Modulators fc-receptor and their use

 

The present invention relates to the field of medicine and relates to pharmaceutical compositions comprising a compound for modulation of Fc receptor, and a pharmaceutically acceptable carrier. The present invention also relates to a method of treatment of various diseases using the compounds for modulation of Fc receptor. 2 N. and 96 h.p. f-crystals, 20 ill., table 2.

The SCOPE of the INVENTION

The present invention relates to compounds that modulate the binding of antibodies to Fc receptors and their use.

BACKGROUND of the INVENTION

Fc receptors (FcR) are a family of closely related receptors that are specific for the Fc fragment of immunoglobulin (Ig). These receptors are essential for normal immunity and resistance to infection and provide humoral immune system capabilities of cellular effector. Receptors are specific for each of the classes of immunoglobulins and thus are characterized by the Ig class with which they are associated (that is, Fc gamma receptor (FcgR) associated with gamma immunoglobulin (IgG), Fc Epsilon receptor (FcgR) associated with the Epsilon immunoglobulin (IgE), Fc alpha receptor (FcaR) sviazyvalsia highly specific receptor relative to IgG; FcgRII, which is the receptor with low affinity for IgG, which is energetically associated with aggregates of immune complexes; and FcgRIII, which is the receptor with low affinity, which are associated with immune complexes. These receptors are structurally closely related, but perform different functions. Of interest is the structure and function FcgRII due to its interaction with immune complexes and its relationship to disease.

FcgR expressed by the majority of hematopoietic cells by binding to IgG, play a key role in the homeostasis of the immune system and protect the host from infection. FcgRII is a receptor with low affinity for IgG and significantly associated only with immune complexes of IgG and is expressed by cells of various types, including, for example, monocytes, macrophages, neutrophils, eosinophils, platelets and b lymphocytes. FcgRII involved in various immune and inflammatory responses, including antibody-dependent cell-mediated cytotoxicity, clearance of immune complexes, the selection of mediators of inflammation and regulation of antibody formation. Binding of IgG with FcgR may cause indications for diseases, which include regulation of FcgR. For example, autoimmune Zab is th activation of platelet immune complex IgG or their destruction FcgR+ phagocytes. In addition, various inflammatory diseases involving immune complexes of IgG (e.g., rheumatoid arthritis, systemic lupus erythematous), including allergic reaction, type II and type III. Allergic reactions type II and type III are carried out with the participation of IgG, which can activate complementary-mediated or fagozyt-effector mechanisms that cause tissue damage.

Because FcR is involved in various biological mechanisms, there is a need for compounds that affect the binding of immunoglobulins with FcR. There is also a need in the use of such compounds for the treatment of various diseases.

The INVENTION

The present invention features a pharmaceutical composition that includes:

(a) a compound selected from the group comprising an aromatic compound of the formula:

heteroaromatic compound of the formula:

the cyclic compound of the formula:

bicyclic compound of the formula:

and amino acid derivative of the formula:

or R15C(=NH)NH2, OPO(OR15)2With(=O)CF3or PO(OR15)2;

each AG1, AG2, AG4and AG5independently represents a C6-C20aryl or C1-C20heteroaryl;

AG3represents a C1-C20heteroaryl;

each of X1X2X3X4X5X6X7and X8independently represents a methylene, O, S or NR16;

each R1and R2independently represents a bond, C1-C6alkylene or halogenated C1-C6alkylen;

each R3and R4independently represent halogen, -Z1or C1-C6alkyl;

each X9, Y1and Z1independently represents OR17, SR17or NR17R18;

each R5and R6independently represents an amino acid residue side chain or a particle of formula R19-W3;

each R8, R9and R11independently represents an amino acid residue side chain, provided that R11does not represent N or CH3;

R7is a OR20, NR21R22or about 1 to 10 amino acids;

R10not onlyaralkyl;

W3represents C(=O)X10;

X10is a OR23or NR24R25;

each R13, R15, R17. R18, R20, R21, R23and R24independently represents hydrogen or C1-C6alkyl;

each R16independently represents H, C6-C20aryl or a protective group amide;

R19represents a C1-C6alkylen;

each R22and R25independently represents H, C1-C6alkyl or a protective group amide;

R14represents H, C1-C6alkyl or a protective group of the amine;

L represents a linking group comprising from 1 to 20 atoms; and

each m and n independently represents an integer from 0 to 2; and

(b) a pharmaceutically acceptable carrier.

The present invention also proposes a method of applying a compound selected from the group comprising substituted or unsubstituted benzoic acid; nucleosides and their analogs; folic acid and its derivatives; peptides comprising from about 2 to 10 amino acid residues or derivatives thereof, preferably the tripeptides or Hexapeptide; macrocyclic compounds, the IDA or their derivatives, and connection with the above formulas for modulating, for example inhibiting or enhancing binding of antibodies to Fc receptors of the patient. In a separate embodiment of the present invention is the modulation of Fc receptors by the above-mentioned compounds used to treat diseases in which produces aggregates of antibodies or where produced by immune complexes in the contact antibodies with internal or external antigen. Modulation of Fc receptors of the above compounds can also be used to reduce IgG-dependent tissue damage, to reduce IgE-dependent reactions and/or to reduce inflammation in the patient.

BRIEF DESCRIPTION of DRAWINGS

In Fig. 1 schematically depicts the binding site on the receptor FcgRIIa.

In Fig. 2 shows a side schematic view of a groove shown only one surface with interest the protein residues.

In Fig. 3 shows, as a separate ligand correlates with the General structure of the compounds of the present invention.

Fig. 4 displays the different hydrogen bonds between amino acids in the binding site of the receptor FcgIIa and specific modulator.

In Fig. 5A and 5B presents some compounds fashion.

In Fig. 6 shows the activity of modulating some of the connections shown in Fig. 5A and 5B, binding FcgRIIa with human IgG1.

In Fig. 7 shows the activity of modulating some of the connections shown in Fig. 5A and 5B, binding FcgRIIa with human IgG3.

In Fig. 8 shows the activity of modulating some of the connections shown in Fig. 5A and 5B, binding FcgRIIa with human IgG1.

In Fig. 9 shows the activity of modulating some of the connections shown in Fig. 5A and 5B, binding FcgRIIa with human IgG3.

In Fig. 10 shows the increased binding sFcgRII with IgG1 and IgG3 in the presence of the Hexapeptide.

In Fig. 11 shows the inhibition of binding sFcgRII with IgG1 and IgG3 in the presence of Tripeptide.

In Fig. 12 presents a graph of increasing transparency in the presence of agonist.

In Fig. 13 presents a plot of the transparency from time to time in the presence of agonist and connections BRI6855.

In Fig. 14 presents a graph of % of platelet aggregation at various concentrations of the compounds BRI6728.

DETAILED description of the INVENTION

The present invention offers a variety of compounds that can modulate the interaction between Fc recipe is deistvuut area (see Fig. 1) Fc receptor, for example FcgRII. Thus, it is believed that these compounds inhibit the dimerization of two FcgRII proteins, affecting, therefore, the transmission of cellular signals via one or both of these FcR protein. In particular, it is believed that the peptide residues 117-131 and 150-164 FcgRII form the border area FcgIIa dimer, and it is expected that compounds having a proper structure or the ability to communicate with these areas, are a good modulators bind. For example, natural Hexapeptide Phe121 - Ser126 or more short segments overlap the region of a significant interaction due to the presence of hydrogen bonds, and thus are suitable modulators of the dimerization of two molecules FcgRIIa. This protein fragment is described as part of SEQ ID No. 3 of the patent application U.S. No. 09/245764, "3-dimensional structures and models that have Fc receptors and their application", filed February 5, 1999.

Compounds of the present invention were obtained by random screening, and the purposeful creation of medicines, for the modulation of Fc receptors. FcgR expressed by the majority of hematopoietic cells by binding to IgG, play a key role in the homeostasis of the immune system and protecting hosei nimi complexes of IgG and expressed by cells of different types, including, for example, monocytes, macrophages, neutrophils, eosinophils, platelets and b lymphocytes. FcgRII is involved in various immune and inflammatory responses, including antibody-dependent cell-mediated cytotoxicity, clearance of immune complexes, the selection of mediators of inflammation and regulation of antibody formation.

Binding of IgG with FcgR can cause disease, which is associated with regulation by FcgR. For example, an autoimmune disease thrombocytopenic purpura causes tissue damage (platelets), derived from FcgR-dependent activation of platelet immune complex IgG or their destruction FcgR+ phagocytes. In addition, various inflammatory diseases involving immune complexes of IgG (e.g., rheumatoid arthritis, systemic lupus erythematous), including allergic reaction, type II and type III. Allergic reactions type II and type III are carried out with the participation of IgG, which can activate complementary-mediated or phagocyte-effector mechanisms that cause tissue damage.

Knowledge of the three-dimensional structure of FcgRIIa, or indeed any FcR can simplify the preparation of therapeutic and reactivate connection which can modulate the binding of immunoglobulins with FcgRIIa. The structure of a number of Fc receptors, including FcgRIIa, FceRI and FcgRIIIb be found in the provisional patent application U.S. No. 60/073972, filed February 6, 1998, and in the aforementioned patent application U.S. No. 09/245764, "3-dimensional structures and models that have Fc receptors and their application", filed February 5, 1999.

FcgRIIa is a protein dimer and has a symmetry axis C2. In Fig. 1 shows the structure of the binding region FcgRIIa according to x-ray analysis. Out of touch with any of theories is that sites a and a1must be the areas of interaction with Fc-antibodies; thus, a compound that binds to or interacts with sites a or a1most likely interferes with the normal binding of this receptor with IgG. In addition, the connection that is associated with sites b, C and/or D may prevent or reduce the binding of an antibody, if the connection changes the structure of the receptor so that destabilizes the binding of antibody or promotes receptor dimerization, respectively.

In Fig. 2 shows a side schematic view of the site, i.e. the groove, showing only one surface, with representing the interest is made a target for interaction with vodorodovozdushnoi and/or acid groups, a suitable modulator. The surface of the grooves contains phenylalaninamide ring and may be targeted in a hydrophobic interaction, in particular when the p-p interactions. "Floor" of the grooves contains the remains of Phe121, Thr152, Leu159 and Ser161 together with Asn154, Lys117 (frame carbonyl) and Thr119. It is assumed that these proteins are arranged so that they form a pocket that is capable of strong bonding with hydrogen and/or van der Waals interactions with the modulator or ligand.

The features described above, the grooves cause the design and synthesis of compounds, which generally depicted as follows:

where "core" is a lipophilic group, such as an aromatic ring, and "linker" (binder group) is a related collection of from 1 to 20 atoms, preferably from 1 to 10 atoms, and more preferably from 2 to 8 atoms. The presence of acid groups, forming a pocket, which is directly connected to a connecting group, is optional. To ensure positive interaction with major groups, for example, Lys117 and His131, on the edge of the grooves, acid group ("acid") can branch from the "core" and/or "linking group". "Pocket" is that h is or to take only pocket of the receptor. These guidelines are illustrated by the example in Fig. 3, which shows, as a separate modulator is correlated with the General construction described above and illustrated in Fig. 4, which shows the point of interaction between the modulator and protein FcgRIIa.

Example compounds containing residues, forming a "pocket", as shown in Fig. 3, where casinozone ring is present in the area linking group connection. Other suitable binder particles pockets include nucleic acids and associated structures, such as hydrazides and nicomachean listed below, or their derivatives.

Preferably, these residues forming the pocket, would be represented by a dimer compounds, such as dimer nucleic acids, hydrazides, nicomachean or their derivatives.

Compounds of the present invention, which possess the above-mentioned main features include aromatic compound of the formula:

heteroaromatic compound of the formula:

the cyclic compound of the formula:

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or its salts, where each W1and W2independently represents a CO2R15C(=NH)NH(OH), SO3R15C(=NH)NH2, OPO(OR15)2With(=O)CF3or PO(ORI5)2; each AG1, AG2, AG4and AG5independently represents a C6-C20aryl or C1-C20heteroaryl; AG3represents a C1-C20heteroaryl; each X1X2X3X4X5X6X7and X8independently represents a methylene, O, S or NR16; each R1and R2independently represents a bond, C1-C6alkylen, or halogenated C1-C6alkylene; each R3and R4independently represent halogen, -Z1or C1-C6alkyl; each X9, Y1and Z1independently represents OR17, SR17or NR17R18; each R5and R6independently represents an amino acid residue side chain or a particle of formula R19-W3; each R8, R9and R11independently represents an amino acid residue side chain, provided that R11does not represent N or CH3; R7pre is employed, a C1-C6alkylene; R12represents a C1-C6alkyl or C6-C20aralkyl; W3represents C(=O)X10; X10is a OR23or NR24R25; each R13, R15, R17, R18, R20, R21, R23and R24independently represents hydrogen or C1-C6alkyl; each R16independently represents H, C6-C20aryl or protective amide group; R19represents a C1-C6alkylene; each R22and R25independently represents H, C1-C6alkyl or a protective group amide; R14represents H, C1-C6alkyl or a protective group of the amine; L represents a linking group containing from 1 to 20 atoms; and each of m and n independently represents an integer from 0 to 2.

