Novel polycyclic compounds


FIELD: chemistry.

SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

 

The present invention relates to compounds, compositions and methods for modulation of in vitro and in vivo processes, mediated by adhesion molecules of the cells. Described low-molecular compounds include dimethoxy - and dihydroxyphenyl subunit and effectively modulate the functions mediated by adhesion molecules of the cells.

Mediated by adhesion molecules cells are part of a complex cascade leading to migration of circulating white blood cells (leukocytes) from the bloodstream into the surrounding tissue (transmigrate). Physiologically, transmigrated leukocytes is critical for homeostasis and immunological regulation or control in living organisms, including humans. Lymphocytes, for example, constrictive direct the blood flow in the lymphatic tissue to control harmful antigens. However, in pathological cases, such as local or systemic inflammation and/or damage to the vascular system, the regulation of this fundamental process is broken, at least partially due to the increased surface expression of E - and P-selectin. Therefore, excessive transmigrated leukocytes leads to abnormal cell infiltration with subsequent tissue damage in some clinically relevant conditions. Pathological conditions, such as acute damages is the light (ALI), acute respiratory distress syndrome (ARDS), asthma (asthma), chronic obstructive pulmonary disease (COPD), psoriasis, rheumatoid arthritis, and sepsis, all associated with tissue inflammation, induced and supported pathologically activated leukocytes, infiltrometer appropriate fabric. In addition, infiltration exagirowydup leukocytes contributes to the pathogenesis of ischemic-reperfusion injury (IRI)associated with organ transplantation, extracorporeal circulation or subcutaneous intraluminal angioplasty.

For transmigration leukocytes need to contact with the wall of the vascular endothelium to diffuse through the cell membrane of the capillaries into the surrounding tissue. Therefore, leukocytes must roll on the cell membrane and then to stick to the cell membrane of the endothelium (the initial process prokachivanija or "binding"). This is the main event in transmigration is mediated by adhesion molecules cells family of selectins. In addition to direct binding to endothelial leukocytes may adhere to other cells, particles leukocytes, platelets, or formed from platelet particles that have stuck to the endothelium.

Family selectieve adhesion molecules consists of three structurally related calcium-dependent, tie the state of carbohydrates proteins on the cell surface, selectins E, P and L. E-selectin is expressed only on the inflamed endothelium, P-selectin is expressed on inflamed endothelium, and platelets and L-selectin is expressed on leukocytes. The selectins consist of aminoanisole pectinophora domain, domain, similar to epidermal growth factor (EGF), variable number of iterations related to the receptors of complement, a hydrophobic transmembrane domain and C-terminal cytoplasmic domain. It is assumed that the binding interaction, leading to leukocyte adhesion, mediated by contacts pectinophora domain of selectins and various carbohydrate ligands on the surface of leukocytes. All three selectin can bind with low affinity to carbohydrate sialyl-Lewisx(sLex), picatinney part present on the surface of most leukocytes. Structurally related glycosamino part, sialyl-Lewisa(sLea), predominantly found on the surface of cancer cells [K. Okazaki et al., J Surg. Res., 1998, 78(1). 78-84; R.P. McEver et al., Glycoconjugate Journal, 1997, 14(5), 585-591]. In the case of P-selectin described glycoprotein ligand with apparent high affinity [R.P. McEver, R.D. Cummings, J. Clin. Invest., 1997, 100, 485-492], the so-called glycoprotein ligand-1 P-selectin (PSGL-1), which promotes the binding of selectin with high affinity via its sLexpart and through parts of its peptide components, in particular residues sulfated tyrosine [R.P. McEver, Ernst Schering Res. Found. Workshop, 2004, 44, 137-147]. PSGL-I is one of the most important ligands of selectins, bind with highest affinity to P-selectin, but it is also associated with E - and L-selectin [G. Constantin; Drug News Perspect; 2004; 17(9); 579-586]. He is homodimers sialomucins, predominantly expressed on leukocytes.

In inflammatory diseases of the misaligned transmigrate at least partially mediated by increased expression of E - and P-selectin on the cell surface. In contrast to their low basal expression expression of E - and P-selectin during inflammation is regulated by increasing the way that leads to a significant attraction of leukocytes into inflamed tissue. Although infection control is required mediated by selectin adhesion of cells, there are various situations in which such adhesion of cells is undesirable or excessive and causes serious tissue damage instead of healing. In the case of many acute and chronic inflammatory disorders [e.g., asthma, chronic obstructive pulmonary disease (COPD), psoriasis, etc.] shows the relationship between the infiltration of activated leukocytes into the tissue simultaneously with the visible surface to the solution expression in tissues relevant adhesion molecules, specifically, E - and P-selectin [Muller et al., J. Pathol., 2002, 198(2), 270-275; Di Stefano et al., Am. J. Respir. Crit. Care. Med., 1994, 149(3) 803-810; Terajima et al., Arch. Dermatol. Res., 1998, 290, 246-252].

Infiltration of leukocytes may also play a role in the symptoms of inflammation at the time of transplantation and transplant rejection. In addition, the process of blood coagulation is additionally stimulated by the binding of leukocyte-leukocyte and leukocyte-platelet, which occurs because leukocytes have both L-selectin and its corresponding ligand PSGL-1, and therefore, they can communicate with each other via PSGL-1 and can also be contacted with the platelets, which contain P-selectin.

Therefore, modulation mediated by the selectin adhesion of cells and other mediated by selectin functions, such as activation of leukocytes, provides a promising opportunity to prevent the cascade of inflammation and stop it at a very early stage. Which selectin antagonists of low molecular weight compounds should modulate all three selectin at the same time as antagonists at the pan-selectin, in order to overcome the differences between these selectins [M. Sperandio et al., Vascular Disease Prevention, 2004, 1, 185-195].

In addition to sLex/sLeanatural, having a high affinity ligand PSGL-1 is another matrix structure for the development of low molecular weight antagonists of selectins. Compared sLe x/sLeaPSGL-1 shows high affinity for all three selectins. Therefore, to search for and identify new molecular drugs that compete with PSGL-1 and similar PSGL-1 ligands, a promising strategy is to develop a new class of effective antagonists pan-selectin for the treatment of inflammatory disorders. The selectin antagonists can be developed using selectins, and with the use of a ligand, such PSGL-1 as a matrix structure, since it is assumed that they modulate binding between selectins and PSGL-1 or other ligands with the same binder.

New low-molecular-weight antagonists of selectins must meet certain requirements in order to be such medicines and have potential oral bioavailability. The term similarity medicinal product described in the literature [Lipinski; Adv. Drug Dev. Rev., 1997, 23, 3-25]. It is assumed that, in addition to other molecular properties, passively transported molecules have an average relative molecular weight less than 500, to be like a drug. According to these rules usually joined with a relative molecular mass less than 500 or a little above 500 is considered a low-molecular compounds. It is unlikely that the connections with a relative molecular mass above 500 are orally bioavailable. The presence of high polarity carbohydrate parts or peptide component is also not consistent with the concept of similarity medicines [H. Ulbrich et al., Trends Pharmacol. Sci, 2003, 24(12), 640-647; D. Slee et al., J. Med. Chem., 2001, 44, 2094-2107]. The same is the inability to develop drugs based on antibodies, because they are the polypeptides and, therefore, oral administration of them is problematic. In addition, the required connections must be stable during passage through the gastrointestinal tract, so that they could be assimilated/absorbed later by the cells of the small intestine. This is not the case for most glycoside molecules and peptide structures.

Conducted various studies to develop low molecular weight compounds with modulating action mediated by selectins processes. These compounds include disalicylate and C-glycosides based disalicylate [WO 99/29706], benzylaminocarbonyl acid [WO 03/097658], diglycolamine 1,2-diols [WO 97/01569], substituted 5-membered heterocycles [WO 00/33836], mannopyranoside acid [EP 0758243 B1], based connection piperazine (US V], peptides derived Gallic acid [WO 2004/018502], derivatives of Gallic acid [C.C.M. Appeldoorn et al., Circulation 2005, 111, 106-112; EP 1481669A1] and Hinn acid [N. Kaia et al., J. Med. Chem. 2005, 48, 4346-4357]. However, none of these antagonizers the selectins compounds is still not successful clinical trials [S.J. Romano, Treat. Respir Med 2005, 4(2), 85-94; M. P. Schön, Therapeutics and Clinical Risk Management, 2005, 1(3), 201-208]. This is a result of the fact that many of these structures were developed based on the matrix sLexwith low efficiency. Perhaps that is why sLex-imitating patterns find low efficiency. Other compounds exhibit specificity against different members of the family of selectins, but showing the antagonism only for the selected selectins may not show antagonism to other selectins [M.P. Schön, Therapeutics and Clinical Risk Management, 2005, 1(3), 201-208]. In addition, most of the compounds developed to date, have high molecular weight and often contain carbohydrates and/or peptides, which gives them a tendency to degradation and modification under the action of peptidases and/or field of glycosidase inhibition. Carbohydrate structures have the additional disadvantages, such as high degree of chirality, anominity and low probability of migrating through of lipid bilayers. These shortcomings are known for containing peptides compounds. Some other compounds designed to create antagonism to mediated by selectins processes contain patterns pyragollole and catechin. This page is ktory are prone to oxidation [Kumamoto M. et al., Biosci. Biotechnol. Biochem., 2001, 65(1), 126-132], which complicates the pharmaceutical development of these compounds. In addition, it is known that compounds with structures pyragollole, such as Gallic acid, are cytotoxic [E. Sergediene et al., FEBS Letters, 1999, 462, 392-396] and induce apoptosis [K. Satoh et al., Anticancer Research, 1997, 17, 2487-2490; N. Sakaguchi et al., Biochemical Pharmacology, 1998, 55, 1973-1981]. The main connection of the antagonists of the selectins is bimosiamose [S.J. Romano, Treat. Respir Med 2005, 4(2), 85-94]. Currently bimosiamose [D. Bock et al., New Drugs, 2003, D04, 28, p.28; EP 0840606 Bl] is the most advanced compound in clinical trials. Recent studies confirm the hypothesis that bimosiamose can be seen as a mimetic PSGL-1 [E. Aydt, G. Wolff; Pathobiology; 2002-2003; 70; 297-301]. This distinguishes bimosiamose from other antagonists selectins. However, it is a high-molecular compound and carbohydrate structure. Apparently, the antagonist pan-selectin bimosiamose no oral bioavailability. Some observations indicate that bimosiamose exhibits good affinity for P-selectin and moderate affinity for the E - and L-selectin.

There is an urgent medical need for new, very potent pan-selectieve the antagonists that modulate mediated by selectin function, for example selecteddevice adhesion CL is current, and in developing ways of using these compounds for modulation States associated with the interaction of the selectin-ligand. Most of the available anti-inflammatory pharmaceutical drugs that are available on the market include mainly corticosteroids or NSAIDs (non-steroidal anti-inflammatory drug)that has several serious negative/adverse action and having as a target the different stages of the inflammatory cascade. In contrast modulation function selectin is a therapeutic concept, interfere with the inflammatory cascade at a very early stage. Almost all promising antagonists selectins still were not selling drugs, mainly because of low efficiency and/or high molecular weight, which causes problems in the system of absorption-distribution-metabolism-excretion (ADME) and thus in oral bioavailability required for treatment of the majority of inflammatory disorders like rheumatoid arthritis, septic shock, atherosclerosis, damage during reperfusion, and many others.

The objective of the invention is the provision of new low molecular weight compounds, especially deglycosylation/neglecting and ones connections, which is osobni efficiently create antagonism mediated by selectins processes and which have less negative side effects at the time of their application, than compounds of the prior art.

Unlike most sLeX-mimic compounds developed in this area, the compounds of this invention are not susceptible to the action field of glycosidase inhibition or peptidases. Most of selectin antagonists, developed so far, structurally and biologically based on the properties sLexor sLea. Therefore, these compounds obtained showed low biological activity that is similar to their matrix structures. This invention, however, provides a new, potent, low molecular weight and similar medicines pan-selective antagonists, which is invented on the basis of biological tests in vitro, simulating PSGL-1 and similar PSGL-1 ligand or any ligands with sLexor sLeaand thyroidzoloftyi motifs [N.V. Bovin; Biochem Soc Symp.; 2002; (69): 143-60. N.V. Bovin; Glycoconj. J; 1998; 15(5); 431-46. T.V. Pochechueva et al.; Bioorg Med Chem Lett; 2003; 13(10); 1709-12. G. Weitz-Schmidt et al.; Anal. Biochem.; 1996; 238; 184-190].

The present invention provides pharmaceutical compositions comprising at least one compound having the General structure of formula (Ia)or (Ib)or (IIa)or (IIb), and pharmaceutically acceptable carrier, which is suitable in therapy.

where the symbols and substituents have the following meanings:

-X - represents

where m is 0, 1; n is an integer from 1 to 3;

(b)

where the "ring" is a

where R1represents H, NO2, CF3, F, Cl, Br, I, CN, CH3, NH2, NH, NH, N and k is 0, 1;

(C)

where T represents O, S, or [H,H]; R is 0, 1, 2;

(d)

where the double bond is E or Z configuration;

(e)

(f)

where E - represents -(CH2-)qNH - and q is 0, 1, 2, 3;

-Y represents a

(a)

where s is 0 or 1,

R2is a CO2H, CO2alkyl, CO2aryl, CO2NH2, CO2aralkyl, SO3H, SO2NH2, PO(OH)2, 1-H-tetrazolyl-CHO, COCH3CH2OH, NH2, NH, N(alkyl)alkyl', OCH3CH2OCH3, SH, F, Cl, Br, I, CH3CH2CH3CN, CF3;

R3regardless of R2represents H, CH3CH2CH3, CF3, F, Cl, Br, I, CN, NO2and

R4regardless of R2and R3represents H, CH3CH2CH3, CF3, F, Cl, Br, I, CN, NO2, R2,

R5represents H, NO , CF3, F, Cl, Br, I, CN, CH3, OCH3, SH, NH2

and-W - represents -(CH2-)V, CIS-CH=CH - or TRANS-CH=CH-, where v is 0, 1, 2;

in the case when W is a CIS-CH=CH - or TRANS-CH=CH-, R2cannot be NH2or SH;

(b)

where R6regardless of R2represents H, F, Cl, Me, tert-Bu, CN, NH2;

(c)

(d)

(e)

where t is 0, 1, 2;

(f)

(g)

-Z represents

(i)

R7regardless of R2represents H, NO2, CF3, F, Cl, Br, I, CN, CH3, OCH3, SH, NH2,

(ii)

R8regardless of R2represents H, F, Cl, Me, tert-Bu, CN, NH2,

(iii)

(iv)

where K represents NH, NMe, O, S,

(v)

(vi)

(vii)

-W-R2,

or pharmaceutically acceptable salts, esters or amides and prodrugs of the foregoing compounds of formula (Ia)or (Ib)or (IIa)or (IIb).

In the following embodiment, the invention apply is to pharmaceutical compositions, comprising at least one compound of formula (Ia)or (Ib)or (IIa)or (IIb), and pharmaceutically acceptable carrier that is suitable for therapy,

where the symbols and substituents have the following meanings:

-X - represents

(a)

where m is 0, 1; n is an integer from 1 to 3;

(b)

where the "ring" is a

where R1represents H, NO2, CF3, F, Cl, Br, I, CN, CH3, NH2, NH, NH, N and k is 0, 1;

(C)

where T represents O, S, or [H,H]; R is 0, 1, 2;

(d)

where the double bond is either E-or Z-configuration;

-Y represents a

(a)

where s is 0 or 1,

R2is a CO2H, CO2alkyl, CO2aryl, CO2NH2, CO2aralkyl, SO3H, SO2NH2, PO(OH)2, 1-H-tetrazolyl-CHO, COCH3CH2OH, NH2, NH, N(alkyl)alkyl', OCH3CH2OCH3, SH, F, Cl, Br, I, CH3CH2CH3CN, CF3,

R3regardless of R2represents H, CH3CH2CH3, CF3, F, Cl, Br, I, CN, NO2and

R4regardless of 2and R3represents H, CH3CH2CH3, CF3, F, Cl, Br, I, CN, NO2, R2,

R5represents H, NO2, CF3, F, Cl, Br, I, CN, CH3, OCH3, SH, NH2

and-W - represents -(CH2-)V, CIS-CH=CH - or TRANS-CH=CH -, and v is 0, 1, 2,

in the case when W is a CIS-CH=CH - or TRANS-CH=CH-, R2cannot be NH2or SH;

(e)

where t is 0, 1, 2;

(f)

(g)

-Z represents

(i)

where R7regardless of R2represents H, NO2, CF3, F, Cl, Br, I, CN, CH3, OCH3, SH, NH2;

(iv)

where K represents NH, NMe, O, S;

(v)

or pharmaceutically acceptable salts, esters or amides and prodrugs of the foregoing compounds of formulas (Ia)or (Ib)or (IIa)or (IIb).

Preferred pharmaceutical compositions comprise compounds of formula (IIIa)or (IIIb), or (IVa)or (IVb)

where Y has the meanings indicated above and X'represents X(a)X(b)X(c) X(d), which have the values specified above. Preferably X'represents X(a)X(b) and X(s).

Following the provision of the equipment pharmaceutical compositions include compounds of the formula (A1), (A2), (B1), (B2), (C1), (C2), (D1) or (D2)

where X'and Y have the meanings given above and X represents a

and where Y' represents a

where all indices, symbols and substituents have the meanings specified above.

The invention relates also to pharmaceutical compositions in which compounds have the formula (A1)or (A2)or (B1)or (B2)or (C1)or (C2)or (D1)or (D2)

where X'and Y have the meanings given above and X represents a

and where Y' represents a

where all indices, symbols and substituents have the meanings specified above.

Especially preferred pharmaceutical compositions comprise compounds of the formula (E1), (E2), (F1) or (F2)

where X ' and Y' have the meanings specified above.

The most preferred pharmaceutical compositions comprise compounds of the formula (G1), (G2), (H1) or (H2)

where X has the values listed above, and Y represents a

where R9is a CO2H, CO2alkyl, CO2aryl, CO2NH2, CO2aralkyl, CH2SO3H, CH2SO2 NH2CH2PO(OH)2, 1-H-tetrazolyl, CHO, COCH3CH2OH, CH2NH2CH2NH, CH2N(alkyl)alkyl', CH2OCH3CH2SH.

The next aspect of the invention is a pharmaceutical composition where the compounds have the formula (G1)or (G2), or (H1)or (H2)

where X has the values listed above, and Y represents a

where R9is a CO2H, CO2alkyl, CO2aryl, CO2NH2, CO2aralkyl, CH2SO3H, CH2SO2NH2CH2PO(OH)2, 1-H-tetrazolyl, CHO, COCH3CH2OH, CH2NH2CH2NH, CH2N(alkyl)alkyl', CH2OCH3CH2SH,

where all indices, symbols and substituents have the meanings specified above.

These chemical compounds (E1), (E2), (F1), (F2), (G1), (G2), (H1) and (H2) are also new compounds.

All connections described above, have the ability to modulate cell adhesion and modulate the binding, mediated by selectin, and PSFL-1-like ligand. The compounds possess the ability to modulate the interaction of selectins with sLex/sLeaand the interaction between selectins and thyroidzoloftyi remains. They are therefore useful for the treatment of acute and chronic is their inflammatory disorders, as well as other pathological conditions, which play a role mediated by selectin processes.

The term "pharmaceutical" also includes the diagnostic application.

The term "pharmaceutical" includes prophylactic use to prevent pathological conditions, which play a role mediated by selectin processes.

The term "pharmaceutical" also includes the application, in which the compounds of the present invention can be used as excipients for delivery of the drug in the target organ for diagnostic or therapeutic purposes.

In the following a preferred embodiment, the invention relates to pharmaceutical compositions comprising at least one compound of the formula (A1), (A2), (B1), (B2), (C1), (C2), (D1), (D2), (E1), (E2), (F1), (F2), (G1), (G2), (H1) or (H2).

The invention provides pharmaceutical compositions comprising the compounds of formula (Ia)or (Ib)or (IIa)or (IIb) and in a preferred embodiment of formula (IIIa)or (IIIb), or (IVa)or (IVb).

In the following a preferred embodiment, the invention provides pharmaceutical compositions comprising at least one compound of the formula (A1), (A2), (B1), (B2), (C1), (C2), (D1) or (D2).

In a particularly preferred embodiment, the invention provides pharmaceutical compositions comprising at least one shall Obedinenie formula (E1), (E2), (F1) or (F2).

