Novel floroglucin derivatives, possessing activity with respect to selectin ligand

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry. Pharmaceutical compositions including, at least, one compound of formula where -X- represents, for instance, group of formula and Y represents, for instance, group of formula or its pharmaceutically acceptable salts, esters or amides, or pro-drugs and pharmaceutically acceptable carrier, which is acceptable in therapy, can be applied for modulation in vitro and in vivo processes of binding, mediated by binding of E-, P- or L- selectin.

EFFECT: obtaining novel floroglucin derivatives.

9 cl, 10 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 small molecules include 2,4,6-trihydroxyphenyl 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 surveillance or control in living organisms, including humans. Lymphocytes, for example, constituitive out of the blood flow in the lymphatic tissue in order 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 damaged the e 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 wall of the capillaries into the surrounding tissue. Therefore, leukocytes should slide on the cell membrane and then to stick to the cell membrane of the endothelium (the initial process of sliding 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.

The family of selectins adhesion molecules consists of three structurally related, Kalnyshevsky, link is their 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), changed the 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 ligands of different carbohydrates 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 to its high affinity sLex-part of, and what authorities its peptide components, in particular residues sulfated tyrosine [R.P. McEver, Ernst Schering Res. Found. Workshop, 2004, 44, 137-147]. PSGL-1 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 recruitment 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 a marked increase in expression in the tissue of the corresponding m is of molecules of adhesion 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 antagonists selectin molecules of small size 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 template structure for development with small molecule antagonists of selectins. Compared to se x/sLeaPSGL-1 shows high affinity for all three selectins. Therefore, for detection and detection of new drugs in the form of small molecules 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 the template structure, since it is assumed that they modulate binding between selectins and PSGL-1 or other ligands with the same motifs bind.

New antagonists of selectins with small molecules, can 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 compounds with small moleculaire, that connection with a relative molecular mass above 500 are orally bioavailable. The presence of high polarity carbohydrate parts or peptide component also is not in accordance 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 reason for the unsuitable development of drugs based on antibodies, because they are polypeptides, and therefore, oral administration 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, of which proizvodi the mi Gallic acid [WO 2004/018502], derivatives of Gallic acid [C. C. M. Appeldoom et al., Circulation 2005, 111, 106-112; EP 1481669A1] and Hinn acid [N. Kaila et al., J. Med. Chem. 2005, 48, 4346-4357]. However, none of these compounds, creating antagonism to the selectins, still not successful clinical trials [S. J. Romano, Treat. Respir Med 2005, 4(2), 85-94; M. P. Schon, Therapeutics and Clinical Risk Management, 2005, 1(3), 201-208]. This is a result of the fact that many of these structures were developed on the basis of a template sLexwith low efficiency. Perhaps that is why sLex-imitating patterns find low efficiency. Other compounds exhibit specificity against various members of the family of selectins, but showing the antagonism only for the selected selectins may not show antagonism to other selectins [M. P. Schon, Therapeutics and Clinical Risk Management, 2005, 1(3), 201-208]. In addition, most of the compounds developed so far, 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 antagon the ZMA for mediated by selectins processes, contain patterns pyragollole and catechin. These structures are prone to oxidation [Kumamoto M. et al., Biosci. Biotechnol. Biochem., 2001, 65(1), 126-132], which makes pharmaceutical development of these compounds difficult. 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 B1] 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, she is having a high molecular weight compound with a 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, much selenocysteines pan-selectin, which modulate mediated by selectin function, for example selecteddevice cell adhesion, and in developing methods 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 in 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 their behavior 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 creation of new molecules is not what alsogo size, especially deglycosylation/neglecting ones and compounds that are able to effectively create antagonism mediated by selectins processes and which have less negative side effects during 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, similar to their template structures. This invention, however, provides a new, potent, small and similar medicines antagonists pan-selectin, 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 relates to pharmaceutical compositions comprising at least one compound having the General structure formula (I), and f is rmaceuticals acceptable carrier, which is useful in medicine

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

in which 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, NO2, 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-, R2should not 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 p is ielemia salt, esters or amides and prodrugs of the foregoing compounds of formula (I).

In the following embodiment, the invention relates to pharmaceutical compositions comprising at least one compound of formula (I) and a pharmaceutically acceptable carrier which is useful in medicine,

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

in which 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;

-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 R2is the Wallpaper 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, 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-, R2should not be NH2or SH;

(b)

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

(c)

(e)

where t is 0, 1, 2;

-Z represents

(i)

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 formula (I).

Preferred pharmaceutical compositions comprise compounds of formula (II)

where Y has the meanings indicated above and X'represents X(the), X(b)X(c) X(d), which have the values specified above. Preferred are the compounds of formula (II), where X'represents X () or X(b).

The following preferred pharmaceutical compositions comprise compounds of formula (A) or (B)

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.

In the following embodiment, the invention relates to pharmaceutical compositions in which compounds have the formula (A) or (B)

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

and where Y' represents a

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

Especially preferred pharmaceutical compositions comprise compounds of formula (C)

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

The most preferred pharmaceutical compositions comprise compounds of formula (D)

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

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

In the following embodiment, the invention relates to a pharmaceutical composition where the compounds have the formula (D)

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,

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

These chemical compounds (C) and (D) are themselves new compounds.

All connections described above, have the ability to modulate cell adhesion and modulate the binding, mediated by selectin and PSGL-1-like ligand. The compounds possess the ability to modulate the interaction of selectins sLe x/sLeaalso the interaction between selectins and thyroidzoloftyi remains. They are therefore suitable for the treatment of acute and chronic inflammatory disorders and 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" includes also applications 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.

The invention relates to pharmaceutical compositions comprising the compounds of formula (I) and in a preferred embodiment of formula (II).

In the following a preferred embodiment, the invention relates to pharmaceutical compositions comprising at least one compound of the formula (A) or (B).

In a particularly preferred embodiment, the invention relates to pharmaceutical compositions comprising at least one compound (C).

In the preferred embodiment, the invention relates to F. rmaceuticals songs comprising at least one compound (D).

The present invention further relates to 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 (I), to modulate the binding of P-, E - or L-selectin with sLexor sLeaand trainsurfing. Discovered that compounds having the formula (I)shown above, act as modulators of binding of E-, P - or L-selectin.

Used in the description, 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, phenyl, 1-naphthyl, 2-naphthyl, fluorenyl, (1,2)-dihydronaphtho, indenyl, indanyl, thienyl, benzothiazyl, cyanopyridyl and the like.

The term "aralkyl" (also called arylalkyl) is used to 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 in the description of 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 assessment, are suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response and the like, have a reasonable ratio of benefit/risk and are effective for intended for their use, and, when possible, victorianism 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 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 the allocation 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, Tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.

Examples of pharmaceutically acceptable, non-toxic complex is s esters of the compounds of this invention include 1-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, primary1-With2- and3-and secondary alkylamines followed With1-C2-dialkylamino. 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 "parent" compounds of the above formula (I), 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 (I), 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 may include one or more compounds having the above structure (I), in combination with one or more physiologically acceptable carriers, adjuvants or excipients, which are collectively referred to in the description of the carriers, for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration and the like.

Composition m is tenderly to 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 translating them into 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, by applying a coating such as lecithin, by 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 disperser the matter of 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 granules. 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 RA is basicalyy, 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 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 can also include buffering agents.

Solid compositions of a similar type can also be used as fillers 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, 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 "covering" songs 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, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, canola oil, castor oil and sesame oil, glycerine, t is traditionally alcohol, the 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 the local introduction of the compounds of this invention include ointments, powders, sprays and forms for inhalation.

The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any necessary is entered 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 in the form limosum. As is well known in this field, liposomes is usually derived from phospholipids or other lipid substances. Liposomes form a mono - or mnogosloinye 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 (e.g., modulators of enzymes, antioxidants), suitable to protect the joints from damage. The actual dose levels of active ingredient in the composition of this image is to be placed can be varied so that to get the 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. Standard pharmaceutical compositions may contain such subprogramme number of them that you can apply 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 treatment of disease.

In particular, the compounds of the present 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 it is possible to enter the PAC is into 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, 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. Since the present compounds modulate 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.