In accordance with the present invention, "alkyl" groups are aliphatic hydrocarbons, which can be groups with straight or branched chain. Alkyl groups may be substituted by one or more than one Deputy, such as halogen, alkenyl, quinil, aryl, hydroxy, amino, thio, alkoxy, carboxy, oxo or cycle is s or unsubstituted nitrogen atoms. Examples of alkyl groups include methyl, ethyl, ISO-propyl, n-butyl, tert-butyl, vermeil, deformity, trifluoromethyl, chloromethyl, trichloromethyl, methoxyethyl, aminomethyl and pentaverate.

"Aryl" groups are monocyclic or bicyclic carbocyclic or heterocyclic aromatic ring particles. Aryl groups can be substituted by one or more than one Deputy, such as halogen, alkenyl, alkyl, quinil, hydroxy, amino, thio, alkoxy or cycloalkyl.

"Monoaryl or heteroaryl" refers to a monocyclic carbocyclic or heterocyclic aromatic ring. Examples monoallelic or heteroaryl rings include pyrrole, thiophene, furan, imidazole, pyrazole, 1,2,4-triazole, pyridine, pyrazin, pyrimidine, pyridazine, thiazole, isothiazol, oxazol, isoxazol, s-triazine and benzene. The preferred group is phenyl.

"Diaryl or heteroaryl" means a bicyclic ring system containing two condensed carbocyclic and/or heterocyclic aromatic ring. Examples dialling or heteroaryl rings include inden, itingen, benzofuran, dihydrobenzofuran, benzothiophene, indole, 1H-indazole, indoline, azulene, the Rin, naphthalene, tetralin, coumarin, chrome, chrome, 1,2-dihydrobenzofuran, tetrahydrobiopterin, quinoline, isoquinoline, hinzelin, pyrido[3,4-b]-pyridine and 1,4-benzoxazin.

"Aralkyl" refers to an alkyl group, substituted aryl group. Suitable kalkilya groups include, but are not limited to benzyl, 2-ventilation and pikolinos. Aryl groups may also be replaced by other suitable functional groups. Kalkilya group include the group of heterocyclic and carbocyclic aromatic groups.

"The linking group (L1refers to the chain of atoms that binds AG1with AG2a certain number of atoms. This is the number that corresponds to a connecting group, refers only to the number of atoms that are directly associated AG1and AG2. Group L1may contain groups that can participate in the formation of hydrogen bonds and/or van der Waals interactions with amino acid residues in the groove of the receptor, such as TRIFLUOROACETYL, imide, urea, amicin, amidoxime or their derivatives.

"Amino acid residue side chain" refers to an amino acid side chain, which is located at-plasticky side chain include hydrogen (glycine), methyl (alanine), -CH2CH2CH2NHC(=NH)NH2(arginine), CH2C(=O)NH2(asparagine), -CH2CO2N (aspartic acid), -CH2S (cysteine), -CH2CH2C(=O)NH2(glutamine), -CH2CH2CO2N (glutamic acid), -CH2-(4-imidazole) (histidine), -CH(Et)CH3(isoleucine), -CH2CH(CH3) (leucine), -(CH2)4NH2(lysine), -(CH2)2SCH3(methionine), -CH2Ph (phenylalanine), -CH2-CH2-CH2- (Proline), -CH2HE (serine), -CH(OH)CH3(threonine), -CH2-(3-indole) (tryptophan), -CH2-(4-hydroxyphenyl) (tyrosine) and-CH(CH3)2(valine).

pKa of the corresponding acid groups W1and W2less than 9, more preferably less than 7, and most preferably less than 5. "Appropriate acid group1and W2" refer to the parent acid group W1and W2for example, if W1and W2are the esters, the corresponding acid corresponds to the carboxylic acid, and if W1and W2are alkylphosphonate, this acid corresponds to the phosphonic acid. It is important that the RCA W1and W2depends not only on the type rolnych or heteroaryl groups, attached W1and W2. For example, the presence of one or more than one group, dilatory electron density, such as nitro, nitroso, carbonyl, cyano and galactography, reduces the pKa value of the corresponding W1and W2acid groups. the RCA is defined as-log(Ka), where Ka is the dissociation constant. On the strength of the acid or base in this environment specifies the value of its (his) dissociation constants. For example, strong bases are strong acceptors of protons (or donor-electron pairs) and have a higher pKa value. PKa value depends on various factors such as the nature of the solvent and the temperature. For example, water (H2About), but not associated water acid, which is an H3About+has a pKa in water 15,7 at 25With, 16,7 when 0With and 14.7 at 60C. In addition, in dimethyl sulfoxide (DMSO) at 25With its pKa equal to 27.5. In this document pKa value related to the pKa values, which correspond to the pKa value of water corresponding to about 15.7, unless otherwise specified.

In addition to the formulas given here:

ub> or PO(OR5)2.

Preferably, R1and R2independently represents a bond, C1-C6alkylene or fluorinated C1-C6alkylen. More preferably, R1and R2independently represents a bond, methylene or deformation.

Preferably, each AG1, AG2and AG5independently, would have constituted monoaryl or heteroaryl. More preferably, AG1, AG2and AG3would represent phenyl.

Preferably, AG3was a 2-pyridinyl, and more preferably, Ar3was a 4-Ar4-(2-pyridinyl), i.e., 2-pyridone, 4-position is attached to the group of AG4.

Preferably, AG4was a C1-C20heteroaryl. More preferably, AG4represented pyridyl. Most preferably AG4was a 4-pyridyl, i.e., 4-pyridine, 4-position is attached to the group of AG3.

Preferably, Y1represented NR17R18. More preferably, Y1represented the NH2. Preferably, each R15independently represents a hydrogen>C6albaniles, including groups with unsaturated bond,-carbon atoms (for example, -CH=CH-C(=O)-); or a group of the formula-R33-X14-, -R34-X15-R35or X16-R36-Ar7-R37-X17-. Each of R33, R34, R35, R36and R37independently represents a C1-C6alkylene (including substituted alkylene), preferably methylene. Each X14X15X16and X17independently represents O, S or NR38preferably O or NR38. Each AG6and AG7independently represents a C6-C20aryl or C1-C20heteroaryl, preferably 2-pyridone. And R38represents H, C1-C6alkyl or a protective group of the amine, preferably-CH2CO2N. More preferably, L1represented a sulfonamide (-SO2NH-), ethylene (-CH2CH2-), -CH2O-, -SN=SNA(=O)-, -CH2CH2CH(OH)-, -CH=CH-, -CH(OH)CH(OH)-, -CH2N(R38)CH2-, a group of the formula:

or a group of the formula:

where each R27and R28independently presented/sup> and R28independently represent H or a protective group. More preferably R27and R28independently represent H or 4-methoxybenzyl.

Preferably m and n are equal to 0.

Alternative, R1and W1and/or R2and W2together form -(CH2)aCH(other29)CO2R39and -(CH2)bCH(other30)CO2R40accordingly, where a and b independently represent an integer from 0 to 2, R29and R30independently represent H or a protective group of the amine, and R39and R40independently represent N or C1-C6alkyl. Preferably, a and b would be equal to 1. Preferably, R29and R30independently represent H, C1-C6alkyl or a protective group of the amine.

Preferably, R5represented the balance of the side chain of asparagine.

Preferably, R6represented the balance of the side chain of glutamine.

Preferably, R7represented approximately 1 to 10 amino acid residues or derivatives thereof, more preferably from 1 to 6 amino acid residues or derivatives thereof, even more preferably at least 2 amino acid ostack)4NH2]CONHCH(CH2OH)CONHCH3.

Preferably, X1X2X3X4X5X6X7and X8independently represent O or NR16. More preferably, X1X2X3X4X5X6X7and X8represented NR16.

Preferably, X represented OR17or NR17R18more preferably NR17R18and most preferably NH2.

Preferably, R8represented the balance of the side chain of glycine (i.e., N).

Preferably, R9represented the balance of the side chain of tyrosine (i.e., 4-hydroxybenzyl).

Preferably, R10represented propylene.

Preferably, R11represented the balance of the side chain of lysine, i.e., a particle of the formula -(CH2)4NH2.

Preferably, R12represented With6-C20aralkyl, and more preferably 2-phenylethyl.

Preferably, R13represented N.

Preferably, R14was a H or a protective group of the amine, more preferably a protective group of the amine, and most preferably acetylen a N or C6-C20aryl. More preferably, each R16independently represents H or phenyl.

In a particular embodiment of the present invention, the above aromatic compound is a compound of the formula:

More preferably, an aromatic compound is the compound of the formula:

In another private embodiment of the present invention described above aromatic compound is a compound of the formula:

In a particular embodiment of the present invention described above heteroaromatic compound is a compound of the formula:

More preferably, described above heteroaromatic compound was a compound of the formula:

In another private embodiment of the present invention described above, the cyclic compound is a compound of the formula:

In a particular embodiment of the present invention described above bicyclic compound is a compound of the formula:

In another formula:

or its salts. Preferably, the above-described amino acid derivative was derived formula:

or was it a salt.

Compounds of the present invention, modulation of Fc receptors may also include nucleosides or derivatives thereof. Preferably, the nucleosides of the present invention have the formula:

where Q represents O or methylene. Preferably Q is O. X11is a OR31or OPO(OR31). Preferably X11is a HE or ORO3H2. Each X12and X13independently represents H or or15. Preferably, each X12and X13independently represent H or HE. Each R31and R32independently represents N or C1-C6alkyl.

Compounds of the present invention, modulation of Fc receptors may also include folic acid or its derivatives.

Compounds of the present invention, modulation of Fc receptors can also include peptides that can modulate the interaction between the Fc receptors have with the area (see Fig. 1) Fc receptors, for example FcgRII. Thus, it is believed that these peptides inhibit the dimerization between two FcgRII proteins, affecting, therefore, signal transmission from the cell through one or both FcR protein. In this case, residues and residues 117-131 150-164 form the border area FcgIIa dimer, and peptides with sequences or with such properties are inhibitors of binding. For example, natural Hexapeptide Phe121 - Ser126 or more short segments overlap the region with a large number of hydrogen bonds, causing significant interaction, and, thus, are suitable modulators of the dimerization of two molecules FcgRIIa. This protein fragment is described as part of SEQ ID No. 3 in the aforementioned patent application U.S. No. 09/245764, "3-dimensional structures and models that have Fc receptors and their application", filed February 5, 1999 Thus, these researchers found that the Tripeptide sequence GKS (gly-lys-ser) or its derivatives and Hexapeptide sequence FQNGKS (phe-gln-asn-gly-lys-ser) or their derivatives modulate the binding of FcgRII with IgG. Cm. experience 24 and Fig. 10 and 11.

These researchers also found that macrocyclic compounds with a specific conformation modulate the behavior of FcR protein is in the ring, which includes from 8 to 18 atoms of atoms. Preferably, the macrocyclic ring of the compound of the present invention include from about 10 to 16 atoms, more preferably from 12 to 14 atoms and most preferably from 13 to 14 atoms. Especially useful macrocyclic compound of the present invention is a cyclic peptide or its derivatives. Such a cyclic peptide having the formula:

was described above. The upper portion of the FG cycle FcR was determined in studies on mutagenesis, which are important when studying binding Ig. Peptide plot FG contains extended b-a fold in which the amino acid side remains FG loops are oriented in a certain position. This orientation Fc protein described in the aforementioned patent application U.S. No. 09/245764, "3-dimensional structures and models that have Fc receptors and their application", filed on 5 February 1999, it Was also found that the molecules, which can reproduce the coils of the b-helix so that its side remains occupy a position in the upper part of the FG loop, i.e. in the same way as for the side residues of the receptor, effectively modulate the behavior of the FcR receptor. Thus, in one embodied the crystals of:

where macrocyclic fragment contains the same number of atoms as described above. One private embodiment of such a playback loop b-helix is the connection described above, which has the formula:

Compounds of the present invention can be synthesized from readily available starting materials. Different substituents in the compounds of the present invention may be present in the source connections, be entered in any of the intermediates or to be entered after the formation of the final products by known methods of substitution or conversion. If the substituents which are reactive, these substituents may be protected in accordance with known methods. There are various protective groups that can be used. Examples of the many possible groups can be found in the publication "Protective Groups in Organic Synthesis" by T. W. Green, John Wiley and Sons, 1981. For example, the nitro group may be introduced by nitration, and the nitro-group can be converted into other groups such as amino group - recovery and galactography - by diazotization of the amino group and replacement of this diazogroup halogen. Acyl groups can wodis the ilen groups in different ways, including the restoration of the wolf-Kizaru and recovery Clemenson. The amino group can alkylaromatic with the formation of mono - and di-alkylamino; and mercapto and hydroxy-group can alkylaromatic with formation of the corresponding esters. Primary alcohols can be oxidized known from the practice of oxidants with the formation of carboxylic acids or aldehydes and secondary alcohols can be oxidized with the formation of ketones. Thus, it is possible to apply substitution reactions or changes to input various substituents in the molecule of the original substance in the intermediate or final product, including the selected products. Since the compounds of the present invention may have some alternates, who must be present, the introduction of each Deputy, of course, depends on the nature of the involved deputies and the chemistry of the reactions necessary for their education. Thus, the question of how to separate the Deputy will be affected by the chemical reaction in the formation of a second alternate, will be associated with in ways that are familiar to the average person. Also it will depend on the nature of the ring.

