MX2008003700A - Novel phloroglucinol derivatives having selectin ligand activity - Google Patents

Abstract

Pharmaceutical compositions comprising at least one compound of the formula (I) and a pharmaceutically acceptable carrier which is useful in a medicine wherein the symbols and substituents have the following meaning -X- is e.g. and Y being e.g. or the pharmaceutically acceptable salts, esters or amides and prodrugs can be applied to modulate the in-vitro and in-vivo binding processes mediated by E-, P- or L-selectin binding.

Description

NEW FLOROGLUCINOL DERIVATIVES THAT HAVE SELECTINE LIGAND ACTIVITY FIELD OF THE INVENTION The present invention relates to compounds, compositions and methods for modulating in vitro and in vivo processes, mediated by cell adhesion molecules. The small molecules described comprise 2,4,6-trihydroxy phenyl subunits and potentially modulate the functions mediated by cell adhesion molecules.

BACKGROUND OF THE INVENTION The functions mediated by cell adhesion molecules are part of a complex cascade that leads to the migration of white blood cells (leukocytes) circulation from the bloodstream into the surrounding tissue (transmigration). Physiologically, leukocyte transmigration is of critical importance for the homeostasis and immune-survival of living beings including humans. Lymphocytes, for example, are constitutively leaving the bloodstream in lymphatic tissues to monitor for dangerous antigens. Under pathological circumstances, however, for example, local or systemic inflammation and / or injury to the vascular system, this fundamental process is dis-regulated, at least Ref.: 191123 in part, due to the increased surface expression of E and P selectin. Consequently, excessive leukocyte migration leads to a pathological cellular infiltrate with subsequent tissue damage in several clinically relevant settings. Disease states such as Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), Bronchial Asthma (Asthma), Chronic Obstructive Pulmonary Disease (COPD), Psoriasis, Rheumatoid Arthritis and Sepsis, are all associated with induced tissue inflammation and perpetuated by pathologically activated leukocytes that infiltrate the respective tissue. In addition, exaggerated leukocyte infiltration contributes to the pathogenesis of Ischemic Reperfusion (IR) lesion, associated with organ transplantation, cardiopulmonary bypass or percutaneous transluminal angioplasty. To transmigrate, the leukocytes must bind to the wall of the vascular endothelium to diffuse through the capillary cell wall into the surrounding tissue. Therefore, leukocytes have to be rolled over and then adhered to the endothelial cell wall (coiled or "braided" initial). This primary event in transmigration is mediated by the selectin family of cell adhesion molecules. In addition, to bind directly to the endothelium, the leukocytes can adhere to other leukocytes, leukocyte particles, platelets or particles derived from platelets, which are, either, attached to the endothelium. The selectin family of adhesion molecules is comprised of three surface proteins of structurally related calcium-dependent carbohydrate-binding cells, E, P and L selectin. Selectin E is expressed only in inflamed endothelium, P-selectin is expressed in Inflammed endothelium, as well as in platelets and selectin L is expressed on leukocytes. Selectins are composed of an amino-terminus lectin domain, a domain similar to epidermal growth factor (EGF), a variable number of repeats related to the complement receptor, a hydrophobic transmembrane domain and a C-terminal cytoplasmic domain. The binding interactions that lead to the adhesion of leukocytes are assumed to be mediated by contact of the lectin domain of the selectins and various carbohydrate ligands on the surface of the leukocytes. The three selectins can be linked with low affinity to the sialyl carbohydrate Lewis * (sLex), a glycosyl moiety present on the surface of most leukocytes. A structurally related glycosyl moiety, sialyl Lewisa (sLea), is found predominantly on the surface of cancer cells [K. Okazaki et al., J Surg. Res. , 1998, 78 (1). 78-84; R. P. McEver et al., Glycoconjugga Journal, 1997, 14 (5), 585-591].