SIP the mo 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 the possibility of 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 (I) 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 person skilled in the art can determine an effective amount, which depends on the derivative, of the individual to whom it is applied, and the time of its application. To ensure the order amount is s the compounds of formula (I) or its stereoisomeric forms in cosmetic or dermatological compositions according to the invention the compound of formula (I) or its stereoisomeric form, you can enter in the amount of from 0.001 wt.% to 40 wt.%, preferably 0.005 wt.%-30 wt.% and, more preferably from 0.01 wt.% up to 20 wt.%.

Another aspect includes a cosmetic composition comprising the compound of formula (I) 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 fatty phase may range from 2 wt.% up to 80 wt.% and preferably from 5 wt.% up 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 solution, suspension, emulsion or dispersion with more or less fluid consistency, especially liquid or semi-liquid consistency, obtained by dispersion of a fatty phase in an aqueous phase (O/W) or conversely (W/O)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 linking the 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 of the other ingredients usually 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 surfactants, 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 is also the cosmetic compositions, comprising the compound of formula (I) or its stereoisomeric form, which is used for the cosmetic treatment or cosmetic prevention micropopulation States.

Cosmetic compositions comprising a compound of formula (I) 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 include one or more cosmetically active ingredients with beneficial effect on the skin. Therefore, the present invention relates to cosmetic compositions comprising a compound of formula (I) or its stereoisomeric form, and at least one additional cosmetically active ingredient, for example a UV protective agent or proteins.

Dermatological compositions comprising a compound of formula (I) or its stereoisomeric form, and at least one dermatologically tolerable component, such as dermatologistskincare component for application to the skin, also are 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 (I) 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 (I) or its stereoisomeric form, which is used for the dermatological treatment, dermatological diagnosis or dermatological prophylaxis 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 field, g is aviacija, lifestyle (for example, excessive alcohol consumption), the repetitive facial expressions, body position during sleep and physiological stress factors.

In addition dermatologically inactive ingredients dermatological composition may include also dermatologically or pharmaceutically active ingredients. Therefore, the present invention relates to dermatological compositions comprising a compound of formula (I) 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 may be identical cosmetically active ingredients specified in this invention.

Another object of the present invention are dermatological compositions comprising a compound of formula (I) 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 di is the fore cast or dermatological prophylaxis micropopulation States.

In particular, the present invention relates to dermatological compositions comprising a compound of formula (I) 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 (I) or its stereoisomeric form, and at least one additional pharmaceutically or cosmetically active ingredient, characterized in that it is used for cosmetic and dermatological treatment and cosmetic and dermatological prevention of aging of the skin 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 (I) or its stereoisomeric form, at least one cosmetically portable component and in the end additional cosmetically active ingredients.

In particular, the subject data is the first invention is a method of obtaining a cosmetic composition by mixing the compounds of formula (I) or its stereoisomeric form, at least one cosmetically portable component and in the end additional cosmetically active ingredients, where the composition includes from 0.01 wt.% up to 20 wt.% the compounds of formula (I) 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 (I) 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.

According to scheme 1 aniline type (1) is subjected to interaction in an inert atmosphere with N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC), triethylamine, 4-dimethylaminopyridine (DMAP) and carboxylic acid type (2) in dichloromethane, while receiving amide type (3). Amide type (3) is further subjected to interaction with tribromide boron in dichloromethane at -78°C, thus obtaining the corresponding 2,4,6-trihydroxyphenyl connection type (4). The sequence of the synthesis shown in scheme 1 leading to compounds similar to (4)suitable not only for blocks build Y-H, similar (1), but it is usually used for all other blocks is stroenie type Y-H.

Scheme 2 commercially available brominated aromatic or heteroaromatic ester of General type (5) is subjected to interaction in inert conditions with 2,4,6-trimethoxyphenylacetic acid (6) in basic conditions such as the Suzuki reaction (Pd(PPh3)4water and sodium bicarbonate in dimethoxyethane, while receiving biaryl type (7), which is then hydrolyzing aqueous lithium hydroxide in acetonitrile to obtain the corresponding carboxylic acid (8), which in turn block the building of type (9) interaction with oxalylamino in anhydrous dichloromethane.

Scheme 3 the acid chloride of the acid that is similar to (9), is subjected to the interaction with the aniline of General type (10) in basic conditions (pyridine in dichloromethane), while receiving appropriate anilide (11). In the alternative case for this stage of the reaction, you can apply triethylamine. Ester (11) hydrolyzing LiOH in MeCN or THF/Meon obtaining carboxylic acids, similar to (12), which then is subjected to interaction with tribromide boron in dichloromethane at -78°C, while receiving after subsequent water treatment appropriate demetilirovanie acid type (13). The sequence of the synthesis shown in scheme 3, leading to compounds similar to (13), suitable not only for blocks build Y-H, 10), but it is usually used for all other building blocks of the type Y-H.

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

EXAMPLE 1

3-[2-(2,4,6-Trihydroxyphenyl)acetylamino]benzoic acid (18)

Stage 1. (The following reaction is carried out in an anhydrous atmosphere N2). Hydrochloride EDC (122 mg, 0.64 mmol) and triethylamine (89 μl, 0.64 mmol) dissolved in anhydrous dichloromethane (3.2 ml) and the solution stirred for 5 min at room temperature. Add 2-(2,4,6-trimethoxyphenyl)acetic acid (14) (101 mg, 0.45 mmol) and DMAP (8 mg, 0.6 mmol) and the mixture is stirred for 10 minutes Add complex ethyl ester (15) (70 mg, 0.42 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 the combined organic layers washed 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 the methyl ester of 3-[2-(2,4,6-trimethoxyphenyl)acetylamino]benzoic acid (16) in the form of a white solid (145 m is, 95%). [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): 3,68 (s, 2 H); a 3.83 (s, 3 H); of 3.84 (s, 6 H); a 3.87 (s, 3 H); 6,18 (s, 2 H); 7,33 (t, 1 H, J = 8.0 Hz); 7,56 (user. s, 1 H); 7,69 (user. DD, 1 H, J = 7.8 Hz); 7,78 (t, 1 H, J = 1.8 Hz); of 7.90 (DD, 1 H, J1= 8,1 Hz, J2= 1.3 Hz).

Stage 2.Methyl ester of 3-[2-(2,4,6-trimethoxyphenyl)acetylamino]benzoic acid (16) (140 mg, 0,39 mmol) dissolved in THF (25,0 ml) at room temperature was added 1 M aqueous LiOH (2.0 ml, 2.0 mmol). The reaction mixture is stirred for 40 hours at room temperature. The reaction mixture is quenched (cooling bath) and 2 M aqueous HCl. The mixture is extracted with EtOAc (3×), the combined organic layer was washed with saturated salt solution and dried Na2SO4while receiving 3-[2-(2,4,6-trimethoxyphenyl)acetylamino]benzoic acid (17) (134 mg, 99%) as a beige solid.1H NMR (400 MHz, CD3OD): 3,71 (s, 2 H); of 3.84 (s, 3 H); 3,85 (s, 6 H); 6,29 (s, 2 H); the 7.43 (t, 1 H, J = 7.8 Hz); 7,76 (d, 1 H, J = 7.8 Hz); 7,83 (d, 1 H, J= 8.1 Hz); 8,19 (user. s, 1 H).

Stage 3. (The following reaction is carried out in an anhydrous atmosphere N2). 3-[2-(2,4,6-Trimethoxyphenyl)acetylamino]benzoic acid (17) (134 mg, 0,39 mmol) dissolved in anhydrous DCM (5,3 ml), the solution cooled to -78°C and added dropwise BBr3(240 μl, 2.55 mmol). The reaction mixture was stirred for 30 min at -78°C. after slowly heated for an additional 2 h at whom atoi temperature. Dropwise add 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 3-[2-(2,4,6-trihydroxyphenyl)acetylamino]benzoic acid (18) (29 mg, 22%) as a yellowish solid.1H NMR (400 MHz, CD3OD): at 3.69 (s, 2 H); 5,97 (s, 2 H); the 7.43 (t, 1 H, J = 8.0 Hz); 7,76 (user. DD, 1 H, J1= 7,6 Hz); 7,84 (user. DD, 1 H, J1= 8.1 Hz); 8.17 and (t, 1 H, J= 1,8 Hz).