In a very particularly preferred embodiment, the invention provides pharmaceutical compositions comprising at least one compound of the formula (G1), (G2), (H1) or (H2).

The present invention further provides a method of modulating the binding of P-selectin, L-selectin or E-selectin with sLexor sLeaand thyroidzoloftyi residues, including the stage of the introduction to the patient an effective amount of at least one compound having the structure of formula (Ia)or (Ib)or (IIa)or (IIb), to modulate the binding of P-, E - or L-selectin with sLexor sLeaand trainsurfing. Discovered that compounds having the formula (Ia)or (Ib)or (IIa)or (IIb)shown above, act as modulators of binding of E-, P - or L-selectin.

Used here, the terms "alkyl" means a monovalent group with a non-branched chain or branched chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 carbon atoms, including but not limited to the above, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like. "Alkali" do not depend on each other and may be different or identical.

The term "aryl" shall mean carbocyclic and heterocyclic aromatic groups including, but not limited to the above, the dryer is l, 1-naphthyl, 2-naphthyl, fluorenyl, (1,2)-dihydronaphtho, indenyl, indanyl, thienyl, benzothiazyl, cyanopyridyl and the like.

The term "aralkyl" (also called arylalkyl) will denote aryl group attached to the alkyl group, and includes, but is not limited to, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, tormentil, chlorbenzyl, bromobenzyl, iodobenzyl, alkoxybenzyl (where "alkoxy" means methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy and the like), hydroxybenzyl, aminobenzyl, nitrobenzyl, guanidines, fluorenylmethyl, phenylmethyl(benzyl), 1-phenylethyl, 2-phenylethyl, 1-naphtalate and the like.

The term "acyl" shall mean -(SNO), or -(C=O)-alkyl, or -(C=O)-aryl, or -(C=O)-aralkyl and includes, but is not limited to, formyl, acetyl, n-propionyl, Isopropenyl, n-butyryl, isobutyryl, pivaloyl, benzoyl, 4-nitrobenzoyl and the like.

Used here, the term "pharmaceutically acceptable salts, esters, amides and prodrugs" refers to carboxylate salts, additive salts of amino acids, esters, Amida and prodrugs of the compounds of the present invention, which are within the scope of the research drug assessments are suitable for use in contact with the tissues of patients without excessive toxicity, irritation, lergicescoe reaction and the like, have an acceptable ratio of benefit/risk and are effective for their intended use, and, when possible, zwitterionic forms of the compounds of the present invention. The term "salt" refers to a relatively non-toxic additive salts of the compounds of the present invention and inorganic and organic acids. These salts can be obtained in situ during the final isolation and purification of the compounds or separately by the reaction of purified compounds in their free form with a suitable organic or inorganic acid or base and selection, thus formed salts. Representative salts of the compounds of the present invention include hydrobromide, cleaners containing hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumaric, succinate, tartrate, naphthalate, mesylate, glucoheptonate, lactobionate, laurylsulphate salt and the like. These may include cations based on the alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium cations, Quaternary ammonium and amines, including but not limited to the above, the cations ammonium, tetramerium the tion, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.

Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include1-With2-With3-With4-With5- and6-alkalemia esters, where the alkyl group is unbranched or branched chain. Acceptable esters also include With5-With6- and7-cycloalkyl esters, and arylalkylamine esters, such as, but not limited to, benzyl ether. With1-With2-With3-With4-With5- and6-alkalemia esters are preferred. Esters of the compounds of the present invention can be obtained according to conventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary1-With2-With3-With4-With5- and6-and secondary alkylamines followed With1-With2-With3-With4-With5- and6-dialkylamino, where the alkyl groups are unbranched or branched chain. In the case of secondary amines amine may be in the form of a 5 - or 6-membered heterocycle containing one nitrogen atom. Preferred are amides derived from ammonia, per the ranks With 1-With2- and3-alkylamino and secondary1-C2-dialkylamides. Amides of the compounds of the present invention can be obtained according to conventional methods.

The term "prodrug" refers to one or more compounds that are rapidly transformed in vitro and converted from the inactive to the active state in vivo with the formation of the "source" of the compounds of the above formula (Ia)or (Ib)or (IIa)or (IIb), for example, by hydrolysis in blood or metabolism in vivo.

It is also expected that the pharmaceutically active composition may contain the compound of the present invention or other compounds that modulate the binding of E-selectin or P-selectin or L-selectin or compete with this binding.

Pharmaceutically active compositions of the present invention include pharmaceutically acceptable carrier and a compound of formula (Ia)or (Ib)or (IIa)or (IIb), resulting in a pharmaceutically acceptable carrier may also be suitable drug nanoparticle, a dendrimer, liposome, mikrobasic or polyethylene glycol (PEG). The pharmaceutical compositions of the present invention can include one or more compounds having the above structure (Ia)or (Ib)or (IIa)or (IIb), in combination with one or more physiologically acceptable carriers, adjus nami or fillers, which is called here the carriers, for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration and the like.

Songs you can enter humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, intradermally or subcutaneously), by intracavitary, intrawaginalno, intraperitoneally, locally (powders, ointments or drops), or transbukkalno or inhalation (spray or nazalnam spray).

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, stabilizers, antioxidants, preservatives (e.g., ascorbic acid, sodium sulfite, hydrosulfite sodium, benzyl alcohol, EDTA), dispersions, suspensions or emulsions and sterile powders for recreation in a sterile injectable solution or dispersion. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyol (propylene glycol, polyethylene glycol, glycerin and the like), suitable mixtures, vegetable oils (such as olive oil or canola oil) and injectable organic esters, such as etiloleat. Proper fluidity can be maintained, for example, application of coatings, such as l titin, the maintenance of the required particle size in the case of dispersions and by the use of surface-active substances.

These compositions can also contain adjuvants such as preserving, moisturizing, emulsifying and dispersing agents. Prevention of the action of microorganisms can be guaranteed of various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable for inclusion isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical form can be achieved by the use of agents which delay absorption such as aluminum monostearate and gelatin.

If desired, and for more effective distribution, the compounds can be included in the system for slow or controlled time release or for delivery to the target organ, such as polymer matrices, liposomes, and microspheres. They can be sterilized, for example, by filtration through inhibiting bacteria filter or the introduction of sterilizing agents in the form of sterile water or some other sterile injectable media immediately before use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and gra the uly. In such solid dosage forms the active compound or prodrug is mixed, with at least one inert customary excipient (or carrier)such as sodium citrate or dicalcium phosphate or (i) fillers or diluents, such as, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (ii) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and the Arabian gum, (iii) humectants, such as, for example, glycerol, (iv) dezinfeciruyuhimi agents, such as, for example, agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (v) the dissolution retarders, such as, for example, paraffin, (vi) absorption accelerators, such as, for example, Quaternary ammonium compounds, (vii) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, (viii) adsorbents, such as, for example, kaolin and bentonite, and (ix) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type can also be used in kachestvennaia in soft and hard filled gelatin capsules using excipients, such as lactose or milk sugars, as well as glycols of high molecular weight and the like. Solid dosage forms such as tablets, coated tablets, capsules, pills and granules can be obtained with coatings and shells, such as intersolubility coatings and others well known in this field. They may contain agents that give the song an opacity, and can also be such compositions, which release the active compound or compounds in a certain part of the intestinal tract in a slow way. Examples of "penetrating" compositions that can be used are polymeric substances and waxes. The active compounds may be also, if it is acceptable, in microencapsulated form with one or more of the above excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in this field, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimetilan the amide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, canola oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters sorbitan or mixtures of these substances, and the like. Besides such inert diluents, compositions can also include adjuvants, such as moistening agents, emulsifying and suspendresume agents, sweetening agents, corrigentov and fragrances.

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

Compositions for rectal injection are preferably suppositories which can be obtained by mixing the compounds of the present invention with suitable non-irritating with excipients or carriers such as cocoa butter, polyethylene glycol or wax for suppositories, which are solid at ordinary temperature but liquid at body temperature and therefore melt in the rectal or vaginal cavity and release the active component. Dosage forms for topical administration the compounds of this image is to be placed include ointments, powder, sprays and forms for inhalation.

The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any needed preservatives, buffers or propellants, if they may be needed. Ophthalmic preparations ophthalmic ointments, suspensions, powders and solutions are also regarded as included within the scope of this invention.

Compounds of the present invention can also be incorporated into liposomes or to associate with them or to enter it in the form of liposomes. As is well known in this field, liposomes is usually derived from phospholipids or other lipid substances. Liposomes are formed by mono - or multi-layer hydrated liquid crystals that are dispersed in the aquatic environment. You can use any non-toxic, physiologically acceptable metabolized lipid capable of forming liposomes. These compositions in the form of liposomes can contain, in addition to the binding of selectin antagonists of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are phospholipids and phosphatidylcholine (lecithins), both natural and synthetic. Methods for formation of liposomes are well known in the art.

Aparentally dosage forms may contain also increases the bioavailability of the agent (which, for example, modulators of enzymes, antioxidants), suitable to protect the joints from damage. The actual dose levels of active ingredient in the composition of the present invention can be varied to obtain an amount of active ingredient that is effective to achieve a desired therapeutic response for a particular composition and method of administration. Therefore, the selected dosage depends upon the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors. The total daily dose of the compounds of this invention administered to the host in single or divided doses may be in the range of 50 mg per kg of body weight. Compositions in the form of standard dosage forms may contain such subprogramme number that can be used to get a daily dose. It should be clear, however, that the specific dose level for any particular patient, regardless of whether it is man or other animals, will depend on a number of factors, including body weight, General health, sex, diet, time and route of administration, rate of absorption and excretion, combination with other drugs and the severity of concrete subjected to the treatment of disease.

In particular, the compounds of the crust is asego of the invention can be used to treat a number of diseases, related to inflammation and intercellular recognition and adhesion. For example, the compounds of the present invention can be entered for the patient for the treatment of chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), in the extracorporeal circulation, the treatment of acute respiratory distress syndrome (ARDS), Crohn's disease, septic shock, sepsis, chronic inflammatory diseases, such as psoriasis, atopic dermatitis and rheumatoid arthritis, and reperfusion injury, which occurs after a heart attack, brain haemorrhage, arteriosclerosis and organ transplants, traumatic shock, failure of many organs, autoimmune diseases such as multiple sclerosis, in subcutaneous intraluminal angioplasty, the treatment of asthma and inflammatory bowel disease. In each case, an effective amount of the compounds of the present invention is administered either as such or as part of a pharmaceutically active composition to a patient in need of such treatment. It is also clear that the patient in need of such introduction, you can enter a combination of compounds. Compounds of the present invention can also enter for the treatment of other diseases that are associated with intercellular adhesion. Because these connection modules the comfort of the binding of E-selectin, or P-selectin or L-selectin, any disease that is associated with this interaction, can potentially be treated by modulation of this binding interaction.

In addition to detection on some leukocytes, sLeadetected in various cancer cells, including cancer cells of the lung and colon. It has been suggested that the adhesion of cells, including participation sLeamay participate in the metastasis of some cancers, and antagonists bind sLeacan be useful in the treatment of some forms of cancer.

The use of active ingredients according to the invention in cosmetic or local dermatological compositions with an effective content of active ingredient according to the invention unexpectedly provides effective treatment and prevention of skin aging caused by external and internal factors.

The invention applies in particular to the use of compounds of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric forms for obtaining a cosmetic or dermatological composition.

The applied amount of active compound or its stereoisomeric form corresponds to the number required to achieve the desired result of applying a cosmetic or dermatological compositions. The special is the worksheet in this area are able to determine this effective amount, which depends on the derivative, individual, on whom it is applied, and the time of its application. To provide order of magnitude in cosmetic or dermatological compositions according to the invention the compound of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, you can enter in the amount of 0.001 to 40 wt.%, preferably from 0.005 to 30% by weight. and more preferably from 0.01 to 20 wt.%.

Another aspect includes cosmetic compositions comprising a compound of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, and at least one cosmetically tolerable component, such as cosmetically tolerable component for application to the skin.

The number of different components of the physiological medium of the cosmetic composition according to the invention are the quantities usually used in areas under review. When the cosmetic composition is an emulsion, the content of oil phase can comprise from 2 to 80 wt.%. and preferably from 5 to 50% wt. relative to the total mass of the cosmetic compositions.

Thus, the cosmetic composition must contain a non-toxic physiologically acceptable medium that can be applied to human skin. For local application to the skin a cosmetic composition may be in the form of a solution, suspense and, emulsion or dispersion with more or less fluid consistency, especially liquid or semi-liquid consistency, obtained by dispersing an oil phase in the aqueous phase (oil/water) or Vice versa (water/oil), or in the form of a gel. You can also apply a cosmetic composition in the form of a mousse or in the form of a spray or aerosol, in this case comprising a pressurized propellant. The composition may also be in the form of a lotion for hair care, shampoo or hair conditioner, liquid or solid soap, cosmetic masks or foaming cream or gel to wash your hair. They can also be in the form of a hair dye or paint for eyebrows and eyelashes.

Cosmetic compositions of the invention may also include one or more other ingredients commonly used in the fields and selected from additives to drugs, such as thickeners for the aqueous phase or oil phase, or gelling agents, dyestuffs that are soluble in the medium of the cosmetic composition, solid particles such as mineral or organic fillers or pigments in the form of microparticles or nanoparticles, preservatives, fragrances, hydrotop or electrolytes, neutralizing means (acidifying or alkalizing agents, propellants, anionic, cationogenic or amphoteric surface is IDT-active substances, polymers, in particular water-soluble or water-dispersible anionic, nonionic, cationogenic or amphoteric film-forming polymers, mineral or organic salts, chelating agents; and mixtures thereof.

Cosmetic compositions can be used for inhibiting microasperities cycle. Therefore, the present invention relates to cosmetic compositions comprising a compound of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, which is used for the cosmetic treatment or cosmetic prevention micropopulation States.

Cosmetic compositions comprising a compound of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, which is used for the cosmetic treatment or cosmetic prevention of skin aging caused by internal factors, are also subject of the present invention. Internal factors responsible for skin aging are genetically programmed determinants, including age, hormonal status, and physiological factors.

Besides cosmetically inactive ingredients of the cosmetic composition of the present invention may also comprise one or more cosmetically active ingredients with beneficial effect on the skin. Therefore, the present invention Rel is applicable to cosmetic compositions comprising the compound of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, and at least one additional cosmetically active ingredient, for example UV-protective agent or proteins.

Dermatological compositions comprising a compound of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, and at least one dermatologically tolerable component, for example dermatologically tolerable component for use on the skin, are also the subject of invention.

Dermatologically portable components that can be used for dermatological compositions described herein are identical cosmetically portable components specified in this invention.

The following embodiment of the present invention are dermatological compositions comprising a compound of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, which is used for the dermatological treatment, dermatological diagnosis or dermatological prophylaxis micropopulation States.

In particular, the invention includes a dermatological composition comprising a compound of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, which is used for the dermatological treatment, dermatological diagnosis or dermatolo the practical prevention of itching and skin aging, caused by external factors. External factors include General environmental factors; more specifically causing skin aging effects of ultraviolet rays due to solar irradiation, the action of light or any other radiation, atmospheric contamination, wounds, infections, injuries, hypoxia, smoke cigarettes, hormonal state as a reaction to internal factors, neuropeptides, electromagnetic fields, gravitation, lifestyle (for example, excessive alcohol consumption), the repetitive facial expressions, body position during sleep and physiological stress factors.

In addition dermatologically inactive ingredients dermatological compositions can include a dermatologically or pharmaceutically active ingredients. Therefore, the present invention relates to dermatological compositions comprising a compound of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, and at least one additional dermatologically or pharmaceutically active ingredient. Dermatologically or pharmaceutically active ingredients that can be used for dermatological compositions described herein, is defined as cosmetically active ingredients mentioned above. Dermatologically or pharmaceutically active ingredients can be the identical cosmetically active ingredients, specified in this invention.

Another object of the present invention are dermatological compositions comprising a compound of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, and at least one additional dermatologically or pharmaceutically active ingredient, characterized in that it is used for the dermatological treatment, dermatological diagnosis or dermatological prophylaxis micropopulation States.

In particular, the present invention relates to dermatological compositions comprising a compound of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, and at least one additional dermatologically or pharmaceutically active ingredient, characterized in that it is used for the dermatological treatment, dermatological diagnosis or dermatological prophylaxis of itching and skin aging caused by external factors.

Skin aging can be caused by a combination of internal and external factors. Therefore, the present invention relates to dermatological compositions comprising a compound of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, and at least one additional pharmaceutically or cosmetically active ingredient, characterized by the fact that h is of it is used for cosmetic and dermatological treatment and cosmetic and dermatological prevention of skin aging, caused by a combination of internal and external factors.

Another embodiment of the present invention is a method for obtaining a cosmetic composition by mixing the compounds of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, at least one cosmetically portable component and, eventually, additional cosmetically active ingredients.

In particular, the object of this invention is a method of obtaining a cosmetic composition by mixing the compounds of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, at least one cosmetically portable component and, eventually, additional cosmetically active ingredients, where the composition includes from 0.01 to 20 wt.%. the compounds of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form calculated on the total weight of the composition.

Another aspect relates to a method for dermatological composition by mixing the compounds of formula (Ia)or (Ib)or (IIa)or (IIb) or its stereoisomeric form, at least one dermatologically portable component and in the end additional cosmetically active ingredients.

Many of the compounds of the present invention can be synthesized according to the following General synthetic schemes.

Scheme 1

According to scheme 1, the amino acid type (1) is subjected to reaction with Fmoc-Cl in dioxane in basic conditions (10% Na2CO3in water) to give the corresponding N-Fmoc-protected acid (2). Carboxylic acid (2) immobilized 2 horticulturally resin (3) with the formation fixed on the solid phase 2-hortatives of ester (4). Unprotect (4) - piperidine in DMF gives the amine type (5). Further reaction of the amine (5) with carboxylic acid (6) under standard conditions condensation (DIC and HOBt in DMF) gives the amide (7), which is easily otscheplaut from resin hexafluoroisopropanol (HFIP) in dichloromethane, while receiving carboxylic acids of type (8). In an alternative case for the reaction of amide condensation can be applied N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC), triethylamine and 4-dimethylaminopyridine (DMAP) in a chlorinated solvent. The sequence of the synthesis shown in scheme 1 leading to compounds similar to (8), is used not only for the building blocks of Y-H, similar (1), but it is usually used for all other building blocks of the type Y-H, having the functional group of carboxylic acids and functional NH2group.

Scheme 2

Scheme 2 carboxylic acid type (8) is subjected to reaction with tribromide boron in dichloromethane at -40°C, while receiving water after processing soo is relevant demetilirovanie acid type (9). The sequence of the synthesis shown in scheme 2 and leading to compounds similar to (9), is used not only for the building blocks of the X-Y-H and Y-H similar to (8), but it is usually used for all other building blocks of the type X-Y-H and Y-h

Scheme 3

Scheme 3 aniline type (10) is subjected to reaction under conditions of inert atmosphere with N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC), triethylamine, 4-dimethylaminopyridine (DMAP) and carboxylic acid type (11) in dichloromethane, while receiving amide type (12). Further hydrolysis of ester (12) aqueous LiOH and THF and the Meon gives carboxylic acids of the type (13).

Scheme 4

Scheme 4 carboxylic acid of the type (13) is subjected to reaction with tribromide boron in dichloromethane at -40°C, while receiving water after processing the corresponding demetilirovanie acid type (14). The sequence of the synthesis shown in scheme 4 and leading to compounds similar to (14), is used not only for the building blocks of the X-Y-H and Y-H similar to (13), but it is usually used for all other building blocks of the type X-Y-H and Y-h

The present invention also is illustrated by the following representative examples.

Example 1

3-[4-(3,5-Dihydroxybenzylamine)bucillamine]benzoic acid (21) and methyl ester of 3-[4-(3,5-dihydroxybenzyl is ylamino)bucillamine]benzoic acid (22)

Scheme 5

Stage 1. 3-Aminobenzoic acid ((15); 1,00 g, 7,30 mmol) dissolved in 1,4-dioxane (12.0 ml) and 10% aqueous Na2CO3(20,8 ml) and added Fmoc-Cl (of 2.26 g, 8,76 mmol). The reaction mixture was stirred for 2.5 h at room temperature. To the mixture is added 1M aqueous HCl (42,0 ml) and extracted with her EtOAc (3 times). The combined organic layers washed with 1M aqueous HCl, water and saturated salt solution, the combined aqueous layers are extracted once again EtOAc, the combined organic layers are dried Na2SO4and the solvent is removed under reduced pressure. The remaining crude product is washed with ice EtOAc and dried in the vacuum created by the oil pump, while receiving (16) in the form of a white solid (1,61 g, 61%). Further purification is not used. [M. Nichifor; E. H. Schacht; Tetrahedron; 1994; 50; 12; 3747-3760].1H NMR (400 MHz, DMSO-d6): or 4.31 (t, 1H, J=6.6 Hz); of 4.49 (d, 2H, J=6.6 Hz); 7,31 was 7.45 (m, 5H); 7,56 (d, 1H, J=7,6 Hz); 7,60-7,70 (osirm, 1H); of 7.75 (d, 2H, J=7,3 Hz); of 7.90 (d, 2H, J=7,3 Hz); 8,11 (s, 1H); 9,88 (s, 1H).

