mmol) p is a (0,38 ml, 3.10 mmol) and the reaction mixture stirred for 90 minutes. The reaction mixture was diluted with ethyl acetate and washed with two portions of water, then 1H NaOH, water and saturated sodium chloride solution. The resulting solution was dried (MgSO4) and concentrate under reduced pressure. The residue is purified by chromatography on silica gel (15: 1 hexane : ethyl acetate) to give the product (0.45 g, 82%).1H NMR (400 MHz, CDCl3): WAS 7.45 (7H), TO 7.15 (7H), 5,32 (8H), 4,14 (4H), 3,86 (4H), AND 3.72 (4H), OF 3.54 (2H), 3,40 (4H), 2,59 (4H), OF 1.85 (4H), OF 1.62 (4H), OF 1.46 (4H), OF 1.36 (4H), 1.26 IN (24) AND 1.15 (18H), 1,10 (36H).

Stage 8: Di-6-[3-(3-carbomethoxybiphenyl)-4-(2,3,4,6 - Tetra-pivaloyl - a-D-mannopyranosyl]hexylester (0.45 g, 0.27 mmol) dissolved in anhydrous tetrahydrofuran (0.9 ml) and methanol (1.8 ml). Add sodium methoxide (49 mg, 0.84 mmol) and the reaction mixture was stirred at room temperature overnight. Add another portion of sodium methoxide (50 mg, of 0.93 mmol), four hours later a third portion (112 mg, 2,07 mmol). The reaction continued for another four hours, then the mixture is filtered and the collected solid is washed with 2: 1 mixture of tetrahydrofuran and methanol. Then the solid is dissolved in water (1 ml) and add a solution (1M) of sodium hydroxide up until pH reaches 14. This solution parametr> form). The resin is filtered off and the filtrate lyophilized. Then the product is dried in vacuo over P2O5receiving di-6-[3-(3-carboethoxy - were)-4- ( -D - mannopyranoside)phenyl]hexylester (0.21 g, 78%).1H NMR (400 MHz, CD3CN/D2O): 7,46 (2H), 7,34 (2H), 7,16 (10H), 5,31 (2H), WITH 3.79 (2H), 3,66 (2H), 3,57 (4H), 3,42 (5H), OF 3.28 (2H), 2,56 (4H), OF 1.80 (4H), TO 1.60 (4H), OF 1.36 (6H).

EXAMPLE 6

S,S-Bis-[3-(3-carboxymethyl)-4-( -D-mannopyranosyl) - 3-phenylprop-1-yl]-1,3-citypaper

Stage 1: part a: Ethyl ester of 3-(2-methoxyphenyl)-phenylacetic acid (5,04 g, 18,66 mmol) and 3-bromopropionyl chloride (1,88 ml, 18,66 mmol) is mixed with dichloroethane (30 ml). The mixture is cooled in a bath with a mixture of ice-water and treated with aluminum chloride (7.6 g, 57 mmol). After 15 minutes the reaction mixture is mixed with ice water (100 ml) and the organic matter is separated. The aqueous portion is extracted with dichloromethane (3 x 5 ml) and organics combined, dried (MgSO4), concentrated under reduced pressure. The rest is used in the next stage without additional purification.