In the case of P-selectin, a different high affinity glycoprotein ligand has been described [R.P. McEver, R.D. Cummings, J.Clin. Invest., 1997, 100, 485-492], the so-called P-selectin glycoprotein ligand-1 (PSGL-1), which contributes to a high affinity selectin binding for its sLex portion, as well as for parts of its peptide components, in particular, sulphated tyrosine residues [RP McEver, Ernst Schering Res. Found. Workshop, 2004, 44, 137-147]. PSGL-1 is one of the most important selectin ligands that binds with higher affinity to P-selectin, but also binds to E and L selectin [G. Constantin; Drug News Perspect; 2004; 17 (9); 579-586]. It is a homodimeric sialomucin predominantly expressed in leukocytes. In inflammatory diseases, the disregulated transmigration is, at least in part, mediated due to an increased expression of E and P selectin cell surface. Contrary to its low basal expression, the expression of E and P selectin is over-regulated during inflammation, leading to a substantial recruitment of leukocytes into the inflamed tissue. Although selectin-mediated cell adhesion is required to combat infection, there are several situations in which such cell adhesion is undesirable or excessive, resulting in severe damaged tissue instead of repaired. In the case of many disorders Acute as well as chronic inflammatory diseases [eg, asthma, chronic obstructive pulmonary disease (COPD), psoriasis, etc.], an association between infiltration of activated leukocytes in the tissue has been demonstrated simultaneously with a marked elevation of tissue expression of molecules of corresponding adhesion, particularly E and P selectin [Muller et al., J. Pa thol, 2002, 198 (2), 270-275; Di Stefano et al., Am. J. Respir. Cri t. Care Med., 1994, 149 (3) 803-810; Terajima et al., Arch. Derma tol. Res. , 1998, 290, 246-252]. Leukocyte infiltration may also play a role in inflammatory symptoms in the course of transplantation and rejection of the graft. Also, the blood coagulation process is further promoted by the leukocyte-leukocyte and leukocyte-tablet link, which occurs because the leukocytes possess both L-selectin and its corresponding ligand PSGL-1, and can thus interact with them same via PSGL-1, and can also bind to platelets which carry P-selectin. Therefore, the modulation of cell adhesion mediated by selectin and other functions mediated by selectin, for example, leukocyte activation, offer a promising possibility to interfere with and stop the cascade of inflammation at a very early stage. The small molecule selectin antagonist must modulate three selectins simultaneously as bread selectin antagonists to avoid possible redundancies between the selectins [M. Sperandio et al., Vascular Disease Prevention, 2004, 1, 185-195]. In addition to sLex / sLea, the high affinity ligand, natural PSGL-1, is another template structure for the design of small molecule selectin antagonists. As compared to sLex / sLea, PSGL-1 shows high affinity for the three selectins. Finding and detecting new small molecule drugs that compete with PSGL-1 ligands and similar to PSGL-1 for binding to selectin is, therefore, a promising strategy to develop a new class of pan-selective selectin antagonists to treat inflammatory disorders . Selectin antagonists can be designed using selectin as well as using a ligand similar to PSGL-1, as a template structure, since they are proposed to modulate the binding between selectins and PSGL-1 or other ligands with similar linking moieties. New small molecule selectin antagonists could meet certain requirements to be similar to the drug and have potential oral bioavailability. The term "drug" is similarly described in the literature [Lipinski; Adv. Drug Dev. Rev., 1997, 23, 3-25]. In addition to other molecular properties, Passively transported molecules are supposed to have on average, a relative molecular weight of less than 500 to be similar to the drug. In accordance with these rules, it is common to define compounds with a relative molecular weight of less than 500 or closely above such small molecules. The compounds with relative molecular weights above 500 are indistinctly orally bioavailable. Also, the presence of highly polar carbohydrate moieties or a peptide component is not in accordance with the concept of drug similarity. [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 considered for the development of antibody-based drugs, because they are polypeptides and thus oral administration is a problem. However, the desired compounds can be stable during the passage through the gastrointestinal tract, so that they can be ingested / absorbed at least, by the cells of the small intestines. This is not the case for most glycosidic molecules and peptide structures. There have been several investigations to develop compounds of low molecular weight with a modulating effect of processes mediated by selectin. These compounds include, disalicylates and C-glycosides based on disalicylates [WO 99/29706], benzyl aminosulfonic acids [Document 03/097658], glycosylated 1,2-diols [WO 97/01569], substituted 5-element heterocycles [WO 00/33836], mannopyranosyloxy-phenyl-benzoic acids [EP0758243 Bl], piperazine-based compounds [document US6432957B1], gallic acid derivatives of peptides [WO 2004/018502], gallic acid [CCM] Appeldoorn et al., Circulation 2005, 111, 106-112; EP 1481669A1], and quinic acid derivatives [N. Kaila et al., J. Med. Chem. 2005, 48, 4346-4357]. However, none of these compounds that antagonize selectin have successful clinical trials to date [S. J. Romano, Trea t. Respir Med 2005, 4 (2), 85-94; M. P. Schon, Therapeutics and Clinical Risk Management, 2005, 1 (3), 201-208]. This is due to the fact that many of these structures have been designed based on the low power sLex template. Therefore, sLex imitative structures are different because they show low power. Other compounds show specificity against different elements of the selectin family, but the antagonization only of selected selectins can be derived by other selectins [M. P. Schon, Therapeutics and Clinical Risk Management, 2005, 1 (3), 201-208]. In addition, most of the compounds thus developed, have high molecular weights and often carry carbohydrates and / or peptides that make them more prone to degradation and modification by peptidase and / or glycosidases. Carbohydrate bearing structures have additional advantages, such as the high degree of chirality, anomericity, and low probability of transport through the lipid bilayers. Similar disadvantages are known for compounds that carry peptides. Some other compounds developed by antagonizing the processes mediated by selectin, contain substructure pyrogallol- and catechol. These portions are prone to oxidation processes [Kumamoto M. et al., Biosci. Biotechnol. Biochem. , 2001, 65 (1), 126-132], making the pharmaceutical development of these compounds difficult. In addition, compounds with pyrogallol substructures, such as gallic acid, are known to be 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 Pharma cology, 1998, 55, 1973-1981]. The conductive compound in the field of selectin antagonists is bimosiamosa [S. J. Romano, Treat. Respir Med 2005, 4 (2), 85-94]. Currently, the bimosiamosa [D. Bock et al., New Drugs, 2003, D04, 28, p.28; EP 0 840 606 Bl] is the most advanced compound in clinical studies. Recent research supports the hypothesis that bimosiamosa can be considered as PSGL-1 mimic [E. Aydt, G. Wolff; Pathobiology; 2002-2003; 70; 297-301]. This bimosiamosa is distinguished from other selectin antagonists.