EXAMPLE 2

2-Methyl-5-{4-[2-(2,4,6-trihydroxyphenyl)acetylamino]phenyl}furan-3-carboxylic acid (19)

According to the method described in example 1, 2-methyl-5-{4-[2-(2,4,6-trihydroxyphenyl)acetylamino]phenyl}furan-3-carboxylic acid (19) are obtained in the form of a beige solid.1H NMR (400 MHz, CD3OD): to 2.66 (s, 3 H); 3,68 (s, 2 H); 5,97 (s, 2 H); 6.89 in (s, 1 H); of 7.60 (DD, 2 H, J1= 9.1 Hz, J2= 2.3 Hz); to 7.64 (DD, 2 H, J1= 9.1 Hz, J2= 2.3 Hz).

Below is described the production of intermediate compounds.

Methyl ester [5-(2-AMINOPHENYL)thiophene-2-yl]acetic acid (44)

Stage 1. (The following reaction is carried out in an anhydrous atmosphere N2). Methyl ester thiophene-2-luxusni acid (42) (2.0 g, 12.8 mmol) dissolved in anhydrous chloroform is e (9,0 ml) and glacial acetic acid (9.0 ml), portions add 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 is washed several times in 1 M aqueous NaOH and water and once with saturated salt solution and dried Na2SO4. The crude product is purified preparative radial chromatography (CyH/EtOAc, 5+1], while receiving methyl ester (5-bromothiophene-2-yl)acetic acid (43) as a yellow oil (2,46 g, 81%), which is used without any additional purification.1H NMR (400 MHz, CDCl3): 3,71 (s, 3 H); of 3.75 (s, 2 H); to 6.67 (d, 1 H, J = 3.8 Hz); to 6.88 (d, 1 H, J = 3.8 Hz).

Stage 2. (The following reaction is carried out in an atmosphere of N2). 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 successively added to a solution of the hydrochloride of 2-aminobenzeneboronic acid (910 mg, the 5.25 mmol) in toluene (52 ml). The reaction mixture carefully (5 times) Tegaserod and again washed with a stream of N2. Add a solution of methyl ester (5-bromothiophene-2-yl)acetic acid (43) (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 a saturated solution of salt and from lenny the aqueous layer was extracted with EtOAc (3 times). The combined organic layer was washed with water and saturated salt solution and dried his Na2SO4. The crude product is purified preparative radial chromatography (CyH/EtOAc, 5+1), while receiving methyl ester [5-(2-AMINOPHENYL)thiophene-2-yl]acetic acid (44) as a brown oil (634 mg, 51%).1H NMR (400 MHz, CDCl3): to 3.73 (s, 3 H); a 3.83 (s, 2 H); 3,92-4,07 (user. s, 2 H); 6,74 (d, 1 H); 6,76 (TD, 1 H, J1= 7,6 Hz, J2= 1.3 Hz); 6,92 (d, 1 H, J = 3.5 Hz); 7,02 (d, 1 H, J = 3.5 Hz); 7,11 (TD, 1 H, J1= 7,6 Hz, J2= 1.5 Hz); 7.23 percent (DD, 14 H, J1= 7,6 Hz, J2= 1.5 Hz).

Methyl ester 5-(2-AMINOPHENYL)thiophene-2-carboxylic acid (47)

Stage 1. LE23 5-Bromothiophene-2-carboxylic acid (45) (1.50 g, from 7.24 mmol) dissolved in methanol (10 ml) and add conc. sulfuric acid (0,39 ml of 7.24 mmol). The reaction mixture is stirred for 20 hours at 75°C. the Mixture is cooled to room temperature, the solvent is removed under reduced pressure and the residue dissolved in EtOAc. This 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 complex EPE is (46) as a white solid (1.48 g, 92%).1H NMR (400 MHz, CDCl3): 3,85 (s, 3 H); 7,05 (d, 1 H, J= 4.0 Hz); 7,53 (d, 1H, J= 4.0 Hz).

Stage 2. LE29 (the Following reaction is carried out in an atmosphere of N2). Tetrakis(triphenylphosphine)palladium(0) (510 mg, 0.45 mmol) and ester (46) (1.97 g, 8,91 mmol) dissolved in DME (16 ml), the reaction mixture is carefully Tegaserod (5 times) and washed with a stream of N2. Add 2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenylamine (2.15 g, 9,80 mmol) and 1 M aqueous solution of NaHCO3(27,0 ml of 27.0 mmol), the reaction mixture is again carefully Tegaserod (5 times) and washed with a stream of N2. The mixture is stirred for 18 hours at 95°C. Reaction solution was 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 with Na2SO4. The crude product was purified flash chromatography (silica gel, CyH/EtOAc, 5+1], while receiving methyl ester 5-(2-AMINOPHENYL)thiophene-2-carboxylic acid (47) as a yellow solid (1,41 g, 67%).1H NMR (400 MHz, CDCl3): 3,88 (s, 3 H); 4,00 (s, 2 H); 6.73 x-PC 6.82 (m, 2 H); 7,13-7,21 (m, 2 H); 7,26 (DD, 1 H, J1= 7,6 Hz, J2= 1.0 Hz); for 7.78 (d, 1 H, J = 3.8 Hz).

2',4',6'-Trimethoxyphenyl-3-carbonylchloride (51)

Stage 1. KM03 1,3,5-Trimethoxybenzene (10.0 g, 59,46 mmol) dissolved in anhydrous dichloromethane (100 ml), the reaction mixture was cooled to -78°C, what about the drops is added bromine (3.0 ml, 59,44 mmol), the mixture is stirred for 1 hour at a temperature of between -70°C and -40°C. the Solution is heated to 0°C. and add water. Separated the layers and the aqueous layer was extracted with EtOAc (3 times). The combined organic layer was washed with water and saturated salt solution and dried Na2SO4. The solvent is removed and the crude product is purified by recrystallization from hot EtOAc and cyclohexane, thus obtaining 2-bromo-1,3,5-trimethoxybenzoyl (48) as a white solid (8,84 g, 60%).1H NMR (400 MHz, CDCl3): of 3.80 (s, 3 H); 3,86 (s, 6 H); x 6.15 (s, 2 H).

Stage 2:FR542 (the Following reaction is carried out in an atmosphere of N2). Pd(PPh3)4(342 mg, 0.30 mmol) and 2-bromo-1,3,5-trimethoxybenzoyl (48) (2,44 g, 9,87 mmol) dissolved in DME (20 ml) and the solution stirred for 15 min at room temperature. Add ethyl ester 3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid (and 3.16 g of 11.45 mmol) followed by addition of an aqueous 1 M sodium bicarbonate solution (up 29.6 ml, 29.6 mmol). The reaction mixture is carefully Tegaserod, washed with a stream of N2(5 times) and stirred for 20 h at 100°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), the combined organic is the third layer is washed with water and saturated salt solution and dried Na 2SO4. The resulting crude product was then purified preparative radial chromatography (silica gel, EtOAc/CyH, 1+3), while receiving the biphenyl (49) (2,41 g, 77%) as a brown oil.1H NMR (400 MHz, CDCl3): of 1.35 (t, 3 H, J= 7,1 Hz); 3,70 (s, 6 H); 3,85 (s, 3 H); 4,35 (square, 2 H, J = 7.8 Hz); 6,21 (s, 2 H); 7,42 (t, 1 H, J = 7,6 Hz); 7,95 (user. d, 1 H, J= 7.8 Hz); 7,99 (user. s, 1 H).