Part B: the Product from part A (8.5 g, 19 mmol) dissolved in dichloromethane (40 ml) and cooled in a bath with a mixture of ice-water. Add triperoxonane acid (5,9 ml, 76 mmol), triethylsilane (6,1 ml, 38 mmol), then epiretinal night, then cooled in a bath with ice and quenched with cold water (100 ml). Organic matter is separated, the aqueous portion extracted with dichloromethane (3 x 10 ml) and organic substances combine, washed with a saturated solution of sodium chloride (50 ml), dried (MgSO4) and concentrated under reduced pressure, obtaining the ethyl ester of 3-(2-methoxyphenyl-5- (3-bromopropyl))phenylacetic acid (6,53 g, 90%).1H NMR (400 MHz, CDCl3): 7,41 was 7.45 (m, 2H), was 7.36 (t, J=8 Hz, 1H), 7,25-7,28 (m, 1H), 7,12-7,16 (m, 2H), make 6.90 (d, J=8.6 Hz, 1H), 4,15 (K, J=7,0 Hz, 2H), of 3.78 (s, 3H), to 3.67 (s, 2H), 3,41 (t, J=6.6 Hz, 2H), 2,75 (t, J=7,0 Hz, 2H), 2,15 (m, 2H), 1.26 in (t, J=7,3 Hz, 3H), PC (NaCl): 1736 cm-1< / BR>
Stage 2: a Solution of 1,3-propanedithiol (0,109 g of 0.94 mmol) in THF (4.5 ml) Tegaserod in a stream of nitrogen and cooled in a bath with a mixture of ice-water. Add sodium hydride (86,5 mg, 2.1 mmol) and the mixture is stirred at room temperature for 2 hours. Add a solution of the bromide from step 1 (0,83 g, 2,12 mmol) in THF (1.0 ml) and the mixture is stirred at the boiling temperature of phlegmy during the night. The reaction mixture was partitioned between water and ethyl acetate (20 ml of 1:1 mixture) and organic matter was separated, washed with saturated sodium chloride (20 ml) and dried (MgSO4), then concentrated under reduced pressure. The residue is purified on a flash chromatography (SiOthe hydroxy)-3-phenylprop-1-yl] -1, 3-citypaper (to 166.2 mg, 24%).1H NMR (400 MHz, CDCl3): 7,39 was 7.45 (m, 4H), 7,32-7,38 (m, 2H), 7,21-7,28 (m, 2H), 7,08-to 7.15 (m, 4H), 6,85-6,92 (m, 2H), 4,14 (K, J=7,0 Hz, 4H), of 3.77 (s, 6H), of 3.65 (s, 4H), 2,80-2,95 (m, 2H), 2,77 (t, J=7,3 Hz, 2H), 2,68 (t, J= 8.0 Hz, 4H), 2,60 (t, J=7,0 Hz, 2H), 2,52 (t, J=7,0 Hz, 2H), 2,04-of 2.16 (m, 2H), 1,81-of 1.93 (m, 4H), 1,25 (t, J=7.0 Hz, 6H). IR(NaCl): 1731 cm-1.

Stage 3: a Solution of bis-tiefer from stage 2 (70,7 mg, 0.1 mmol) in dichloromethane (2 ml) is cooled in a bath with a mixture of dry-ice/acetone and treated with tribromide boron (0.8 ml 1M solution in dichloromethane, 0.8 mmol) and the mixture was kept at -10oC during the night. The reaction mixture is mixed with water (10 ml) and the mixture extracted with dichloromethane (3 x 2 ml). Organic substances combine, dried (MgSO4) and concentrated under reduced pressure, obtaining the S, S-bis-[3-(3-carbomethoxybiphenyl)-4-(hydroxy)-3-phenylprop-1-yl] -1,3-citypaper (68 mg, 100%).1H NMR (400 MHz, CDCl3): the 7.43 (t, J=7.7 Hz, 2H), 7,34-7,39 (m, 4H), 7,30 (sm, J=7,3 Hz, 2H), 7.03 is-was 7.08 (m, 4H), 6.87 in (sm, J= 8,8 Hz, 2H), 4,96-5,30 (CL, 2H), 4,15 (K, J=7,0 Hz, 4H), 3,66 (s, 4H), to 2.66 (t, J=7,3 Hz, 4H), 2,60 (t, J=7,0 Hz, 2H), 2,52 (t, J=7,0 Hz, 4H), 1,80-of 1.92 (m, 6H), of 1.26 (t, J=7,3 Hz, 6H), 1,21-of 1.27 (m, 2H). IR (NaCl): 3420, 1726 cm-1.

Stage 4: Phenol (0,47 g of 0.68 mmol) and pentaacetate-D-mannose (0.8 g, 2.0 mmol) is mixed with dichloroethane (8 ml) and treated with efratom of boron TRIFLUORIDE (1.0 ml, 8.0 mmol who ski substance is separated and the aqueous portion extracted with dichloromethane (3 x 2 ml). Organic substances combine, dried (MgSO4), then concentrated under reduced pressure. The residue is purified on a flash chromatography (SiO2, gradient elution, 3: 1 hexane/ethyl acetate to 1:1 hexane/ethyl acetate) to give S,S-bis-[3-(3-carbomethoxybiphenyl)-4- (2,3,4,6-Tetra-acetyl-D - mannopyranosyl)-3-phenylprop-1-yl] -1,3-citypaper (0,331 g, 36%). IR (NaCl): 1752 cm-1.