However, it is a high molecular weight compound with carbohydrate structures. The bimaniamosa bread selectin antagonist seems to lack oral bioavailability. Some observations indicate that bimosiamosa shows good affinity for P-selectin and a moderate affinity for selectin E and L. There is a strong medical need for new highly potent pan selectin antagonists, which modulate the selectin-mediated function, eg, adhesion of selectin-dependent cells and for the development of methods employing such compounds to modulate conditions associated with selectin-ligand interaction. Most of the available anti-inflammatory pharmaceutical therapies, which are available on the market, mainly comprise corticosteroids or NSAIDs (non-steroidal anti-inflammatory drugs), which have serious disadvantages / side effects, and different stages of the inflammatory cascade. Other than this, the modulation of the selectin function is a therapeutic concept that intervenes in the cascade of inflammation at a very early stage. Almost all promising selectin antagonists thus fail to become marketed drugs, mainly due to the low potency and / or high molecular weight that causes problems in their absorption-distribution-metabolism-excretion (ADME) behavior, and This way, in the oral bioavailability required for the treatment of most inflammatory disorders such as rheumatoid arthritis, septic shock, atherosclerosis, reperfusion injury and many others.

BRIEF DESCRIPTION OF THE INVENTION The object of the invention is to provide new small molecules, especially non-glycosylated / non-glycosidic and non-peptidic compounds, which are capable of potentially antagonizing the processes mediated by selectin, and which have less negative side effects during their application than the prior art compounds. Unlike most of the sLex mimic compounds developed in this field, the inventive compounds are not prone to glycosidases or peptidases. The majority of the selectin antagonists developed in this way are structurally and biologically based on the properties of sLex or sLea. These resulting compounds therefore show low biological activity as their template structures. This invention, however, provides novel small-potent, drug-like bread selectin antagonists that have been invented on the basis of in vitro biological assays that mimic PSGL-1 and similar ligands to PSGL-1 or any of the ligands that carry sLex or sLea and portions of tyrosinulfate [N. V. Bovin; Biochem Soc Symp .; 2002; (69): 143-60. N. V. Bovin; Glycoconj. J; 1998; 15 (5); 431-46. TV. Pochechueva et al .; Bioorg Med Chem Lett; 2003; 13 (10); 1709-12. G. Weitz-Schmidt et al .; Anal. Biochem .; nineteen ninety six; 238; 184-190].