It should be borne in mind that the present invention kwathu be formed.

If the connection according to the present invention contains one or more than one chiral center, it is possible to synthesize enantioselective or in the form of a mixture of enantiomers, and/or can be obtained diastereomers followed by separation. Separation of the compounds of the present invention, the raw materials for their production and/or intermediate compounds can be obtained by known methods, for example as described in the four-volume compendium Optical Resolution Procedures for Chemical Compounds: Optical Resolution Information Center, Manhattan College, Riverdale, N. Y., and in Enantiomers, Racemates and Resolution, Jean Jacques, Andre Collet and Samuel H. Wilen; John Wiley & Sons, Inc., New York, 1981. In General, the separation of compounds based on differences in physical properties of diastereomers by chemical or enzymatic joining of enantiomerically pure group with the formation of forms, which are separated by fractional crystallization, distillation or chromatography.

If the connection according to the present invention contains olefinic group, and this group may have either CIS-or TRANS-configuration, the connection can be synthesized with the formation of either CIS-or TRANS-olefin as the predominant product. Alternatively, a compound containing olefinic group, can be obtained in the form of a mixture C is al., J. Am. Chem. Soc., 1974, 96, 3642.

Compounds of the present invention form salts formed by the addition of acid, if present, the main aminophenol, and salts formed by the addition of bases, if the acid function, for example, carboxylic acid or phosphonic acid. All such salts are useful in the isolation and/or purification of new products. Of particular importance are the pharmaceutically acceptable salts with both acids and bases. Suitable acids include, for example, chloride-hydrogen, oxalic, sulphuric, nitric, benzosulfimide, toluensulfonate, acetic, maleic, tartaric and the like acids which are pharmaceutically acceptable. Basic salts for pharmaceutical use include salts of Na, K, CA and Mg.

In addition to and/or instead of targeted drug development other Fc receptor modulators can be identified by the screening method, in which different compounds are tested to determine their activity in modulating the Fc receptor. In this way were identified various modulators Fc receptor. Thus, the compounds of the present invention include substituted and unsubstituted benzoyl acid and its derivatives.

Compounds of the present invention are modulators Fc receptor, for example, they modulate the binding of the Fc receptor with immunoglobulins. Preferably, the compounds of the present invention would modulated Fc receptors selected from the group comprising FcaR, FcgR, FcgR and mixtures thereof, more preferably from the group comprising FcgRI, FcgRII, FcgRIII, and mixtures thereof, even more preferably from the group comprising FcgRIIa, FcgRIIb, FcgRIIc and mixtures thereof, and most preferably FcgRIIa receptor. Compounds of the present invention can be used for a variety of purposes, including the treatment or diagnosis of any disease in which the formation of aggregates of the antibody and which in case of contact antibodies with internal or external antigen to form immune complexes. Examples of compounds of the present invention for the treatment and diagnosis include immune complex diseases; autoimmune diseases, including, but not limited to rheumatoid arthritis, systemic lupus erythematous, immune thrombocytopenia, neutropenia, hemolytic anemia, vasculitis, including but not limited to polyarthritis thickening, systemic vasculitis; ottersen is not limited to flavivirus infections, such as hemorrhagic fever caused by Dengue virus, and viral infection measles. Compounds of the present invention can also be applied to reduce IgG-mediated tissue damage and to reduce inflammation.

Compounds of the present invention can also improve the function of leukocytes as a result of improved FcR function. These features include antibody-dependent cell-mediated cytotoxicity, phagocytosis, release of inflammatory cytokines. Examples of diagnostics and treatment with improved FcR functions include any infection in which produced normal antibodies to eliminate pathogenic factors; and any disease requiring FcR function, which can be used natural or recombinant antibodies for the treatment of diseases such as cancer and infections, for example, antibodies can be administered together with a compound of the present invention to improve the effect in the treatment of antibodies.

Compounds of the present invention can be administered to a patient to achieve the desired physiological effect. Preferably, the patient was an animal, preferably a mammal and most preferably a human. Audiorenderer. In this regard, parenteral administration includes the introduction of the following routes: intravenous; intramuscular; subcutaneous; intraocular, intrasynovial; transepithelial, including transdermal, ophthalmalgia, sublingual and transbukkalno; local introduction, including italianno, dermal, ocular, rectal and naselenie inhalation via insufflation and aerosol; IPR; and rectal systematically.

The active compound may be administered orally, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft gelatin capsules, or it may pressoffice into tablets, or it may directly be incorporated in food or diet. For oral therapeutic injection of the active compound may be included in excipient and applied in the form of a swallow tablets, transbukkalno of tablets, pellets, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and pharmaceutical preparations can contain at least 0.1% of active compound. The percentage composition of the compositions and pharmaceutical preparations can, of course, subject to change and may vary from about 1 to 10% who were Cigalas suitable dose. Preferred compositions or pharmaceutical preparations in accordance with the present invention are prepared so that the dosage form for oral administration containing from 1 to 1000 mg of active compound.

Tablets, pellets, pills, capsules and the like may also contain the following: a binder such as resin tragakant, Arabian gum, corn starch or gelatin; excipients such as dicalcium phosphate; a leavening agent, such as corn starch, potato starch, alginic acid and the like; a lubricating substance, such as magnesium stearate; and can be added sweetener, such as sucrose, lactose or saccharin, or corrigent, such as peppermint oil, oil of gaultheria, or cherry corrigent. If the dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be used as coatings or to modify the physical form of the drug. For example, tablets, pills or capsules can be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweeten the orange corrigent. Of course, any material used in the manufacture of any drug form should be pharmaceutically pure and non-toxic in the quantities used. In addition, the active compound may be included in the pharmaceutical preparations and compositions for long periods.

The active compound may also be administered parenterally. Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water, respectively, mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and their mixtures and oils. Under normal conditions of storage and use to prevent the growth of microorganisms, these pharmaceutical preparations contain a preservative.

The pharmaceutical forms suitable for use in injection include sterile aqueous solutions or dispersions and sterile powders for the preparation of sterile injectable solutions or dispersions for immediate introduction. In all cases, the introduction of using a standard syringe, the form must be sterile and must be fluid. It must be stable under the conditions of production and storage and which may be a solvent in the form of a dispersion medium, containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol, and liquid polyethylene glycol and the like), suitable mixtures thereof and vegetable oils. The proper fluidity can be achieved, for example, by applying a coating such as lecithin, by the establishment of the required particle size in the case of dispersion and by the use of surfactants. Preventing exposure of microorganisms can be performed by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases it is preferable to include isotonic agents such as sugars or sodium chloride. The prolonged absorption of injectable compositions can be realized by using agents that prolong the time of absorption such as aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by introduction of active compound in an appropriate solvent in the required quantity, which contains various other above ingredients, as appropriate, with the subsequent sterilizing filtration. Generally, dispersions are prepared by introduction of a range of sterile active Ingram is s of the numbers listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of obtaining methods are vacuum drying and freeze drying, which allow to obtain a powder of the active ingredient containing any additional desired ingredient from their solution, which was previously subjected to sterilizing filtration.

Therapeutic compounds of the present invention may be introduced mammal alone or together with pharmaceutically acceptable above carriers, which ratio is determined by the solubility and chemical properties of the compounds, chosen route of administration and standard pharmaceutical practice.

The attending physician determines the dosage of the present therapeutic agents which will be most suitable for prophylaxis or treatment and will vary depending on the form of administration and specifically selected connection, and will also change with treatment depending on the characteristics of the individual patient. Usually the doctor wants to start treatment with a low dosage and gradually increasing them until such time as in the circumstances is reached an optimum effect. Therapeutics of body weight per day and preferably from 0.1 to 20 mg/kg of body weight per day and can be administered in several different dosage units. When oral administration may take from 2 to 4 times larger dosage.

Additional objectives, advantages and new features of the present invention will be obvious to experts in the study of the following examples which are not limiting.

EXPERIMENTAL DATA

In this document the following abbreviations are used:

K. T. - room temperature,

Et2O - diethyl ether (i.e., ether or ethyl ether),

MS (head) and chemical ionization at atmospheric pressure,

THF is tetrahydrofuran,

tO - ethyl acetate,

l - trimethylsilyloxy,

CH3CN - acetonitrile,

DMF - dimethylformamide.

Experience 1

In this experience and presents a synthesis of 1,2-bis(m-carboxyphenyl)ethane:

Stage 1: 1,2-bis(m-bromophenyl)ethane get in the way Lindsay et al (JACS, 1961, 83, 943) as follows. To a solution of 3-bromobenzylamine (1.0 g, 4.0 mmol) in Et2O (10 ml) at K. I. add magnesium (0.05 g, 2.0 mmol). After 20 min at room temperature all the magnesium has dissolved, and then add anhydrous ferric chloride (5 mg). The reaction mixture is heated to the temperature of reflux distilled for 1 hour, cooled, acidified to about pH 1 1 M water H2SO4and extracted with Etsub>SO4), filtered and concentrated under vacuum to obtain a yellow solid. After recrystallization from petroleum ether obtain 1,2-bis(m-bromophenyl)ethane as a colorless solid. MS (head) m/z 338 (50%), 340 (100), 342 (50).1H NMR (200 MHz, CDCl3): d 2,85, s, 2H; 7,02-of 7.25, m, 2H; 7,30-7,39, m, 2H.

Step 2: tert-utility (2,1 ml of 1.7 M solution in pentane, of 3.60 mmol) are added dropwise to a solution of 1,2-bis(m-bromophenyl)ethane (305 mg, 0.90 mmol) in THF (10 ml) at -78C. After 20 min at this temperature through the reaction mixture bubbled CO2up until the temperature of the reaction mixture in the absence of a cooling bath reaches K. I. This reaction mixture was partitioned between water (50 ml) and Et2O (50 ml), the aqueous phase is separated and acidified to about pH 1 with concentrated aqueous Hcl, keeping the internal temperature below 25C. the Aqueous phase is extracted with tO (350 ml) and the combined organic extracts dried (Na2SO4), filtered and concentrated under vacuum to obtain 1,2-bis(m-carboxyphenyl)ethane as a white solid. MS (head) m/z 269 (M+1, 100%).13With NMR (50 MHz, d6-DMSO): d 38,4, 128,8, 130,3, 131,1, 132,5, 134,8, 143,5, 169,2. The pace is Yong synthesis of 3-[(m-carboxyphenyl)methoxy]benzoic acid:

Stage 1: a mixture of 3-bromophenol (13.8 g, 80 mmol), 3-bromobenzylamine (10 g, 40 mmol), K2CO3(16.6 g, 120 mmol) and NaI (300 mg, 2 mmol) in acetone (100 ml) is heated to the temperature of reflux distilled within 12 hours. The reaction mixture is cooled to K. T., concentrated under vacuum and partitioned between Et2O (300 ml) and water (300 ml). The organic phase is washed with aqueous solution of NaOH (1 M, 300 ml), dried (Na2SO4), filtered and concentrated under vacuum to obtain 3-[(m-bromophenyl)methoxy]bromine benzol in the form of a clear oil. MS (head) m/z 339 (M+-3,50%), 341 (M+-1, 100%), 343 (M++3,50%).13With NMR (50 MHz, CDCl3); d 68,9, 113,4, 117,9, 122,5, 122,6, 124,1, 125,6, 129,9, 130,0, 130,4, 130,9, 138,4, 158,9.

Stage 2: Using 3-[(m-bromophenyl)methoxy]bramasol and applying the method described in Example 1, stage 2, get 3-[(m-carboxyphenyl)methoxy]-benzoic acid as a white solid. MS (head) m/z 271 (M+-1, 100%).13With NMR (50 MHz, d6-DMSO): d 68,3, 114,5, 119,3, 121,5, 127,8, 128,3, 129,3, 130,5, 131,5, 131,8, 137,0, 157,7, 166,6, 166,7.

Experience 3

This experience presents a synthesis of 1,2-bis(3-postnominal)ethane:

Stage 1: 1,2-bis(3-bromophenyl)ethane (obtained using the method of Example 1, stage 1) (440 mg, 1,29 mmol), dietert who have Pd(PPh3)4(185 mg, 0.16 mmol) and the reaction mixture heated to 90C for 16 hours. The reaction mixture is cooled to room temperature and purified column chromatography (SiO2, 50% tO in petroleum ether100% tO100% EtOH) to give 1,2-bis[3-(diethoxypropane)phenyl]-ethane as a white solid. MS(head) m/z 455 (M++1, 100%).31P NMR (81 MHz, interchange of protons, Dl3): d +19,5.

Stage 2: Trimethylsilylpropyne (of 1.03 ml, 7.8 mmol) is added dropwise to a solution of the above ester (586 mg, of 1.30 mmol) in CH2Cl2(10 ml) at K. I. the Reaction mixture is stirred for 16 hours at room temperature and concentrated in vacuo. Then add Meon (5 ml) and the solution was concentrated in vacuo. This operation is repeated two more times to obtain 1,2-bis(3-postnominal)ethane as a white solid. MS (head) m/z 341 (M+-1, 100%).31P NMR (81 MHz, interchange of protons, CDCl3): d +14,6.