Stage 5: Per-acetate (0.64 g, 0.47 mmol) was dissolved in acetonitrile (5 ml) and treated with sodium hydroxide solution (5.0 ml 2H solution, 10 mmol), then stirred at room temperature overnight. The mixture is acidified with concentrated hydrochloric acid to pH 2 and the volatiles removed under reduced pressure. The aqueous residue purified using chromatography with reversed phase, receiving S,S-bis-[3-(3-carboxymethyl)-4- -D-mannopyranosyl) -3-phenylprop-1-yl]-1,3-citypaper in the form of a white solid substance, so pl. 96-100oC.1H NMR (400 MHz, DMSO-d6): 7,31-7,39 (m, 6H), 7,20-7,27 (m, 4H), 7,11-to 7.15 (m, 4H), of 5.26 (s, 2H), 3,30 of 3.75 (m, 28H), of 2.64 (t, J=7.7 Hz, 4H), to 2.57 (t, J=7,0 Hz, 4H), 2,45 - 2,52 (m, 4H), 1,75-of 1.84 (m, 4H), 1,66-of 1.74 (m, 2H). IR (KBr): 3430, 1711 cm-1.

EXAMPLE 7

1,6-Bis-[3-(3-carboxymethyl)-4-( -D-mannopyranosyl - hydroxy)phenyl]-1,6-bis-oxohexyl

Stage 1: e is l chloride (0,068 ml, 0.47 mmol) dissolved in dichloroethane (5 ml), cooled in a bath with a mixture of ice-water and treated with aluminum chloride (2,56 g, 19.2 mmol). After 1.5 h, the reaction mixture is mixed with ice water (25 ml) and stirred for 15 minutes. Organic matter is separated and the aqueous portion extracted with dichloromethane (3 x 2 ml). Organic substances combine, dried (MgSO4), then concentrated under reduced pressure. The residue is purified on a flash chromatography (SiO2, 1:1 hexane/ethyl acetate) to give 1,6-bis-[3-(3-carbomethoxybiphenyl)-4-(2,3,4,6-Tetra-acetyl-D - mannopyranoside)phenyl] -1,6-bis-oxohexyl (0,43 g, 35%).1H NMR (400 MHz, CDCl3): 8,00 (d, J= 2.2 Hz, 2H), to 7.93 (DD, J=8,6, 2,2 Hz, 2H), 7,42-of 7.48 (m, 6H), 7,31-7,35 (m, 2H), 7,25-7,29 (m, 2H), ceiling of 5.60 (d, J =0.2 Hz, 2H), 5,31-of 5.34 (m, 2H), 5,28 (d, J= 9.1 Hz, 2H), 5,23 is 5.28 (m, 2H), is 4.21 (DD, J=12,3, 5,1 Hz, 2H), 4,15 (K, J= 7,4 Hz, 4H), 3,98 (DD, J=12,4, 2,2 Hz, 2H), 3,79-of 3.85 (m, 2H), of 3.73 (s, 4H), 3.00 and-a 3.06 (m, 4H), 2,17 (s, 6H), 2,03 (s, 6H), for 2.01 (s, 6H), to 1.98 (s, 6H), 1,81-of 1.85 (m, 4H), of 1.26 (t, J=7.5 Hz, 6H). IR (NaCl): 1747, 1680 cm-1.

Stage 2: TRANS-acetate (0,43 g, 0.33 mmol) dissolved in acetonitrile (4 ml) and mixed with a solution of 2H sodium hydroxide (1.8 ml, 3.6 mmol). After 18 h at RT, the reaction mixture is neutralized ionoobmennoi resin Dowex 50W in the acidic form and the volatiles removed under reduced pressure. Part of the OST is bis-oxohexyl in the form of a white solid product, so pl.: 127-129oC.1H NMR (400 MHz, DMSO-d6): 7,98 (d, J=8,8 Hz, 2H), of 7.90 (s, 2H), 7,35-of 7.48 (m, 8H), 7,27 (d, J=8.6 Hz, 2H), of 5.53 (S, 2H), 3,71(s, 2H), 3,66 (s, 4H), 3,60 (d, J=11,4 Hz, 2H), 3,42-3,51 (m, 6H), 3,28-to 3.35 (m, 2H), 3,07 is 3.15 (m, 4H), 1,67-of 1.73 (m, 4H). IR (KBr): 3430, 1716, 1672 cm-1. Analysis: calculated for C46H50O180,6 TFU: 59,10%, 5,32% H. Found: 58,92% C, 5,68% h