DETAILED DESCRIPTION OF THE INVENTION The present invention provides pharmaceutical compositions comprising at least one compound having the general structure of formula (I) and a pharmaceutically acceptable carrier which is employed in a medicine. where the symbols and substituents have the following meanings -X- = (a) with m = 0, 1; n = an integer from 1 to 3 (b) where "ring" is and with R1 being H, N02, CF3, F, Cl, Br, I, CN, CH3, NH2, NHA alkyl, NHArilo, NHAcilo and k = 0.1. (c) T being O, S or [H, H]; p = 0, 1, 2. the double bond is either E or Z (e) configuration (0 with -E- being - (CH2-) qNH- and q = 0, 1, 2, 3 -Y = (a) with s being 0 or 1, R2 being C02H, C02Alkyl, C02Aryl, C02NH2, C02Aralkyl, S03H, S02NH2, P0 (0H) 2, 1-H-tetrazolyl-, CHO, COCH3, CH20H, NH2, NHAalkyl, N (Alkyl) Alkyl ', OCH 3, CH 2 OCH 3, SH, F, Cl, Br, I, CH 3, CH 2 CH 3, CN, CF 3. R3 independently of R2 is H, CH3, CH2CH3, CF3, F, Cl, Br, I, CN, N02 and R4 independently of R2 and R3 is H, CH, CH2CH3, CF3, F, Cl, Br, I, CN, N02, R2.

R5 is H, N02, CF3, F, Cl, Br, I, CN, CH? OCH 3? SH, and -W- = - (CH2) V, cis-CH = CH- or trans-CH = CH-, and v being 0, 1, 2; in case -W- is cis-CH = CH- or trans-CH = CH, R2 should not be NH2 or SH; (b) R6 independently of R2 is H, F, Cl, Me, tere-Bu, CN, NH2 (c) (d) with t being 0, 1, 2 (F) (g) (i) R7 independently of R2 is H, N02, CF3, F, Cl, Br, I, CN, CH3, 0CH3, SH, NH2. (or) R independently of R is H, F, Cl, Me, tere-Bu, CN, NH2 (iv) with K = NH, NMe, O, S (v) saw) (vii) -W-R2 or the pharmaceutically acceptable salts, esters or amides and prodrugs of the compounds identified above of formulas (la) or (Ib) or (lia) or (Ilb). In a further embodiment, the invention relates to to pharmaceutical compositions comprising at least one compound of the formula (1) and a pharmaceutically acceptable carrier, which is employed in a medicine, where the symbols and substituents have the following meaning -X- = with m = 0, 1; n = an integer from 1 to 3 (b) where "ring" is and with R1 being H, N02, CF3, F, Cl, Br, I, CN, CH3, NH2, NHA alkyl, NHA, NHA, and k = 0.1 (c) T being O, S or [H, H]; p = 0, 1, 2 -Y = (a) with s being 0 or 1, R2 being C02H, C02Alkyl, C02Aryl, C02NH2, C02Aralkyl, S03H, S02NH2, PO (OH) 2, 1-H-tetrazolyl-, CHO, COCH3, CH20H, NH2, NHAalkyl, N (Alkyl) Alkyl ', OCH 3, CH 2 OCH 3, SH, F, Cl, Br, I, CH 3, CH 2 CH 3, CN, CF 3. R3 independently of R2 is H, CH3, CH2CH3, CF3, F, Cl, Br, I, CN, N02 and R4 independently of R2 and R3 is H, CH, CH2CH3, CF3, F, Cl, Br, I, CN, N02, R2. R5 is H, N02, CF3, F, Cl, Br, I, CN, CH3, OCH3, SH, NH2. and -W- = - (CH2) V, cis-CH = CH- or trans-CH = CH-, and v being 0, 1, 2; in case -W- is cis-CH = CH- or trans-CH = CH, R2 it should not be NH2 or SH; (b) R6 independently of R2 is H, F, Cl, Me, tere-Bu, CN, NH2, (c) with t being 0, 1, 2 -Z 0) R7 independently of R2 is H, N02, CF3, F, Cl, Br, I, CN, CH3, OCH3, SH, NH2. (iv) with K = NH, NMe, 0, S (v) or the pharmaceutically acceptable salts, esters or amides and prodrugs of the above-identified compounds of formulas (I). The pharmaceutical compositions comprise compounds of the formula (II) where -Y is as defined above and where -X'- is X (a), X (b), X (c) and X (d) as defined above. Preferably they are compounds of formula (II) wherein -X'- is X (a) or X (b). Additional preferred pharmaceutical compositions comprise compounds of formulas (A) or (B).