Stage 2. (16) (180 mg, 0.5 mmol) dissolved in DCM (0.5 ml) and DMF (0.25 ml) at room temperature in a pre-dried ampoule add DIEA (0.52 in ml, 1.5 mmol) and this solution is added to the polymer 2-horticulture-polystyrene (3) (82 mg, 0.13 mmol (loading 1.6 mmol/g)), which was previously subjected to swelling in DCM (15 ml). The reaction suspension is shaken for 14 h at room temperature. Associated with resin product (17) is washed with a mixture of DCM/MeOH/DIEA (17+2+1, 3 times), DCM (once), DMF (3 times) and then DCM (twice) and dried in vacuum [i.e., Novabiochem®2000 Catalog; 2000; S15-Sl8].

Stage 3. The whole amount of the resin (17) from stage 2 are suspended in DMF (0.4 ml) and piperidine (0.1 ml) and the suspension shaken for 1.5 h at room temperature. Associated with resin product (18) was washed with DMF (3 times) and DCM (3 times for 30 min) and dried in vacuum.

Stage 4. The whole amount of the resin (18) with stage 3 again subjected to swelling in DMF (0.8 ml) for 20 min. Acid (6) (158 mg, 0.59 mmol) and HOBt (90 mg, 0.59 mmol) dissolved in DMF (2.8 ml) at room temperature, add DIC (75 mg, 0.59 mmol), stirred for 15 min and the solution added to the pre-swollen resin (18). A suspension of resin gently shaken for 20 h at room temperature. Associated with resin product (19) is washed with DMF (3 times) and DCM (4 times) and dried in vacuum.

Stage 5. The whole amount of the resin (19) with stage 4 suspended in 1.5 ml DCM+HFIP (2+1) and the suspension shaken for 45 min at room temperature. The remaining solution is separated by filtration and the resin washed once with DCM. The method of removal of repeat and rinse hold once. The solvent of the combined filtrates is pariwat under reduced pressure, while receiving the crude product (20). Additional cleaning is not performed.

Stage 6. (The following reaction is carried out in an atmosphere of anhydrous N2). The whole amount of the crude product (20) from the stage 5 is suspended in anhydrous DCM (2.0 ml), the suspension is cooled to -40°C and add it to the BBr3(0.15 ml, of 1.59 mmol). The reaction suspension is shaken for 1 h at -40°C, 2 h at -25°C and 30 minutes at +5°C. With vigorous stirring, add dropwise water and then adding the Meon. The solvent is removed under reduced pressure. Purification of the crude product of preparative RP-HPLC (gradient, water/MeCN, 95:5) gives 3-[4-(3,5-dihydroxybenzylamine)bucillamine]benzoic acid (21) in (8.9 mg, yield 19% after 5 stages) and methyl ester of 3-[4-(3,5-dihydroxybenzylamine)bucillamine]benzoic acid (22) (3.0 mg, yield 6% after 5 stages), both as white solids.1H NMR (400 MHz, CD3OD) (21): 2,03 (Quint, 2H, J=7,1 Hz); of 2.51 (t, 2H, J=7.5 Hz); 3,47 (t, 2H, J=6,7 Hz); 6,44 (users, 1H); 6.75 in (users, 2H); 7,44 (DD, 1H, J1=8,3 Hz, J2=7,8 Hz); for 7.78 (d, 1H, J=7.8 Hz); a 7.85 (d, 1H, J=8.6 Hz); compared to 8.26 (users, 1H); (22): 2,03 (Quint, 2H, J=6.9 Hz); of 2.51 (t, 2H, J=7.5 Hz); 3,47 (t, 2H, J=6.9 Hz); of 3.94 (s, 3H); to 6.43 (ushort, 1H, J=2.0 Hz); 6,74 (d, 2H, J=2.0 Hz); 7,44 (t, 1H, J=8,1 Hz); to 7.77 (d, 1H, J=7,6 Hz); 7,83 (userd, 1H, J=8,1 Hz); 8,28 (users, 1H).

EXAMPLE 2

{4-[4-(3,5-Dihydroxybenzylamine)butyryl]piperazine-1-yl}acetic acid (23)

Scheme 6

According to the method described in example 1, {4-[4-(3,5-dihydroxybenzylamine)butyryl]piperazine-1-yl}acetic acid (23) are obtained in the form of a yellowish oil (6,8 mg, yield 14% after 5 stages).1H NMR (400 MHz, CD3OD): a 1.96 (Quint, 2H, J=6,7 Hz); of 2.54 (t, 2H, J=6.9 Hz); 3,41-3,51 (m, 4H); 3,90 (users, 4H); of 4.12 (s, 2H); 6,46 (users, 1H); 6,74 (d, 2H, J=2.0 Hz).

EXAMPLE 3

4-[4-(3,5-Dihydroxybenzylamine)bucillamine]benzoic acid (24)

Scheme 7

According to the method described in example 1, 4-[4-(3,5-dihydroxybenzylamine)bucillamine]benzoic acid (24) are obtained in the form of a white solid (1.2 mg, yield 2% after 5 stages).1H NMR (400 MHz, CD3OD): 2,03 (Quint, 2H, J=6.9 Hz); 2,52 (t, 2H, J=7.8 Hz); 3,47 (t, 2H, J=6.6 Hz); 6,44 (users, 1H); 6.75 in (users, 2H); 7,71 (d, 2H, J=8,3 Hz); 7,99 (d, 2H, J=8,3 Hz).

EXAMPLE 4

Ethyl ester of 5-{4-[2-(2,4-acid)acetylamino]phenyl}-2-methylfuran-3-carboxylic acid (27) and 5-{4-[2-(2,4-acid)acetylamino]phenyl}-2-methylfuran-3-carboxylic acid (28)

Scheme 8

Stage 1. (The following reaction is carried out in an anhydrous atmosphere N2). The EDC hydrochloride (117 mg, 0.61 mmol) and triethylamine (85 μl, 0.61 mmol) dissolved in anhydrous dichloromethane (2.0 ml) and the solution stirred for 5 min at room temperature. Add acid (26) (84 mg, 0.43 mmol) and DMAP (8 mg, 0.06 mmol) and the ect is stirred for 10 minutes Add ethyl ester (25) (100 mg, 0.41 mmol) and the reaction solution is stirred over night at room temperature. The reaction solution hydrolyzing saturated aqueous NH4Cl, followed by hydrolysis with water, the layers separated, the aqueous layer was extracted with dichloromethane (3 times) and wash the combined organic layers with water and saturated salt solution and dried Na2SO4. The solvent is removed under reduced pressure. The crude product is purified preparative radial chromatography (silica gel 60PF, EtOAc/CyH, 1+1), thus obtaining the ethyl ester of 5-{4-[2-(2,4-acid)acetylamino]phenyl}-2-methylfuran-3-carboxylic acid (27) in the form of a yellow solid. (153 mg, 88%). [K.C. Nicolaou; P.S. Baran; Y.L. Zhong; K. Sugita; J Am. Chem. Soc.; 2002; 124; 10; 2212-2220].1H NMR (400 MHz, CDCl3): of 1.34 (t, 3H, J=7.2 Hz); 2,61 (s, 3H); 3,63 (s, 2H); 3,81 (s, 3H); to 3.89 (s, 3H); to 4.28 (q, 2H, J=7.2 Hz); 6.48 in-6,53 (m, 2H); 6,77 (s, 1H); 7,19 (d, 1H, J=8,1 Hz); 7,42 (d, 2H, J=8.6 Hz); 7,52 (d, 2H, J=8,8 Hz); 7,60 (users, 1H).

Stage 2. Ethyl ester of 5-{4-[2-(2,4-acid)acetylamino]phenyl}-2-methylfuran-3-carboxylic acid (27) (150 mg, 0.35 mmol) in Meon (0.5 ml) dissolved in Meon (0.5 ml) and THF (8 ml) at room temperature and added 1M aqueous LiOH (3.6 ml, 3.6 mmol). The reaction mixture was stirred 18 h at room temperature. The reaction mixture is quenched (cooling bath) 2M aqueous HCl. The mixture is extracted with EtOAc (3×), the combined organic is a mini layer was washed with saturated salt solution and dried Na 2SO4while receiving 5-{4-[2-(2,4-acid)acetylamino]phenyl}-2-methylfuran-3-carboxylic acid (28) (136 mg, 97%) as a white solid.1H NMR (400 MHz, CD3OD): to 2.66 (s, 3H); the 3.65 (s, 2H); a 3.83 (s, 3H); 3,86 (s, 3H); is 6.54 (DD, 1H, J1=8,3 Hz, J2=2.3 Hz); 6,59 (d, 1H, J=2.3 Hz); 6,91 (d, 1H); 7.18 in (d, 1H, J=8,3 Hz); to 7.64 (s, 4H).

EXAMPLE 5

5-{4-[2-(2,4-Dihydroxyphenyl)acetylamino]phenyl}-2-methylfuran-3-carboxylic acid (29)

Scheme 9

(The following reaction is carried out in an anhydrous atmosphere N2). 5-{4-[2-(2,4-Acid)acetylamino]phenyl}-2-methylfuran-3-carboxylic acid (28) (100 mg, 0.25 mmol) dissolved in anhydrous DCM (2.5 ml), the solution cooled to -78°C and added dropwise BBr3(95 μl, 1.01 mmol). The reaction mixture was stirred for 30 min at -78°C and after a slow heat for an additional 2 h at room temperature. Dropwise add ice water, the layers separated and the aqueous layer was extracted with DCM (3 times). The combined organic layer was washed with saturated salt solution and dried Na2SO4. The crude product is purified preparative RP-HPLC (gradient, water/CH3CN, 95:5 - 5:95), while receiving 5-{4-[2-(2,4-dihydroxyphenyl)acetylamino]phenyl}-2-methylfuran-3-carboxylic acid (29) (30 mg, 32%).1H NMR (400 MHz, CD3OD): to 2.65 (s, 3H); 3,62 (s, 2H); 6,33 (DD, 1H, J1=8,3 Hz, J2=2.3 Hz); to 6.39(d, 1H, J=2.3 Hz); 6.89 in (s, 1H); 7,02 (d, 1H, J=8,3 Hz); a 7.62 (s, 4H).

EXAMPLE 6

5-{4-[2-(3,5-Acid)acetylamino]phenyl}-2-methylfuran-3-carboxylic acid (30)

Scheme 10

According to the method described in example 4 5-{4-[2-(3,5-acid)acetylamino]phenyl}-2-methylfuran-3-carboxylic acid (30) are obtained in the form of a white solid (138 mg, yield 85% after two steps).1H NMR (400 MHz, CD3OD): to 2.66 (s, 3H); the 3.65 (s, 2H); 3,81 (s, 6H); to 6.43 (t, 1H, J=2.0 Hz); to 6.58 (d, 2H, J=2.0 Hz); 6,92 (s, 1H); the 7.65 (s, 4H).

EXAMPLE 7

5-{4-[2-(3,5-Dihydroxyphenyl)acetylamino]phenyl}-2-methylfuran-3-carboxylic acid (31)

Scheme 11

According to the method described in example 5 5-{4-[2-(3,5-dihydroxyphenyl)acetylamino]phenyl}-2-methylfuran-3-carboxylic acid (31) are obtained in the form of a white solid (57 mg, yield 55%).1H NMR (400 MHz, CD3OD): to 2.66 (s, 3H); of 3.57 (s, 2H); from 6.22 (t, 1H, J=2.0 Hz); 6,35 (d, 2H, J=2.0 Hz); 6,91 (s, 1H); the 7.65 (s, 4H).

Below is described the production of intermediate compounds.

Methyl ester [5-(2-AMINOPHENYL)thiophene-2-yl]acetic acid (43)

Scheme 13

Stage 1. (The following reaction is carried out in an anhydrous atmosphere N2). Methyl ester thiophene-2-luxusni acid (41) (2.0 g, 12.8 mmol) dissolved in anhydrous chloroform (9.0 ml) and glacial acetic acid (9.0 ml), portions on billaut N-bromosuccinimide (2.3 g, 13,0 mmol) and the mixture is stirred for 3 days at room temperature. To the reaction mixture, water is added, the layers separated and the aqueous layer was extracted with dichloromethane. The combined organic layer washed several times with 1M aqueous NaOH and water and once with saturated salt solution and dried Na2SO4. Purification of the crude product of preparative radial chromatography (silica gel 60PF, CyH/EtOAc, 5+1) to obtain methyl ester (5-bromothiophene-2-yl)acetic acid (42) as a yellow oil (2,46 g, 81%), which is used without any additional purification.1H NMR (400 MHz, CDCl3): 3,71 (s, 3H); 3.75 to (s, 2H); to 6.67 (d, 1H, J=3.8 Hz); to 6.88 (d, 1H, J=3.8 Hz).

Stage 2. (The following reaction is carried out in an atmosphere of N2). Then ethanol (3,7 ml), tetrakis(triphenylphosphine)palladium(0) (289 mg, 0.25 mmol) and decahydrate Na2CO3(4.0 g, 14.0 mmol)dissolved in water (5.2 ml), are added to a solution of the hydrochloride of 2-aminobenzeneboronic acid (910 mg, the 5.25 mmol) in toluene (52 ml). The reaction mixture is carefully Tegaserod (5 times) and again rinsed with a jet of N2. Add a solution of methyl ester (5-bromothiophene-2-yl)acetic acid (42) (1,17 g, 5.0 mmol) in toluene (4.5 ml). The mixture is again Tegaserod (5 times) and stirred for 22 h at 100°C. the Reaction solution was partitioned between EtOAc and saturated salt solution and the separated aqueous layer extracted with EtOAc (3 times). Volume of the United organic layer is washed with water and saturated salt solution and dried Na 2SO4. Purification of the crude product of preparative radial chromatography (silica gel 60PF, CyH/EtOAc, 5+1) to obtain methyl ester [5-(2-AMINOPHENYL)thiophene-2-yl]acetic acid (43) as a brown oil (634 mg, 51%).1H NMR (400 MHz, CDCl3): to 3.73 (s, 3H); a 3.83 (s, 2H); 3,92-4,07 (users, 2H); 6,74 (d, 1H); 6,76 (TD, 1H, J1=7,6 Hz, J2=1.3 Hz); 6,92 (d, 1H, J=3.5 Hz); 7,02 (d, 1H, J=3.5 Hz); 7,11 (TD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7.23 percent (DD, 14H, J1=7,6 Hz, J2=1.5 Hz).

Methyl ester 5-(2-AMINOPHENYL)thiophene-2-carboxylic acid (45)

Scheme 14

Stage 1. 5-Bromothiophene-2-carboxylic acid (1.50 g, from 7.24 mmol) dissolved in Meon (10 ml) and added dropwise concentrated sulfuric acid (0,39 ml of 7.24 mmol). The reaction mixture is stirred for 20 h at 75°C. the Mixture is cooled to room temperature, the solvent is removed under reduced pressure and the residue dissolved in EtOAc. The organic layer is washed 3 times with 5% aqueous Na2CO3and the combined aqueous layer was extracted with EtOAc. The combined organic layers washed with saturated salt solution and dried Na2SO4. The solvent is removed under reduced pressure and the residue is dried without further purification in the vacuum created by the oil pump, while receiving ester (44) as a white solid (1.48 g, 92%).1H NMR (400 MHz, CDCl3): 3,85 (s, 3H); 7,05 (d 1H, J=4.0 Hz); 7,53 (d, 1H, J=4.0 Hz).

Stage 2. (The following reaction is carried out in an atmosphere of N2). Tetrakis(triphenylphosphine)palladium(0) (510 mg, 0.45 mmol) and ester (44) (1.97 g, 8,91 mmol) dissolved in DME (16 ml), the reaction mixture is carefully Tegaserod (5 times) and rinsed with a jet of N2. Add 2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenylamine (2.15 g, 9,80 mmol) and 1M aqueous solution of NaHCO3(27,0 ml of 27.0 mmol), the reaction mixture is again carefully Tegaserod (5 times) and rinsed with a jet of N2. The mixture is stirred for 18 h at 95°C. the Mixture is cooled to room temperature, partitioned between EtOAc and water and the separated aqueous layer extracted with EtOAc (3 times). The combined organic layer was washed with saturated salt solution and dried Na2SO4. The crude product was purified flash chromatography (silica gel 60, CyH/EtOAc, 5+1), while receiving methyl ester 5-(2-AMINOPHENYL)thiophene-2-carboxylic acid (45) as a yellow solid (1,41 g, 67%). NMR (400 MHz, CDCl3): 3,88 (s, 3H); 4,00 (users, 2H); 6.73 x-PC 6.82 (m, 2H); 7,13-7,21 (m, 2H); 7,26 (DD, 1H, J1=7,6 Hz, J2=1.0 Hz); for 7.78 (d, 1H, J=3.8 Hz).

Methyl ester 5-(4-AMINOPHENYL)-2-methylfuran-3-carboxylic acid (47)

Scheme 15

Stage 1. (The following reaction is carried out in the absence of light). Methyl ester 2-methylfuran-3-carboxylic acid (of 3.60 ml, 28.5 mmol) was dissolved in holdem is reforme (20 ml) and glacial acetic acid (20 ml) and portions add NBS (6,90 g, to 38.8 mmol) in 95 minutes, the Reaction suspension is stirred for an additional 19 hours at room temperature. To the reaction mixture, water is added and the aqueous layer was extracted with dichloromethane (2 times), the combined organic layer was washed with 2M aqueous NaOH, water (3 times) and saturated salt solution and dried Na2SO4thus the methyl ester of 5-bromo-2-methylfuran-3-carboxylic acid (46) (4,90 g, 78%) as a red-brown oil. Further purification is not carried out.1H NMR (400 MHz, CDCl3): of 2.54 (s, 3H); of 3.80 (s, 3H); 6,53 (s, 1H).

Stage 2. (The following reaction is carried out in an atmosphere of N2). Pd(PPh3)4(1.26 g, of 1.09 mmol) and methyl ester of 5-bromo-2-methylfuran-3-carboxylic acid (46) (4.77 g, to 21.77 mmol) dissolved in DME (116 ml) and the solution stirred for 15 min at room temperature. Add 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenylamine (5,25 g, 23,96 mmol) followed by addition of an aqueous 1M solution of sodium bicarbonate (65,4 ml, 65.3 mmol). The reaction mixture is carefully Tegaserod, rinsed with a jet of N2(5 times) and stirred for 4 h at 95°C (boiling under reflux). The reaction mixture is cooled to room temperature, the organic solvent is removed under reduced pressure and the residue partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3 times), obyedinenny the organic layer is washed with water and saturated salt solution and dried Na 2SO4. The resulting crude product was then purified flash chromatography (silica gel 60, EtOAc/CyH, 1+2), while receiving methyl ester 5-(4-AMINOPHENYL)-2-methylfuran-3-carboxylic acid (47) (2.35 g, 46%) as a yellow-brown solid.1H NMR (400 MHz, CDCl3): 2,60 (s, 3H); 3,74 (users, 2H); is 3.82 (s, 3H); only 6.64 (s, 1H); to 6.67 (dt, 1H, J1=8.6 Hz, J2=2.3 Hz); 7,42 (dt, 2H, J1=8,8 Hz, J2=2.3 Hz).