Example 8

1,3,5-Tris-[3-(3-carboxymethyl)-4-(2- -D - mannopyranoside)phenylmethyl]benzene

Stage 1: 1,3,5 - Benzotrichloride (1.0 g, 3.8 mmol) dissolved in 1,2 - dichloroethane (20 ml). Added aluminium chloride (2.6 g, 18,8 mmol) and then methyl ester 3-(2-methoxyphenyl)-phenylacetic acid (4.8 g, 18,8 mmol) and the mixture is heated at 65oC during the night. After cooling in an ice bath, slowly add ice water (20 ml). Organic matter is separated and the aqueous portion extracted with methylene chloride (3 x 5 ml). Organic substances combine, dried (MgSO4) and concentrate under reduced pressure. The residue is purified on a flash chromatography (SiO2, gradient elution from hexane to 1:1 hexane/ethyl acetate) to give tritton (f=1), (1,05 g, 30%).1H NMR (400 MHz, CDCl3): scored 8.38 (d, J=1.5 Hz, 3H), of 7.93 (m, 3H), 7,80-7,83 (m, 3H), 7,45 (m, 6H), 7,38 (t, J=7,3 Hz, 3H), 7,21-7,29 (m, 3H), 6,95 (DD, J-8,76, the 1.44 Hz, 3H), 3,88 (s, 9H), to 3.67 (s, 6H), 3,66 (s, 9H) ppm. IR (NaCl): danoy bath and treated with triethylsilane (3.8 ml, of 23.7 mmol), triperoxonane acid (2.6 ml, 33.8 mmol) and vetilation of boron TRIFLUORIDE (4.3 ml, 33.8 mmol). The mixture is stirred at room temperature for 1 hour, then mixed with water (25 ml). Organic matter is separated, and the aqueous portion extracted with methylene chloride (3 x 5 ml). Organic substances combine, dried (MgSO4), then concentrated under reduced pressure. The residue is washed through a silica gel with a mixture of hexane:ethyl acetate/3: 1 and concentrate, receiving 1,3,5-Tris-[3-(3-carbomethoxybiphenyl)-4-(2-methoxy)phenylmethyl] benzene (0.88 g, 28%).1H NMR (400 MHz, CDCl3): 7,38-the 7.43 (m, 6H), 7,33 (t, J=7.68 per Hz, 3H), 7.23 percent (s, 3H), 7,14 (d, J=2.2 Hz, 3H), was 7.08 (DD, J=8,08, of 1.84 Hz, 3H), 6.90 to (s, 3H), 6,85 (d, J=8,4 Hz, 3H), with 3.89 (s, 6H), 3,76 (s, 9H), 3,68 (s, 9H), 3,66 (s, 6H) ppm. IR (NaCl): 1738 cm-1.

Stage 3: part a: 1,3,5-Tris-[3-(3-carbomethoxybiphenyl)-4-(2-methoxy)phenylmethyl] benzene (0.88 g, 1 mmol) dissolved in dichloromethane (5 ml) and cooled in a bath with a mixture of dry ice-acetone. Slowly add tribromide boron (0.7 ml, 7.0 mmol) and the mixture was stirred at 0oC for 2 hours, then mixed with ice water (10 ml). Organic matter is separated and the aqueous portion extracted with methylene chloride (3 x 5 ml). Organic substances combine, dried (MgSO4) and conc the Ute with methanol (20 ml) and added dropwise sulfuric acid (1 ml). The mixture is refluxed overnight, then concentrated under reduced pressure. The residue is mixed with dichloromethane (20 ml) and saturated sodium bicarbonate solution (10 ml). The organic phase is separated, dried (MgSO4) and concentrate under reduced pressure. The residue is washed through a silica gel with a mixture of hexane : ethyl acetate/1:1 and concentrate, receiving 1,3,5-Tris-[3-(3-carbomethoxybiphenyl) - 4-(2-hydroxy)phenylmethyl]benzene (0,63 g, 75%).1H NMR (400 MHz, CDCl3): 7,20 is 7.50 (m, 12H), 7,0 (d, J 2.2 Hz, 2H), 6,98 (s, 2H), 6,95 (DD, J=8,08 and 2.2 Hz, 2H), 6,83 (s, 3H), 6,77 (d, J=8,44, 3H), 3,85 (s, 6H), of 3.69 (s, 9H), 3,66 (s, 6H) ppm. IR (NaCl): 3429, 1737 cm-1.