Experience 4

In this experience and presents a synthesis of 3,3’-dicarboxy-halkon:

Stage 1: 3-Cyanobenzaldehyde (3.0 g, 23,0 mmol), 3-cyanoacetate (3,34 g, 23,0 mmol) in glacial acetic acid (5 ml) and koncentrirovatb water (200 ml) and the reaction mixture is filtered. The precipitate was washed with water (2200 ml) and dried in vacuum to obtain 3,3’-dicyanobutane in the form of a whitish solid. MS (head) m/z 258 (M+-1, 100%).13With NMR (50 MHz, d6-DMSO): d 111,7, 117,8, 118,0, 123,0, 129,7, 131,6, 132,1, 132,4, 133,3, 133,5, 135,3, 136,1, 137,4, 142,1, 187,3.

Stage 2: a Solution of 3,3’-dicyanobutane obtained in stage 1 (2.0 g, of 7.75 mmol) in glacial acetic acid (30 ml) is treated with a mixture of concentrated H2SO4(10 ml) and water (10 ml). This reaction mixture is heated to 130C for 12 hours, cooled to room temperature and filtered. The precipitate was washed with water (3100 ml) and dried in vacuum to obtain 3,3’-decarboxylase in the form of a yellow solid. MS (head) m/z 295 (M+-1, 100%).13With NMR (50 MHz, d6-DMSO); d 122,5, 128,6, 128,7, 129,2, 130,8, 131,0, 131,2, 132,4, 132,5, 133,1, 134,5, 137,2, 143,1, 166,3, 166,5, 188,2.

Experience 5

In this experience and presents a synthesis of 1,3-bis (m-carboxy-phenyl)-1-propanol:

3,3’-dicarboxylate (Example 4, step 2) (430 mg, 1,45 mmol) in ethanol (10 ml) containing an aqueous solution of NaOH (1 M, 2,90 mmol), hydronaut at a pressure of 310 kPa within 48 hours in the presence of a catalyst Wilkinson (67 mg, 0.07 mmol). The reaction mixture is filtered and K. The reaction mixture is stirred for 16 hours at K. T., quenched by careful addition of a saturated aqueous solution of NH4Cl and partitioned between tO (50 ml) and aqueous Hcl solution (1 M, 50 ml). The organic extract is dried (Na2SO4filter and concentrate under vacuum to obtain 1,3-bis (m-carboxyphenyl)-1-propanol in the form of a viscous oil. MS (head) m/z 299 (M+-1, 100%).1H NMR (200 MHz, CDCl3); d 1,95-2,10, m, 2H; 2,68-2,83, m, 2H; 4,62-4,78, m, 1H; 7,03-7,60, m, 4H; 7,75-8,03, m, 4H.

Experience 6

This experience presents and synthesis of TRANS-3,3’-bis-carboxyterminal:

Stage 1: Methyl 3-bromobenzoate (of 21.5 g, 100 mmol), Pd(OAc)2(224 mg, 1 mmol), tri-o-tolylphosphino (608 mg, 2 mmol) and tributylamine (26,2 ml, 110 mmol) in DMF (100 ml) Tegaserod with argon, heated to 130C for 6 hours and bubbled through the solution to ethylene. The reaction mixture is cooled to room temperature and filtered. The precipitate was washed with cold Et2O (250 ml) and dried in vacuum to obtain dimethyl ester of TRANS-3,3’-bis-carboxyterminal in the form of a whitish solid.13With NMR (50 MHz, CDCl3): d 52,2, 127,5, 128,8, 130,6, 130,9, 137,2, 166,9.

Stage 2: the Above fluids (500 mg, 1.7 mmol) in 16 hours at K. T. the reaction mixture was partitioned between Et2O (50 ml) and water (50 ml). The aqueous phase is separated and the organic phase extracted with water (25 ml). The combined aqueous extracts acidified with concentrated aqueous Hcl (while holding the internal temperature below 10C). The aqueous phase is extracted with CH2Cl2(350 ml) and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to obtain TRANS-3,3’-bicarboxylic in the form of a white solid. MS (head) m/z 267 (M+-1, 100%).1H NMR (200 MHz, d6-DMSO): d 7,28-7,56, m, 2H; 7,78-of 7.90, m, 2H; 8,20, s, 1H.

Experience 7

In this experience and presents the synthesis of (S,S)-1,2-bis-(3-carboxyphenyl)ethane-1,2-diol:

Step 1: Dimethyl ester of TRANS-3,3’-bicarboxylic (Example 6, step 1) (5.0 g, 16.9% mmol) and N-methylmorpholin-N-oxide (2.2 g, to 18.6 mmol) in acetone (50 ml) and water (20 ml) is treated at room temperature with an aqueous solution OsO4(4.3 ml, 39.4 mm, 0,17 mmol). The reaction mixture is stirred for 16 hours at K. T., quenched by the addition of sodium metabisulfite (3.0 g) and adjusted the pH to approximately pH 7 with 2 M aqueous solution of sulfuric acid. The acetone is removed in vacuo, and the remaining RA is e organic extracts dried (Na2SO4), filtered and concentrated in vacuo to obtain (R,R)-1,2-bis-[3-(carbomethoxy)-phenyl]ethane-1,2-diol as a white solid.1H NMR (200 MHz, CDCl3): d 3,2, bs, 1H; 3,82, s, 3H; 4,77, s, 1H; 7,20-7,31, m, 2H; 7,80-7,89, m, 2H.

Stage 2: the Above fluids (500 mg, 1.5 mmol) hydrolyzing using the procedure described in Example 6, step 2, to obtain the (S,S)-1,2-bis-(3-carboxyphenyl)ethane-1,2-diol as a white solid. MS (head) m/z 301 (M+-1, 100%).1H NMR (200 MHz, d6-DMSO): d 3,40, bs, 1H; 4,76, s, 1H; 5.56mm, bs, 1H; 7,20-7,29, m, 2H; 7,80-to $ 7.91, m, 2H.

Experience 8

In this experience and presents a synthesis of 3,3'-bis-(carboxy-methyl)stilbene:

Stage 1: Methyl 3-bromophenylacetate (8.0 g, is 34.9 mmol) is subjected to interaction with ethylene, using the method described in Example 6, step 1. The crude reaction product is purified column chromatography (SiO2with 5% EtOAc in petroleum ether) to give 3,3’-bis-[(Carbo-methoxy)methyl]stilbene and methyl 3-(ethynyl)phenyl-acetate as a white solid mixture.

3,3’-bis-[(Carbo-methoxy)methyl]stilbene:1H NMR (200 MHz, Dl3): d 3,65, s, 2H; 3,70, s, 3H; 7,1, s, 1H, 7,15-7,50, m, 4H.13With NMR (50 MHz, CDCl3): d 41,2, 52,1, 125,3, 127,4, 128,6. 128,7, 128,9, 134,4, 137,6, 171,9.

Methyl 3-(ethynyl)phenyl acetate:1H NMR (200 MHz, CDCl3is Il]stilbene hydrolyzing, using the procedure described in Example 6, step 2, to obtain 3,3’-bis-[(carboxy)methyl]stilbene in the form of a white solid. MS (head) m/z 295 (M+-1, 100%).1H NMR (200 MHz, d6-DMSO): d of 3.60, s, 2H; 7,00-7.62mm, m, 5H.

Experience 9

This experience presents a synthesis of 1,2-bis[m-(carboxymethyl)phenyl]ethane:

Stage 1: 3,3’-bis-[(carbomethoxy)methyl]stilbene (Example 8, step 1) (500 mg, 1.5 mmol) and palladium on carbon (10%, 200 mg) in methanol (20 ml) hydronaut in an atmosphere of hydrogen for 16 hours at K. I. the Reaction mixture is filtered and concentrated in vacuo to obtain 1,2-bis-[m-(carbomethoxy)phenyl]ethane as a colorless oil.1H NMR (200 MHz, CDCl3): d 2,91, s, 2H; 3,63, s, 2H; and 3.72, s, 3H; 7,08-7,31, m, 4H.

Stage 2: the Above ester hydrolyzing using the procedure described in Example 6, step 2, to obtain 1,2-bis-[m-(carboxymethyl] ethane as a white solid. MS (head) m/z 297 (M+-1, 100%).1H NMR (200 MHz, d6-DMSO): d 2,82, s, 2H; 3,56, s, 2H; 7,06-7,06-7,27, m, 4H; 12,25, bs, 1H.

Experience 10

This experience presents a synthesis of 1-[m-(carboxymethyl)phenyl]-2-[m-(carboxyphenyl)]ethane:

Stage 1: Methyl 3-(ethynyl)phenyl acetate (Example 8, step 1) (1.1 g, of 6.25 mmol), methyl 3-bromobenzoate (960 mg, of 4.46 mmol) was dissolved in N-methylpyrrolidinone, Tegaserod with argon and heated to 130C for 5 hours. The reaction mixture is cooled to K. T., bred tO (100 ml) and the organic phase washed with water (100 ml), aqueous solution of Hcl (1 M, 100 ml) and saturated aqueous Panso3(100 ml). The organic extracts are dried (Na2SO4), filtered and concentrated in vacuo to obtain TRANS-1-[m-(3-carboxymethoxy)-phenyl]-2-[3-(carbomethoxy-phenyl)] ethane as a colorless oil. MS (head) m/z 309 (M+-1, 100%).1H NMR (200 MHz, CDCl3): d of 3.64, s, 2H; 3,68, s, 3H; 7,16-7,56, 6N; 7,63-7,71, m, 1H; of 7.90-7,98, m, 1H; 8,20, m, 1H.

Stage 2: the Above connection hydronaut in accordance with the method described in Example 9, step 1, obtaining 1-[m-(carbomethoxyamino)-phenyl]-2-[m-(carbomethoxybiphenyl)]ethane as a colorless oil.1H NMR (200 MHz, CDCl3): d 2,87, m, 4H; 3,56 s, 2H; of 3.60, s, 3H; of 3.84, s, 3H; 6,95 WAS 7.36, 6N; to 7.77-of 7.90, m, 2H.

Stage 3: the Ester obtained in Stage 2 hydrolyzing using the method described in Example 6, step 2, to obtain 1-[m-(carboxymethyl)phenyl]-2-[m-(carboxyphenyl)]ethane as a white solid. MS (head) m/z 283 (M+-1, 100%).1H NMR (200 MHz, d6-DMSO): d 2,92, m, 4H; 3,55, s, 2H; 7,02-7,35, m, 4H; of 7.36-7,60, m, 2H; 7,71-to 7.93, m, 2H.13With NMR (50 MHz, d6-DMSO): d 38,6, 38,7, 40,9, 128,5, the ZIL)glycine:

Stage 1: m-Cyanobenzeneboronic (2.35 g, 12,0 mmol) is added slowly to a solution of hydrochloride licensedialog ether (0,63 g, 5.0 mmol), Panso3(1.4 g of 17.0 mmol) and NaI (0,37 g, 2.4 mmol) in DMSO (5 ml) and THF (20 ml). The reaction mixture is heated to the temperature of reflux distilled for 2 hours, cooled to room temperature and diluted tO (50 ml) and water (40 ml). The organic phase is washed with water (340 ml), saturated aqueous NaCl (40 ml), dried (Na2SO4), filtered and concentrated in vacuo to obtain N,N-bis(m-cyanobenzyl)licensedialog ester as colorless oil of sufficient purity for subsequent reactions. Further purification may be effected by extraction with dilute aqueous acid solution, alkalization and extraction with an organic solvent.1H NMR (200 MHz, CDCl3): d 3,39, s, 2H; 3,71, s, 3H; 3,86, s, 4H; 7,39-7,73, m, 10H.

Stage 2: the Above nitrile (1.5 g, 5,02 mmol) hydrolyzing in accordance with the method described in Example 4, step 2, to obtain N,N-bis(m-carboxymethyl)glycine (sulfate salt) in the form of a whitish solid. MS (head) m/z 342 (M+-1, 100%).13With NMR (50 MHz, d4-MeOH): d 53,8, 59,0, 130,2, 131,5, 132,7, 132,8, 134,2, 136,1, 169,1, na:

Stage 1: the p-Methoxybenzylamine (7,42 g, 54 mmol) in CH2CL2(100 ml) containing anhydrous MgSO4handle m-bromobenzaldehyde (10.0 g, 54 mmol) at 0C. the Reaction mixture was allowed to mix at room temperature for 16 hours, filtered and concentrated in vacuo to obtain N-p-methoxybenzylamine m-bromobenzaldehyde in the form of a colorless oil.1H NMR (200 MHz, CDCl3): d 3,82, s, 3H; 4,78, s, 2H; 6,92, d, J=7.5 Hz, 2H; 7,16, d, J=7.5 Hz, 2H; 7,52-7,60, m, 1H; 7,62-7,72, m, 1H; 7,98, m, 1H; 8,29, m, 1H.

Stage 2: 1,2-Dibromoethane (0.5 ml) is added to the zinc (1.31 g, 20.0 mmol) in CH3CN (5 ml), and the mixture is heated to a temperature of phlegmy within 1 minute. As soon as the reaction mixture cooled to K. so, it adds a l (1 ml) and the reaction mixture stirred at room temperature for 1 hour. The above Imin (between 6.08 g, 20 mmol) in CH3CN (20 ml) is added in one portion followed by the addition l (3.8 ml) for 30 minutes. Then the reaction mixture is stirred for 4 hours at 35-40C. the Reaction mixture was quenched with aqueous solution of NH4OH (6 ml) and saturated aqueous NH4Cl (14 ml) and filtered. The aqueous phase is separated and the water phase will centerour in vacuum to obtain an orange oil. After carrying out column chromatography (SiO225% Et2O in petroleum ether) to obtain (1R,2R)-N,N’-(p-methoxybenzyl)-1,2-(m-bromophenyl)ethane-1,2-diamine as a colourless oil.13With NMR (50 MHz, CDCl3): d 50,5, 55,3, 67,4, 113,8, 122,4, 126,7, 129,2, 129,6, 130,3, 130,7, 132,1, 143,4, 158,7.