Stage 3. FR543 Biphenyl (49) (2,41 g, 7.62 mmol) dissolved in MeCN (76 ml) and was added 1 M aqueous LiOH (38,0 ml, 38,0 mmol). The reaction mixture is stirred for 4 hours while boiling under reflux. The cooled reaction mixture (cooling bath) and quenched with 1 M aqueous HCl (to establish a pH of approximately 3). The mixture is extracted with EtOAc (3×), the combined organic layer was washed with water and saturated salt solution and dried Na2SO4. The solvent is removed and the residue is dried without further purification in the vacuum created by the oil pump, while receiving carboxylic acid (50) as a yellow solid (2.25 g, yield quantities.).1H NMR (400 MHz, CDCl3): 3,71 (s, 6 H); 3,85 (s, 3 H); 6,21 (s, 2 H); 7,45 (t, 1 H, J = 7,7 Hz); 7,56 (user. d, 1 H, J= 7.8 Hz); 8,00 (user. d, 1 H, J= 7,6 Hz); 8,06 (user. s, 1 H).

Stage 4. DU011 (the Following reaction is carried out in an anhydrous atmosphere N2). Carboxylic acid (50) (1,00 g, 3.50 mmol) dissolved in anhydrous dichloromethane (23 ml) and add anhydrous DMF (5 drops). Slowly add oxalyl is Lorig (460 μl, the 5.25 mmol) while maintaining the temperature at approximately 20°C in a water bath and the mixture is stirred for additional 2 hours at room temperature. The solvent is removed and the residue is dried under vacuum, thus obtaining the crude 2',4',6'-trimethoxyphenyl-3-carbonylchloride (51) (1.10 g, yield quantities.) in the form of a yellow solid. Additional cleaning is not performed.

Methyl ester 5-(4-AMINOPHENYL)-2-methylfuran-3-carboxylic acid (54)

Stage 1. DK001 (the Following reaction is carried out in the absence of light). Methyl ester 2-methylfuran-3-carboxylic acid (52) (of 3.60 ml, 28.5 mmol) was dissolved in chloroform (20 ml) and glacial acetic acid (20 ml) and portions to the solution was added NBS (6,90 g, to 38.8 mmol) over a period of 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 2 M aqueous NaOH, water (3 times) and saturated salt solution and dried Na2SO4thus the methyl ester of 5-bromo-2-methylfuran-3-carboxylic acid (53) (4,90 g, 78%) as a red-brown oil. Further purification is not carried out.1H NMR (400 MHz, CDCl3): of 2.54 (s, 3 H); of 3.80 (s, 3 H); 6,53 (s, 1 H).

Stage 2: DC+003 (Following Rea is the operation carried out in an atmosphere of N 2). Pd(PPh3)4(1.26 g, of 1.09 mmol) and methyl ester of 5-bromo-2-methylfuran-3-carboxylic acid (53) (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 1 M sodium bicarbonate solution (65,4 ml, 65.3 mmol). The reaction mixture is carefully Tegaserod, washed with a stream 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), the combined organic layer was washed with water and saturated salt solution and dried Na2SO4. The resulting crude product was then purified flash chromatography (silica gel, EtOAc/CyH, 1+2), while receiving methyl ester 5-(4-AMINOPHENYL)-2-methylfuran-3-carboxylic acid (54) (2.35 g, 46%) as a yellow-brown solid.1H NMR (400 MHz, CDCl3): 2,60 (s, 3 H); 3,74 (user. s, 2 H); is 3.82 (s, 3 H); only 6.64 (s, 1 H); to 6.67 (dt, 1 H, J1= 8.6 Hz, J2= 2.3 Hz); 7,42 (dt, 2 H, J1= 8,8 Hz, J2= 2.3 Hz).

2-Thiophene-2-elfenlied (55)

Stage 1. AV (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 washed with a stream of N2. After stirring 10 min add 2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenylamine (1.24 g, 5,64 mmol) and 1 M aqueous solution of NaHCO3(with 15.4 ml of 15.4 mmol), the reaction mixture is again carefully Tegaserod (5 times) and washed with a stream of N2. The mixture is stirred for 3 hours 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), thus obtaining 2-thiophene-2-elfenlied (55) as a brown solid (825 mg, 92%).1H NMR (400 MHz, CDCl3): 4,40-6,00 (m, 2 H); to 6.88 (TD, 1 H, J1= 7,6 Hz, J2= 1.0 Hz); 6,93 (DD, 1 H, J1= 8.0 Hz, J2= 1.0 Hz); 7,07 (DD, 1 H, J1= 5.3 Hz, J2= 3.5 Hz); 7,17 (TD, 1 H, J1= 8.0 Hz, J2= 1.5 Hz) 7,22 (DD, 1 H, J1= 3.5 Hz, J2= 1.3 Hz); 7,30 (DD, 1 H, J1= 7,6 Hz, J2= 1.5 Hz); 7,33 (DD, 1 H, J1= 5.3 Hz, J2= 1.3 Hz).

Methyl ester [5-(3-AMINOPHENYL)thiophene-2-yl]acetic acid (57)

. FR544 (the Following reaction is carried out in an atmosphere of N2). Tetrakis(triphenylphosphine)palladium(0) (1.12 g, 0.97 mmol) and ester (43) (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 washed with a stream of N2. Add 3-nitrophenylarsonic acid (3.57 g, 21,38 mmol) and 3 M aqueous solution of Na2CO3(18,1 ml of 54.3 mmol), the reaction mixture is again carefully Tegaserod (5 times) and washed with a stream of N2. The mixture is stirred for 18 h at 100°C. the Reaction solution was 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 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 (56) as a yellow solid (3.15 g, 58%).1H NMR (400 MHz, CDCl3): of 3.75 (s, 3 H); 3,85 (s, 2 H); 6,94 (user. d, 1 H, J = 3.8 Hz); 7,27 (d, 1 H, J = 3.8 Hz); 7,51 (t, 1 H, J = 8.0 Hz); to 7.84 (DDD, 1 H, J1= 7.8 Hz, J2= 1.5 Hz, J3= 0.8 Hz); 8,08 (DDD, 1 H, J = 8,3 Hz, J2= 2.1 Hz, J3= 1.0 Hz); 8,39 (t, 1 H, 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 (56) (3,15 mg, 11,35 mmol) dissolved in Meon (225 ml) and DOB is given in 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 (washed with a stream of N2) and stirred for 22 h at room temperature. The reaction mixture was filtered through a short layer of celite and remove the solvent. 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 (57) (2,08 g, 74%) as a yellow solid.1H NMR (400 MHz, CDCl3): to 3.73 (s, 3 H); 3,81 (s, 2 H); 6,59 (DD, 1 H, J1= 7.8 Hz, J2= 2.0 Hz); 6,86 (user. d, 1 H, J = 3.5 Hz); 6,88 (t, 1 H, J = 1.9 Hz); 6,97 (user. d, 1 H, J = 7,6 Hz); to 7.09 (d, 1 H, J = 3.5 Hz); 7,13 (t, 1 H, J = 7,7 Hz).

EXAMPLE 3

2-Methyl-5-{4-[(2',4',6'-trihydroxyphenyl-3-carbonyl)amino]phenyl}furan-3-carboxylic acid (60) REV968

Stage 1. AV (the Following reaction is performed in a dry atmosphere N2). Aniline (54) (150 mg, of 0.65 mmol) dissolved in anhydrous dichloromethane (10.0 ml), add anhydrous pyridine (1.7 ml) and the acid chloride of carboxylic acid (51) (218 mg, 0.71 mmol). The reaction mixture is stirred for 20 hours at room temperature. The reaction mixture was poured into ice 1 M aqueous HCl, extracted with EtOAc (3×), the combined organic layer was washed with water and neymann the m salt solution and dried Na 2SO4. The resulting crude product was then purified preparative radial chromatography (silica gel, EtOAc/CyH, 1+5, then 1+3, then 1+1), while receiving amide (58) as a yellow solid (95 mg, 29%).1H NMR (400 MHz, CDCl3): 2,63 (s, 3 H); and 3.72 (s, 6 H); a 3.83 (s, 3 H); 3,86 (s, 3 H); 6,23 (s, 2 H); for 6.81 (s, 1 H); 7,46-7,53 (m, 2 H); to 7.61 (d, 2 H, J = 8.5 Hz); 7,66 (d, 2 H, J = 8.6 Hz); 7,76-of 7.82 (m, 3 H).