Stage 4: Triphenol (0,62 g, 0.7 mmol) dissolved in 1,2-dichloroethane (4 ml), add pentaacetate-D-mannose (1.4 g, 3.7 mmol) and then slowly add apirat triforia (1.6 ml, 13.3 mmol). The mixture is stirred over night at room temperature, then mixed with water (10 ml). Organic matter is separated and the aqueous portion extracted with dichloromethane (3 x 2 ml). The organic fractions combined, dried (MgSO4), then concentrated under reduced pressure. The residue is purified on a flash chromatography (SiO2, gradient elution, hexane to 2:1/ ethyl acetate : hexane) to give 1,3,5-Tris-[3-(3-carbomethoxy>
): 6,98 is 7.50 (m, 21H), 6,86 (s, 3H), 5,26 (m, 3H), 3,90-3,93 (m, 6H), to 3.89 (s, 6H), 3,71 (s, 6H), 3,66 (s, 9H), 1,94 and 2.13 (m, 36H) ppm. IR (NaCl): 1745 cm-1.

Stage 5: Per-acetate (0.88 g, 0.48 mmol) dissolved in acetonitrile (2 ml) and treated with monohydrate of lithium hydroxide (0.4 g, 9.6 mmol) in water (2 ml). The mixture is stirred over night at room temperature, then acidified to pH 2 with concentrated hydrochloric acid. The mixture is concentrated under reduced pressure and the residue purified by HPLC (C-18 reversed phase gradient elution 20-80% acetonitrile in water control at 254 nm) to give 1,3,5-Tris-[3-(3-carboxymethyl)-4-(2- -D-mannopyranoside) phenylmethyl] benzene (0.35 g, 57%) as a white solid product, so pl. 155-158oC.1H NMR (400 MHz, DMSO-d6): 7,27-7,34 (m, 9H), 7,17-7,22 (m, 9H), 7,08-7,10 (DD, J=8,44, 1.70 Hz, 3H), 7,01 (s, 3H), 5,24 (s, 3H), 3,85 (s, 6H), 3.33 and-to 3.64 (m, 24H) ppm. IR (KBr): 3431, 1710 cm-1. Anal.: the expect. for C69H27O241,0 TFU: 60,94% C, 5,26% H. Found: 60,85% C, 5,23% h

Example 9

1,3,5-Tris-[4-[3-(3-carboxymethyl)-4- -D - mannopyranoside)phenyl]-4-oxo-2-dibutyl]benzene

Stage 1: Ethyl ester of 3-(2-(2,3,4,6-Tetra-acetyl- -D-mannopyranoside)phenyl)phenylacetic acid (0.32 g, 0,547 mmol) and bromoacetamide (0.06 g, 0,689 mmol) is dissolved in dichlorethane replace bath with a mixture of ice-water. After 15 minutes the reaction mixture is mixed with ice, water (25 ml) and stirred for 15 minutes Organic matter is separated and the aqueous portion extracted with dichloromethane (3 x 2 ml). Organic substances combine, dried (MgSO4), then concentrated under reduced pressure, getting 0,387 g of product, which is used without further purification.1H NMR (400 MHz, CDCl3): 8,03 (d, J=2.5 Hz, 1H), 7,95 (DD, J=8,8, 2.5 Hz, 1H), 7,41-7,47 (m, 3H), 7,35 (m, 1H), 7,31 (d, J=8,8 Hz, 1H), 5,62 (d, J=l,8 Hz, 1H), to 5.21-of 5.34 (m, 3H), 4,42 (s, 2H), 4,10-of 4.25 (m, 5H), 3,99 (DD, J=12,1, 2.2 Hz, 1H), 3,80-of 3.85 (m, 1H), 3,74 (s, 2H), 2,18 (s, 3H), 2,03 (s, 3H), 2,02 (s, 3H), of 1.98 (s, 3H), of 1.26 (t, J= 8.0 Hz, 3H). IR (NaCl): 1746, 1220 cm-1.