2-Thiophene-2-elfenlied (48)

Scheme 16

(The following reaction is carried out in an atmosphere of N2). Tetrakis(triphenylphosphine)palladium(0) (297 mg, 0.26 mmol) and 2-bromothiophene (837 mg, 5,13 mmol) dissolved in DME (42 ml), the reaction mixture is carefully Tegaserod (5 times) and rinsed with a jet of N2. After 10 min stirring 2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenylamine (1.24 g, 5,64 mmol) and 1M aqueous solution of NaHCO3(with 15.4 ml of 15.4 mmol), the reaction mixture is again carefully Tegaserod (5 times) and rinsed with a jet of N2. The mixture is stirred for 3 h at 95°C. the Mixture is cooled to room temperature, the solvent is removed under reduced pressure and the residue partitioned between EtOAc and water. The separated aqueous layer extracted with EtOAc (3 times). The combined organic layer was washed with saturated salt solution and dried Na2SO4. The crude product was purified flash chromatography (silica gel 60, CyH/EtOAc, 15+1), while it is 2-thiophene-2-elfenlied (48) as a brown solid (825 mg, 92%).1H NMR (400 MHz, CDCl3): 4,40-6,00 (m, 2H); to 6.88 (TD, 1H, J1=7,6 Hz, J2=1.0 Hz); 6,93 (DD, 1H, J1=8.0 Hz, J2=1.0 Hz); 7,07 (DD, 1H, J1=5.3 Hz, J2=3.5 Hz); 7,17 (TD, 1H, J1=8.0 Hz, J2=1.5 Hz); 7,22 (DD, 1H, J1=3.5 Hz, J2=1.3 Hz); 7,30 (DD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,33 (DD, 1H, J1=5.3 Hz, J2=1.3 Hz).

Methyl ester [5-(3-AMINOPHENYL)thiophene-2-yl]acetic acid (50)

Scheme 17

Stage 1. (The following reaction is carried out in an atmosphere of N2). Tetrakis(triphenylphosphine)palladium(0) (1.12 g, 0.97 mmol) and ester (42) (4,57 g, 19,44 mmol) dissolved in toluene (200 ml) and EtOH (20,0 ml), the reaction mixture is carefully Tegaserod (5 times) and rinsed with a jet of N2. Add 3-nitrophenylarsonic acid (3.57 g, 21,38 mmol) and 3M aqueous solution of Na2CO3(18,1 ml of 54.3 mmol), the reaction mixture is again carefully Tegaserod (5 times) and rinsed with a jet of N2. The mixture is stirred for 18 h at 100°C. the Reaction solution was partitioned between EtOAc and water and extracted with separated water layer EtOAc (3 times). The combined organic layer was washed with saturated salt solution and dried Na2SO4. The resulting crude product was then purified preparative radial chromatography (silica gel, EtOAc/CyH, 1+5), while receiving methyl ester [5-(3-nitrophenyl)thiophene-2-yl]acetic acid (49) in the form of yellow is on solid (3.15 g, 58%).1H NMR (400 MHz, CDCl3): of 3.75 (s, 3H); 3,85 (s, 2H); 6,94 (userd, 1H, J=3.8 Hz); 7,27 (d, 1H, J=3.8 Hz); 7,51 (t, 1H, J=8.0 Hz); to 7.84 (DDD, 1H, J1=7.8 Hz, J2=1.5 Hz, J3=0.8 Hz); 8,08 (DDD, 1H, J1=8,3 Hz, J2=2.1 Hz, J3=1.0 Hz); 8,39 (t, 1H, J=1.9 Hz).

Stage 2. (The following reaction is carried out in an atmosphere of N2). Methyl ester [5-(3-nitrophenyl)thiophene-2-yl]acetic acid (49) (3.15 g, 11,35 mmol) dissolved in Meon (225 ml) and added Pd on coal (Pd content 10% (wt./wt.), 1.20 g, 1.13 mmol) followed by addition of NH4CO2H (7,15 g to 113.4 mmol) at room temperature. The reaction mixture is carefully Tegaserod (purge stream of N2) and stirred for 22 h at room temperature. The reaction mixture is filtered through a low layer of celite and the solvent is removed. The resulting crude product was then purified preparative radial chromatography (silica gel, EtOAc/CyH, 1+3), while receiving methyl ester [5-(3-AMINOPHENYL)thiophene-2-yl]acetic acid (50) (2,08 g, 74%) as a yellow solid.1H NMR (400 MHz, CDCl3): to 3.73 (s, 3H); 3,81 (s, 2H); 6,59 (DD, 1H, J1=7.8 Hz, J2=2.0 Hz); 6,86 (userd, 1H, J=3.5 Hz); to 6.88 (t, 1H, J=1.9 Hz); 6,97 (userd, 1H, J=7,6 Hz); to 7.09 (d, 1H, J=3.5 Hz); 7,13 (t, 1H, J=7,7 Hz).

Methyl ester 5-(6-aminopyridine-3-yl)-2-methylfuran-3-carboxylic acid (51)

Scheme 18

Stage 1. (The following reaction is carried out is the atmosphere of N 2). 5-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)pyridin-2-ylamine (500 mg, of 2.27 mmol) and tetrakis(triphenylphosphine)palladium(0) (114 mg, 0.10 mmol) dissolved in DME (12.5 ml). The reaction mixture is carefully Tegaserod (5 times) and rinsed with a jet of N2. The mixture is stirred for 10 min at room temperature, add methyl ester 5-bromo-2-methylfuran-3-carboxylic acid (46) (433 mg, 2.00 mmol) and 1M aqueous solution of NaHCO3(of 5.9 ml, 5.9 mmol), the reaction mixture is again carefully Tegaserod (3 times) and rinsed with a jet of N2. The mixture is stirred for 3 h at 95°C. the Mixture is cooled to room temperature, diluted with EtOAc and filtered through a low layer of silicon dioxide. The solvent is removed under reduced pressure and the crude product is purified preparative radial chromatography (silica gel 60PF, CyH/EtOAc, 2+1), while receiving methyl ester 5-(6-aminopyridine-3-yl)-2-methylfuran-3-carboxylic acid (51) as a yellow solid (382 mg, 82%).1H NMR (400 MHz, CDCl3): 2,61 (s, 3H); is 3.82 (s, 3H); 4,55 (users, 2H); 6,51 (d, 1H, J=8.6 Hz); 6,69 (s, 1H); the 7.65 (DD, 1H, J1=8.6 Hz, J2=2.3 Hz); 8,35 (d, 1H, J=2.3 Hz).

2',4'-Dimethoxybiphenyl-3-carbonylchloride (54)

Scheme 19

Stage 1. (The following reaction is carried out in an atmosphere of N2). Tetrakis(triphenylphosphine)palladium(0) (410 mg, 0.35 mmol) and methyl-3-bromobenzoate (of 2.51 g, 11.7 mmol) is dissolved DME (22 ml). Add 2,4-dimethoxyaniline acid (2.50 g, 13.7 mmol) and 1M aqueous solution of NaHCO3(of 35.5 ml, 35.5 mmol), the reaction mixture is carefully Tegaserod (5 times) and rinsed with a jet of N2. The mixture is stirred for 2.5 h at 100°C. the Reaction solution is cooled to room temperature, partitioned between EtOAc and water and the separated aqueous layer was repeatedly extracted with EtOAc. The combined organic layer was washed with saturated salt solution and dried his Na2SO4. The crude product was purified flash chromatography (silica gel 60, CyH/EtOAc, 7+1, then 4+1), thus obtaining the biphenyl (52) as a yellow oil (2,95 g, 93%).1H NMR (400 MHz, CDCl3): of 3.78 (s, 3H); of 3.84 (s, 3H); 3,90 (s, 3H); 6,55 (s, 1H); 6,56 (DD, 1H, J1=7,6 Hz, J2=2.3 Hz); 7.23 percent (DD, 1H, J1=7,6 Hz, J2=1.0 Hz); the 7.43 (t, 1H, J=7.8 Hz); to 7.68 (dt, 1H, J1=7.8 Hz, J2=1.5 Hz); 7,94 (dt, 1H, J1=7.8 Hz, J2=1.5 Hz); 8,14 (t, 1H, J=1.5 Hz).

Stage 2. Methyl ester of 2',4'-dimethoxybiphenyl-3-carboxylic acid (52) (2,95 g to 10.8 mmol) dissolved in MeCN (110 ml) at room temperature and added 1M aqueous LiOH (154 ml, 154 mmol). The reaction mixture was stirred over night at room temperature and 1 hour at 50°C. the Reaction mixture is quenched (cooling bath) 1M aqueous HCl (160 ml, to achieve a pH of approximately 3). The mixture is extracted with EtOAc (3×), the combined organic layer was washed with saturated salt solution is dried Na 2SO4thus the 2',4'-dimethoxybiphenyl-3-carboxylic acid (53) as a white solid (2,59 g, 93%).1H NMR (400 MHz, CDCl3): 3,79 (s, 3H); of 3.84 (s, 3H); 6,55 (s, 1H); 6,54 return of 6.58 (m, 1H); 7.23 percent-7,26 (m, 1H); 7,46 (t, 1H, J=7.8 Hz); 7,73 (dt, 1H, J1=7.8 Hz, J2=1.5 Hz); 7,98 (dt, 1H, J1=7.8 Hz, J2=1.5 Hz); 8,19 (t, 1H, J=1.5 Hz).

Stage 3. (The following reaction is carried out in an anhydrous atmosphere N2). 2',4'-Dimethoxybiphenyl-3-carboxylic acid (53) (2,59 g, 10.0 mmol) dissolved in anhydrous dichloromethane (71 ml) and add anhydrous DMF (4 ml), catalytic amount). Then slowly add oxalicacid (1.3 ml, 15.0 mmol) while maintaining the temperature at approximately 15°C (water bath) and the yellow solution stirred for additional 3 h at room temperature. The solvent is removed under reduced pressure and the residue is dried under vacuum, thus obtaining 2',4'-dimethoxybiphenyl-3-carbonylchloride (54) as a yellow solid (3.2 g, quantities. output). Additional cleaning is not performed.

(2',4'-Dimethoxybiphenyl-3-yl)acetic acid (57)

Scheme 20

Stage 1. (3-Bromophenyl)acetic acid (4,00 g of 18.6 mmol) was dissolved in Meon (74 ml) and the solution was added concentrated sulfuric acid (1,00 ml of 18.6 mmol). The reaction mixture is stirred for 65 h at 45°C. the Mixture is cooled to whom atoi temperature, the solvent is removed under reduced pressure and the residue partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted 3 times with EtOAc and the combined organic layers washed with saturated salt solution and dried Na2SO4. The solvent is removed under reduced pressure, thus obtaining methyl ether (3-bromophenyl)acetic acid (55) as a colourless oil (4,25 g, 99%).1H NMR (400 MHz, CDCl3): to 3.58 (s, 2H); of 3.69 (s, 3H); 7,17 (t, 1H, J=7,6 Hz); 7.18 in-7,21 (m, 1H); 7,39 (dt, 1H, J1=6,8 Hz, J2=2.0 Hz); 7,41-the 7.43 (m, 1H).

Stage 2. (The following reaction is carried out in an atmosphere of N2). Methyl ether (3-bromophenyl)acetic acid (55) (2.00 g, 8,73 mmol) and tetrakis(triphenylphosphine)palladium(0) (303 mg, 0.26 mmol) dissolved in DME (18 ml). Add 2,4-dimethoxyaniline acid (1.84 g, 10,12 mmol) and 1M aqueous solution of NaHCO3(26 ml, 26 mmol), the reaction mixture is carefully Tegaserod (3 times) and rinsed with a jet of N2. The mixture is stirred over night at 100°C. the Reaction solution is cooled to room temperature, partitioned between EtOAc and water and the separated aqueous layer was repeatedly extracted with EtOAc. The combined organic layer was washed with saturated salt solution and dried his Na2SO4. The crude product is purified preparative radial chromatography (silica gel 60PF, CyH/EtOAc, 3+1), while receiving IU the silt ether (2',4'-dimethoxybiphenyl-3-yl)acetic acid (56) as a yellow oil (2.25 g, 90%).1H NMR (400 MHz, CDCl3): the 3.65 (s, 2H); 3,68 (s, 3H); of 3.77 (s, 3H); a 3.83 (s, 3H); is 6.54 (s, 1H); 6,55 (DD, 1H, J1=7,0 Hz, J2=2.3 Hz); 7.18 in-7,21 (m, 1H); 7,22 (DD, 1H, J1=6,8 Hz, J2=2.3 Hz); to 7.32 (t, 1H, J=8.0 Hz); 7,39 (d, 1H, J=1.5 Hz); 7,38-7,41 (m, 1H).

Stage 3. Methyl ether (2',4'-dimethoxybiphenyl-3-yl)acetic acid (56) (2.25 g, 7,86 mmol) dissolved in MeCN (79 ml) at room temperature and the solution was added 1M aqueous LiOH (40 ml, 40 mmol). The reaction mixture was stirred over night at room temperature. The reaction mixture is quenched (cooling bath) 1M aqueous HCl to achieve a pH of approximately 3) and MeCN removed under reduced pressure. The aqueous residue was diluted with EtOAc, the layers separated and the aqueous layer was extracted with EtOAc several times. The combined organic layer was washed with saturated salt solution and dried Na2SO4thus (2',4'-dimethoxybiphenyl-3-yl)acetic acid (57) as a yellow oil (2.16 g, quantities. output).1H NMR (400 MHz, CDCl3): to 3.67 (s, 2H); 3,76 (s, 3H); a 3.83 (s, 3H); 6,53 (s, 1H); 6,52-6,56 (m, 1H); 7.18 in-7,22 (m, 1H); 7,22 (DD, 1H, J1=7,3 Hz, J2=1.5 Hz); 7,33 (t, 1H, J=7.8 Hz), 7,39-7,42 (m, 2H).

3',5'-Dimethoxybiphenyl-3-carbonylchloride (60)

Scheme 21

Stage 1. (The following reaction is carried out in an atmosphere of N2). Tetrakis(triphenylphosphine)palladium(0) (410 mg, 0.35 mmol) and 1-bromo-3,5-dimethoxybenzene (1.80 g, 8,29 mmol) is dissolved is in DME (17 ml). Add ethyl ester 3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid (2.66 g, 9,62 mmol) and 1M aqueous solution of NaHCO3(25 ml, 25 mmol), the reaction mixture is carefully Tegaserod (5 times) and rinsed with a jet of N2. The mixture is stirred over night at 100°C. the Reaction solution is cooled to room temperature, partitioned between EtOAc and water and the separated aqueous layer was repeatedly extracted with EtOAc. The combined organic layer was washed with saturated salt solution and dried Na2SO4. The crude product is purified preparative radial chromatography (silica gel 60PF, CyH/EtOAc, 10+1), thus obtaining the ethyl ester of 3',5'-dimethoxybiphenyl-3-carboxylic acid (58) as a yellow oil (2,04 g, 86%).1H NMR (400 MHz, CDCl3): of 1.37 (t, 3H, J=7,1 Hz); of 3.84 (s, 6H); 4,39 (q, 2H, J=7,1 Hz); 6.48 in (t, 1H, J=2.3 Hz); 6.73 x (d, 2H, J=2.3 Hz); of 7.48 (t, 1H, J=7,6 Hz); 7,74 (d, 1H, J1=7,6 Hz); 8,01 (dt, 1H, J1=7,6 Hz, J2=1.5 Hz); 8,23 (t, 1H, J=1.5 Hz).

Stage 2. Ethyl ester of 3',5'-dimethoxybiphenyl-3-carboxylic acid (58) (2,04 g, 7,13 mmol) dissolved in MeCN (71 ml) and added 1M aqueous LiOH (36 ml, 36 mmol). The reaction mixture was stirred at room temperature and the solvent is removed under reduced pressure. Add 1M aqueous HCl to achieve a pH of approximately 3) and EtOAc, the layers separated and the aqueous layer was extracted with EtOAc (several times). The combined organic layer washed the t saturated salt solution and dried his Na 2SO4thus the 3',5'-dimethoxybiphenyl-3-carboxylic acid (59) as a white solid (1.73 g, 93%).1H NMR (400 MHz, CDCl3): 3,85 (s, 6H); of 6.49 (t, 1H, J=2.3 Hz); 6,74 (d, 2H, J=2.3 Hz); 7,52 (t, 1H, J=7.8 Hz); 7,80 (DDD, 1H, J1=7.8 Hz, J2=1.5 Hz, J3=1.3 Hz); 8,07 (dt, 1H, J1=7.8 Hz, J2=1.3 Hz); 8,30 (t, 1H, J=1.5 Hz).

Stage 3. (The following reaction is carried out in an anhydrous atmosphere N2). 3',5'-Dimethoxybiphenyl-3-carboxylic acid (59) (950 mg, 3,68 mmol) dissolved in anhydrous dichloromethane (25 ml) and add anhydrous DMF (3 ml) until a clear solution is formed). Then slowly add oxalicacid (of 0.48 ml, 5,52 mmol) while maintaining the temperature at approximately 15°C (water bath) and the mixture is stirred for additional 3 h at room temperature. The solvent is removed under reduced pressure and the residue is dried under vacuum, thus obtaining 3',5'-dimethoxybiphenyl-3-carbonylchloride (60) as a yellow solid (1.22 g, quantitative yield). Additional cleaning is not performed.

EXAMPLE 8

Methyl ester of (5-{2-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (61) and (5-{2-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (62)

Scheme 22

Stage 1. (The following reaction is carried out in an atmosphere of N2). milovy ester [5-(2-AMINOPHENYL)thiophene-2-yl]acetic acid (43) (62,0 mg, 0.25 mmol) dissolved in anhydrous dichloromethane (3,7 ml) and anhydrous pyridine (1.1 ml) and the reaction mixture is cooled to 0°C. Add a solution of 2',4'-dimethoxybiphenyl-3-carbonylchloride (54) (69 mg, 0.25 mmol) in dichloromethane (1.5 ml) and the reaction mixture stirred for 1 h at 0°C and overnight at room temperature. The reaction mixture was poured into ice water HCl, the layers separated, the aqueous layer was extracted with dichloromethane (3×), the combined organic layer was washed with saturated salt solution and dried Na2SO4. The crude product is purified preparative radial chromatography (silica gel 60PF, EtOAc/CyH, 3+1), while receiving methyl ester (5-{2-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (61) as a yellow solid (4.2 mg, 37%).1H NMR (400 MHz, CDCl3): 3,71 (s, 3H); 3,76 (s, 3H); 3,82 (s, 2H); 3,85 (s, 3H); 6,55 (d, 1H, J=2.3 Hz); to 6.57 (DD, 1H, J1=8.0 Hz, J2=2.3 Hz); to 6.95 (d, 1H, J=3.5 Hz); 7,02 (d, 1H, J=3.5 Hz); to 7.15 (TD, 1H, J1=7,6 Hz, J2=1.0 Hz); 7,21 (d, 1H, J=8.0 Hz); 7,39 (d, 1H, J=7,6 Hz); 7,40 (d, 1H, J=7,6 Hz); 7,44 (t, 1H, J=7,6 Hz); to 7.61-to 7.67 (m, 2H); 7,89 (t, 1H, J=1.5 Hz); 8.34 per (users, 1H); and 8.50 (d, 1H, J=8.0 Hz).

Stage 2. Methyl ester of (5-{2-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (61) (45.0 mg, 0.09 mmol) dissolved in MeCN (0.9 ml) and added 1M aqueous LiOH (0.5 ml, 0.5 mmol). The reaction mixture was stirred over night etc is room temperature. Added dropwise 1M aqueous HCl to achieve a pH of approximately 3) and the solvent is removed under reduced pressure. The residue is dissolved in EtOAc and water and the separated aqueous layer was repeatedly extracted with EtOAc. The combined organic layer was washed with saturated salt solution and dried his Na2SO4thus (5-{2-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (62) as a yellow solid (48 mg, quantitative yield). Further purification is not used.1H NMR (400 MHz, CD3OD): 3,84 (users, 5H); to 3.89 (s, 3H); 6,65-6,70 (m, 2H); 6,98 (d, 1H, J=3.5 Hz); 7.18 in (d, 1H, J=3.5 Hz); 7,31 (d, 1H, J=8.0 Hz); 7,37 (TD, 1H, J1=7,6 Hz, J2=1.3 Hz); the 7.43 (TD, 1H, J1=7.8 Hz, J2=1.5 Hz); 7,52 (t, 1H, J=7.8 Hz); 7,63 (DD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,70-7,76 (m, 2H); 7,83 (d, 1H, J=7.8 Hz); 8,01 (users, 1H).