Stage 2. AV ester (58) (71 mg, 0.14 mmol) dissolved in THF (2.4 ml) and Meon (0.6 ml) and was added 1 M aqueous LiOH (710 μl, 0.71 mmol). The reaction mixture is stirred for 24 hours at room temperature. The solvent is removed under reduced pressure and the residue partitioned between EtOAc and 1 M HCl. The aqueous layer was separated and extracted 3 times with EtOAc. The combined organic layer was washed with water and 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, thus obtaining the crude product (59) in the form of a beige solid (68 mg, 99%).1H NMR (400 MHz, DMSO-d6): at 2.59 (s, 3 H); to 3.67 (s, 6 H); a 3.83 (s, 3 H); 6,34 (s, 2 H); 6,99 (s, 1 H); 7,38 (user. d, 1 H, J = 7,6 Hz); of 7.48 (t, 1 H, 7,7 Hz); to 7.67 (d, 2 H, J = 8,8 Hz); to 7.77 (user. s, 1 H); 7,81-7,87 (m, 3 H); 10,29 (s, 1 H); 12,60 (user. s, 1 H).

Stage 3. AV (the Following reaction is carried out in an anhydrous atmosphere N2). Carboxylic acid (59) (65 mg, 0.13 mmol) is suspended in b is Sodnom dichloromethane (2.7 ml) and anhydrous 1,2-dichloroethane (2.0 ml), the solution is cooled to -78°C and added dropwise a 1 M solution of BBr3in dichloromethane (800 μl, 0.80 mmol). The reaction mixture was stirred for 10 min at -78°C and after slow heating stirred for additional 4 h at room temperature. The reaction mixture was cooled to 0°C. add dropwise water and dichloromethane, followed by addition of EtOAc. The aqueous layer was separated and extracted 3 times with EtOAc. The combined organic layer was washed with saturated salt solution and dried Na2SO4. The solvent is removed under reduced pressure and the crude product is purified preparative RP-HPLC (gradient, water/CH3CN, 95:5 - 5:95), thus obtaining 2-methyl-5-{4-[(2',4',6'-trihydroxyphenyl-3-carbonyl)amino]phenyl}furan-3-carboxylic acid (60) (11 mg, 19%) as a yellow solid.1H NMR (400 MHz, CD3OD): in 2.68 (s, 3 H); 6,03 (s, 2 H); to 6.95 (s, 1 H); 7,52 (t, 1 H, J= 7,7 Hz); to 7.61 (dt, 1 H, J1= 7,6 Hz, J2= 1.3 Hz), 7,71 (d, 2 H, J = 8,8 Hz); 7,81 (d, 2 H, J = 8,8 Hz); 7,83 (dt, 1 H, J1= 8,1 Hz, J2= 1.4 Hz), 7,95 (t, 1 H, J= 1.5 Hz).

EXAMPLE 4

(5-{2-[(2',4',6'-Trihydroxyphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (63) REV974

Stage 1. FR600 (the Following reaction is carried out in an anhydrous atmosphere N2). Aniline (44) (823 mg, of 3.33 mmol) dissolved in anhydrous dichloromethane (17,0 ml), add anhydrous pyridine (680 is CL, with 8.33 mmol) and the acid chloride of carboxylic acid (51) (1,67 g, 4,32 mmol). The reaction mixture is stirred for 20 hours at room temperature. The reaction mixture was poured into ice 1 M aqueous HCl, extracted with EtOAc (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, CyH/EtOAc, 3+1), while receiving amide (61) as a yellow solid (722 mg, 41%).1H NMR (400 MHz, CDCl3): of 3.69 (s, 6 H); and 3.72 (s, 3 H); of 3.80 (s, 2 H); 3,86 (s, 3 H); 6,21 (s, 2 H); 6,92 (d, 1 H, J = 3.5 Hz); 7,01 (d, 1 H, J = 3.5 Hz); 7,14 (t, 1 H, J = 7,3 Hz); of 7.36-7,42 (m, 2 H); 7,44 (d, 1 H, J = 7,8 Hz); of 7.48 (user. d, 1 H, J = 7,6 Hz); to 7.61 (user. d, 1 H, 7,3 Hz); 7,78 (user. s, 1 H); 8,35 (user. s, 1 H); and 8.50 (d, 1 H, J = 8,3 Hz).

Stage 2. FR601 ester (61) (722 mg, of 1.39 mmol) dissolved in MeCN (14,0 ml) and was added 1 M aqueous LiOH (7,0 ml of 7.00 mmol). The reaction mixture is stirred for 20 hours at room temperature. The solvent is removed under reduced pressure and the residue partitioned between EtOAc and 1 M HCl (1+1). The aqueous layer was separated and extracted 3 times with EtOAc. The combined organic layer was 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, thus obtaining the crude product (62) in the form of VC the CSO solids (714 mg, quantity. output).1H NMR (400 MHz, CD3CN): at 3.69 (s, 6 H); of 3.80 (s, 2 H); 3,85 (s, 3 H); 6.30-in (s, 2 H); 6,92 (d, 1 H, J = 3.5 Hz); 7,14 (d, 1 H, J = 3.8 Hz); 7,28 (TD, 1 H, J1= 7,6 Hz, J2= 1.3 Hz); 7,39 (TD, 1 H, J1= 7.8 Hz, J2= 1.3 Hz); 7,42-7,49 (m, 2 H); rate of 7.54 (DD, 1 H, J1= 7.8 Hz, J2= 1.3 Hz); 7,69 (user. s, 1 H); 7,73 (dt, 1 H, J1= 7,3 Hz, J2= 1,8 Hz); 7,89 (d, 1 H, J = 7,6 Hz); 8,53 (user. s, 1 H).

Stage 3. FR602 (the Following reaction is carried out in an anhydrous atmosphere N2). Carboxylic acid (62) (700 mg, of 1.39 mmol) dissolved in anhydrous dichloromethane (28,0 ml), the solution cooled to -78°C and added dropwise a 1 M solution of BBr3in dichloromethane (8.5 ml, 8.50 mmol). The reaction mixture was stirred for 10 min at -78°C and after slow heating stirred for additional 4 h at room temperature. The reaction mixture was cooled to 0°C and added dropwise water and dichloromethane, followed by addition of EtOAc. The aqueous layer was separated and extracted 3 times with EtOAc. The combined organic layer was washed with saturated salt solution and dried Na2SO4. The solvent is removed under reduced pressure and the crude product is purified preparative RP-HPLC (gradient, water/CH3CN, 95:5 - 5:95), while receiving (5-{2-[(2',4',6'-trihydroxyphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (63) (146 mg, 22%) as a beige solid.1H NMR (400 MHz, CD3OD) of 3.85 (s, 2 ); of 6.02 (s, 2 H); 6,97 (d, 1 H, J = 3.5 Hz); 7.18 in (d, 1 H, J = 3.5 Hz); to 7.35 (TD, 1 H, J1= 7,6 Hz, J2= 1.3 Hz); 7,42 (TD, 1 H, J1= 7,6 Hz, J2= 1.5 Hz); 7,50 (t, 1 H, J = 7,7 Hz); to 7.61 (user. d, 2 H, J = 7,6 Hz); 7,79 (user. d, 2 H, J = 7,6 Hz); 7,93 (user. s, 1 H).

EXAMPLE 5

(5-{2-[2-(2,4,6-Trihydroxyphenyl)acetylamino]phenyl}thiophene-2-yl)acetic acid (25) REV989, DU27

(5-{2-[2-(2,4,6-Trihydroxyphenyl)acetylamino]phenyl}thiophene-2-yl)acetic acid (25) is obtained from the amine (44) and the acid chloride of the carboxylic acid (14) according to the procedure described in stages 1-3 of example 1. (5-{2-[2-(2,4,6-Trihydroxyphenyl)acetylamino]phenyl}thiophene-2-yl)acetic acid (25) (25 mg, yield 16% after 3 stages) are obtained as a brown solid.1H NMR (400 MHz, CD3OD): to 3.58 (s, 2 H); 3,88 (s, 2 H); 5,88 (s, 2 H); to 6.67 (d, 1 H, J = 3.3 Hz); at 6.84 (d, 1 H, J= 3.3 Hz); 7,14 (t, 1 H, J = 7,3 Hz); 7,31-7,37 (m, 2 H); compared to 8.26 (d, 1 H, J = 8.6 Hz).