Stage 3: N,N’-Disuccinimidyl (160 mg, 0.64 mmol) are added to a solution of the above diamine (260 mg, 0.43 mmol) in CH3CN (10 ml). The reaction mixture is heated to the temperature of reflux distilled for 2 hours. Then add a further portion of N,N’-disuccinimidyl (160 mg, 0.64 mmol) and the reaction mixture is heated to a temperature of phlegmy within the next 2 hours. The reaction mixture was concentrated and partitioned between tO (40 ml) and aqueous Hcl solution (1 M, 40 ml). The organic phase is washed with saturated aqueous Panso3(40 ml), saturated NaCl (40 ml), dried (Na2SO4), filtered and concentrated in vacuo to obtain an orange oil. After carrying out column chromatography (SiO2, 25% Et2O in petroleum ethertO) receive (3R,4R)-1,3-bis-(p-methoxybenzyl)-4,5-bis(m-bromophenyl)-imidazole-2-it is in the form of a white solid.13With NMR (50 MHz, CDCl3): d 45,3, 55,2, 65,0, 111,4, 123,1, 125,9, 128,1, 129,8, 130,2,x, described in Example 3, step 1, to obtain (3R,4R)-1,3-bis-(p-methoxybenzyl)-4,5-bis[m-(diethoxy-phosphono)phenyl]-imidazole-2-it is in the form of a colorless oil. MS (head) m/z 750 (M+-1, 100%).31P NMR (81 MHz, interchange of protons, CDCl3): d +18,4.

Stage 5: the Above phosphonate (340 mg, 0.45 mmol) is treated with trimethylsilylpropyne under the conditions described in Example 3, step 2, to obtain (3R,4R)-1,3-bis-(p-methoxybenzyl)-4,5-bis(m-postnominal)-imidazole-2-it is in the form of a whitish solid.31P NMR (81 MHz, interchange of protons, CDCl3): d +11,5.

Experience 13

This experience presents a synthesis of 6-amino-4-(4'-pyridyl)-2-(1H)-pyridone:

Stage 1: in the interaction of 4,4’-bipyridine with NaNH2in accordance with JOC, 1997, 62, 2774 receive, in addition described 2,2’-diamino-4,4’-bipyridine, not previously described 2-amino-4,4’-bipyridine.13With NMR (50 MHz, d6-DMSO): d 105,0, 109,5, 120,9, 145,4, 148,9, 150,3, 160,5.

Stage 2: the Above-mentioned amino-pyridine (1.5 g, 10.5 mmol) dissolved in acetic anhydride (20 ml) and heated to 60C for 3 hours. The reaction mixture is cooled to room temperature and filtered. The solid is washed with Et2O (250 ml) and dried in vacuum to receive the 6-DMSO): d 2,12, s, 3H; 7,40-7,58, m, 1H; 7,60-7,83, m, 2H; 8,30-8,58, m, 2H; 8,62-8,88, m, 2H.

Stage 3: the Above pyridine (0.9 g, 4.2 mmol) dissolved in CH2Cl2(50 ml) and treated with m-chloroperbenzoic acid (a 4.86 g, 60 wt.%) and the reaction mixture is heated to a temperature of phlegmy for 16 hours. The reaction mixture is cooled to K. T., filtered and the precipitate washed with Et2O (250 ml). The precipitate is added to acetic anhydride (25 ml) and heated to a temperature of phlegmy for 4 hours, cooled to room temperature and collect the precipitate. The residue is added to a methanol (5 ml), treated with PA2CO3(50 mg) and heated to a temperature of phlegmy for 5 hours. The reaction mixture is cooled to K. T., filtered and the filtrate concentrated in vacuo. After trituration with Et2O get 6-amino-4-(4’-pyridyl)-2-(1H)-pyridone as a yellow solid. MS (HI) m/z 188 (M+-1, 100%).1H NMR (200 MHz, d4-MeOH): d of 5.83, d, J=1 Hz, 1H, 5,90, d, J=1 Hz, 1H; to 7.67, d, J=7 Hz, 2H; 8,16, d, J=7 Hz, 2H.

Experience 14

This experience shows the activity of some compounds of the present invention when the modulation Fc receptor.

The interaction between recombinant soluble FcgRIIa and human immunoglobulin in the presence of small amounts of "https://img.russianpatents.com/chr/176.gif">C in Hepes buffer saline [NBR: 10 mM Hepes (pH 7.4), 150 mm NaCl, 3.4 mm etc, 0.005% surfactant P20 (Pharmacia)]. Monomeric human IgG1, IgG3 and IgE (50 mg/ml) (control for nonspecific binding) covalently associated with the surface carboxymethylamino dextran on the sensor chip CM-5 (BIAcore, Uppsala, Sweden) using the Protocol binding with the amino group (BIAcore, Uppsala, Sweden). An additional channel is chemically treated using the Protocol binding. Recombinant soluble FcgRIIa primeneniya at a concentration of 125 mg/ml, which is equivalent to 50% of the binding. Recombinant soluble FcgRIIa pre-incubated with each of the compounds at room temperature for 30 minutes before application to the surface of sensor chip in for 1 minute at a rate of 10 ml/min, with subsequent 3-minute phase dissociation. All surfaces Regenerist 50 mm diethylamine (about pH of 11.5), 1 M NaCl between analyses of each of the compounds. Then measure the maximum response for each of the interactions. Responses in non-specific binding (channel IgE) is subtracted from the values when binding to IgG1 and IgG3. Measurement adjust depending on differences in the composition buffer between compounds and receptor.

Using the sensitivity of surface LVII different compounds. Connection BRI6728, BRI6734, BRI6813, BRI6800, BRI6801, BRI6802, BRI6803, BRI6814, BRI6817, BRI6822, BRI6823 and BRI6824 inhibit the interaction of soluble FcgRIIa with IgG1 (Fig. 6 and 8). At a concentration of 5 mg/ml compound BRI6798, BRI6799, BRI6815 and BRI6825 enhances interaction between soluble FcgRIIa with IgG1 (Fig. 6 and 8). Connection BRI6728, BRI6734, BRI6813, BRI6800, BRI6801, BRI6802, BRI6803, BRI6814, BRI6816, BRI6817, BRI6822, BRI6823 and BRI6824 inhibit the interaction of soluble FcgRIIa with IgG3 (Fig. 7 and 9). Connection BRI6727, BRI6798, BRI6815 and BRI6825 enhances interaction between soluble FcgRIIa with IgG3 at a concentration of about 5 mg/ml and 10 mg/ml

Experience 15

This experience shows the synthesis of N-(3’-carboxyphenyl)-2-(carboxybenzoyl)sulfonamida:

Stage 1: Methyl 2-(chlorosulfonyl)-benzoate (2.25 g, 8,73 mmol) in methylene chloride (20 ml) was added dropwise to a solution of ethyl 3-aminobenzoate (1.44 g, 8,73 mmol) and triethylamine (1,21 ml, 8,73 mmol) in methylene chloride (10 ml) at 0C. the Reaction mixture was left to warm to room temperature and stirred over night. The reaction mixture was washed with water (20 ml), aqueous solution of Hcl (1 M, 20 ml) and aqueous NaOH solution (1 M, 20 ml), dried (MgSO4), filtered and concentrated under vacuum to obtain an orange oil. After trituration with ethyl ether to obtain N-(3 Is Cl3): d 1,31, t, J=6.0 Hz, 3H); 4,00, s, 3H; 4,29, q, J=6.0 Hz, 2H; 7.23 percent-to 7.61, m, 5H; 7,66-7,92, m, 3H; compared to 8.26. br s, 1H.

Stage 2: the Above fluids (1.0 g, to 2.75 mmol) hydrolyzing using the procedure described in Example 6, step 2, to obtain N-(3’-carboxyphenyl)-2-(carboxybenzoyl)sulfonamida in the form of a white solid. MS (HI) m/z 320 (M+-1, 100%).13With NMR (50 MHz, d6-DMSO): d 168,0, 166,3, 137,3, 135,8, 133,4, 132,6, 131,3, 130,1, 129,0, 128,8, 128,0, 124,5, 123,8 120.5.

Experience 16

This experience presents and synthesis of TRANS-3,3'-bis-(N-hydroxyamino)stilbene:

Step 1: TRANS-3,3’-Dicyanomethylene obtained from 3-bromobenzonitrile method of Example 6, step 1. MS (HI) m/z 230 (M+, 100%).

Stage 2: TRANS-3,3’-Dicyanomethylene (1.5 g, of 6.52 mmol), hydroxylamine hydrochloride (3,26 g, 50 mmol) and Na2CO3(totaling 3.04 g, 30 mmol) in tO (40 ml) and water (15 ml) is heated to the temperature of reflux distilled for 3 hours. The reaction mixture is cooled to room temperature and the ethanol removed under vacuum. The remaining solution was extracted with EtOAc (250 ml) and the combined organic extracts washed with aqueous solution of Hcl (1 M, 220 ml). The combined aqueous extracts alkalinized and extracted with EtOAc (350 ml). Combine the aqueous solids. MS (HI) m/z 297 (M++1, 100%).13With NMR (50 MHz, d6-DMSO): d 123,3, 124,8, 127,1, 128,6, 133,8, 136,8 and to 150.7.

Experience 17

This experience presents and synthesis (d,1)- and meso-2-acetylamino-3-(3-{2-[3-(2-acetylamino-2-carboxyethyl)phenyl]ethyl}-phenyl)-propionic acid:

Stage 1: 3-Bromobenzaldehyde (23.7 g, 128,2 mmol), N-acetylglycine (10.0 g, to 85.5 mmol) and sodium acetate (5,26 g, 64.1 mmol) in acetic anhydride (60 ml) is heated to the temperature of reflux distilled for 1 hour. The reaction mixture is cooled to room temperature and add water (100 ml). The resulting suspension is filtered, and the solid is washed with water (250 ml). The remaining solid is dissolved in methylene chloride (100 ml), dried (MgSO4), filtered and concentrated under vacuum to obtain a yellow solid. This solid is suspended in dry Meon (200 ml) and heated to a temperature of phlegmy for 9 hours. The reaction mixture was concentrated under vacuum to obtain a yellow solid. After recrystallization from EtOAc and petroleum ether to obtain methyl m-bromo--acetamidocinnamate in the form of a yellow solid. MS (HI) m/z 298 (M++1 (Br=79), 100%), 300 (M++1 (Br=81), 100%).13With NMR (RANS-(TRANS-2-acetylamino-2-carbomethoxyamino)phenyl]ethynyl}phenyl)prop-2-ENOAT obtained from the above compound by the method of Example 6, stage 1. MS (HI) m/z 461 (M+-1, 100%).

Stage 3: Connection from stage 2 (380 mg, 0.82 mmol) and Pd/C (300 mg, 10%) in the Meon (20 ml) is stirred under hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered and concentrated under vacuum to obtain (d,1)- and meso-methyl 2-acetylamino-3-(3-{2-[3-(2-acetylamino-2-carbomethoxy-ethyl)-phenyl]-ethyl}-phenyl)-propanoate in the form of a clear viscous oil which is used without further purification.

Stage 4: the Compound from step 3 (280 mg, of 0.60 mmol) hydrolyzing using the method described in Example 6, step 2, obtaining (d,1)- and meso-2-acetylamino-3-(3-{2-[3-(2-acetylamino-2-carboxyethyl)phenyl]ethyl}-phenyl)propionic acid in the form of a clear viscous oil. MS (HI) m/z 440 (M+-1, 100%).

Experience 18

This experience shows the synthesis of (3R,4R)-4,5-bis(m-carboxyphenyl)imidazole-2-it:

Step 1: To a solution of (R,R)-1,2-bis-[3-(carbomethoxy)phenyl]ethane-1,2-diol (Example 7, step 1) (1.5 g, of 4.54 mmol) in pyridine (10 ml) at 0With added dropwise methanesulfonanilide (1,01 ml of 13.1 mmol). The reaction mixture was left to warm to room temperature and stirred over night. The reaction mixture was diluted with water (30 ml) and 30 ml of methylene chloride and is washed with 220 ml of 1 M aqueous solution of Hcl, 20 ml of an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filter and concentrate under vacuum to obtain di-methanesulfonate (R,R)-1,2-bis-[3-(carbomethoxy)phenyl]ethane-1,2-diol as a yellow viscous oil.

Stage 2: a Solution of the above nelfinavir (505 mg, 1.0 mmol) and NaN3(150 mg, 2,31 mmol) in 6 ml DMF was heated to 90C for 17 hours. The reaction mixture is cooled to K. T., diluted with 50 ml diethyl ether and washed 350 ml of water. The organic phase is dried over MgSO4filter and concentrate under vacuum to obtain (R,R)-1,2-bis-3-(carbomethoxy)phenyl]-1,2-diazo-ethane in the form of a yellow viscous oil.1H NMR (200 MHz, CDCl3): d 3,93, s, 3H; 4,73, s, 1H; 7,17-7,39, m, 2H; 7,78-8, 01, m, 2H.