EXAMPLE 9

(5-{2-[(2',4'-Dihydroxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (63) and methyl ester of (5-{2-[(2',4'-dihydroxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (64)

Scheme 23

(The following reaction is carried out in an atmosphere of N2). (5-{2-[(2',4'-Dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (62) (48,0 mg, 0.10 mmol) dissolved in anhydrous dichloromethane (1.5 ml), the solution cooled to -78°C and added dropwise 1M solution of BBr3in dichloromethane (0.63 ml, 0,63 the mol). The reaction mixture was stirred for 30 min at -78°C and after a slow heat for an additional 2 h at room temperature. The mixture is cooled to 0°C., water is added dropwise followed by the addition with vigorous stirring of the Meon. The resulting mixture was concentrated under reduced pressure. The crude product is purified preparative RP-HPLC (gradient, water/CH3CN, 95:5 - 5:95), while receiving (5-{2-[(2',4'-dihydroxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (63) (3.7 mg, 8%) and methyl ester of (5-{2-[(2',4'-dihydroxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (64) (7,1 mg, 15%), both in the form of a yellow solid substance.1H NMR of compound (63) (400 MHz, CD3OD): 3,85 (s, 2H); 6.42 per-6,47 (m, 2H); 6,98 (d, 1H, J=3.5 Hz); 7.18 in (d, 1H, J=7,6 Hz); 7,19 (d, 1H, J=3.5 Hz); of 7.36 (dt, 1H, J1=7,6 Hz, J2=1.3 Hz), the 7.43 (TD, 1H, J1=7.8 Hz, J2=1.3 Hz); 7,51 (t, 1H, J=7.8 Hz); a 7.62 (DD, 1H, J1=7,6 Hz, J2=1.3 Hz); 7,75-7,81 (m, 3H); 8,08 (users, 1H),1H NMR of compound (64) (400 MHz, CD3OD): 3,66 (s, 3H); to 3.89 (s, 2H); 6,44 (DD, 1H, J1=7,0 Hz, J2=2.3 Hz); of 6.45 (s, 1H); 6,97 (d, 1H, J=3.5 Hz); 7.18 in (d, 1H, J=7,0 Hz); 7,19 (d, 1H, J=3.5 Hz); 7,37 (TD, 1H, J1=7,6 Hz, J2=1.3 Hz); the 7.43 (TD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,51 (t, 1H, J=7.8 Hz); 7,63 (DD, 1H, J1=7.8 Hz, J2=1.3 Hz); 7,72 (d, 1H, J=7.8 Hz); 7,80 (d, 1H, J=8.0 Hz); 7,81 (t, 1H, J=7,6 Hz); 8,07 (s, 1H).

EXAMPLE 10

Methyl ester of (5-{2-[(2',4'-dimethoxybiphenyl-3-carbonyl) - Amin is]phenyl}thiophene-2-carboxylic acid (65)

Scheme 24

Methyl ester of (5-{2-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (65) synthesized according to the procedure described in stage 1 of example 8, on the basis of aniline (45) and the acid chloride of the carboxylic acid (54), and was isolated as a yellow solid (147 mg, 62%).1H NMR (400 MHz, CDCl3): of 3.75 (s, 3H); 3,85 (s, 3H); a 3.87 (s, 3H); is 6.54 (s, 1H); to 6.57 (DD, 1H, J1=8.6 Hz, J2=2.0 Hz); 7,17 (d, 1H, J=4.3 Hz); 7,19 (d, 1H, J=9.0 Hz); then 7.20 (t, 1H, J=8.6 Hz); 7,41 (d, 1H, J=7.8 Hz); 7,44 (t, 1H, J=7.8 Hz); 7,46 (t, 1H, J=8.0 Hz); to 7.64 (d, 1H, J=8,3 Hz); 7,66 (d, 1H, J=7,8 Hz); 7,80 (d, 1H, J=4.0 Hz); 7,83 (s, 1H); 8,19 (users, 1H); of 8.47 (d, 1H, J=8,3 Hz).

EXAMPLE 11

(5-{2-[(2',4'-Dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (66)

Scheme 25

Saponification of the methyl ester of carboxylic acid (65) in a mixture of THF and the Meon (3+2) according to the procedure described in step 2 of example 8, gives (5-{2-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (66) as a yellow oil (130 mg, quantities. output).1H NMR (400 MHz, CD3OD): a 3.83 (s, 3H); 3,88 (s, 3H); 6,66 (DD, 1H, J1=8.0 Hz, J2=2.3 Hz); to 6.67 (s, 1H); 7,31 (d, 1H, J=8.0 Hz); of 7.36 (d, 1H, J=4.0 Hz); 7,44 (TD, 1H, J1=7.8 Hz, J2=1.0 Hz); of 7.48-7,53 (m, 1H); 7,52 (t, 1H, J=7.8 Hz); the 7.65 (d, 1H, J=7.8 Hz); 7,71 (d, 1H, J=7.8 Hz); 7,73 (d, 1H, J=8,3 Hz); 7,76 (d, 1H, J=4.0 Hz); to 7.84 (d, 1H, J=7.8 Hz); 8,01 (s, 1H).

EXAMPLE 12

(5-{2-[(2',4'-Dihydroxybiphenyl-3-arbonyl)amino]phenyl}thiophene-2-carboxylic acid (67)

Scheme 26

(The following reaction is carried out in an atmosphere of N2). (5-{2-[(2',4'-Dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (66) (88,6 mg, 0,19 mmol) suspended in anhydrous dichloromethane (4.0 ml), the mixture is cooled to -78°C and added dropwise 1M solution of BBr3in dichloromethane (to 0.80 ml, 0.80 mmol). The reaction mixture was stirred for 30 min at -78°C and after a slow heat for an additional 2 h at room temperature. The reaction mixture was cooled to 0°C., added dropwise ice water, the layers separated and the aqueous layer was extracted with EtOAc (3 times). The combined organic layer was washed with saturated salt solution and dried Na2SO4. The crude product is purified preparative RP-HPLC (gradient, water/CH3CN, 95:5 - 5:95), while receiving (5-{2-[(2',4'-dihydroxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (67) in the form of not-quite-white solid (23 mg, 26%).1H NMR (400 MHz, CD3OD): 6,44 (DD, 1H, J1=7.8 Hz, J2=2.3 Hz); of 6.45 (s, 1H); 7,19 (d, 1H, J=7.8 Hz); to 7.35 (d, 1H, J=4.0 Hz); 7,42 (t, 1H, J=7,6 Hz); 7,50 (TD, 1H, J1=7,6 Hz, J2=1.3 Hz); 7,51 (t, 1H, J=7.8 Hz); of 7.69 (d, 2H, J=7,6 Hz); 7,72 (d, 1H, J=3.8 Hz); 7,80 (d, 2H, J=7.8 Hz); of 8.09 (s, 1H).

EXAMPLE 13

Methyl ester of (5-{2-[2-(2',4'-dimethoxybiphenyl-3-yl)acetylamino]phenyl}thiophene-2-yl)acetic acid (68)

Scheme 27

Methyl ester of (5-{2-[2-(2',4'-dimethoxybiphenyl-3-yl)acetylamino]phenyl}thiophene-2-yl)acetic acid (68) synthesized according to the procedure described in stage 1 of example 4, based on the aniline (43) and carboxylic acid (57), and was isolated as a white solid (117 mg, 57%).1H NMR (400 MHz, CDCl3): 3,66 (s, 2H); 3,71 (s, 3H); and 3.72 (s, 2H); to 3.73 (s, 3H); of 3.84 (s, 3H); to 6.39 (d, 1H, J=3.0 Hz); 6,53 (s, 1H); 6,51-to 6.57 (m, 2H); 7,06 (t, 1H, J=8,3 Hz); 7,07 (d, 1H, J=8.0 Hz); 7,13 (d, 1H, J=8.6 Hz); 7,22-7,27 (m, 1H); 7,28 (t, 1H, J=7.8 Hz); 7,31 (t, 1H, J=7.8 Hz); 7,33 (s, 1H); 7,42 (d, 1H, J=7.8 Hz); 7,66 (s, 1H); scored 8.38 (d, 1H, J=8,3 Hz).

EXAMPLE 14

(5-{2-[2-(2',4'-Dimethoxybiphenyl-3-yl)acetylamino]phenyl}thiophene-2-yl)acetic acid (69)

Scheme 28

Saponification of the methyl ester acetic acid (68) in MeCN according to the procedure described in step 2 of example 8, gives (5-{2-[2-(2',4'-dimethoxybiphenyl-3-yl)acetylamino]phenyl}thiophene-2-yl)acetic acid (69) as a yellow oil (117 mg, 96%).1H NMR (400 MHz, CD3OD): and 3.72 (s, 2H); 3.75 to (s, 2H); of 3.80 (s, 3H); 3,88 (s, 3H); only 6.64 (DD, 1H, J1=8.6 Hz, J2=2.3 Hz); 6,66 (m, 1H); 6,70 (d, 1H, J=3.0 Hz); is 6.78 (d, 1H, J=3.5 Hz); 7,22-7,27 (m, 1H); to 7.25 (d, 1H, J=8.6 Hz); 7,26 (t, 1H, J=7,6 Hz); of 7.36 (t, 2H, J=7.8 Hz); 7,42-7,49 (m, 3H); 7,74 (d, 1H, J=8.0 Hz,).

EXAMPLE 15

(5-{2-[2-(2',4'-Dihydroxybiphenyl-3-yl)acetylamino]phenyl}thiophene-2-yl)acetic acid (70)

Scheme 29

According to the method described in example 12, reaction of carboxylic acid is you (69) with a 1M solution of BBr 3give (5-{2-[2-(2',4'-dihydroxybiphenyl-3-yl)acetylamino]phenyl}thiophene-2-yl)acetic acid (70) in the form of not-quite-white solid (61 mg, 55%).1H NMR (400 MHz, CD3OD): 3,75 (s, 2H); 3,76 (s, 2H); 6.42 per (DD, 1H, J1=8,3 Hz, J2=2.3 Hz); 6,44 (d, 1H, J=2.3 Hz); 6,74 (d, 1H, J=3.5 Hz); for 6.81 (d, 1H, J=3.5 Hz); 7,11 (d, 1H, J=8,3 Hz); 7,22 (d, 1H, J=7,6 Hz); 7,26 (t, 1H, J=7,6 Hz); to 7.35 (t, 2H, J=7.8 Hz); 7,46 (d, 1H, J=7,8 Hz); of 7.48-7,52 (m, 1H); 7,51 (s, 1H); for 7.78 (d, 1H, J=8,1 Hz).

EXAMPLE 16

[5-(2-{[5-(2,4-Dihydroxyphenyl)pyridine-3-carbonyl]amino}phenyl)thiophene-2-yl]acetic acid (73) and methyl ester [5-(2-{[5-(2,4-dihydroxyphenyl)pyridine-3-carbonyl]amino}phenyl)thiophene-2-yl]acetic acid (74)

Scheme 30

Stage 1. (The following reaction is carried out in an atmosphere of N2). Methyl ester [5-(2-AMINOPHENYL)thiophene-2-yl]acetic acid (43) (250 mg, 1.01 mmol) was dissolved in anhydrous6H6(4,0 ml). Add a solution of 5-bromonicotinate (223 mg, 1.01 mmol) and the resulting suspension is stirred over night at room temperature. The solvent is removed under reduced pressure. The crude product is purified preparative radial chromatography (silica gel 60PF, CyH/EtOAc, 3+1, then 1+1 and then EtOAc and EtOAc/Meon, 1+1), while receiving methyl ester (5-{2-[(5-bromopyridin-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (71) as a yellow solid (216 mg, 49%).1H YAM who (400 MHz, CD3OD): 3,71 (s, 3H); 3,90 (s, 2H); 6,97 (d, 1H, J=3.5 Hz); 7.18 in (d, 1H, J=3.5 Hz); 7,41 (TD, 1H, J1=7,3 Hz, J2=1,8 Hz); was 7.45 (TD, 1H, J1=7,3 Hz, J2=2.0 Hz); to 7.59 (DD, 1H, J1=7,3 Hz, J2=2.0 Hz); to 7.67 (DD, 1H, J1=7,1 Hz, J2=2.0 Hz); charged 8.52 (s, 1H); 8,88 (m, 1H); 9,05 (s, 1H).

Stage 2. (The following reaction is carried out in an atmosphere of N2). Tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) and methyl ester of (5-{2-[(5-bromopyridin-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (71) (150 mg, 0.35 mmol) dissolved in DME (1,4 ml). Add 2,4-dimethoxyaniline acid (95,0 mg, 0.52 mmol) and 1M aqueous solution of NaHCO3(1.0 ml, 1.0 mmol), the reaction mixture is carefully Tegaserod (5 times) and rinsed with a jet of N2. The resulting mixture is stirred for 1 h at 90°C. and again cooled to room temperature. The solvent is removed under reduced pressure, the residue is dissolved in Meon and the filtrate is passed through a low layer of silica gel. The filtrate is concentrated under reduced pressure and the crude product is purified preparative radial chromatography (silica gel 60PF, CyH/EtOAc, 1+1), while receiving methyl ester [5-(2-{[5-(2,4-acid)pyridine-3-carbonyl]amino}phenyl)thiophene-2-yl]acetic acid (72) as a yellow sticky oil (121 mg, 71%).1H NMR (400 MHz, CD3OD): to 3.64 (s, 3H); 3,89 (users, 5H); 3,90 (s, 3H); 6,70 to 6.75 (m, 1H); 6,74 (s, 1H); 6,97 (d, 1H, J=3.3 Hz); then 7.20 (d, 1H, J=3.5 Hz); 7,37-7,44 (m, 2H); 7,4 (TD, 1H, J1=7,3 Hz, J2=1.3 Hz); to 7.61-7,72 (m, 3H); 8,44 (s, 1H); 8,87 (s, 1H); 8,97 (s, 1H).

Stage 3. (The following reaction is carried out in an atmosphere of N2). Methyl ester [5-(2-{[5-(2,4-acid)pyridine-3-carbonyl]amino}phenyl)thiophene-2-yl]acetic acid (72) (50 mg, 0.10 mmol) dissolved in anhydrous dichloromethane (1.2 ml), the solution cooled to -78°C and added dropwise 1M solution of BBr3in dichloromethane (of 1.10 ml, 1.10 mmol). The reaction mixture was stirred for 30 min at -78°C and for an additional 1 h at room temperature. The mixture is cooled to 0°C. add dropwise water and concentrated under reduced pressure. The crude product is purified preparative RP-HPLC (gradient, water/CH3CN, 95:5 - 5:95), while receiving [5-(2-{[5-(2,4-dihydroxyphenyl)pyridine-3-carbonyl]amino}phenyl)thiophene-2-yl]acetic acid (73) as a yellow solid (12.6 mg, 46%) and methyl ester [5-(2-{[5-(2,4-dihydroxyphenyl)pyridine-3-carbonyl]amino}phenyl)thiophene-2-yl]acetic acid (74) as a brown solid (to 21.9 mg, 47%).1H NMR of compound (73) (400 MHz, CD3OD): 3,86 (s, 2H); of 6.49 (DD, 1H, J1=9.1 Hz, J2=2.3 Hz); of 6.49 (d, 1H, J=2.0 Hz); 6,98 (d, 1H, J=3.5 Hz); then 7.20 (d, 1H, J=3.5 Hz); 7,26 (d, 1H, J=9.1 Hz); 7,40 (TD, 1H, J1=7,6 Hz, J2=1.5 Hz); was 7.45 (TD, 1H, J1=7,6 Hz, J2=1,8 Hz); 7,66 (DD, 1H, J1=7,6 Hz, J2=1,8 Hz); 7,66-of 7.70 (m, 1H); 8,50 (users, 1H); 8,92 (users, 1H); of 8.95 (s, 1H).1H NMR of compound (7) (400 MHz, CD3OD): the 3.65 (s, 3H); to 3.89 (s, 2H); 6,51 (s, 1H); of 6.52 (DD, 1H, J1=8,3 Hz, J2=2.3 Hz); 6,97 (d, 1H, J=3.5 Hz); 7,21 (d, 1H, J=3.5 Hz); of 7.36 (d, 1H, J=8,3 Hz); the 7.43 (TD, 1H, J1=7,3 Hz, J2=1.5 Hz); 7,46 (TD, 1H, J1=7,6 Hz, J2=1,8 Hz); 7,63-of 7.69 (m, 2H); 8,80 (users, 1H); 9,00 (users, 1H); 9,11 (s, 1H).

EXAMPLE 17

Methyl ester 5-(4-{[5-(2,4-acid)pyridine-3-carbonyl]amino}phenyl)-2-methylfuran-3-carboxylic acid (75)

Scheme 31

Methyl ester 5-(4-{[5-(2,4-acid)pyridine-3-carbonyl]amino}phenyl)-2-methylfuran-3-carboxylic acid (75) synthesized according to the procedure described in stages 1 and 2 of example 16, on the basis of aniline (47) and 5-bromonicotinate, and isolated in the form of a gray solid (103 mg, yield 32% after 2 stages).1H NMR (400 MHz, CD3OD): in 2.68 (s, 3H); to 3.89 (s, 3H); 3,90 (s, 3H); 3,91 (s, 3H); of 6.71-6,76 (m, 2H); 6,99 (s, 1H); 7,42 (d, 1H, J=8,1 Hz); 7,74 (d, 2H, J=8.6 Hz); to 7.84 (d, 2H, J=8.6 Hz); of 8.47 (t, 1H, J=2.0 Hz); 8,87 (d, 1H, J=2.0 Hz); 9,00 (d, 1H, J=2.0 Hz).

EXAMPLE 18

5-(4-{[5-(2,4-Dihydroxyphenyl)pyridine-3-carbonyl]amino}phenyl)-2-methylfuran-3-carboxylic acid (76)

Scheme 32

According to the method described in stage 3 of example 16, the reaction of the amide (75) with a 1M solution of BBr3gives 5-(4-{[5-(2,4-dihydroxyphenyl)pyridine-3-carbonyl]amino}phenyl)-2-methylfuran-3-carboxylic acid (76) as a brown solid (22 mg, 24%).1H NMR (400 MHz, CD3 OD): 2,69 (s, 3H); 3,39 (s, 1H); 6,51 (s, 1H); of 6.52 (DD, 1H, J1=8,1 Hz, J2=2.3 Hz); 6,98 (s, 1H); of 7.36 (d, 1H, J=8,1 Hz); 7,74 (userd, 2H, J=8.6 Hz); a 7.85 (userd, 2H, J=8.6 Hz); 8,73 (s, 1H); remaining 9.08 (users, 2H).

EXAMPLE 19

Methyl ester of 3-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]benzoic acid (77)

Scheme 33

Methyl ester of 3-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]benzoic acid (77) synthesized according to the procedure described in stage 1 of example 8, based on the methyl ester of 3-aminobenzoic acid and 2',4'-dimethoxybiphenyl-3-carbonylchloride (54), and was isolated as a colourless oil (143 mg, 73%).1H NMR (400 MHz, CDCl3): of 3.80 (s, 3H); 3,85 (s, 3H); 3,91 (s, 3H); to 6.57 (s, 1H); to 6.58 (DD, 1H, J1=8,1 Hz, J2=2.3 Hz); 7,26 (d, 1H, J=8,1 Hz); was 7.45 (t, 1H, J=7.8 Hz); 7,50 (t, 1H, J=7.8 Hz); to 7.68 (dt, 1H, J1=7.8 Hz, J2=1.3 Hz); 7,78 (DDD, 1H, J1=7.8 Hz, J2=1.8 Hz, J3=1,3H); 7,81 (dt, 1H, J1=7.8 Hz, J2=1.3 Hz); 7,88 (users, 1H); 7,97 (t, 1H, J=1.8 Hz); 8,04 (DDD, 1H, J1=8,1 Hz, J2=2.3 Hz, J3=1.0 Hz); 8,13 (t, 1H, J=1.8 Hz).

EXAMPLE 20

3-[(2',4'-Dimethoxybiphenyl-3-carbonyl)amino]benzoic acid (78)

Scheme 34

Saponification of the methyl ester of carboxylic acid (77) in MeCN according to the procedure described in step 2 of example 8, gives 3-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]benzoic acid (78) as a white solid (109 mg, 80%).1H NMR (400 is Hz, (CD3)2SO): of 3.77 (s, 3H); 3,81 (s, 3H); of 6.65 (DD, 1H, J1=8,3 Hz, J2=2.3 Hz); 6,69 (d, 1H, J=2.3 Hz); to 7.32 (d, 1H, J=8,3 Hz); was 7.45 (t, 1H, J=7.8 Hz); 7,52 (t, 1H, J=7.8 Hz); 7,66 (userd, 2H, J=7,6 Hz); 7,87 (dt, 1H, J1=7.8 Hz, J2=1.5 Hz); 8,00-with 8.05 (m, 1H); 8,01 (t, 1H, J=1.5 Hz); scored 8.38 (users, 1H); accounted for 10.39 (s, 1H).