EXAMPLE 6

5-{2-[(2',4',6'-Trihydroxyphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (26) REV971, LE37

5-{2-[(2',4',6'-Trihydroxyphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (26) is obtained from the amine (47) and the acid chloride of the carboxylic acid (51) according to the method described above in stages 1-3 of example 4. 5-{2-[(2',4',6'-Trihydroxyphenyl-3-carbonyl)amino]phenyl}thiophene-2-carboxylic acid (26) (44 mg, yield 22% after 3 stages) are obtained in the form of a white solid. 1H NMR (400 MHz, CD3OD): of 6.02 (s, 2 H); to 7.32 and 7.36 (m, 1 H); 7,41 (t, 1 H, J = 7,6 Hz); 7,46-7,53 (m, 2 H); a 7.62 (dt, 1 H, J1= 7,6 Hz, J2= 1.3 Hz); the 7.65 7,73 (m, 3 H); 7,80 (dt, 1 H, J1= 8,1 Hz, J2= 1.4 Hz); of 7.96 (user. s, 1 H).

EXAMPLE 7

(5-{3-[(2',4',6'-Trihydroxyphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (64) REV996, KM

(5-{3-[(2',4',6'-Trihydroxyphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (64) is obtained from the amine (57) and the acid chloride of the carboxylic acid (51) according to the method described above in stages 1-3 of example 4. (5-{3-[(2',4',6'-Trihydroxyphenyl-3-carbonyl)amino]phenyl}thiophene-2-yl)acetic acid (64) (3 mg, yield 4% after 3 stages) are obtained as a brown solid.1H NMR (400 MHz, CD3OD): 3,88 (s, 2 H); 6,03 (s, 2 H); 6,97 (d, 1 H, J = 3.5 Hz); 7,29 (d, 1 H, J = 3.8 Hz); of 7.36-7,44 (m, 2 H) 7,53 (t, 1 H, J = 7,7 Hz); to 7.61 (dt, 1 H, J1= 7,6 Hz, J2= 1.4 Hz); 7,66 (dt, 1 H, J1= 7,3 Hz, J2= 1,8 Hz), the 7.85 (dt, 1 H, J1= 7.8 Hz, J2= 1.5 Hz); of 7.96 (t, 1 H, J = 1.5 Hz); 8,05 (user. s, 1 H).

EXAMPLE 8

(2-Thiophene-2-ylphenyl)amide 2',4',6'-trihydroxyphenyl-3-carboxylic acid (65) REV965, AB437

(2-Thiophene-2-ylphenyl)amide 2',4',6'-trihydroxyphenyl-3-carboxylic acid (65) is obtained from the amine (55) and the acid chloride of the carboxylic acid (51) according to the method described above in stages 1 and 3 of example 4. (2-Thiophene-2-ylphenyl)amide 2',4',6'-Triger xiufen-3-carboxylic acid (65) (12 mg, exit 9% after 2 stages) are obtained in the form of a beige solid.1H NMR (400 MHz, CD3OD): of 6.02 (s, 2 H); 7,13 (DD, 1 H, J1= 5,1 Hz, J2= 3.8 Hz); to 7.35 (DD, 1 H, J1= 3.5 Hz, J2= 1.0 Hz); 7,38 (DD, 1 H, J1= 7,6 Hz, J2= 1.3 Hz); 7,41-of 7.48 (m, 2 H); 7,50 (d, 1 H, J = 7,6 Hz); to 7.61 (dt, 1 H, J1= 7.8 Hz, J2= 1.4 Hz); to 7.64 (DD, 1 H, J1= 7,6 Hz, J2= 1.5 Hz); 7,73 (DD, 1 H, J1= 7.8 Hz, J2= 1.3 Hz); to 7.77 (dt, 1 H, J1= 8,1 Hz, J2= 1.4 Hz); 7,92 (t, 1 H, J = 1.5 Hz).

EXAMPLE 9

(3-Triptoreline)amide 2',4',6'-trihydroxyphenyl-3-carboxylic acid (66) REV961, DU15

(3-Triptoreline)amide 2',4',6'-trihydroxyphenyl-3-carboxylic acid (66) is obtained from 3-triptoreline and acid chloride of the carboxylic acid (51) according to the method described above in stages 1 and 3 of example 4. (3-Triptoreline)amide 2',4',6'-trihydroxyphenyl-3-carboxylic acid (66) (54 mg, yield 54% after 2 stages) are obtained in the form of a beige solid.1H NMR (400 MHz, CD3OD): of 6.02 (s, 2 H); 7,45 (user. d, 1 H, J = 7,6 Hz); 7,53 (t, 1 H, J = 7,7 Hz); 7,58 (t, 1 H, J = 8.0 Hz); a 7.62 (dt, 1 H, J1= 7.8 Hz, J2= 1.4 Hz); a 7.85 (DDD, 1 H, J1= 7.8 Hz, J2= 1.8 Hz, J3= 1.3 Hz); 7,95-to 7.99 (m, 2 H); 8,21 (user. s, 1 H).

EXAMPLE 10

3-[(2',4',6'-Trihydroxyphenyl-3-carbonyl)amino]benzoic acid (67) REV1007, LE80

3-[(2',4',6'-Trihydroxyphenyl-3-Carbo who yl)amino]benzoic acid (67) is obtained from the methyl ester of 3-aminobenzoic acid and acid chloride of the carboxylic acid (51) according to the method described above in stages 1-3 of example 3. 3-[(2',4',6'-Trihydroxyphenyl-3-carbonyl)amino]benzoic acid (67) (22 mg, yield 14% after 3 stages) will get not quite a white solid.1H NMR (400 MHz, CD3OD): of 6.02 (s, 2 H); of 7.48 (t, 1 H, J = 8.0 Hz); 7,52 (t, 1 H, J = 7.8 Hz); to 7.61 (user. d, 1 H, J = 7.8 Hz); 7,84 (t, 2 H, J = 7.2 Hz); of 7.96 (user. s, 1 H); 8,01 (user. d, 1 H, J = 8,3 Hz); 8.34 per (user. s, 1 H).

The compounds indicated in the following scheme 6, are the compounds specifically referred to in the description of the preferred connections.

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 of the IC50.

Titration microplates incubated for coverage through the night in carbonate buffer, pH 9,6, with goat antibody against the 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 Chimera the P-selectin-IgG-man (0,61 nm, accordingly, 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, comprising 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)/N2About2and the reaction stopped 20 ál of 1 M 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 IC50sLex-TSA for E-/R-/L-select the
ConnectionIC50E-selectin [µm]IC50P-selectin [µm]IC50L-selectin [µm]
Bimosiamose>50095,0>500
1841,237,135,1
1912,420,722,1
25105,487,995,9
2633,327,828,2
607,85,26,1
63of 21.917,417,4
64the 5.76,06,3
6528,1 8,215,5
6727,323,325,2

Analysis in a flow chamber/adhesion and slip cells in the 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 cover for 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 is suspended 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 the compound compared to the absence 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 of bimosiamose.

ConnectionE-Selectin
[Attitude]
P-Selectin
[Attitude]
18 0,801,07
190,751,27
ConnectionE-Selectin
[Attitude]
P-Selectin
[Attitude]
250,941,65
261,110,77
601,050,99
631,230,87
641,061,23
651,130,99
661,471,19
670,790,95

1. Pharmaceutical compositions comprising at least one compound of formula (I) and a pharmaceutically acceptable carrier which is useful in medicine,

where the symbols and substituents have the following value is of:
where-X - is a



and where Y' is a

where s is 0 or 1,
R2is a CO2H, CO2alkyl, CO2aryl, CO2NH2, CO2aralkyl, SO3H, SO2NH2, RHO(OH)2, 1-N-tetrazolyl-, SNO, PINES3CH2HE, NH2The N, N(alkyl)alkyl', och3CH2Och3, SH, F, Cl, Br, I, CH3CH2CH3CN, CF3;
R3regardless of R2represents N, CH3CH2CH3, CF3, F, Cl, Br, I, CN, NO2and
R4regardless of R2and R3represents N, CH3CH2CH3, CF3, F, Cl, Br, I, CN, NO2, R2,
R5represents H, NO2, CF3, F, Cl, Br, I, CN, CH3, OCH3, SH, NH2and-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-,
R2should not be NH2or SH; or

where t is 0, 1, 2;
-Z is a

R 7regardless of R2represents H, NO2, CF3, F, Cl, Br, I, CN, CH3, OCH3, SH, NH2,

where K represents NH, NMe, O, S,

or pharmaceutically acceptable salts, esters or amides of the abovementioned compounds of the formula (C).