A B where -X '- and -Y- are as defined above, and where -X "- is and where -Y 'is wherein all indices, symbols and substituents are similar defined above. In a further embodiment, the invention relates to pharmaceutical compositions, wherein the compounds are defined by the formulas (A) or (B) B where -X '- and -Y are as defined above and where -X "- is and where -Y 'is wherein all indices, symbols and substituents are as defined above. Particularly preferred pharmaceutical compositions comprise compounds of formulas (C) C wherein -X "- and -Y 'are as defined above .. Very particularly preferred pharmaceutical compositions comprise compounds of formulas (D) D where -X "is as defined above and -Y 'is wherein R9 is C02H, C02alkyl, C02aryl, C02NH2, C02aralkyl, CH2S03H, CH2S02NH2, CH2P0 (0H) 2, 1-H-tetrazolyl, CHO, COCH3, CH20H, CH2NH2, CH2NHalkyl, CH2N (alkyl) alkyl ', CH2OCH3, CH2SH. In a further embodiment, the invention relates to pharmaceutical compositions, wherein the compounds are defined by the formula (D). where -X "- is as defined above and - is wherein R9 is C02H, C02alkyl, C02aryl, C02NH2, C02aralkyl, CH2S03H, CH2S02NH2, CH2PO (OH) 2, 1-H-tetrazolyl, CHO, COCH3, CH2OH, CH2NH2, CH2NHalkyl, CH2N (alkyl) alkyl ', CH2OCH3, CH2SH, where all the indices, symbols and substituents are These chemical compounds (C) and (D) are also new compounds themselves.All the compounds described above, have the ability to modulate cell adhesion and modulate selectin, as well as the binding mediated as PSGL-1. The compounds have the ability to modulate the interaction of selectins with sLex / sLea and also, the interaction between selectins and residues tyrosinsulfate. Therefore, they are useful for the treatment of acute and chronic inflammatory disorders, as well as, other medical conditions where the processes mediated by selectin play a role. The term "pharmaceutical" also includes diagnostic applications. The term "pharmaceutical" also includes prophylactic applications to prevent medical conditions where processes mediated by selectin play a role. The term "pharmaceutical" also includes applications, wherein compounds of the present invention can be used as vehicles for the purpose of diagnostic or therapeutic drugs. The invention provides pharmaceutical compositions comprising at least one compound of formula (I) and in a preferred variant of formula (II). In a further preferred variant, the invention provides pharmaceutical compositions comprising at least one compound of formula (A) or (B). In a particularly preferred variant, the invention provides pharmaceutical compositions comprising at least one compound of formula (C).

In a very particularly preferred variant, the invention provides pharmaceutical compositions comprising at least one compound of formula (D). The present invention further provides a method for nodulating the binding of P-selectin, L-selectin or E-selectin or sLex or sLea and tyrosin sulfate residues comprising the step of administering to a 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 to sLex or sLea and tyrosin sulfate. It has been found that the compounds having the formula (I) shown above, act to modulate the E, P or L-selectin bond. As used herein, the terms "alkyl", shall mean a straight chain monovalent group of 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 12 or 12 carbon atoms including, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tere-butyl and the like. "Rent" are independent of each other and may be different or identical. The term "aryl" should mean heterocyclic or carbocyclic aromatic groups including, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, fluorenyl, (1, 2) -dihydronaphthyl, indenyl, indanyl, thienyl, benzothienine, thienopyridyl and similar.