Stage 2: 1,3,5-Tris-(mercaptomethyl) benzene (102 mg, 0.47 mmol) in THF (1 ml) is treated with sodium hydride (to 59.8 mg, 1,49 mmol) and the mixture is stirred at room temperature for 30 minutes. Add a solution of bracelona with stage 1 (1,02 g, 1.44 mmol) in THF (2.0 ml) and the mixture is stirred at room temperature overnight. The reaction mixture is mixed with water (10 ml) and extracted with ethyl acetate (3 x 5 ml). Organic substances combine, dried (MgSO4) and concentrate under reduced pressure. The residue is purified on a flash chromatography (SiO2, gradient elution, 3:1 hexane/ethyl acetate to 1: 1 hexane/this is o-2-dibutyl]benzene (0,59 g, 60%).1H NMR (400 MHz, CDCl3): 7,98 (d, J= 2,5 Hz, 3H), 7,89 (DD, J=8,8, 2,5 Hz, 3H), 7,40-7,46 (m, 6H), 7,25-7,35 (m, 12H), 5,61 (s, 3H), 5,22-5,33 (m, 9H), 4,10-of 4.25 (m, 10H), of 3.97 (DD, J= 12, l, 2,2 Hz, 3H), 3,78-a-3.84 (m, 3H), and 3.72 (s, 6H), of 3.69 (s, 3H), of 3.64 (s, 3H), of 2.16 (s, 9H), 2,02 (s, 9H), for 2.01 (s, 9H), of 1.97 (s, 9H), 1,25 (t, J=8.0 Hz, 9H); IR (NaCl): 1747, 1290 cm-1/

Stage 3: Triavir of peracetate from stage 2 (0,59 g, 0.28 mmol) in THF (3 ml) is treated with a solution of their sodium methoxide (93 mg, 4.04 mmol in 3 ml of methanol) and the mixture is stirred at room temperature overnight. The precipitate which formed is collected by filtration under vacuum and washed several times with a mixture of 2:1 THF/methanol and dried in vacuum, obtaining of 0.38 g of white solid product. The solid product is dissolved in water (12 ml), add 2H sodium hydroxide to pH 14 and the mixture is stirred at room temperature for 4 hours. The reaction mixture is acidified with acidic ion exchange resin Dowex 50W, filtered and volatiles removed under reduced pressure. The aqueous residue purified using chromatography with reversed phase, receiving 1,3,5-Tris-[4- [3-(3-carboxymethyl)-4- -D-mannopyranoside)phenyl] - 4-oxo-2-dibutyl]benzene in the form of a white solid substance, so pl. 140-143oC.1H NMR (400 MHz, DMSO-d6): of 7.95 (DD, J=8,8 Hz, 2.5 Hz, 3H), 7,89 (d, J=2.2 Hz, 3H), 7,32-7,45 (, ,30-3,40 (m, 6H plus H2O). IR (KBr): 3429, 1708, 1669 cm-1. Analysis: calculated for C75H78O27S31,8 TFU: 55,12%, 4,79%H. Found: 55,14%, 5,20% h

Example 10

Analyses of the binding.

Compounds analyzed for their ability to inhibit the binding of E-, P - and/or E-selectin with sialyl-Lewisx.

Analyses on the binding of E-selectin include an assessment of the ability of HL60 cells, which Express sialyl-Lewisxand Lewisxto connect with purified E-selectin, P-selectin and L-selectin recombinant proteins (cell-protein analysis). Similar tests for linkage using glycolipids and purified L-selectin recombinant protein (glycolipid-protein) is used to assess the binding of L-selectin.

Cell protein analysis

E-selectin, P-selectin and L-selectin Express in recombinant soluble form in the form of a fused protein with aminocentesis pectin, EGF, and complementary regulatory-like repeats (CR) 1 and 2, attached to the hinge and constant areas of heavy chains 1 and 2 cDNA of mouse immunoglobulin IgG2A. All the selectin fused tapes generated by PCR (PCR) from cDNA of E-selectin, supplied from R & D Systems (Minneapolis, MN), options man. Mouse lgG cDNA clone of PCR amplified cDNA generated from RNA extracted from hybridoma cell line S. All merged cartridge Express from baculovirus vectors using BakPAK way and SF21 cells supplied from Clonetech.

Recombinant fused proteins purified from culture supernatants infected with baculovirus using thus, using DynalTMmagnetic beads coated with goat anti-mouse lgG. Surrogate bulbs generate from supernatants uninfected SF21 culture. After thus beads, incubated with supernatants surrogate culture, not associated HL60 cells, which Express sialyl-Lewisxserving as a negative (negative) control. Beads, incubated from supernatants with the culture of E-, L - or P-selectin, really connect HL60 cells.