Stage 3: the Above DIACID (611 mg, of 1.61 mmol) and Pd on carbon (10%, 50 mg) in methanol is treated with concentrated aqueous Hcl (3,86 ml, 3,86 mmol).

The reaction mixture is placed in an atmosphere of hydrogen and stirred at room temperature for 30 hours. The reaction mixture was filtered through celite and concentrate to obtain cleaners containing hydrochloride salt of (R,R)-1,2-bis-[3-(carbomethoxy)phenyl]-1,2-diamino-ethane. MS (HI) m/z 329 (M++1 for the free amine, 70%), 312 (100%).

Is DMAP (DMAP) (104 mg, 0.85 mmol) a solution of di-tert-butyl dicarbonate (204 mg, of 0.94 mmol) in 1 ml of acetonitrile at K. I. the Reaction mixture is stirred for 25 min at room temperature and partitioned between 50 ml of ether and 50 ml of 1 M HCl. The organic phase is separated, dried over sodium sulfate, filtered and concentrated under vacuum. After column chromatography receive (3R,4R)-4,5-bis-(m-carbomethoxybiphenyl)imidazole-2-it is in the form of a white solid. MS (head) m/z 355 (M++1, 100%).1H NMR (200 MHz, d6-DMSO): d 3,86, s, 6N; 4,57, s, 2H; 7,16, br s, 2H; 7,46-to 7.61, m, 4H; 7,88-8,00, m, 4H.

Stage 5: the Above fluids (68 mg, 0,19 mmol) hydrolyzing using the procedure described in Example 6, step 2, to obtain (3R,4R)-4,5-bis(m-carboxyphenyl)imidazole-2-it is in the form of a white solid. MS (electrospray) m/z 327 (M++1, 100%).13With NMR (50 MHz, d6-DMSO): d 64,3, 127,4, 129,1, 129,3, 131,1, 131,4, 142,1, 162,5, 167,3.

Experience 19

This experience presents a synthesis 3-([3’-(1’-oxo-2’,2’,2’-triptorelin)phenoxy]methyl)phenyltrichlorosilane:

To a solution of 3-[(m-bromophenyl)methoxy]bromo-benzene (Example 2, step 1) (233 mg, 3,68 mmol) in 6 ml THF at -78With added dropwise tert-utility (1.6 ml, 1.7 M in pentane, of 2.72 mmol). After 20 minutes at this src="https://img.russianpatents.com/chr/176.gif">C. the Reaction mixture is stirred for 16 hours during which time the reaction mixture reaches K. so the Reaction mixture was partitioned between 20 ml of 1 M Hcl and 50 ml of ether. The organic phase is separated, dried over sodium sulfate, filter and concentrate under vacuum to obtain 3-([3’-(1’-oxo-2’,2’,2’-triptorelin)phenoxy]methyl)phenyltrimethylsilane in the form of a colorless oil. MS (HI) m/z 377 (M++1, 100%),19F NMR (188 MHz, CDCl3-): d-71,76 and -71,90.

Experience 20

This experience presents and synthesis of Ac-Phe-Gln-Asn-Gly-Lys-Ser-NH2:

This peptide synthesized by the method of synthesis of a peptide on a solid phase. After N-acylation and tear due to tar get mentioned in the title compound as a white solid. HPLC and MS analyses confirmed the purity and identity of this material.

Experience 21

In this experience and presents a synthesis of cyclo-[N-phenylglycine-Gln-sn-(D)-s]-Ls-Ser-NH2:

Stage 1: N-[(4S)-3-benzyloxycarbonyl-5-oxo-oxazolidin-4-yl]-acetylchloride (3.00 g, 10 mmol) in dichloromethane (20 ml) was added dropwise to a solution of tert-butyl N-phenylglycinate (2,3 mg, 11 mmol) in pyridine (10 ml) at 0C. the Reaction mixture is left is ml) and tO (150 ml). The organic phase is separated and successively washed with citric acid (10%, 2100 ml) and brine (100 ml), dried (MgSO4), filtered and concentrated in vacuo to obtain a yellow viscous oil. After column chromatography (SiO2, 20-50% EtOAc in petroleum ether) to obtain tert-butyl N-[(4S)-3-benzyloxycarbonyl-5-oxo-oxazolidin-4-yl-acetyl]-N-phenylglycinate in the form of a white foam. MS (head) m/z 467 (M+-1, 100%).

Stage 2: an Aqueous solution of NaOH (3 ml, 1 M, 3 mmol) are added dropwise to a solution of the above dipeptide (570 mg, 1,22 mmol) in methanol (20 ml) at 0C. the Reaction mixture was left to warm to room temperature and controlled with the help of TLC. Next, the reaction mixture was concentrated and partitioned between Et2O (30 ml) and citric acid (10%, 30 ml) at 0C. the Aqueous phase extracted with Et2O (330 ml) and the combined organic extracts dried (MgSO4), filtered and concentrated under vacuum to obtain white solids. After column chromatography (SiO2, 2-5%, Meon in dichloromethane) to obtain tert-butyl N-[(2S)-N-benzyloxycarbonyl-aspartyl]--N-phenylglycinate*) in the Meon (40 ml), containing palladium on carbon (10%, 500 mg), placed in an atmosphere of hydrogen and stirred at room temperature for 16 hours. The reaction mixture was filtered and concentrated in vacuo to obtain tert-butyl N-[(2S)-aspartyl])--N phenylglycinate in the form of a white solid.

Stage 4: the Aforementioned compound (890 mg, was 2.76 mmol), Fmoc-O-Su, i.e. N-(9-formicoxenini)succinimide (932 mg, was 2.76 mmol), Na2CO3(880 mg, 8,29 mmol) in dioxane (15 ml) and N2About (15 ml) was stirred at room temperature for 16 hours. The reaction mixture was diluted Et2O (100 ml) and H2O (100 ml). The organic layer is separated and extracted with aqueous solution of Na2CO3(5%, 3100 ml). The combined aqueous extracts acidified with 10% aqueous citric acid and extracted with EtOAc (3100 ml). These organic extracts are combined, dried (MgSO4), filtered and concentrated under vacuum to obtain tert-butyl N-[(2S)-N-Fm-aspartyl])--N phenylglycinate in the form of a white solid.13With NMR (50 MHz, d6-DMSO): d 28,0, 36,7, 47,0, 50,4, 52,4, 67,0, 67,3, 82,3, 119,9, 125,2, 125,3, 127,1, 127,7, 127,8, 128,8, 130,1, 141,2, 142,8, 143,7, 143,9, 156,1, 167,6, 171,6, 174,5.

Stage 5: Tverdofazno is of resin and disconnection get cyclo-[N-phenylglycine-Gln-sn-(D)-s]-Ls-Sr-NH2.

Experience 22

In this experience and presents the synthesis of 2-(2’-phenylethyl)--N-acetyl-liinamaa and his hydrochlor IGNOU salt:

Step 1: To a mixture of metallic sodium (138 mg, 5,98 mmol) in dry ethanol (16 ml) is added 2-cyano-4-(phenethyl)ethylbutanal (1.0 g, 4.6 mmol) and the mixture was stirred at room temperature for 30 minutes Then add 4-bromo-but-1-ene (0.6 ml, 6 mmol) and the mixture is heated at a temperature of phlegmy for 16 hours. The resulting suspension is cooled to room temperature, concentrated under reduced pressure, diluted with ether (100 ml) and NH4Cl (100 ml saturated aqueous solution). The aqueous layer was separated and extracted with ether (350 ml). The organic layers are combined, dried (MgSO4), filtered and concentrated to obtain a light brown oil. After column chromatography (silica, elution with a mixture of 20% ether/petrol) to obtain ethyl 2-cyano-2-(2’-phenethyl)-Gex-5-ENOAT in the form of a clear, colorless oil.1H NMR (200 MHz, CDCl3): d is 1.35 (t, J=7.0 Hz, 3H), 1,82 at 2.45 (m, 6H), 2,65 (td, J=12,4 Hz and 7.0 Hz, 1H), 2,90 (td, J=12,4 Hz and 7.0 Hz, 1H), 4,24 (q, J=7,0 Hz, 2H), 5,00-5,13 (m, 2H), 5,67-USD 5.76 (m, 1H), 7,15-to 7.35 (m, 5H).

Stage 2: the above Mixture is within 18 hours. This reaction mixture was diluted with ether (100 ml) and water (100 ml) and the phases are separated. The aqueous layer was acidified to about pH 2 with 2 M aqueous solution of Hcl and transferred into a separating funnel containing ether (100 ml). The separated aqueous layer extracted with ether (350 ml). The organic fractions combined, dried (MgSO4), filtered and concentrated under reduced pressure to obtain 2-cyano-2-(2’-phenethyl)-5-hexenoic acid as a viscous, colorless oil. This material is used in the next reaction without further purification. MS (head) m/z 244 (M++1, 55%), 242 (M+-1, 63%).

Stage 3: Diphenylphosphinite (2,75 ml, 12.8 mmol) and triethylamine (1.75 ml, 12.6 mmol) are added to a solution of the above acid (2.6 g, is 10.7 mmol) in toluene (35 ml). This solution is heated at 100C for 1 hour and then added tert-butanol (35 ml). This mixture is heated at 100With in the next 2 hours, cooled to room temperature and concentrate under reduced pressure. The obtained yellow oil diluted with ether (300 ml) and water (300 ml). The organic layer was separated, sequentially washed with citric acid (100 ml of 5% aqueous solution), Panso3(100 ml of 5% aqueous solution) and the saône rivers chromatography (silicon dioxide, elution with a mixture of 2% ethyl acetate/chloroform) to obtain 2-(N-BOC-amino)-2-(2+-phenethyl)-5-hexenenitrile in the form of a colorless oil. MS (head) m/z 316 (M++1, 5%), 313 (M+-1, 2%).13With NMR (50 MHz, CDCl3): d 28,4, 30,5, 36,3, 38,9, 54,9, 116,3, 119,7, 126,6, 128,4, 128,8, 136,3, 140,1, 153,5.

Stage 4: NaOH (9,2 ml, 1.0 M) and H2O2(38 ml 30% (V/o) aqueous solution) are added to a solution of the above nitrile (523 mg, of 1.93 mmol) in ethanol (20 ml) at 0C. the Reaction mixture was stirred at 0C for 30 min and at room temperature for 18 hours. The ethanol is removed under reduced pressure, the residue diluted with ether (100 ml) and brine (100 ml). The aqueous layer was separated and extracted with ether (420 ml). The organic layers are combined, dried (MgSO4), filtered and concentrated to obtain 2-(N-BOC-amino)-2-(2’-phenethyl)-5-hexanamide in the form of colorless adhesive foam. This material is used in the next reaction without further purification R 0,3 (elution with a mixture of 30% ethyl acetate/petrol). MS (head) m/z 333 M++1, 5%), 233 (100%).

Stage 5: To a solution of the above amide (480 mg, 1.44 mmol) in dichloromethane (5 ml) is added triperoxonane acid (2 ml), and the mixture is stirred at room temperature in the brown butter. This material is used in the next reaction without further purification. MS (head) m/z 233 (M++1, 100%).

Stage 6: Acetic anhydride (2.5 ml) are added to a solution of the above amine (335 mg, 1.44 mmol) in pyridine (2.5 ml) and stirred at room temperature for 21 hours. The obtained red-brown reaction mixture is concentrated under reduced pressure. After column chromatography (silica, elution with a mixture of 80% ethyl acetate/petrol, R 0,36) receive (N-acetyl-amino)-2-(2’-phenethyl)-5-hexanamide foam straw color.13With NMR (50 MHz, CDCl3): d 24,2, 28,3, 30,4, 35,2, 37,8, 64,0, 115,2, 126,1, 128,4, 128,5, 137,4, 141,1, 169,4, 175,3.

Step 7: To a solution of the above olefin (130 mg, 0.47 mmol) in dry THF (2 ml) was added dropwise 9-BBN (4.6 ml, 0.5 M solution in THF, 2,30 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. This mixture is cooled to 0With, and successively added water (0.5 ml), NaOAc (5 ml 5.0 M aqueous solution) and H2O2(5 ml). The resulting mixture was stirred at room temperature for 2 hours and diluted with ethyl acetate (30 ml) and brine (30 ml). The aqueous layer was separated and extracted with ethyl acetate (310 ml). Organic yellow oil. After column chromatography (silica, elution with a mixture of 5% Meon/ethyl acetate, R 0,4) receive 2-(N-acetyl-amino)-2-(2’-phenethyl)-6-hydroxy-hexanamide in the form of a colorless, sticky foam. MS (head) m/z 293 (M++1, 35%), 291 (M+-1, 35%).