The term "aralkyl" (also called arylalkyl), should mean an aryl group appended to an alkyl group including, but not limited to, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl, alkoxybenzyl ( wherein "alkoxy" means methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy and the like), hydroxybenzyl, aminobenzyl, nitrobenzyl, guanidinobenzyl, fluorenylmethyl, phenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl, 1-naphthylethyl and the like. The term "acyl" should mean - (CHO) or - (C = 0) -alkyl or - (C = 0) -aryl or - (C = 0) -aralkyl, including but not limited to, formyl, acetyl , n-propionyl, isopropionyl, n-butyryl, isobutyryl, pivaloyl, benzoyl, 4-nitrobenzoyl and the like. The term "pharmaceutically acceptable salts, esters, amides and prodrugs", as used herein, refers to those carboxylate salts, amino acid addition salts, esters, amides and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with tissues of patients without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit / risk ratio, and effective for their proposed use, as well as zwitterionic forms, in where possible, of the compounds of the present invention. The term "salts" refers to the relatively non-toxic organic and inorganic acid addition salts of the compounds of the present invention. These salts can be prepared in itself during the isolation and final purification of the compounds or separately by reacting the purified compounds in their free form with a suitable organic or inorganic acid or base and isolating the salt thus formed. Representative salts of the compounds of the present invention include, the salts of hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, laurylsulfonate and the like. These may include cations based on alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium cations, quaternary ammonium and amine, including but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Examples of pharmaceutically acceptable non-toxic esters of the compounds of this invention include C, C2, C3, C4, C5 and C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5, C ?, cycloalkyl esters, and C, as well as arylalkyl esters such as, but not limited to, benzyl. Alkyl esters Ci, C2, C3, C4, C5 and C6 are preferred. Esters of the compounds of the present invention can be prepared according to conventional methods. Examples of amides of non-toxic, pharmaceutically acceptable compounds of this invention include amides derived from ammonia, primary alkylamines Ci, C2, C3, C4, C5 and C6 and secondary dialkylamines Ci, C2, C3, C4, C5, and Ce, in where the alkyl groups are straight or branched chains. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing a nitrogen atom. Amides derived from ammonia, primary alkylamides Ci, C2 and C3 and secondary dialkylamides Ci to C2 are preferred. Amides of the compounds of the present invention can be prepared according to conventional methods. The term "prodrug" refers to one or more compounds that are rapidly transformed in vi tro and from a non-active to active state in vivo, to provide the precursor compound of the above formula (I), for example, by hydrolysis in blood or metabolism in vivo. It is also contemplated that the compositions Pharmaceutically active agents may contain a compound of the present invention or other compounds that modulate or compete with E-selectin or P-selectin or L-selectin linkage. Pharmaceutically active compositions of the present invention, comprise a pharmaceutically acceptable carrier and a compound of formula (I), by means of which, a pharmaceutically acceptable carrier can also be medically appropriate nanoparticles, dendrimers, liposome, microtubule or polyethylene glycol (PEG). The pharmaceutical compositions of the present invention may include one or more of the compounds having the structure (I) formulated together with one or more physiologically acceptable carriers, adjuvants or vehicles, which are collectively referred to herein as carriers, for parenteral injection, by oral administration in solid or liquid form, for rectal or topical administration and the like. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, intradermally or subcutaneously), intracisternally, intravaginally, interperitoneally, locally (powders, ointments or drops), or as a mouth or by inhalation (nebulized , or as nasal sprays). Compositions suitable for parenteral injection may comprise aqueous or non-aqueous solutions sterile, physiologically acceptable, stabilizers, antioxidants, preservatives (for example, ascorbic acid, sodium sulfite, sodium hydrogen sulfide, benzyl alcohol, EDTA), dispersions, suspensions or emulsions and sterile powders for reconstitution in sterile injectable solutions or dispersions. Examples of suitable carriers, diluents, solvents or aqueous and non-aqueous vehicles include, water, ethanol, polyol, (propylene glycol, polyethylene glycol, glycerol and the like), suitable mixtures thereof, vegetable oils (such as olive oil or canola) and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers and dispersing agents. The prevention of the actions of microorganisms can be ensured by various antifungal and antibacterial agents, for example, parabens, chlorbutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents that delay absorption, for example, aluminum monostearate and gelatin. If desired, and for more effective distribution, the compounds can be incorporated into synchronized or slow delivery or delivery systems, such as polymer matrices, liposomes, and microspheres. They can be sterilized for example, by filtration through a filter that retains the bacteria, or by incorporating sterilizing agents in the form of sterile water, or some other sterile injectable medium 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 usual inert (or carrier) excipient, such as sodium citrate or dicalcium phosphate or (i) fillers or extenders, such as, for example, starches, lactose , sucrose, glucose, mannitol and silicic acid, (ii) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (iii) humectants such as glycerol (div disintegrating agents, such as agar, for example). -gar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicate and sodium carbonate complexes, (v) solution retardants, such as, for example, paraffin (vi) absorption accelerators, such as compounds of quaternary ammonium, (vii) agents humectants, 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, lauryl sulfate of sodium and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in hard and soft filled gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules, can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and may also be of such compositions that they may release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of inhibition compositions that can be used are polymeric substances and waxes. The active compounds may also be in microencapsulated form, if appropriate, with one or more of the aforementioned 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 the art such as water or other solvents, solubilizing agents and emulsifiers, such as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, peanut oil, wheat germ oil, olive oil, cañola oil, castor oil and Sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids or mixtures of these substances and the like. In addition to such inert diluents, the compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavors and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth or mixtures of these substances and the like.