EXAMPLE 21

3-[(2',4'-Dihydroxybiphenyl-3-carbonyl)amino]benzoic acid (79)

Scheme 35

According to the method described in example 12, reaction of carboxylic acid (78) with a 1M solution of BBr3gives 3-[(2',4'-dihydroxybiphenyl-3-carbonyl)amino]benzoic acid (79) in the form of not-quite-white solid (19 mg, 26%).1H NMR (400 MHz, (CD3OD): 6,45 (DD, 1H, J1=8,1 Hz, J2=2.3 Hz); 6,46 (s, 1H); 7,22 (d, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,44 (t, 1H, J=7.8 Hz); 7,53 (t, 1H, J=7.8 Hz); to 7.77-of 7.82 (m, 2H); a 7.85 (d, 1H, J=7.8 Hz); 8,04 (d, 1H, J=8,1 Hz); 8,10-of 8.15 (m, 1H); to 8.12 (t, 1H, J=1.8 Hz).

EXAMPLE 22

Methyl ester of (5-{2-[(3',5'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (80)

Scheme 36

Methyl ester of (5-{2-[(3',5'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (80) synthesized according to the procedure described in stage 1 of example 8, on the basis of aniline (43) and 3',5'-dimethoxybiphenyl-3-carbonylchloride (60). In contrast to the methods of purification described here, the crude product (80) is suspended in EtOAc, filtered and the filter residue p is washed by EtOAc (2 times). Connection (80) receives a yellow solid (187 mg, 68%).1H NMR (400 MHz, CDCl3): 3,71 (s, 3H); of 3.84 (s, 6H); a 3.87 (s, 2H); 6.48 in (t, 1H, J=2.3 Hz); 6,69 (d, 2H, J=2.3 Hz); 6,99-7,02 (m, 1H); 7.03 is (d, 1H, J=3.5 Hz); 7,17 (DD, 1H, J1=7,6 Hz, J2=1.3 Hz); 7,39-7,44 (m, 2H); to 7.50 (t, 1H, J=7.8 Hz); 7.68 per-7,73 (m, 2H); of 7.90-7,94 (m, 1H); 8,43 (s, 1H); 8,53 (d, 1H, J=7,6 Hz).

EXAMPLE 23

(5-{2-[(3',5'-Dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (81)

Scheme 37

Saponification of the methyl ester of carboxylic acid (80) in MeCN in accordance with the method described above in stage 2 of example 8, gives (5-{2-[(3',5'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (81) as a yellow solid (188 mg, quantitative yield).1H NMR (400 MHz, CD3OD): a 3.83 (s, 2H); 3,89 (users, 6H); 6,56 (t, 1H, J=2.3 Hz); 6,86 (d, 2H, J=1,8 Hz); 6,97-7,00 (m, 1H); 7,19 (d, 1H, J=3.5 Hz); 7,38 (TD, 1H, J1=7,6 Hz, J2=1.3 Hz); 7,44 (TD, 1H, J1=7,6 Hz, J2=1.5 Hz); to 7.61 (t, 1H, J=7.8 Hz); to 7.64 (DD, 1H, J1=7.8 Hz, J2=1.3 Hz); 7,72-7,76 (m, 1H); 7,84-7,87 (m, 1H); of 7.90-7,94 (m, 1H); 8,16 (users, 1H).

EXAMPLE 24

(5-{2-[(3',5'-Dihydroxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (82)

Scheme 38

According to the method described above in example 12, reaction of carboxylic acid (81) with a 1M solution of BBr3give (5-{2-[(3',5'-dihydroxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid is the (82) as a pale yellow solid (33 mg, 35%).1H NMR (400 MHz, CD3OD): a 3.87 (s, 2H); 6,34 (t, 1H, J=2.0 Hz); 6,63 (d, 2H, J=2.0 Hz); 7,01 (d, 1H, J=3.5 Hz); then 7.20 (d, 1H, J=3.5 Hz); 7,38 (TD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,44 (TD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,58 (t, 1H, J=7.8 Hz); to 7.64 (DD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,74 (d, 1H, J=7.8 Hz); 7,79 (DD, 1H, J1=7.8 Hz, J2=1.0 Hz); 7,89 (d, 1H, J=7,6 Hz); 8,10 (s, 1H).

EXAMPLE 25

Methyl ester 5-{2-[(3',5'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (83)

Scheme 39

Methyl ester of (5-{2-[(3',5'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (83) synthesized according to the procedure described in stage 1 of example 8, on the basis of aniline (45) and the acid chloride of the carboxylic acid (60). In contrast to the methods of purification described here, the crude product (80) is suspended in EtOAc, filtered and the filter residue washed with EtOAc (2 times). Connection (83) receives a yellow solid (168 mg, 63%).1H NMR (400 MHz, CDCl3): of 3.84 (s, 6H); a 3.87 (s, 3H); 6.48 in (t, 1H, J=2.0 Hz); 6.89 in (d, 2H, J=2.0 Hz); then 7.20 (d, 1H, J=3.8 Hz); 7,21-7,25 (m, 1H); the 7.43 (TD, 1H, J1=7.8 Hz, J2=1.5 Hz); 7,47 (t, 1H, J=7.8 Hz); 7,49 (t, 1H, J=7.8 Hz); the 7.65 (d, 1H, J=7.8 Hz); 7,72 (DD, 1H, J1=7.8 Hz, J2=1.0 Hz); to 7.84 (d, 1H, J=3.8 Hz); of 7.97 (d, 1H, J=1.5 Hz); by 8.22 (s, 1H); 8,46 (d, 1H, J=7,8 Hz).

EXAMPLE 26

5-{2-[(3',5'-Dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (84)

Scheme 40

Saponification of the methyl ester of carboxylic acid (83) in MeCN in accordance with the method described above in stage 2 of example 8, gives (5-{2-[(3',5'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (84) as a white solid (159 mg, 97%).1H NMR (400 MHz, CD3OD): 3,88 (s, 6H); 6,55 (t, 1H, J=2.0 Hz); 6,86 (users, 2H); 7,38 (d, 1H, J=3.8 Hz); 7,46 (TD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,52 (TD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,58-the 7.65 (m, 2H); 7,71-7,74 (m, 1H); of 7.75 (d, 1H, J=3.8 Hz); 7,87 (DD, 1H, J1=7.8 Hz, J2=1.0 Hz); to $ 7.91-of 7.96 (m, 1H); 8,19 (s, 1H).

EXAMPLE 27

5-{2-[(3',5'-Dihydroxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (85)

Scheme 41

According to the method described above in example 12, reaction of carboxylic acid (84) with a 1M solution of BBr3give (5-{2-[(3',5'-dihydroxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (85) as a white solid (24 mg, 50%).1H NMR (400 MHz, CD3OD): 6,33 (t, 1H, J=2.0 Hz); 6,66 (d, 2H, J=2.0 Hz); 7,38 (d, 1H, J=4.0 Hz); 7,46 (TD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,52 (TD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,58 (t, 1H, J=7,6 Hz); 7,63 (d, 1H, J=7,6 Hz); 7,73 (DD, 1H, J1=7,6 Hz, J2=1.3 Hz); of 7.75 (d, 1H, J=4,0); 7,80 (d, 1H, J=7.8 Hz); 7,87-to $ 7.91 (m, 1H); is 8.16 (s, 1H).

EXAMPLE 28

(2-Thiophene-2-ylphenyl)amide 2',4'-dimethoxybiphenyl-3-carboxylic acid (86)

Scheme 42

(2-Thiophene-2-ylphenyl)amide 2',4'-Dimitar biphenyl-3-carboxylic acid (86) synthesized according to the method described above in stage 1 of example 8, on the basis of aniline (48) and 2',4'-dimethoxybiphenyl-3-carbonylchloride (54), and was isolated as a pale yellow solid (159 mg, 58%).1H NMR (400 MHz, C6D6): of 3.27 (s, 3H); 3,50 (s, 3H); of 6.52 (DD, 1H, J1=8,3 Hz, J2=2,5 Hz); to 6.58 (d, 1H, J=2.5 Hz); 6,76 (DD, 1H, J1=5.0 Hz, J2=3.5 Hz); 6.87 in (DD, 1H, J1=3.5 Hz, J2=1.3 Hz); 6,92 (DD, 1H, J1=5.0 Hz, J2=1.3 Hz); 6,98 (TD, 1H, J1=7,6 Hz, J2=1.3 Hz); of 7.23 (t, 1H, J=7,6 Hz); 7,28-7,33 (m, 1H); 7,39 (DD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,71 (dt, 1H, J1=7.8 Hz, J2=1.3 Hz); to 7.77 (DDD, 1H, J1=7.8 Hz, J2=1.5 Hz, J3=1.3 Hz); 8,28 (t, 1H, J=1.5 Hz); 8,46 (users, 1H); 9,18 (d, 1H, J=8,3 Hz).

EXAMPLE 29

(2-Thiophene-2-ylphenyl)amide 2',4'-dihydroxybiphenyl-3-carboxylic acid (87)

Scheme 43

(The following reaction is carried out in an atmosphere of N2). (2-Thiophene-2-ylphenyl)amide 2',4'-dimethoxybiphenyl-3-carboxylic acid (86) (122 mg, 0.29 mmol) suspended in anhydrous dichloromethane (9.7 ml), the mixture is cooled to -78°C and added dropwise 1M solution of BBr3in dichloromethane (1,17 ml of 1.17 mmol). The reaction mixture was stirred for 30 min at -78°C, slowly heated to 0°C. over a period of 2 h) and stirred for an additional 30 min at 0°C. Slowly add ice water, the mixture is stirred for 1 h at room temperature to complete the reaction, the layers based on separate treatment of the t and the aqueous layer was extracted with EtOAc (3 times). The combined organic layer was washed with saturated salt solution and dried Na2SO4. The crude product is purified preparative RP-HPLC (gradient, water/CH3CN, 95:5 - 5:95), while receiving (2-thiophene-2-ylphenyl)amide 2',4'-dihydroxybiphenyl-3-carboxylic acid (87) in the form of not-quite-white solid (35 mg, 31%).1H NMR (400 MHz, CD3OD): 6,41-6,46 (m, 2H); 7,14 (DD, 1H, J1=5.0 Hz, J2=3.5 Hz); 7,17 (d, 1H, J=8,1 Hz); of 7.36 (DD, 1H, J1=3.5 Hz, J2=1.0 Hz); 7,39 (DD, 1H, J1=7,6 Hz, J2=1.0 Hz); was 7.45 (TD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,47-7,49 (m, 1H); to 7.50 (t, 1H, J=7.8 Hz); the 7.65 (DD, 1H, J1=7,6 Hz, J2=1.5 Hz); 7,72 (d, 1H, J=7.8 Hz); 7,75-7,81 (m, 2H); of 8.06 (s, 1H).

EXAMPLE 30

Methyl ester of (5-{3-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (88)

Scheme 44

Methyl ester of (5-{3-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (88) synthesized according to the method described above in stage 1 of example 8, reaction time 3 h, based on aniline (50) and the acid chloride of the carboxylic acid (54), and was isolated as a yellow solid (213 mg, 87%).1H NMR (400 MHz, CDCl3): to 3.73 (s, 3H); of 3.80 (s, 3H); a 3.83 (s, 2H); 3,85 (s, 3H); to 6.57 (s, 1H); to 6.58 (DD, 1H, J1=8,3 Hz, J2=2.3 Hz); 6.89 in (d, 1H, J=3.5 Hz); 7.18 in (d, 1H, J=3.5 Hz); 7,27 (d, 1H, J=8,3 Hz); 7,32-7,37 (m, 2H); to 7.50 (t, 1H, J=7,6 Hz); 7,54-7,58 (m, 1H); to 7.68 (dt, 1H, J1=7.8 Hz, J2=1.3 Hz); 7,79 dt, 1H, J1=7.8 Hz, J2=1.3 Hz); 7,79-of 7.82 (m, 1H); 7,86 (t, 1H, J=1.3 Hz); 7,97 (t, 1H, J=1.5 Hz).

EXAMPLE 31

(5-{3-[(2',4'-Dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (89)

Scheme 45

Methyl ester of (5-{3-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (88) (190 mg, 0,39 mmol) dissolved in MeCN (3,9 ml), add 1M aqueous LiOH (1.9 ml, 1.9 mmol) and the mixture is stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure and add 1M aqueous HCl (approximately 2 ml, to achieve a pH of approximately 3). Add EtOAc and water and the separated aqueous layer is extracted with EtOAc several times. The combined organic layer was washed with saturated salt solution and dried his Na2SO4thus (5-{3-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (89) as an orange solid (185 mg, quantitative yield). Further purification is not used.1H NMR (400 MHz, CD3CN): 3,81 (s, 3H); of 3.84 (s, 3H); 3,85 (s, 2H); only 6.64 (DD, 1H, J1=8,3 Hz, J2=2.3 Hz); 6,66 (d, 1H, J=2.3 Hz); 6,94 (d, 1H, J=3.5 Hz); of 7.25 (d, 1H, J=3.5 Hz); 7,33 (d, 1H, J=8,3 Hz); of 7.36-7,41 (m, 2H); 7,52 (t, 1H, J=7.8 Hz); to 7.67-7,71 (m, 2H); a 7.85 (d, 1H, J=7.8 Hz); 8,02 (users, 2H); 8,80 (s, 1H).

EXAMPLE 32

(5-{3-[(2',4'-Dihydroxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (90)

Scheme 46

img src="https://img.russianpatents.com/1093/10930823-s.jpg" height="46" width="87" />

According to the method described above in example 12, reaction of carboxylic acid (89) with a 1M solution of BBr3give (5-{3-[(2',4'-dihydroxybiphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (90) as a yellow-brown solid (1.2 mg, 1.3 per cent).1H NMR (400 MHz, CD3OD): the 3.89 (s, 2H); 6,45 (DD, 1H, J1=8,1 Hz, J2=2.3 Hz); 6,46 (s, 1H); 6,97 (d, 1H, J=3.5 Hz); 7,22 (d, 1H, J=8,1 Hz); 7,30 (d, 1H, J=3.5 Hz); 7,40 (t, 1H, J=7,6 Hz); 7,41 was 7.45 (m, 1H); rate of 7.54 (t, 1H, J=7,6 Hz); to 7.67 (d, 1H, J=7,3 Hz); 7,80 (d, 1H, J=7,8 Hz); a 7.85 (d, 1H, J=7.8 Hz); 8,07 (s, 1H); to 8.12 (s, 1H).

EXAMPLE 33

Methyl ester 5-{6-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]pyridine-3-yl}-2-methylfuran-3-carboxylic acid (91) and 5-{6-[(2',4'-dihydroxybiphenyl-3-carbonyl)amino]pyridine-3-yl}-2-methylfuran-3-carboxylic acid (93)

Scheme 47

Stage 1. (The following reaction is carried out in an atmosphere of N2). Methyl ester 5-(6-aminopyridine-3-yl)-2-methylfuran-3-carboxylic acid (51) (80.0 mg, 0.34 mmol) dissolved in anhydrous dichloromethane (5.4 ml) and anhydrous pyridine (1.2 ml) and the reaction mixture is cooled to 0°C. is Slowly added a suspension of 2',4'-dimethoxybiphenyl-3-carbonylchloride (54) (105 mg, 0.38 mmol) in dichloromethane (3.0 ml) and the reaction mixture stirred for 1 h at 0°C and 19 h at room temperature. The reaction mixture was separated between water and EtOAc and the aqueous layer was extracted with EtOAc (3×). The combined organic is the cue layer washed with water (6 times) to remove pyridine and saturated salt solution and dried Na 2SO4. The crude product is purified preparative radial chromatography (silica gel, 60PF, CyH/EtOAc, 2+1), while receiving methyl ester 5-{6-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]pyridine-3-yl}-2-methylfuran-3-carboxylic acid (91) in the form of not-quite-white solid (74 mg, 45%).1H NMR (400 MHz, CDCl3): to 2.65 (s, 3H); of 3.80 (s, 3H); of 3.84 (s, 3H); 3,85 (s, 3H); to 6.57 (s, 1H); to 6.58 (DD, 1H, J1=8,1 Hz, J2=2,5 Hz); 6.89 in (s, 1H); 7,26 (d, 1H, J=8,1 Hz); 7,51 (t, 1H, J=7,6 Hz); of 7.70 (dt, 1H, J1=7.8 Hz, J2=1.3 Hz); to 7.84 (dt, 1H, J1=7.8 Hz, J2=1.3 Hz); of 7.97 (DD, 1H, J1=8,8 Hz, J2=2.3 Hz); 8,03 (t, 1H, J=1.5 Hz); to 8.45 (d, 1H, J=8,8 Hz); to 8.57 (d, 1H, J=2.3 Hz); 8,70 (users, 1H).

Stage 2. Methyl ester 5-{6-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]pyridine-3-yl}-2-methylfuran-3-carboxylic acid (91) (67,1 mg, 0.14 mmol) dissolved in THF (3 ml) and Meon (0.5 ml) and added 1M aqueous LiOH (of 0.71 ml, 0.71 mmol). The reaction mixture was stirred 16 h at room temperature. The solvents are removed under reduced pressure and the residue dissolved in a mixture of THF/acetonitrile (2+1). Add amberlit IRC86 and the mixture is stirred an additional 2 h at room temperature. Remove supernatant and the remaining resin is stirred several times (10 min each time) with new portions of THF and acetonitrile. The collected supernatant concentrated under reduced pressure, thus obtaining the crude 5-{6-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]the feast of the DIN-3-yl}-2-methylfuran-3-carboxylic acid (92) as a pale yellow solid (87 mg, quantitative yield) without further purification.1H NMR (400 MHz, (CD3)2SO): 2,61 (s, 3H); of 3.77 (s, 3H); 3,81 (s, 3H); of 6.65 (DD, 1H, J1=8.6 Hz, J2=2,5 Hz); of 6.68 (d, 1H, J=2.5 Hz); 7,19 (s, 1H); 7,38 (d, 1H, J=8,3 Hz); 7,50 (t, 1H, J=7.8 Hz); to 7.68 (dt, 1H, J1=7.8 Hz, J2=1.3 Hz); to $ 7.91 (dt, 1H, J1=7.8 Hz, J2=1.3 Hz); with 8.05 (t, 1H, J=1.5 Hz); 8,13 (DD, 1H, J1=8,8 Hz, J2=2.3 Hz); of 8.27 (d, 1H, J=8,8 Hz); is 8.75 (d, 1H, J=1.3 Hz); 11,00 (s, 1H); 12,69 (users, 1H).

Stage 3. (The following reaction is carried out in an atmosphere of N2). Acid (92) (63,9 mg, 0.14 mmol) dissolved in a mixture of anhydrous 1,2-dichloroethane (4.0 ml) and anhydrous dichloromethane (1.0 ml), the solution is cooled to -50°C and added dropwise 1M solution of BBr3in dichloromethane (to 0.70 ml, 0.70 mmol). The reaction mixture was stirred for 30 min at -78°C and after removal of the cooling bath for an additional 1.5 h at room temperature. The mixture is cooled to 0°C., added dropwise water and the resulting mixture is stirred for 30 min at room temperature. The mixture is concentrated under reduced pressure and the crude product is purified preparative RP-HPLC (gradient, water/CH3CN, 95:5 - 5:95), while receiving 5-{6-[(2',4'-dihydroxybiphenyl-3-carbonyl)amino]pyridine-3-yl}-2-methylfuran-3-carboxylic acid (93) (18 mg, 30%) as not quite white solid.1H NMR (400 MHz, CD3OD): 2,70 (s, 3H); 6,45 (DD, 1H, J1=7.8 Hz, J2=2.3 Hz); 6,47 (s, 1H); 7,09 (OSiR.the, 1H); 7,22 (DD, 1H, J1=7.8 Hz, J2=1.0 Hz); 7,56 (t, 1H, J=7.8 Hz); of 7.82 (d, 1H, J=7.8 Hz); 7,88 (d, 1H, J=7,6 Hz); 8,15 (users, 2H); at 8.36 (userd, 1H, J=7.8 Hz); 8,72 (users, 1H).