Stage 8: Triethylamine (0.1 ml, to 0.72 mmol) and methanesulfonamide (0.05 ml, of 0.65 mmol) are added to a solution of the above alcohol (88 mg, 0.30 mmol) in dichloromethane (2 ml) at 0C. the resulting mixture was stirred at ambient temperature for 19 hours and diluted with ethyl acetate (30 ml) and brine (30 ml). The aqueous layer was separated and extracted with ethyl acetate (310 ml). The organic layers are combined, dried (MgSO4), filtered and concentrated under reduced pressure to obtain 2-(N-acetyl-amino)-2-(2’-phenethyl)-6-methansulfonate-hexanamide as residue yellowish-brown color. The crude product used in the next reaction without further purification. MS (head) m/z 371 (M++1, 45%), 369 (M+-1, 5%).

Step 9: a Solution of the above nelfinavir (110 mg, 0.30 mmol) and sodium azide (54 mg, 0.83 mmol) in dry DMF (2 ml) is heated at a temperature of from 60With up to 65With over 19.5 hours. Orange-okrasheno the rum (30 ml). The aqueous layer was separated and extracted with ethyl acetate (410 ml). The organic fractions combined, dried (MgSO4), filtered and concentrated to obtain 2-(N-acetylamino)-2-(2’-phenethyl)-6-azido-hexanamide in the form of oil, yellowish-brown. This material is used in the next reaction without further purification.1H NMR (200 MHz, CDCl3): d 1,20-of 1.78 (m, 6H), of 1.92 (s, 3H), 2,20-to 3.02 (m, 1H), 3,12-3,30 (m, 2H), to 5.57 (s, 1H), 5,90 (s, 1H), 6,72 (s, 1H),? 7.04 baby mortality-7,30 (m, 5H).

Stage 10: the Suspension of the above azide (95 mg, 0.30 mmol) and 10% Pd on C (to 18.4 mg) in methanol (2 ml) hydronaut at room temperature and atmospheric pressure for 21 hours. The black suspension is filtered through a small layer of silicon dioxide-celite, which is washed with several portions of methanol (approximately 30 ml). After concentration of the filtrate receive light yellowish-brown oil. After column chromatography (silica, elution with a mixture of 10% triethylamine/methanol R 0,22) get amide 2-(2’-phenylethyl)--N-acetyl-lysine in the form of a colorless transparent oil. MS (head) m/z 292 (M++1, 100%) 290 (M+-1, 30%).1H NMR (200 MHz, d4-MeOD): d 1,10-to 1.60 (m, 4H), 1,73-1,90 (m, 1H), 1,95 (s, 3H), of 1.95 to 2.35 (m, 2H), 2.40 a is 2.80 (m, 5H), 7,10-to 7.35 (m, 5H).

Small at 0.5 M aqueous Hcl solution and concentrating the mixture under reduced pressure.

Experience 23

In this experience and presents a synthesis of 4,4’-bis-(3-[(m-carboxyphenoxy)methyl]-2-pyridone):

Step 1: To a solution of 3-formyl-4-iodine-2-methoxypyridine (obtained in accordance with the method of Fang et al., J. Org. Chem., 1994, 59, 6142) (98 mg, and 0.37 mmol) in methanol (4 ml) is added in one portion solid NaBH4when -5With (28 mg, of 0.74 mmol). Thus, there is a vigorous evolution of gas and the yellow reaction solution becomes colorless. The reaction immediately quenched by adding water (2 ml), and methanol is removed under reduced pressure. The resulting residue diluted with ethyl acetate (20 ml) and water (20 ml). The aqueous layer was separated and extracted with ethyl acetate (3x10 ml). The organic fractions combined, dried (MgSO4), filtered and concentrated to obtain 3-(hydroxymethyl)-4-iodine-2-methoxypyridine in the form of a colorless crystalline solid. This material is used in the next reaction without further purification. R 0,4 (elution with a mixture of 30% ethyl acetate/petrol). MS (head) m/z 266 (M++1, 100%).1H NMR (200 MHz, CDCl3): d 3,98 (s, 3H), 4,80 (s, 2H), 7,34 (d, J=4.0 Hz, 1H), of 7.70 (d, J=4.0 Hz, 1H).

Stage 2: Methanesulfonyl chloride (0.5 ml, 6.4 mmol) is added dropwise to a solution of the above alcohol (373 mg, of 1.41 mmol) and trial ambient temperature for 15 hours and diluted with ethyl acetate (150 ml) and brine (150 ml). The aqueous layer was separated and extracted with ethyl acetate (350 ml). The organic fractions combined, dried (MgSO4), filtered and concentrated under reduced pressure to obtain 3-(chloromethyl)-4-iodine-2-methoxypyridine in the form of a light yellow-brown crystalline solid. This material is used in the next stage without further purification. MS (head) m/z 284 (M++1, 100%).1H NMR (200 MHz, CDCl3): d of 3.95 (s, 3H) and 4.65 (s, 2H), 7,28 (d, J=4.0 Hz, 1H), 7,65 (d, J=4.0 Hz, 1H).

Stage 3: Sodium salt of methyl-3-hydroxybenzoate (372 mg, 2.14 mmol) is added in one portion to a solution of the above chloride (399 mg, of 1.41 mmol) in dry DMF (7 ml). The orange-colored reaction mixture is stirred at room temperature for 18 hours and diluted with ethyl acetate (150 ml) and water (150 ml). The aqueous layer was separated and extracted with ethyl acetate (330 ml). The organic layers are combined, dried (MgSO4), filtered and concentrated to obtain a brown oil. After column chromatography of this oil (silica, elution with a mixture of 30% ether/petrol, R 0,35) receive a 4-iodine-2-methoxy-3-{[(m-carbomethoxy)phenoxy]methyl}-pyridine as a colourless oil. MS (head) m/z 400 (M++1, 40%).1H NMR (20 g, 1.25 mmol), PD(h3)4(141 mg, 0.13 mmol), K2CO3(518 mg, 3,76 mmol), tibarenians ester (159 mg, to 0.63 mmol) in DMF (7,6 ml) is heated at 80With, protecting from light, for up to 16 hours. The dark brown reaction mixture is cooled to room temperature and diluted with ethyl acetate (150 ml) and water (150 ml). The aqueous layer was separated and extracted with ethyl acetate (325 ml). The organic layers are combined, dried (MgSO4), filtered and concentrated under reduced pressure to obtain brown oil. After column chromatography of this oil (silica, elution with a mixture of 50% ethyl acetate/petrol, R 5,57) get 4,4’-bis-2-methoxy-3-{[(m-carbomethoxy)phenoxy]methyl}-pyridine in the form of foam. MS (head) m/z 545 (M++1, 100%).

Stage 5: a Solution of the above dimeric diapir (277 mg, 0.51 mmol) LiOH (10 ml, 1.0 M) and THF (10 ml) was stirred at room temperature for 18 hours. Then the crude reaction mixture was diluted with ether (75 ml) and the phases are separated. The aqueous layer was acidified to pH 2 2.0 M aqueous solution of Hcl and then extracted with ethyl acetate (450 ml). The organic fractions combined, dried (MgSO4), filtered and concentrated to obtain 4 is changed to the next stage without further purification. MS (head) m/z 517 (M++1, 100%), 515 (M+-1, 100%).

Stage 6: the Hydrolysis of the above-mentioned methoxy-pyridine get 4,4’-bis-{3-[(m-carboxyphenoxy)methyl]-2-pyridone}.

Experience 24

In this experiment presents the activity modulation of Fc receptor-Tripeptide and Hexapeptide.

Obtaining peptide.

To obtain the acetylated Tripeptide sequence GKS and Hexapeptide sequence FQNGK-S used method of solid-phase peptide synthesis (CFPS). See, for example, Merrifield, J. Am. Chem. Soc., 1963, 85, 2419, and Merrifield et al., Anal. Chem., 1966, 38, 1905. These peptides were synthesized using synergistic peptide synthesizer model A. Assembly of peptides based on the chemical properties of Fmoc (Carpino et al., J. Org. Chem. 1972, 37, 3404), using as source material emitirovannykh resins with C-terminal ends. After the Assembly of the peptides were obtained active ester, which interacted with the peptide with the formation of the acetylated N-Terminus.

Then apply standard operations disconnection using TFU (compatible with Fmoc) and the product purified by high-performance liquid chromatography with reversed phase (HPLC-PF). (See for example, Mant, C. T. and Hodges, R. S. eds, 1991, "High-Performance Liquid Chromatography of Peptides and Proteins: Separation, Analysis and Confirmation is/60% SN3SP/39,9% N2O. Stationary phase is a preparative C8 column Brownlee Column. The final product was subjected to mass spectral analysis confirmed the identity and purity of more than 95% for both peptides.

Analyses linking FcgRIIa in the presence of hexa - or tripeptides

Tests for interaction between the derivative FcgRIIa baculovirus and peptide (Tripeptide: GKS, Hexapeptide: FQNGKS) is conducted using a biosensor BIAcore 2000 (Pharmacia Biotech, Uppsala, Sweden) at 22 EC in Hepes buffer saline (NBR: 10 mm Hepes, (pH 7.4), 150 mm NaCl, 3.4 mm etc, 0.005% surfactant P20 (Pharmacia). Monomeric IgG1, IgG3 and IgE (50 mg/ml) human covalently associated with the surface carboxymethylamino dextran of sensor chip CM-5 (BIAcore, Uppsala, Sweden) using the Protocol binding with the amino group (BIAcore, Uppsala, Sweden). The channel, which are not associated Ig chemically treated using the Protocol binding. FcgRIIa in a certain concentration (50 mg/ml, a concentration that provides 50% binding) is mixed with peptides at various concentrations (see Fig. 10 and 11), for 1 hour at 22 EU before this mixture is applied to the surface of sensor chip for 1 min with a speed of 20 ml/min, with subsequent 3-minute phase dissociation. After measurements cobsy response for each concentration of peptide and put on a graph against the concentration of peptide. Responses from non-specific binding (channel IgE) is subtracted from feedback from binding to IgG1 or IgG3.

Results

Using the sensitivity of surface plasmon resonance (SPR), make the determination of the binding of soluble FcgRIIa with IgG1 and IgG3 in the presence of the Hexapeptide (FQNGKS) or Tripeptide (GKS). In the presence of Hexapeptide binding soluble FcgRIIa with immobilized IgG1 was increased four times and 1.6 times when interacting with IgG3 (Fig. 10). However, the interaction of soluble FcgRIIa with IgG1 or IgG3 in the presence of Tripeptide inhibited by similar concentrations of this peptide (0-4 mg/ml, Fig. 11).

Experience 25

In this experiment presents the activity of inhibition of platelet aggregation for some compounds of the present invention. In General, the method includes adding a connection to a mixture of platelets and gamma-globulin, the aggregate result of heat treatment (HAGG). Out of touch with any of theories is that this method reflects the ability of compounds to inhibit the formation of aggregates of platelets, as well as its ability to destroy the aggregates of platelets, which were formed before adding this connection.

Platelets Express FcgRIIa gamma receptors, belonging to one who completed their aggregation. Using the analysis, which is specially designed for measurement of platelet aggregation was performed measuring the ability of compounds to inhibit the activation of platelets.

Materials and methods

Platelets secrete as follows: 30 ml of fresh whole blood collected in selected tubes with citrate buffer and centrifuged them at 1000 rpm for ten minutes. Plasma enriched with platelets, separated and centrifuged at 2000 rpm for five minutes in four test tubes. Supernatant removed and the platelets carefully resuspended in 2 ml of Tyrodes buffer per tube (137 mm NaCl, 2.7 mm KCl, 0.36 mm NaH2PO4, 0.1% dextrose, 30 mm sodium citrate, 1.0 mm MgCl2·6H2O, pH 6.5) and centrifuged again at 2000 rpm for five minutes. Supernatant again removed and the platelets resuspended in 0.5 ml per tube Hepes containing Tyrodes buffer (137 mm NaCl, 2.7 mm KCl, 0.36 mm NaH2PO4, 0.1% dextrose, 5 mm Hepes, 2 mm CaCl2, 1.0 mm MgCl2·6H2O, pH to 7.35). The platelet count is determined using a Hematology analyzer (Coulter) and adjusted to a concentration of approximately 100105platelets/ml using Hepes containing Tyrodes buffer.

For each experiment on the AOI processing ("HAGG", 200 mg/ml) or collagen (2 mg/ml) incubated with 50 ml of phosphate buffer saline ("FBI": 3.5 mm NaH2PO4, 150 mm NaCl) or BRI connection (5 mg/ml FBI) for 60 minutes at room temperature. Then make an analysis using the two-celled aggregometer at 37As follows: placed in a glass cuvette holders and pre-heated to 37With and add 400 ml of a suspension of platelets. After achieving stability reference line 100 ml compounds GG:FBI, HAGG:BRI or connection collagen:the FBI, collagen:BRI added to a suspension of platelets. Subsequent platelet aggregation register within 15 minutes or as long as the aggregation is completed. The rate of aggregation is determined by measuring the gradient and the slope of the curve aggregation.

Results

Was determined the ability of the compounds (BRI6855, BRI6803, BRI6813, BRI6864, BRI6856, BRI6868, BRI7002) to inhibit HAGG-induced FcgRIIa-dependent aggregation. The rate of platelet aggregation, measured as the ratio of the increment of transparency (u) with time (x), see, for example, Fig. 12 and 13, in the presence of compounds BRI6855, BRI6803, BRI6813, BRI6864 and BRI6856 reduced compared to the speed achieved when using agonist Fcg02 not demonstrate ability to significantly inhibit the rate of platelet activation. Table 1. Connection BRI6855 and BRI6803 lower HAGG-induced platelet aggregation, but does not inhibit significantly platelet aggregation induced by collagen. This indicates that the action BRI6855 and BRI6803 it is specific to the HAGG.