2. The pharmaceutical composition according to claim 1, where the compounds have the formula (D)

where X has the values specified in claim 1, and Y represents a

where R9is a CO2N, CO2alkyl, CO2aryl, CO2NH2, CO2aralkyl, CH2SO3H, CH2SO2NH2CH2PO(OH)2, 1-N-tetrazolyl, SNO, PINES3CH2HE, CH2NH2CH2NH, CH2N(alkyl)alkyl', CH2Och3CH2SH
where all indices, symbols and substituents have the meanings mentioned in claim 1.

3. Chemical compounds with the General structure of formula (C) or (D) according to claim 1 or 2.

4. The use of compounds having the structure of formula (C) 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 (ARS), 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 for the treatment of asthma and inflammatory bowel disease.

5. The use of compounds having the structure of formula (C) according to claim 1, for obtaining a medicinal product for the treatment, diagnosis or prevention of inflammatory disorders.

6. The use of compounds having the structure of formula (C) according to claim 1, to obtain a filler for the delivery of drug to the target organ in the diagnosis or therapy.

7. The use of compounds having the structure of formula (C) according to claim 1, for obtaining a cosmetic or dermatological composition.

8. Cosmetic compositions comprising at least one compound of the formula (C) according to claim 1 and at least one cosmetically tolerable component.

9. Dermatological compositions comprising at least one compound of the formula (C) according to claim 1 and at least one dermatologics the portable component.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: in formula (I) Cy1 is a 6-member heterocyclyl containing N as a heteroatom, a 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S and O, phenyl or phenyl condensed with a 5-member heterocycle containing O as a heteroatom, each optionally having 1-3 identical or different substituting Cy1 groups which are: (C1-C6)-acyl, cyano, carboxy, hydroxy, (C1-C6)alkylsulphonyl, (C3-C6)-cycloalkyl, a 6-member heterocyclyl containing 1-2 heteroatoms selected from O and N, phenyl, a 5-member heteroaryl containing 1-3 heteroatoms selected from N, S and O, Y1Y2N-, Y1Y2NC(=O)-, Y1Y2NSO2-, (C1-C6)-alkyl-SO2-N(R5)-C(=O)-, R6-C(=O)-N(R5)-, R7-NH-C(=O)-NH-; (C1-C6)-alkoxycarbonyl; (C1-C6)-alkyl, which optionally contains 1-3 identical or different substitutes which are halogen, carboxy, cyano, hydroxy, Y1Y2N-, Y1Y2N-C(=O)-, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-, 5-member heterocyclyl, containing N as a heteroatom, 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; or (C1-C6)-alkoxycarbonyl; as well as (C1-C6)-alkoxy which optionally have 1-3 identical or different substitutes which are carboxy, (C1-C6)-alkoxycarbonyl, cyano, 3-member heterocyclyl containing O as a heteroatom, or 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; where phenyl or heteroaryl fragments in the substituting Cy1 groups optionally and independently have substitutes represented by hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6)-alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-; and where cycloalkyl fragments in the substituting Cy1 groups which optionally and independently have substitutes represented by (C1-C6)-alkoxy, carboxy; Cy2 is a 9-member cycloalkenyl, phenyl, 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteratoms selected from N, S and O, or phenyl condensed with a 5,6-member heterocycle containing 1-2 heteroatoms selected from N and O, each independently and optionally having 1-3 identical or different substitutes represented by (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen-(C1-C6)-alkoxy, nitro, Y1Y2N-; L1 is an alkylene with a straight or branched chain containing 1-6 carbon atoms, optionally substituted carboxy; or L1 is -CH2-(C1-C5)halogenalkylene; L2 is a bond, -O- or -CH2-O-. Other values of radicals are given in the formula of invention.

EFFECT: novel compounds have prostaglandin D2 receptor antagonist properties, can be used in treating primarily allergic disorders such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy and other diseases.

39 cl, 1 tbl, 99 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole derivatives of the formula I: , where R1 and R2 independently denote Ph; mono- or disubstituted in different positions of the ring Ph, where substitute denotes -OCH3; C5-heteroaryl with one heteroatom selected from O or S; R2 denotes H, NO2, NH2, C(O)NH2; R4 denotes H, a straight or branched C1-C6-alkyl; n equals the number of methylene groups and is between 1 and 8 inclusively; X denotes O, S, NH; Y NH, -CH2-; Z denotes O, S; W denotes -OH, hydroxylamine, hydrazine, alkylhydrazine.

EFFECT: compounds can inhibit histone deacetylase, which enables their use in cancer treatment.

10 cl, 9 dwg, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopenta[b]benzofuranyl derivatives of formula wherein substitutes R1, R2, R3, R4, R5, R6 and R7 and n are specified in the patent clam. These compounds exhibit properties of NF-kB-activity and/or AP-1 inhibitor/modulator. Also, the inventive subject matter are methods for preparing intermediate compounds thereof, a pharmaceutical composition containing them, administration thereof for prevention and/or treatment of inflammatory and autoimmune diseases, neurodegenerative diseases and hyperproliferative diseases caused by NF-kB- and/or AP-1-activity, and a method for prevention and/or treatment of said diseases.

EFFECT: preparation of new cyclopenta[b]benzofuranyl derivatives.

21 cl, 3 tbl, 151 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compound described by formula where R1 represents a monocyclic nitrogen-containing heterocyclic group optionally condensed with heterocycle with the monocyclic nitrogen-containing heterocyclic group optionally condensed with heterocycle, optionally having 1 to 5 substitutes chosen from a group consisting of (1) halogen atom, (2) cyano, (3) hydroxy, (4) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (5) amino, (6) mono- C1-6 alkylamino, (7) C1-6 alkoxycarbonyl and (8) C1-6 alkyl optionally having 1 to 3 halogen atoms, R2 represents (i) C6-14 aryl group optionally substituted by 1 to 5 substitutes chosen of a group consisting of (1) halogen atom, (2) cyano, (3) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (4) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (5) C1-6alkylcarbonyl, (6) C1-6 alkylsulphonyl, (7) C1-6 alkylthionyl, (8) C3-7 cycloalkyl, (9) C1-6 alkyl group optionally having 1 to 3 halogen atoms, and (10) C1-6 alkyl group substituted by 1 to 3 hydroxy, (ii) a thienyl group optionally substituted by 1 to 4 substitutes chosen from a group consisting of (1) cyano and (2) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (iii) a pyridyl group optionally substituted by 1 to 4 substitutes chosen from a group consisting of (1) halogen atom, (2) 5-10-members aromatic heterocyclic group containing carbon atom, and 1 or 2 presentations of 1-4 heteroatoms chosen from nitrogen atom, sulphur atom and oxygen atom, and (3) C1-6 alkyl group optionally having 1 to 3 halogen atoms, or (iv) a bipyridyl group optionally substituted by 1 to 3 halogen atoms, each R3 and R4 represents hydrogen atom, or one of R3 and R4 represents hydrogen atom, and another represent a lower alkyl group, halogen atom or a cyanogroup, and R5 represents an alkyl group, or to its salt. Also, the invention refers to a pharmaceutical composition showing an acid secretion inhibitory effect enabled by the compound of formula I, to a method for treatment or prevention, besides, to application of the compound of formula I for preparing a pharmaceutical composition for treatment or prevention of a number of diseases presented in the patent claim.

EFFECT: preparation of the new compounds showing the acid secretion inhibitory effect and exhibiting antiulcerant action.