EXAMPLE 34

Ethyl ester of 5-{4-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}-2-methylfuran-3-carboxylic acid (94)

Scheme 48

Ethyl ester of 5-{4-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}-2-methylfuran-3-carboxylic acid (94) synthesized according to the method described above in stage 1 of example 8, on the basis of aniline (25) and the acid chloride of the carboxylic acid (54), and was isolated as a yellow solid (190 mg, 64%).1H NMR (400 MHz, C6D6): of 1.17 (t, 3H, J=7,1 Hz); at 2.59 (s, 3H); of 3.32 (s, 3H); 3,50 (s, 3H); 4,24 (q, 2H, J=7,1 Hz); 6,55 (DD, 1H, J1=8,3 Hz, J2=2.3 Hz); 6,62 (d, 1H, J=2.3 Hz); 7,05 (s, 1H); to 7.32 (d, 1H, J=8,3 Hz); 7,25-7,34 (m, 2H); to 7.61 (d, 2H, J=9.0 Hz); the 7.65 (d, 2H, J=9.0 Hz); 7,71 (d, 1H, J=7.8 Hz); to 7.77 (d, 1H, J=7.8 Hz); 8,82 (s, 1H).

EXAMPLE 35

5-{4-[(2',4'-Dimethoxybiphenyl-3-carbonyl)amino]phenyl}-2-methylfuran-3-carboxylic acid (95)

Scheme 49

Saponification of the methyl ester of carboxylic acid (94) in a mixture of THF and the Meon (2+1) according to the procedure described above in example 31, 5-{4-[(2',4'-dimethoxybiphenyl-3-carbonyl)amino]phenyl}-2-methylfuran-3-carboxylic acid (95) in the form of not-quite-white solid (137 mg, quantitative yield).1H NMR (400 MHz, (CD3)2SO): 2,60 (C, H); of 3.78 (s, 3H); is 3.82 (s, 3H); 6,66 (DD, 1H, J1=8,3 Hz, J2=2.2 Hz); 6,70 (d, 1H, J=2.2 Hz); 7,00 (s, 1H); to 7.32 (d, 1H, J=8,3 Hz); 7,53 (t, 1H, J=7.8 Hz); 7,66 (d, 1H, J=8.6 Hz); of 7.69 (d, 2H, J=8.6 Hz); 7,86 (d, 3H, J=8.6 Hz); 7,99 (s, 1H); to 7.99 (s, 1H); 10,34 (s, 1H).

EXAMPLE 36

5-{4-[(2',4'-Dihydroxybiphenyl-3-carbonyl)amino]phenyl}-2-methylfuran-3-carboxylic acid (96)

Scheme 50

According to the method described above in example 12, reaction of carboxylic acid (95) with a 1M solution of BBr3give 5-{4-[(2',4'-dihydroxybiphenyl-3-carbonyl)amino]phenyl}-2-methylfuran-3-carboxylic acid (96) as a pale yellow solid (24 mg, 32%).1H NMR (400 MHz, CD3OD): to 2.67 (s, 3H); 5,43-6,47 (m, 1H) 6,46 (s, 1H); to 6.95 (s, 1H); 7,21 (d, 1H, J=8.6 Hz); 7,53 (t, 1H, J=7,7 Hz); 7,71 (d, 2H, J=8,8 Hz); 7,78-a 7.85 (m, 2H); 7,81 (d, 2H, J=8,8 Hz); 8,11 (s, 1H).

EXAMPLE 37

(3-Triptoreline)amide 2',4'-dimethoxybiphenyl-3-carboxylic acid (97)

Scheme 51

(3-Triptoreline)amide 2',4'-dimethoxybiphenyl-3-carboxylic acid (97) synthesized according to the method described above in stage 1 of example 8, from 3-triptoreline and acid chloride of the carboxylic acid (54), and was isolated as a yellow oil (32 mg, 31%).1H NMR (400 MHz, CDCl3): of 3.80 (s, 3H); 3,85 (s, 3H); 6,56-6,60 (m, 1H); to 6.57 (s, 1H); 7,26 (d, 1H, J=8.6 Hz); 7,39 (d, 1H, J=7,6 Hz); 7,47 (t, 1H, J=7.8 Hz); 7,50 (t, 1H, J=7.8 Hz); of 7.69 (dt, 1H, J1=7.8 Hz, J2=1.3 Hz); to 7.77 (dt, 1H, J1=7.8 Hz, J2 =1.3 Hz); to 7.84 (d, 1H, J=7.8 Hz); 7,88 (users, 1H); 7,94 (s, 1H); of 7.96 (t, 1H, J=1.5 Hz).

EXAMPLE 38

(3-Triptoreline)amide 2',4'-dihydroxybiphenyl-3-carboxylic acid (98)

Scheme 52

According to the method described above in example 12, reaction of (3-triptoreline)amide 2',4'-dimethoxybiphenyl-3-carboxylic acid (97) with a 1M solution of BBr3gives (3-triptoreline)amide 2',4'-dihydroxybiphenyl-3-carboxylic acid (98) as a brown solid (27 mg, 72%).1H NMR (400 MHz, CD3OD): 6,45 (DD, 1H, J1=8,3 Hz, J2=2,5 Hz); 6,46 (s, 1H); 7,21 (DD, 1H, J1=8.6 Hz, J2=1.3 Hz); 7,47 (d, 1H, J=7.8 Hz); rate of 7.54 (t, 1H, J=7.8 Hz); to 7.59 (t, 1H, J=8.0 Hz); 7,81 (dt, 1H, J1=7.8 Hz, J2=1.3 Hz); a 7.85 (DDD, 1H, J1=7.8 Hz, J2=1.7 Hz, J3=1.0 Hz); 7,99 (d, 1H, J=7.8 Hz); 8,12 (t, 1H, J=1.7 Hz); 8,21 (s, 1H).

The compounds indicated in the following figure 12, are the compounds specifically referred to here as the preferred connection.

Scheme 12

Analysis sialyl-LewisX-trainsurfing (sLeX-TSA)

Compounds of the present invention analyze at the molecular level for their ability to inhibit the binding of the chimeric molecules of the P-, L - or E-selectin with sLeXand thyroidzoloftyi remains associated with the polymer matrix as PSGL-1-substitution. Determine the selected value IC 50.

Titration microplates incubated for coverage through the night in carbonate buffer, pH 9,6), goat antibody to Fc-mAB person (10 µg/ml). After washing in buffer for analysis (25 mm 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 150 mm NaCl, 1 mm CaCl2, pH 7.4) and blocked (3% bovine serum albumin (BSA) in buffer for analysis) tablets incubated for 2 h at 37°C with chimeras P-selectin-IgG-man (0,61 nm, respectively 150 ng/ml), or chimeras L-selectin-IgG-man (0,61 nm, respectively 89 ng/ml), or chimeras E-selectin-IgG-man (0,61 nm, respectively 131 ng/ml). Form a complex 5 ál sLeX-trainsoldat-polyacrylamide (1 mg/ml)containing 15% of sLex10% tyrosinaemia and 5% Biotin, using 20 μl of a solution of streptavidin-peroxidase (1 mg/ml) and 25 μl of buffer for analysis without CaCl2. For use in the analysis of complex ligand is diluted 1:10000 in the buffer for analysis and further diluted as 1:1 variable amounts of compounds in the buffer for analysis with 2% DMSO. This mixture was added to wells pre-coated with E - or P-selectin. After incubation for 2 h at 37°C. the wells are washed six times in buffer for analysis, comprising 0.005% monolaurate of polyoxyethylenesorbitan (tween-20), are within 10-15 min and 20 µl of substrate solution 3,3',5,5'-tetramethylbenzidine (TMB)/N About2and the reaction stopped by 20 μl of 1M H2SO4. The associated complex of ligand sLex-trainsoldat determined by measuring the optical density at 450 nm compared to 620 nm in a tablet reader Fusion alpha-FP (purchased from Packard Bioscience, Dreieich, Germany).

The results of these inhibition sLex-TSA in vitro for E-/R-/L-selectin at 100 µm
ConnectionE-selectin
[% inhib.]
P-selectin
[% inhib.]
L-selectin
[% inhib.]
Bimosiamosea 3.922,66,2
2140,73,018,7
2242,722,721,3
2310,518,9the 11.6
2435,90,55,9
3235,0 1,413,1
3338,610,627,3
3441,012,918,1
3540,8the 15.619,4
3635,81,26,8
3738,95,29,5
38of 40.99,419,3
3924,82,910,9
4034,428,231,1

The results of these IC50sLex-TSA for E-/R-/L-selectin
ConnectionIC50E-selectin [µm]IC 50P-selectin [µm]IC50L-selectin [µm]
62-62,9150,8
63-81,2157,2
64-50,062,3
66-67,8152,2
67-201,2433,9
70-354,10,0
73-260,5502,2
76480,0233,8278,4
81-35,3RB 131.1
84-46,6143,8
90-19,138,7

ConnectionIC50E-selectin [µm]IC50P-selectin [µm]IC50L-selectin [µm]
Bimosiamose>50095,0>500
28200,7237,7318,6
30>500133,5376,1

Analysis in a flow chamber/adhesion and rolling of cells under conditions of flow

To determine the ability of compounds to inhibit the binding of cells under dynamic conditions, similar to the blood flow in the blood vessel in a flow chamber analyze addressed bind/test linking cells HL-60/various cell lines with chimeric molecules P-selectin, L-selectin and E-selectin.

Attaching cells under conditions of flow determined with the use of a system of parallel flow chambers. Polystyrene Cup for the cultivation of 35 mm is near 1 hour at room temperature with a buffer for sensitization of the surface (50 mm Tris(hydroxymethyl)aminobutanoic buffer (Tris), 150 mm NaCl, 2 mm CaCl2; pH 7.4)containing chimeras E - or P-selectin-human IgG at concentrations of 2.5 μg/ml or 10 µg/ml, respectively. After removal of the solution to cover the nonspecific binding sites blocked for an additional hour with 1% BSA in buffer for sensitization of the surface at room temperature. After washing buffer for analysis (“Roswell Park Memorial Institute 1640” (RPMI 1640) + 10 mm HEPES) the Cup is inserted into the camera with a parallel laminar flows (purchased from Glycotech, Rockville, MD) and mounted on an inverted phase-contrast microscope (purchased from Olympus, Hamburg, Germany)equipped with a CCD camera (JVC), which is connected to the PC. Using a peristaltic pump (purchased from Ismatec, Wertheim-Mondfeld, Germany) recirculating system balance buffer for analysis, containing 125 μm compound or filler-control (DMSO). In the camera add cells (1 million/ml) and allow them to be distributed within 2 minutes at high velocity. The flow rate is then reduced, which leads to calculated shear flow 1 Dyne/cm2. Sequence 10 low-power fields recorded digitally after 5 minutes of continuous flow. The percentage inhibition is calculated from the average number of cells that adhere to the surface covered with the Cup in the presence of compounds in comparison with about the lack of connection in independent experiments.

Data analysis in a flow chamber for E - and P-selectin

Values are given as normalized relations as % inhibition of connections divided by the % inhibition bimosiamose.

ConnectionE-selectin
[Attitude]
P-selectin
[Attitude]
280,99n.s.
291,310,74
301,03n.s.
311,160,60
Bimosiamose
621,151,22
631,311,95
64of 1.341,70
661,210,76
671,60 0,92
700,830,82
730,991,20
740,681,02
760,611,26
790,961,19
811,271,55
821,352,11
841,361,02
851,201,90
871,241,05
891,271,41
930,861,13
961,131,02
981,261,00

1. Pharmaceutical composition for modulation of the expression of E - and P-selectin, comprising at least one compound of the formula (IIIa)or (IIIb), or (IVa)or (IVb) in an effective amount and a pharmaceutically acceptable carrier which is useful in medicine,

where the symbols and substituents have the following meanings:
X' represents a
(a)

where m is 0, 1; n is 1;
(b)

where the "ring" represents a phenyl or pyridine

where R1represents N, and k is 0;
(C)

where the "ring" represents a phenyl or pyridine

T represents O; R is 1;
Y represents a
(a)

where s is 1,
R2is a CO2N, CO2-alkyl, CF3;
where the alkyl is a monovalent group with a non-branched chain or branched chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 carbon atoms,
R3regardless of R2the submitted is a N,
R4regardless of R2and R3represents H,
R5represents H,
and W represents -(CH2-)vwhere v is 0, 1;
(e)

where t is 0;
s is 1,
R5represents H,
(f)

where t is 0;
s is 1,
R6represents H,
Z represents a
(i)

R7regardless of R2represents N, CH3The co3,
W represents -(CH2-)vwhere v is 0, 1,
R2is a CO2H, CO2-alkyl, CF3;
where the alkyl is a monovalent group with a non-branched chain or branched chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 carbon atoms,
(iv)

where K represents O, S,
W represents -(CH2-)vwhere v is 0, 1,
R2is a CO2H, CO2-alkyl, CF3;
where the alkyl is a monovalent group with a non-branched chain or branched chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 carbon atoms,
R7regardless of R2represents N, CH3The co3,
or pharmaceutically when mimie salt, esters or amides of the abovementioned compounds of the formula (IIIa)or (IIIb), or (IVa)or (IVb).

2. The pharmaceutical composition according to claim 1, where the compounds have the formula (A1)or (A2)or (B1)or (B2)or (C1)or (C2)or (D1)or (D2)


where X' and Y have the meanings indicated in claim 1, and where X represents a

m=0,1,
and where Y' is a

where all indices, symbols and substituents have the meanings mentioned in claim 1.

3. The pharmaceutical composition according to claim 2, where the compounds have the formula (E1)or (E2), or (F1)or (F2)

where X ' and Y' have the meanings specified in paragraph 2.

4. The pharmaceutical composition according to claim 1, where the compounds have the formula (G1)or (G2), or (H1)or (H2)

where X" them the et values specified in paragraph 2, and Y represents a

where R9is a CO2H, CO2alkyl,
where the alkyl is a monovalent group with a non-branched chain or branched chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 carbon atoms,
where all indices, symbols and substituents have the meanings mentioned in claim 1.

5. Chemical compounds having the General structure formula (E1), (E2), (F1), (F2), (G1), (G2), (H1) or (H2)


where the symbols and substituents have the following meanings:
X represents a


Y' represents a

Y" represents a

where s is 1,
R2is a CO2H, CO2-alkyl, CF3,
where alkyl represents the Wallpaper monovalent group with a non-branched chain or branched chain of 1, or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 carbon atoms,
R3regardless of R2represents N and
R4regardless of R2and R3represents H,
R5represents H,
and W represents -(CH2-)vwhere v is 0, 1;
where t is 0;
where R6represents H,
Z represents a
(i)

R7regardless of R2represents N, CH3The co3,
W represents -(CH2-)vwhere v is 0, 1,
R2is a CO2H, CO2-alkyl, CF3,
where the alkyl is a monovalent group with a non-branched chain or branched chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 carbon atoms,
(iv)

where K represents O, S,
R7regardless of R2represents N, CH3The co3,
W represents -(CH2-)vwhere v is 0, 1,
R2is a CO2H, CO2-alkyl, CF3,
where the alkyl is a monovalent group with a non-branched chain or branched chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 carbon atoms.

6. The use of compounds is within the structure of formula (IIIa), or (IIIb), or (IVa)or (IVb) according to claim 1, for obtaining a medicinal product for the treatment of chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), in the extracorporeal circulation, for the treatment of acute respiratory distress syndrome (ARDS), Crohn's disease, septic shock, sepsis, chronic inflammatory diseases, such as psoriasis, atopic dermatitis and rheumatoid arthritis, and reperfusion injury, which occurs after a heart attack, brain haemorrhage, arteriosclerosis and organ transplants, traumatic shock, the failure of many organs, autoimmune diseases such as multiple sclerosis, in subcutaneous intraluminal angioplasty for the treatment of asthma and inflammatory bowel disease.

7. The use of compounds having the structure of formula (IIIa)or (IIIb), or (IVa)or (IVb) according to claim 1, for obtaining a drug that modulates the expression of E - and P-selectin for the treatment or prevention of inflammatory disorders.

8. The use of compounds having the structure of formula (IIIa)or (IIIb), or (IVa)or (IVb) according to claim 1, in combination with one or more physiologically acceptable carriers, adjuvants or excipients, for parenteral injection, for oral administration in solid or liquid form, for rivers of the social or local injection, for the prevention or treatment of diseases associated with modulation of expression of E - and P-selectin.

9. The use of compounds having the structure of formula (IIIa)or (IIIb), or (IVa)or (IVb) according to claim 1, for obtaining a cosmetic or dermatological compositions for modulation of the expression of E - and P-selectin.

10. Cosmetic compositions for modulation of the expression of E - and P-selectin, comprising at least one compound of the formula (IIIa)or (IIIb), or (IVa)or (IVb) according to claim 1 and at least one cosmetically tolerable component.

11. Dermatological compositions for modulation of the expression of E - and P-selectin, comprising at least one compound of the formula (IIIa)or (IIIb), or (IVa)or (IVb) according to claim 1 and at least one dermatologically tolerable component.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention describes novel carbamoyl benzotriazole derivatives of general formula , (values of radicals are given in the description), tautomers thereof and pharmaceutically acceptable salts and use thereof as endothelial lipase inhibitors.

EFFECT: improved properties of the derivatives.

11 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), which have protein kinase inhibiting properties and can be used in treating diseases which are dependent on any one or more protein kinases from FGFR1, FGFR2, FRF3 and/or FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2 and/or Ret Such diseases can be proliferative diseases, for example bladder cancer, breast cancer and multiple myeloma. In formula

the left-side ring , right-side ring , there are the following fragments, denoted "left-side ring" and "right-side ring", respectively: where X denotes C-R5, and Y and Z both denote N. The left-side ring corresponds to fragment (A):

n equals 0, 1, 2, 3, 4 or 5, X1 denotes hydrogen, where R1 denotes a group of formula Rz-NRa-, where Ra denotes hydrogen and Rz is selected from (1) a straight or branched C1-C4alkyl or (2) a group of formula , where ring A denotes phenyl, cyclohexenyl, cyclohexyl or pyridyl, m equals 0, 1 or 2, one or each of Rb is independently selected from a group -L2-NRcRd; -L2-RING, where RING denotes a 5- or 6-member saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen and oxygen, optionally substituted, as indicated below, halogen; hydroxy; amino; cyano, and a straight or branched C1-C4alkyl optionally substituted with one or more halogens and/or one or two hydroxy groups, wherein the hydroxy and amino groups are in turn optionally substituted on at least one heteroatom with one or, if necessary, more C1-C7aliphatic groups, where L2 denotes a direct bond, a link selected from a group comprising -O-, -S-, -C(O)-, -OC(O)-, -NRaC(O)-, -C(O)-NRa -OC(O)-NRa, -NRa-; or denotes a straight C1-C4alkyl which is optionally interrupted and/or ends in one terminal fragment or in two terminal fragments with the said link, and where Rc and Rd are each independently selected from a group comprising hydrogen and straight or branched C1-C4alkyl, or Rc and Rd together with a neighbouring nitrogen atom form a 5- or 6-member heterocyclic ring which optionally contains an additional heteroatom selected from nitrogen and oxygen, and optionally substituted as indicated below, said optionally substituted rings are independently substituted with 0, 1, 2, 3, 4 or 5 C1-C7aliphatic substitutes which are optionally substituted with one or more halogen atoms; R2 denotes hydrogen or C1-C4alkyl; R3 denotes hydrogen or straight or branched C1-C4alkyl or straight C1-C4alkyl substituted with a 5- or 6-member saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms in the ring, selected from nitrogen, oxygen and sulphur; R4 is selected from hydroxy, protected hydroxy group, alkoxy, alkyl, trifluoromethyl and halogen, where the alkyl or alkyl part of the alkoxy is straight or branched and contains 1, 2, 3 or 4 carbon atoms; or R5 denotes hydrogen or C1-C4alkyl; or pharmaceutically acceptable salts, hydrates, solvates, ethers, N-oxides thereof, optionally in form of trans-isomers thereof.

EFFECT: improved properties of the compound.

38 cl, 1 tbl, 231 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where: X is a nitrogen or carbon atom; Ar is phenyl or a heteroaromatic ring selected from pyrazolyl, furanyl, thiophenyl and isoxazolyl; R1 is hydrogen, halogen, CN or (C1-C4)alkyl; R2 is halogen or (C1-C3)alkoxy optionally fluorinated with 1-3 fluorine atoms; R3 and R5 independently denote hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkenyl or hydroxymethyl; R4 is hydrogen, halogen, optionally fluorinated (C1-C4)alkoxy or aryl(C1-C4)alkoxy; R6 is hydrogen, optionally fluorinated (C1-C4)alkyl; each R7 independenlty denotes hydrogen, halogen, optionally fluorinated (C1-C4)alkyl or (C1-C4)alkoxy optionally fluorinated with 1-3 fluorine atoms; or pharmaceutically acceptable acid addition salts thereof. The invention also relates to use of compounds of formula (I) in a pharmaceutical composition and when preparing a medicinal agent meant for treatment, the aim of which is to change the secondary signal activity level after activation of glucocorticoid receptors.