Experience 26

In this experiment presents the activity of inhibition of platelet aggregation for some compounds of the present invention. In General, the method includes adding a connection to a mixture of platelets and GATO. Out of touch with any of theories is that in contrast to the Experience of 25, this method only displays the ability of compounds to inhibit the formation of aggregates of platelets

Materials and methods

For separation of platelets and the number of platelets was used experimental technique Experience 25.

In contrast to the Experience of 25, the analysis on platelet aggregation carried out by adding 50 ml of the FBI or connection BPI to a suspension of platelets. After about one minute, to a suspension of platelets add 50 ml of agonist (GATO, collagen or ADP). Subsequent platelet aggregation register for 10-15 minutes or up until the aggregation is completed. The rate of aggregation is determined by measuring the gradient and the slope of the cu-dependent aggregation. The rate of platelet aggregation, measured as the ratio of the increment of transparency (u) with time (x), see for example, Fig. 14, in the presence of titrated amounts of compounds BRI6728 reduced compared to the speed achieved when using agonist FcgRIIa, and gamma-globulin, the aggregate result of heat treatment (100%), see Fig. 14. The results of platelet aggregation with other compounds presented in Table 2.

Specialists in this field it is clear that the preferred embodiment of the present invention allows for numerous changes and modifications and that such changes may be made without leaving the scope of the present invention. Thus, it is assumed that the appended claims cover all such equivalent modifications that meet the spirit and scope of the present invention.

Claims

1. Pharmaceutical composition comprising

(a) compound that modulates the activity of Fc-receptor selected from the group comprising an aromatic compound of the formula

heteroaromatic compound of the formula

and amino acid-derived formulas

or their salts,

where each of W1and W2independently represents a CO2R15C(=NH)NH(OH), SO3R15C(=NH)NH2, OPO(OR15)2With(=O)CF3or PO(OR15)2;

each AG1, AG2, AG4and AG5independently represents a C6-C20aryl or C1-C20heteroaryl;

AG3represents a C1-C20heteroaryl;

each of X1X2X3X4X5X6X7and X8independently represents a methylene, O, S or NR16;

each of R1and R2independently represents a bond, C1-C6alkylene or halogenated C1-C6alkylen;

each of R3and R4independently represent halogen, -Z1or C1-C6alkyl;

each of X9, Y1and Z1independently represents OR17, SR17or NR17R18;

each of R5and R6independently represents an amino acid residue side chain or a group of the formula-R19-W3;

each of R8, R9and R11independently n

R7is a OR20, NR21R22or about 1 to 10 amino acids;

R10represents a C1-C6alkylen;

R12represents a C1-C6alkyl or C6-C20aralkyl;

W3represents C(=O)X10;

X10is a OR23or NR24R25

each of R13, R15, R17, R18, R20, R21, R23and R24independently represents hydrogen or C1-C6alkyl;

R16represents H, C6-C20aryl or a protective group amide;

R19represents a C1-C6alkylen;

each of R22and R25independently represents H, C1-C6alkyl or a protective group amide;

R14represents H, C1-C6alkyl or a protective group of the amine;

L represents a linking group comprising from 1 to 20 atoms; and

each of m and n independently represents an integer from 0 to 2,

and (b) a pharmaceutically acceptable carrier.

2. The composition according to p. 1, where the specified connection has the formula

3. The composition according to p. 2, where the aforementioned compound has the formula

6. The composition according to p. 5, where R1and R2are the connection.

7. The composition according to p. 6, where L1represents-CH2CH2.

8. The composition according to p. 6, where L1represents-CH2O-.

9. The composition according to p. 6, where L1represents-SN=SNA(=O)-.

10. The composition according to p. 6, where L1represents-CH2CH2CH(OH)-.

11. The composition according to p. 6, where L1represents-CH=CH-.

12. The composition according to p. 6, where L1represents a-CH(OH)CH(OH)-.

13. The composition according to p. 12, where the stereochemical arrangement of the hydroxyl groups is an (S,S).

14. The composition according to p. 6, where L1represents-CH2N(R26)CH2- where R26represents H, C1-C6alkyl or a protective group of the amine.

15. The composition according to p. 14, where R26represents-CH2CO2N.

16. The composition according to p. 6, where L1represents a group of the formula

17. The composition according to p. 5, where R1and R2represent-CH2.

18. The composition according to p. 17, where L1represents ethylene.

19. The composition according to p. 17, where L1represents-CH=CH-.

20. The composition according to p. 5, where R1represents a methylene, R2p is astavliaut a PO(OR15)2and R1and R2are the connection.

22. The composition according to p. 21, where L1represents ethylene.

23. The composition according to p. 22, where R15represents ethyl.

24. The composition according to p. 22, where R15represents N.

25. The composition according to p. 21, where L1represents a group of the formula

where each of R27and R28independently represent H, C1-C6alkyl, C6-C10aralkyl or a protective group.

26. The composition according to p. 25, where each of R27and R28independently represents a 4-methoxybenzyl or N.

27. The composition according to p. 6, where L1represents a group of the formula

where each of R27and R28independently represents H, C1-C6alkyl, C6-C10aralkyl or a protective group.

28. The composition according to p. 27, where each of R27and R28independently represents a 4-methoxybenzyl or N.

29. The composition according to p. 4, where L1represents-CH=CH-, W1and W2represent C(=NH)NH(OH) and R1and R2are the connection.

30. The composition according to p. 4, where L1represents-CH2O-, W1and W2represent C(=O) is-CH2CH2-, R1and W1together form -(CH2)aCH(other29)CO2H, where a = 0, 1, 2, and R29represents H, C1-C6alkyl or a protective group of the amine.

32. The composition according to p. 31, where R2and W2together form -(CH2)bCH(other30)CO2H, where b = 0, 1, 2, and R30represents H, C1-C6alkyl or a protective group of the amine.

33. The composition according to p. 32, where a and b = 1 and R29and R30represent-C(=O)CH3.

34. The composition according to p. 2, where the aforementioned compound has the formula

35. The composition according to p. 1, where the specified connection has the formula

36. The composition according to p. 35, where the aforementioned compound has the formula

37. The composition according to p. 36, where Y1represents-NH2.

38. The composition according to p. 37, where m and n = 0.

39. The composition according to p. 1, where the specified connection has the formula

where X1X2X3X4represent NR16.

40. The composition according to p. 39, where the aforementioned compound has the formula

41. The composition according to p. 1, where the specified connection has the formula

on p. 42, where R11represents the balance of the side chain of lysine, R12represents a 2’-phenylethyl and R14represents-C(=O)CH3.

44. Method of inhibiting the binding of the Fc receptor and immunoglobulin patient, including the introduction of a specified patient pharmaceutically effective amount of a compound selected from the group comprising an aromatic compound of the formula

heteroaromatic compound of the formula

the cyclic compound of the formula

bicyclic compound of the formula

and amino acid-derived formulas

or their salts,

where each of W1and W2independently represents a CO2R15C(=NH)NH(OH), SO3R15C(=NH)NH2, OPO(OR15)2With(=O)CF3or PO(OR15)2;

each Ar1, Ar2, Ar4and Ar5independently represents a C6-C20aryl or C1-C20heteroaryl;

Ar3represents a C1-C20heteroaryl;

each of X1X2X3X4X5X6X7and X8independently researched the th link, C1-C6alkylene or halogenated C1-C6alkylen;

each of R3and R4independently represent halogen, -Z1or C1-C6alkyl;

each of X9, Y1and Z1independently represents OR17, SR17or NR17R18;

each of R5and R6independently represents an amino acid residue side chain or a group of the formula-R19-W3;

each of R8, R9and R11independently represents an amino acid residue side chain, provided that R11does not represent N or CH3;

R7is a OR20, NR21R22or about 1 to 10 amino acids;

R10represents a C1-C6alkylen;

R12represents a C1-C6alkyl or C6-C20aralkyl;

W3represents C(=O)X10;

X10is a OR23or NR24R25;

each of R13, R15, R17, R18, R20, R21, R23and R24independently represents hydrogen or C1-C6alkyl;

R16represents H, C6-C20aryl or a protective group amide;

R191-C6alkyl or a protective group amide;

R14represents H, C1-C6alkyl or a protective group of the amine;

L represents a linking group comprising from 1 to 20 atoms;

each m and n independently represents an integer from 0 to 2.

45. The method according to p. 44, wherein the specified Fc-receptor is selected from the group comprising FcaR, FcgR, FcgR, and mixtures thereof.

46. The method according to p. 45, wherein the specified Fc-receptor is selected from the group comprising FcgRIIa, FcgRIIb, FcgRIIc and mixtures thereof.

47. The method according to p. 44, which decreases IgG-mediated tissue damage in the specified patient.

48. The method according to p. 44, wherein the method reduces inflammation in the specified patient.

49. The method according to p. 44, in which this method is applied for the treatment of autoimmune diseases.

50. The method according to p. 44, which is used for the treatment of diseases, which are produced aggregates of antibodies or which are produced by immune complexes resulting from the interaction of antibodies with internal or external antigen.

51. The method according to p. 50, wherein the disease is selected from the group including immune complex diseases, autoimmune diseases, infectious ill the emitting rheumatoid arthritis, erythematous systemic lupus, immune thrombocytopenia, neutropenia, and hemolytic anemia.

53. The method according to p. 51, wherein the specified vasculitis is selected from the group comprising polyarthrite thickening and systemic vasculitis.

54. The method according to p. 44, which is used for the treatment of xenograft rejection.

55. The method according to p. 51, in which these infectious diseases are selected from the group comprising hemorrhagic fever caused by Dengue virus, and a viral infection measles.

56. The method according to p. 44, which decreases IgE-mediated reaction in the specified patient.

57. The method according to p. 44, wherein the specified connection has the formula

58. The method according to p. 57, wherein the specified connection has the formula

59. The method according to p. 58, in which m and n = 0.

60. The method according to p. 59, wherein W1and W2represent CO2N.

61. The method according to p. 60, in which R1and R2are the connection.

62. The method according to p. 61, in which L1represents-CH2CH2.

63. The method according to p. 61, in which L1represents-CH2O-.

64. The method according to p. 61, in which L1represents-CH=CHC(=O)-.

65. Str is>represents-CH=CH-.

67. The method according to p. 61, in which L1represents a-CH(OH)CH(OH)-.

68. The method according to p. 67, in which the stereochemical arrangement of the hydroxyl groups is an (S,S).

69. The method according to p. 61, in which L1represents-CH2N(R26)CH2- where R26represents H, C1-C6alkyl or a protective group of the amine.

70. The method according to p. 69, wherein R26represents-CH2CO2N.

71. The method according to p. 61, in which L1represents a group of the formula

72. The method according to p. 60, in which R1and R2represent-CH2.

73. The method according to p. 72, in which L1represents ethylene.

74. The method according to p. 72, in which L1represents-CH=CH-.

75. The method according to p. 60, in which R1represents a methylene, R2is a bond and L1represents ethylene.

76. The method according to p. 59, wherein W1and W2are PO(OR15)2and R1and R2are the connection.

77. The method according to p. 76, wherein L1represents ethylene.

78. The method according to p. 77, wherein R15represents ethyl.

79. The method according to p. 77, when the crystals

where each of R27and R28independently represent H, C1-C6alkyl, C6-C10aralkyl or a protective group.

81. The method according to p. 80, in which each of R27and R28independently represents a 4-methoxybenzyl or N.

82. The method according to p. 61, in which L1represents a group of the formula

where each of R27and R28independently represents H, C1-C6alkyl, C6-C10aralkyl or a protective group.

83. The method according to p. 82, wherein each of R27and R28independently represents a 4-methoxybenzyl or N.

84. The method according to p. 59, in which L1represents-CH=CH-, W1and W2represent C(=NH)NH(OH) and R1and R2are the connection.

85. The method according to p. 59, in which L1represents-CH2O-, W1and W2represent C(=O)CF3and R1and R2are the connection.

86. The method according to p. 59, in which L1represents-CH2CH2-, R1and W1together form -(CH2)aCH(other29)CO2H, where a = 0, 1, 2, and R29represents H, C1-C6alkyl, or the2H, where b = 0, 1, 2, and R30represents H, C1-C6alkyl or a protective group of the amine.

88. The method according to p. 87, in which a and b = 1 and R29and R30represent-C(=O)CH3.

89. The method according to p. 87, wherein the specified connection has the formula

90. The method according to p. 44, wherein the specified connection has the formula

91. The method according to p. 90, wherein the specified connection has the formula

92. The method according to p. 91, wherein Y1represents-NH2.

93. The method according to p. 92, in which m and n = 0.

94. The method according to p. 44, wherein the specified connection has the formula

where X1X2X3X4represent NR16.

95. The method according to p. 94, wherein the specified connection has the formula

96. The method according to p. 44, wherein the specified connection has the formula

97. The method according to p. 44, wherein the specified connection has the formula

98. The method according to p. 97, wherein R11represents the balance of the side chain of lysine, R12represents a 2’-phenylethyl and R14predstavi-70, 72-87, 90-93;

11.08.1999 on PP.1-98.

 

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