20 cl, 92 ex, 24 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel 4-(1H-indol-3-yl)-but-3-en-2-one derivatives of general formula 3: , : which can be used in synthesis of novel preparations for pharmaceutical and agricultural purposes. The method involves mixing 2-alkyl-5-(2-amino-4-alkylphenyl)-furans 1 with aromatic and heteroaromatic aldehydes 2 in acetic acid in equimola ratio at temperature 35°C for 40 minutes in the presence of 0.01 ml hydrochloric acid.

EFFECT: improved method.

2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula Ia and their pharmaceutically acceptable salts, hydrates, solvates, esters and amides. In formula Ia , A is specified from -C(O)OR5 where R5 represents hydrogen; W represents C1-3alkylene; Y is specified from phenyl and 5-6-member heteroaryl containing one heteroatom specified from N, S, O; where any phenyl or heteroaryl Y can be optionally substituted with 1 to 3 radicals specified from halogen, C1-6alkyl, C1-6alkoxygroup, halogen-substituted C1-6alkyl and halogen-substituted C1-6alkoxygroup; Z is specified from: where left and right asterisks Z specify an attachment point between -C(R3)(R4)- and A of formula la; R6 is specified from hydrogen and C1-6alkyl; or R6 can be attached to carbon atom in Y to form a 5-7-member ring; R1 is specified from phenyl and 5-member heteroaryl containing one heteroatom specified from S, O; where any phenyl or heteroaryl R1 is substituted with a radical specified from phenylC0-4alkyl, heteroarylC0-4alkyl where heteroaryl represents 5-6-member heteroary containing one heteroatom specified from N, S, O, C3-8cycloalkylC0-4alkyl, C3-8heterocycloalkylC0-4alkyl which contains nitrogen atom as heteroatom, or C1-6alkyl; where any phenyl, heteroaryl, cycloalkyl or heterocycloalkyl group R1 can be optionally substituted with 1 to 3 radicals specified from halogen, C1-6alkyl, C1-6alkoxygroup, halogen-substituted C1-6alkyl group and halogen-substituted C1-6alkoxygroup; R2 represents C1-6alkyl group; R3 and R4 represent hydrogen.

EFFECT: preparation of the pharmaceutical composition exhibiting EDG/S1P receptor modulating properties, containing therapeutically effective amount of the compound under the invention, development of a method of treating the disease mediated by EDG/S1P receptor activity, application of the compounds for preparing a drug for prevention or treatment of the disease mediated by EDG/S1P receptor activity.

16 cl, 1 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): , optical isomers of said compounds, as well as salts thereof having peroxisome proliferator-activated receptor subtype y (PPARy) modulating property. Values of R1, R2, X, Ar1 and Ar2 are given in the formula of invention.

EFFECT: preparation of compositions based on said compounds, as well as use of said compounds in cosmetic and pharmaceutical industry.

11 cl, 30 ex

FIELD: medicine.

SUBSTANCE: invention relates to amidines of formula (I) and to their derivatives, methods for making thereof and pharmaceutical compositions containing amidines of formula (I). According to said invention, amidines are applicable for inhibition of IL-8 induced chemotactic factor, and can be applied to produce medicine agents for treating psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and for preventing and treating injuries caused by ischemia and reperfusion.

EFFECT: higher clinical effectiveness.

7 cl, 6 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), including its pharmaceutically acceptable salts, solvates, ethers and amides, possessing ability to bind ERα- and ERβ-estrogen receptors, to pharmaceutical composition based on them, to versions of applying claimed compounds in medication preparation and to method of binding ERα- and ERβ-estrogen receptors. (I), where R1 represents H, OH or C1-12alkoxy, or halogen; R2 represents H, OH or halogen; R3 represents C1-12alkyl, halogeno-C1-12alkyl, C3-10cycloalkyl, C1-12alkoxy or C1-12alkoxyC1-12alkyl; R4 represents H or C1-12alkoxy; R5 represents H, halogen or halogeno-C1-12alkyl; R6 represents -(Y)z-R7; R8 represents phenyl or 5- or 6-member heteroaryl, containing N, O or S as heteroatom, where said phenyl and heteroaryl are possibly substituted with OH, halogeno, halogenoC1-12alkyl or C1-12alkoxy. Values R7, Y and z are presented in invention formula.

EFFECT: novel compounds possess useful biological properties.

19 cl, 7 dwg, 1 tbl, 70 ex

FIELD: chemistry.

SUBSTANCE: in acidified indanylamines of general formula (I) R1-R4 have values given in description, A represents CH2, CHOH, B represents CH2 and R5 represents aryl or heteroaryl group, possibly substituted with substituents, listed in description. Said compounds are useful in regulation of endothelial nitrogen oxide synthase (eNOS) and, therefore they can be useful for production of medications for treatment of stable and unstable angina pectoris, Prinzmetal's angina, acute coronary syndrome, impaired heart function, cardiac infarction, stroke, thrombosis, peripheral artery occlusive disease, endothelial dysfunction, atherosclerosis, hypertension, lung hypertension, symptomatic hypertension, renovascular hypertension, erectile dysfunction, diabetes or diabetes complications, nephropathy, retinopathy, limited memory function, limited learning ability.

EFFECT: increase of composition efficiency.

37 cl, 441 ex, 2 tbl

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a new method for synthesis of derivative of thieno[3,2-c]pyridine of the formula (1): (ticlopidine and clopidogrel). Method involves interaction of compound of the formula (2e): with compound of the formula (3): or its salt wherein R represents hydrogen atom or methoxycarbonyl; each among X' and Y' represents independently chlorine, bromine atom, methanesulfonyl or p-toluenesulfonyl, and to novel intermediate compounds and methods for their synthesis. Ticlopidine and clopidogrel possess the high inhibitory activity with respect to blood platelets aggregation and antithrombosis activity.

EFFECT: simplified process of synthesis, valuable medicinal properties of compounds.

15 cl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel ester compounds represented by the formula (1): wherein values for R1, R2, A, X, R3, R4, Alk1, Alk2, l, m, D, R8 and R9 are determined in the invention claim. Also, invention relates to inhibitor of matrix metalloproteinase (MTP), a pharmaceutical composition able to inhibit activity of MTP selectively, agents used in treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes mellitus or hypertension wherein the pharmaceutical composition is prepared in capsulated formulation, and to a biphenyl compound of the formula (100) given in the invention description.

EFFECT: valuable medicinal properties of compounds.

53 cl, 78 tbl, 17 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

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

4 cl, 2 tbl, 568 ex

The invention relates to new N-sulfonylpiperidinylmethylene derivative of the formula I

< / BR>
where n = 1; R1means1-C6alkyl, C3-C6cycloalkyl,2-C6alkenyl, C1-C6haloalkyl or a group NR11R12where R11and R12each independently from one another mean H, C1-C6alkyl; R2means N; R3means1-C6alkyl; R4, R5, R6and R7have the same or different values and each independently from one another mean H, C1-C4alkyl; R8means C1-C6alkyl; a represents C1-C6alkylen; means phenyl, optionally substituted by 1-3 substituents, which may be the same or different and selected from the group comprising C1-C8alkyl, C1-C8haloalkyl,1-C8alkoxy, C1-C8haloalkoxy, C2-C8alkanoyl, halogen, C1-C8alkoxycarbonyl, nitro; or naphthyl or thienyl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of methyl ether of 5-acetyl-2-furan carboxylic acid, which is used as a starting compound in synthesis of pharmaceutical preparations. The method for synthesis of methyl ether of 5-acetylfuran-2-carboxylic acid of formula is characterised by that 2-acetylfuran reacts with CCl4 and methanol in an autoclave under argon in the presence of a catalyst selected from a group comprising ferrocene (Fe(C5H5)2), tris(2,4-pentanedionato)iron (Fe(acac)3), iron bromide (FeBr2) in molar ratio [catalyst]:[2-acetylfuran]:[CCl4]:[methanol]=1:100:100-200:200-2000, at temperature 120°C for 6-9 hours. Output of methyl ether of 5-acetyl-2-furan carboxylic acid can be 87-95% depending on the nature of the catalyst used.

EFFECT: high yield.

1 tbl, 19 ex

Up!