EFFECT: compounds of formula I for changing the secondary signal activity level after activation of glucocorticoid receptors.

7 cl, 5 dwg, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound selected from N-((1S)-1-{4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}ethyl)-2-(7-nitro-1H-benzimidazol-1-yl)acetamide, 2-(7-nitro-1H-benzimidazol-1-yl)-N-{1-[6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl]ethyl}acetamide, N-[1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamde and N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide. The invention also relates to use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds which are useful in treating VR1 mediated disorders or acute and chronic algesic disorders are obtained.

6 cl, 5 tbl, 5 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to drugs and concerns a combination for tumour cell growth inhibition containing a cytotoxic compound selected from camptothecin compounds; metabolic antagonists; periwinkle alkaloids; taxanes; platinum compounds; topoisomerase 2 inhibitors; and a combination of two or more said types, or a signal transfer inhibitor selected from antibodies a target of which is EGFR receptor; tyrosine kinase EGFR inhibitors; from antibodies a target of which is a VEGF/VEGF receptor system; PDGFR inhibitors; Raf inhibitors and PKB transfer inhibitors in an effective amount and a compound of formula (IV).

, where R1, R2, R11, T, U and g have the values specified in formula.

EFFECT: what is offered is a pharmaceutical composition, a method for tumour cell growth inhibition, a method of treating a malignant growth in a patient and application of the combination for preparing a drug; the new effective combinations for tumour cell growth inhibition are presented.

77 cl, 20 dwg, 7 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R1 is a phenyl group (said phenyl group is substituted with one or more C1-6alkyl groups, one C1-3alkyl group (said C1-3alkyl group is substituted with one or more halogen atoms), one C1-3alkoxy group (said C1-3alkoxy group is substituted with one or more halogen atoms) or one or more halogen atoms), R2 is a C1-3alkyl group, R3 is a phenyl group (said phenyl group is substituted with one or more substitutes selected from a group comprising halogen atoms or a (C=O)R5' group (where R5' is NR6'R7', (where R6' is a hydrogen atom, and R7' is a C1-6alkyl group substituted with a hydroxyl group))), a thienyl group (said thienyl group is substituted with one or more substitutes selected from a group comprising hydrogen atoms and a (C=O)R5 group (where R5 is NR6R7 (where R6 is a hydrogen atom or a C1-3alkyl group, and R7 is a C1-6alkyl group (said C1-6alkyl group can be substituted with one or more hydroxyl groups, one C1-3alkoxy group or a 5-6-member aromatic heterocyclic group containing 1-2 heteroatoms selected from oxygen or nitrogen (where the 5-6-member aromatic heterocyclic group can be substituted with one or more C1-3alkyl groups, one or more C1-3alkoxy groups, and in case of a 5-6-member aromatic heterocyclic group containing one nitrogen atom, can be in be in form of N-oxides)), a pyridyl group, or overall NR6R7 is a nitrogen-containing heterocyclic group which is a 5-6-member hetero-monocyclic group which contains one or two nitrogen atoms and can additionally contain on oxygen atom (said nitrogen-containing heterocyclic group can be substituted with one or more hydrogen atoms, one or more C1-6alkyl group, one or more hydroxyl groups)) or C1-6alkyl group (said C1-6alkyl group can be substituted with one or more halogen atoms and is substituted with one cyano group))), and R4 is a hydrogen atom or to a pharmaceutically acceptable salt of said compound. The invention also relates to a medicinal agent for preventing or treating diseases, in which activation of the thrombopoietin receptor is effective, based on said compounds.

EFFECT: obtaining novel compounds and agents based thereon, which can be used in medicine to increase the number of thrombocytes.

33 cl, 7 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting P2X3 receptor antagonist activity. In formula (I), X represents -O-; Y represents -NRdRe where one of radicals Rd and Re means hydrogen, and the other means hydrogen; C1-C12alkyl; C5-C7cycloalkyl; C5-C7cycloalky-C1-C12alkyl; hydroxy-C1-C12alkyl; acetyl; aminocarbonyloxy- C1-C12alkyl or heterocyclyl representing a 6-members saturated ring containing heteroatom S substituted by two oxo groups; D represents optional oxygen; R1 represents isopropyl; R2 represents hydrogen; R5 represents hydrogen or C1-C12alkyl; R4 means hydrogen; C1-C12alkyl; halogen; halogen- C1-C12alkyl; C1-C12alkoxy; hydroxy; halogen- C1-C12alkoxy; nitro; amino; hydroxy- C1-C12alkyl; C1-C12alkoxyalkyl; hydroxy- C1-C12alkoxy; C1-C12alkylsulphonyl; cyano; heteroaryl representing a 5-members aromatic ring containing one, two or three heteroatoms selected from O, S and N which can be optionally substituted by a thio group, C1-C12alkyl or C1-C12alkylsulphonyl; heterocyclyl representing a 6-members saturated ring containing two heteroatoms N, one of which is substituted C1-C12alkylsulphonyl; -(CH2)m-(Z)n-(CO)-Rf or -(CH2)m-(Z)n-SO2-(NRg)n-Rf where each m and n independently represents 0 or 1, Z means NR8, Rf means C1-C12alkyl, hydroxy, amino or hydroxy- C1-C12alkyl, and Rg means hydrogen; R3 represents methoxy; R6 represents hydrogen; and one of radicals R7 and R8 represents hydrogen, and the other represents hydrogen, acetyl or phenyl.

EFFECT: also, the invention refers to a pharmaceutical composition and to an application of the compound of formula (I) for preparing a drug.

8 cl, 3 tbl, 70 ex

FIELD: medicine.

SUBSTANCE: present invention presents new compounds which are modulators of cannabinoid receptors, particularly modulators of cannabinoid receptors 1 (CB1) or cannabinoid receptors 2 (CB2), and an application thereof for treating diseases, conditions and/or disorders regulated by a cannabinoid receptor (such as painful sensations, neurodegenerative disorders, ingestion disorders, weight loss or weight control and obesity), as well as based pharmaceutical compositions. New compounds are characterised by graphic formulas

in which radicals and groups have the values specified in the patent claim.

EFFECT: higher efficiency of applying the composition.

55 cl, 13 tbl, 3 dwg, 802 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , isomer thereof of formula IA , mixture of isomers thereof IA/C , synthesis method thereof, as well as methods of producing compounds of formula IVA from compounds of formula IA, involving reduction and removal of protection from compounds of formula IA via hydrogenolysis using H2 and a catalytic amount of Pd/C, in the presence of trifluoroacetic acid to obtain a compound of formula VA; further reaction of this compound with Cbz-t-leu-OH, EDC and HOBt to obtain a compound of formula VIA; reaction of compound VIA with H2 and a catalytic amount of Pd/C in the presence of citric acid to obtain an amine and reaction of said amine and 4-amino-3-chlorobenzoic acid in the presence of CDMT and NMM to obtain a compound of formula IVA.

EFFECT: fewer synthesis steps and high output while using dynamic crystallisation.

13 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel carbamoyl benzotriazole derivatives of general formula , (values of radicals are given in the description), tautomers thereof and pharmaceutically acceptable salts and use thereof as endothelial lipase inhibitors.

EFFECT: improved properties of the derivatives.

11 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), which have protein kinase inhibiting properties and can be used in treating diseases which are dependent on any one or more protein kinases from FGFR1, FGFR2, FRF3 and/or FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2 and/or Ret Such diseases can be proliferative diseases, for example bladder cancer, breast cancer and multiple myeloma. In formula

the left-side ring , right-side ring , there are the following fragments, denoted "left-side ring" and "right-side ring", respectively: where X denotes C-R5, and Y and Z both denote N. The left-side ring corresponds to fragment (A):

n equals 0, 1, 2, 3, 4 or 5, X1 denotes hydrogen, where R1 denotes a group of formula Rz-NRa-, where Ra denotes hydrogen and Rz is selected from (1) a straight or branched C1-C4alkyl or (2) a group of formula , where ring A denotes phenyl, cyclohexenyl, cyclohexyl or pyridyl, m equals 0, 1 or 2, one or each of Rb is independently selected from a group -L2-NRcRd; -L2-RING, where RING denotes a 5- or 6-member saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen and oxygen, optionally substituted, as indicated below, halogen; hydroxy; amino; cyano, and a straight or branched C1-C4alkyl optionally substituted with one or more halogens and/or one or two hydroxy groups, wherein the hydroxy and amino groups are in turn optionally substituted on at least one heteroatom with one or, if necessary, more C1-C7aliphatic groups, where L2 denotes a direct bond, a link selected from a group comprising -O-, -S-, -C(O)-, -OC(O)-, -NRaC(O)-, -C(O)-NRa -OC(O)-NRa, -NRa-; or denotes a straight C1-C4alkyl which is optionally interrupted and/or ends in one terminal fragment or in two terminal fragments with the said link, and where Rc and Rd are each independently selected from a group comprising hydrogen and straight or branched C1-C4alkyl, or Rc and Rd together with a neighbouring nitrogen atom form a 5- or 6-member heterocyclic ring which optionally contains an additional heteroatom selected from nitrogen and oxygen, and optionally substituted as indicated below, said optionally substituted rings are independently substituted with 0, 1, 2, 3, 4 or 5 C1-C7aliphatic substitutes which are optionally substituted with one or more halogen atoms; R2 denotes hydrogen or C1-C4alkyl; R3 denotes hydrogen or straight or branched C1-C4alkyl or straight C1-C4alkyl substituted with a 5- or 6-member saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms in the ring, selected from nitrogen, oxygen and sulphur; R4 is selected from hydroxy, protected hydroxy group, alkoxy, alkyl, trifluoromethyl and halogen, where the alkyl or alkyl part of the alkoxy is straight or branched and contains 1, 2, 3 or 4 carbon atoms; or R5 denotes hydrogen or C1-C4alkyl; or pharmaceutically acceptable salts, hydrates, solvates, ethers, N-oxides thereof, optionally in form of trans-isomers thereof.

EFFECT: improved properties of the compound.

38 cl, 1 tbl, 231 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (11) given below and pharmaceutically acceptable salts thereof: chemical formula 1

in which: each of G1, G2, G3 and G8 independently denotes -N=, -CR1= or -C(-G9-X)=; one of G1, G2, G3 and G8 is-C(-G9-X)=; X is C1-6 alkyl (where C1-6 can be optionally substituted with a group selected from a halogen atom, hydroxy, cyano and -NR56R57), aryl, heterocycle (where the heterocycle denotes a 5-9-member saturated or unsaturated cyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms, and can be a monocycle or condensed ring, and can be optionally substituted with a halogen atom, C1-6 alkyl; C1-6 alkoxy, R33R34NCS-, R3R4NCO-); G9 denotes a single bond, an oxygen atom, a sulphur atom, ring G6 denotes a divalent aryl group or divalent pyridyl group (where the divalent pyridyl group can be optionally substituted with a halogen atom); A is a group of formula (2) given below, or a group of formula (3) given below. Chemical formula 2

, chemical formula 3 , G4 is an oxygen atom or sulphur atom; G5 is an oxygen atom or sulphur atom; G7 is an oxygen atom, -CR42R43-, -CONR44-, -NR44CO, -NR45-, CR42R43NR45-, -S-, -NR44S(=O)2-; R1 is a hydrogen atom, a halogen atom, cyano, C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a halogen atom), carbamoyl or C2-7 alkynyl (where C2-7 alkynyl can be optionally substituted with C1-4 acyl); when G2 or G3 denotes -CR1=, then G8 is -C(-G9-X)=, and X is R3R4NCO-, R33R34NCS-; when G8 is -CR1=, then G3 denotes -C(-G9-X)=, and X is R3R4NCO, or R33R34NCS-; when G1 or G8 denotes -CR4 then G2 is -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; or when G2 is -CR1=, then G1 denotes -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; R1 can form a single bond or -CH2- with R4 or R34; R2 denotes hydroxy or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from a halogen atom, hydroxy, C1-6 alkoxy, formyl and -CO2R50); R3, R4, R9 and R10 each independently denotes a hydrogen atom, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, a halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R6 and R7 each independently denotes a hydrogen atom, C1-6 alkoxy, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R33 and R34 each independently denotes a hydrogen atom, C1-6 alkyl, the combination of R3 and R4 together with a nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom or C1-6 alkyl; the combination of R6 and R7 together with the nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom, C1-6 alkyl or an oxo group; R45 is a hydrogen atom, R13 and R14 each independently denotes a hydrogen atom, C1-6 alkyl or COR32; R56 and R57 each independently denotes a hydrogen atom or C1-6 alkyl, and R5, R8, R28, R29, R32, R42, R43, R44, and R50 each independently denotes a hydrogen atom or C1-6 alkyl. The invention also relates to a pharmaceutical composition, as well as to a medicinal agent for treating cell proliferative disorder.

EFFECT: obtaining novel biologically active compounds having inhibitory effect on cell proliferation.

15 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound selected from N-((1S)-1-{4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}ethyl)-2-(7-nitro-1H-benzimidazol-1-yl)acetamide, 2-(7-nitro-1H-benzimidazol-1-yl)-N-{1-[6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl]ethyl}acetamide, N-[1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamde and N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide. The invention also relates to use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds which are useful in treating VR1 mediated disorders or acute and chronic algesic disorders are obtained.

6 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of general formula I and pharmaceutically acceptable salts thereof, where R1 is selected from a group comprising aryl and alkyl, optionally substituted hydroxy; R2 is selected from a group comprising hydrogen and alkyl; R3 is selected from a group comprising hydrogen and -X-A, where X is selected from a group comprising -C(O)- and -S(O)2-; and A is selected from a group comprising hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle and optionally substituted cycloalkyl, where the optionally substituted groups are substituted with 1-2 substitutes selected from a group comprising alkyl, substituted alkyl, alkoxy, substituted amine which is a -NRR group, substituted aryloxy, heteroaryl, heterocycle, halogen, hydroxy and -S(O)2-R9, where R9 is an alkyl; or R1 and R3 together with a carbon atom bonded to R1 and a nitrogen atom bonded to R3 form a heterocyclic or substituted heterocyclic group; R4 is selected from a group comprising hydrogen, linear alkyl, -alkylene-aminoacyl-, -alkylene-hydroxy-, -[alkylene]p-nitrogen-containing heterocycle, -[alkylene]p-nitrogen-containing substituted heterocycle, -[alkylene]p-nitrogen-containing heteroaryl, -[alkylene]p-nitrogen-containing substituted heteroaryl and -[alkylene]p-NR10R11, where p equals 0 or 1, the alkylene contains 1-5 carbon atoms and can have 1 or 2 substitutes selected from a group comprising amine, hydroxy and halogen, aminoacyl relates to a group -C(O)NRR, where each R is independently selected from a group comprising hydrogen and alkyl, R10 and R11 are independently selected from a group comprising hydrogen, alkyl, substituted alkyl, -S(O)2-alkyl, substituted aryl, substituted heteroaryl, cycloalkyl, or when R10 is hydrogen, R11 is hydroxy, alkoxy or substituted alkoxy; or when R1 and R3 together with carbon and nitrogen atoms respectively bonded to them do not form a heterocyclic or a substituted heterocyclic group, R3 and R4 together with a nitrogen atom to which they are bonded form a spiro-condensed heterocyclic group; R5 is selected from a group comprising L-A1, where L is selected from a group comprising C1-C5alkylene, where the alkylene is defined above; and A1 is selected from a group comprising aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle; and one of R6 or R7 is selected from a group comprising aryl and heteroaryl, each of which can optionally be substituted with -(R8)m, where m equals a whole number from 1 to 2, and the other of R6 or R7 is selected from a group comprising hydrogen, halogen and alkyl; or R6 as well as R7 denotes hydrogen; R8 is selected from a group comprising cyano, alkyl, -CF3, alkoxy, halogen, where alkyl, aryl, aryloxy, cycloalkyl, heterocycle, heteraryl and substituted alkyl, aryl, aryloxy, cycloalkyl, heterocycle and heteroaryl are described in claim 1. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula I, a method of inhibiting KSP and use of the composition to prepare a medicinal agent.

EFFECT: novel imidazole derivatives are useful as kinesin spindle protein inhibitors for treating cancer.

25 cl, 27 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 5-nitrofuran derivatives of formula I: where R=piperidino, pyrrolidineo, diethylamino, morpholino.

EFFECT: presented preparation of new biologically active compounds which exhibit antimicrobial activity.

1 cl, 4 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: described are novel compounds of general formula

:, where X denotes halogen or (C1-C3)alkyl possibly substituted with a halogen; Y denotes hydrogen; R denotes hydrogen, halogen, cyano, (C1-C6)alkyl or (C2-C6)alkenyl possibly substituted with a halogen, (C2-C6)alkynyl possibly substituted with a halogen or hydroxy, (C1 -C6)alkoxy or (C2-C6)alkenyloxy, possibly substituted with a halogen, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxyamino(C1-C3)alkyl, phenyl, phenoxy, pyridyloxy or pyrimidyloxy, possibly substituted; n is an integer from 1 to 5; a plant disease control agent and a plant disease control method.

EFFECT: obtaining compounds with a wider suppressing spectrum at low doses of chemical processing, thus facilitating use as a plant disease control agent for agricultural and horticultural use, as well as reduced harmful effect on the environment.

4 cl, 6 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting P2X3 receptor antagonist activity. In formula (I), X represents -O-; Y represents -NRdRe where one of radicals Rd and Re means hydrogen, and the other means hydrogen; C1-C12alkyl; C5-C7cycloalkyl; C5-C7cycloalky-C1-C12alkyl; hydroxy-C1-C12alkyl; acetyl; aminocarbonyloxy- C1-C12alkyl or heterocyclyl representing a 6-members saturated ring containing heteroatom S substituted by two oxo groups; D represents optional oxygen; R1 represents isopropyl; R2 represents hydrogen; R5 represents hydrogen or C1-C12alkyl; R4 means hydrogen; C1-C12alkyl; halogen; halogen- C1-C12alkyl; C1-C12alkoxy; hydroxy; halogen- C1-C12alkoxy; nitro; amino; hydroxy- C1-C12alkyl; C1-C12alkoxyalkyl; hydroxy- C1-C12alkoxy; C1-C12alkylsulphonyl; cyano; heteroaryl representing a 5-members aromatic ring containing one, two or three heteroatoms selected from O, S and N which can be optionally substituted by a thio group, C1-C12alkyl or C1-C12alkylsulphonyl; heterocyclyl representing a 6-members saturated ring containing two heteroatoms N, one of which is substituted C1-C12alkylsulphonyl; -(CH2)m-(Z)n-(CO)-Rf or -(CH2)m-(Z)n-SO2-(NRg)n-Rf where each m and n independently represents 0 or 1, Z means NR8, Rf means C1-C12alkyl, hydroxy, amino or hydroxy- C1-C12alkyl, and Rg means hydrogen; R3 represents methoxy; R6 represents hydrogen; and one of radicals R7 and R8 represents hydrogen, and the other represents hydrogen, acetyl or phenyl.

EFFECT: also, the invention refers to a pharmaceutical composition and to an application of the compound of formula (I) for preparing a drug.

8 cl, 3 tbl, 70 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or salts thereof, and compounds of formula or salts thereof, where R3 denotes C1-C7alkyl or C3-C8cycloalkyl, and R4 denotes C1-C7alkyl or C3-C8cycloalkyl, and Act denotes an activating group selected from an amino protective group, mainly carbamate, as well as methods of producing said compounds. The invention also discloses a method, novel steps of the method and novel intermediate compounds for use in synthesis of pharmaceutically active compounds, mainly renin inhibitors, such as aliskiren. Also, when compounds (VI) react with organometallic compounds (VII) , where Y denotes a metal-containing group such as Li, -MgX, magnesate, aryl-magnesium compound, alkylmagnesium compound, -MnX, (alkyl)3MnLi- or -CeX2, where X is a halogen such as Cl, I or Br, more preferably Br, novel compounds are obtained, R3 and R4 assume values given for compounds of formula (II), and Act denotes an activating group selected from an amino protective group, mainly carbamate, R1 denotes a halogen, hydroxyl, halogen(C1-C6)alkyl, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, R2 denotes a halogen, hydroxyl, C1-C4alkyl or C1-C4alkoxy, which are direct precursors for producing aliskiren.

EFFECT: novel compounds and synthesis methods thereof are obtained and described.

61 cl, 13 ex

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