HL60 cells (107cells) fluorescence mark calcein AMC-3099 (Molecular samples) in RPMI 1640 with 10% fetal calf serum (FCS). Magnetic beads (7 μl, 4 x 106beads/ml) are incubated in duplicate wells of a flexible hole 96 tiralongo microplate together with 7 μl of compounds at various concentrations and 7 ál Mechet placed on a magnetic separator and incubated for a further 2 minutes. While the tablet remains in the separator, unrelated HL60 cells were removed and the wells washed twice phosphate buffered saline (SFR, PBS) to remove any remaining unbound cells. HL60 cells that remained associated with the beads, examined by microscopy and then are lysed by adding 50 ml of 1% NP40 solution in SFR. Linking quantitatively evaluated using fluorimetry using fluorimetry Millipore Cytofluor 2350. Build curves dose-response and determine the concentration at which inhibited 50% of the binding of cells (IC50).

The compounds listed in the table represent those compounds that are referred here to the particularly preferred compounds.

The results of these analyses are presented in the table.

1. The compound of formula II

< / BR>
where X is selected from the group comprising-CN, -(CH2)nCO2H, -(CH2)nCONHOH, -O(CH2)mCO2H, -(CH2)nCOZ, -(CH2)nZ, -CH(CO2H), (CH2)mCO2H and-OH;

Y represents -(CH2)f-;

R1and R2independently selected from the group including hydrogen, lower alkyl, halogen, -OZ, -NO2, -NH2;

R3in Borovoy acid;

f is 1 to 6;

n is 0 to 2;

m is 1 to 3;

b is 0 to 2;

Z is lower alkyl, phenyl,

or its pharmaceutically acceptable salts, esters, amides.

2. Connection on p. 1 of formula III

< / BR>
where X represents-COOH, - (CH2)nCOOH, or-O(CH2)nCOOH;

Y represents -(CH2)n-,

or its pharmaceutically acceptable salts, esters, amides.

3. Connection on p. 2, where Y represents -(CH2)f-.

4. Connection on p. 2, where X is 3-CH2CO2H and Y is -(CH2)f-.

5. Connection on p. 1, chosen from:

1,7-bis-[3-(3-carboxymethyl)-4-(2--D-mannopyranoside)phenyl] heptane,

1,6-bis-[3-(3-carboxymethyl)-4-(2--D-mannopyranoside)phenyl] hexane,

1,5-bis-[3-(3-carboxymethyl)-4-(2--D-mannopyranoside)phenyl] pentane,

1,4-bis-[3-(3-carboxymethyl)-4-(2--D-mannopyranoside)phenyl] butane,

N,N'-bis-[4-(3-(3-carboxymethyl)-4-(-D-mannopyranoside)phenyl)butane-1-oil]-4,4'-trimethylenediamine,

S, S'-bis-[3-(3-carboxymethyl)-4-(2--D-mannopyranosyl)-3-phenylprop-1-yl]-1,3-citypaper,

1,7-bis-[3-(3-carboxymethyl)-4-(2--D-mannopyranoside)phenyl] -1,7-bis-ACS is carboxymethyl)-4-(2--D-mannopyranoside)phenyl] -1,5-bis-oxapentane,

1,4'-bis-[3-(3-carboxymethyl)-4-(2--D-mannopyranoside)phenyl] -1,4-bis-oxobutyl,

1,3,5-Tris-[3-(3-carboxymethyl)-4-(2--D-mannopyranoside)phenylmethyl]benzene, and

1,3,5-Tris-[4-(3-(3-carboxymethyl)-4-(-D-mannopyranoside)phenyl] -4-oxo-2-dibutyl]benzene.

6. Connection on p. 1, representing 1,6-bis-[3-(3-carboxymethyl)-4-(2---mannopyranoside)phenyl]hexane.

7. The pharmaceutical composition inhibiting the binding of E-selectin or P-selectin with Slexor Slea, characterized in that it contains an effective amount of the compounds on p. 1 and a pharmaceutically acceptable carrier.

8. Method of inhibiting the binding of E-selectin, P-selectin or L-selectin with Slexor Sleathat includes the introduction to the patient an effective amount of the compounds under item 1.

9. The method according to p. 8, wherein the compound is 1,6-bis-[3-(3-carboxymethyl)-4-(2--D-mannopyranoside)phenyl]hexane.

 

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