Compositions for rectal administration, are preferably suppositories which can be prepared by mixing the compounds of the present invention, with suitable non-irritating excipients or carriers, such as, cocoa butter, polyethylene glycol or a suppository wax, which are solid at temperatures ordinary, but liquid at body temperature and therefore fuse in the rectal or vaginal cavity and release the active component. Dosage forms for topical administration of a compound of this invention include ointments, powder, sprays and inhalants. The active component is mixed under sterile conditions with a physiologically acceptable carrier and any of the necessary preservatives, buffers or propellants as may be required. Ophthalmic formulations, ointments, suspensions, powders and solutions for eyes are also contemplated as being within the scope of this invention. The compounds of the present invention can also be incorporated into or connected to liposomes or administered in the form of liposomes. As is well known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by hydrated mono or multilaminate liquid crystals, which are dispersed in an aqueous medium. Any Physiologically acceptable non-toxic metabolized lipid, metabolized, capable of forming liposomes, can be used. The present compositions in the form of liposomes may contain, in addition to the selectin binding antagonists of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are well known in the art. The non-parenteral dosage forms may also contain an agent that enhances bioavailability (eg, enzyme modulators, antioxidants), suitable for the protection of the compounds against degradation. The current dosage levels of active ingredient in the composition of the present invention can also be varied to obtain an amount of the active ingredient that is effective to obtain the desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends on the desired therapeutic effect, the route of administration, the desired duration of treatment and other factors. The total daily dosage of the compounds in this invention, administered to a host in single or divided doses, may be in the range of up to 50 mg per kilogram of body weight. The dosage unit compositions may contain such submultiples thereof, as may be used to make the daily dosage. It will be understood, however, that the specific dose level for any particular patient, whether human or other animal, will depend on a variety of factors including, body weight, general health, diet, sex, time and route of administration, absorption and excretion, combination with other drugs and the severity of the particular disease to be treated. In particular, the compounds of the present invention can be used to treat a variety of diseases that relate to inflammation and cell-cell adhesion and recognition. For example, the compounds of the present invention can be administered to a patient to treat Chronic Obstructive Pulmonary Disease (COPD), acute lung injury (ALI), cardiopulmonary bypass, respiratory distress syndrome (ARDS), Crohn's disease, septic shock, sepsis, chronic inflammatory diseases such as psoriasis, atopic dermatitis and rheumatoid arthritis, and reperfusion injury, which occurs after heart attacks, strokes, atherosclerosis, and organ transplants, traumatic shock, multiple organ failure, autoimmune diseases such as multiple sclerosis, percutaneous transluminal angioplasty, asthma and inflammatory bowel. In such a case, an effective amount of the compounds of the present invention is administered either alone or as part of a pharmaceutically active composition to a patient in need of such treatment. It is also recognized that a combination of the compounds can be administered to a patient in need of such administration. The compounds of the present invention can also be administered to treat other diseases that are associated with cell-cell adhesion. As the present compounds modulate the linkage of E-selectin or P-selectin or L-selectin, any disease that is related to this interaction, can potentially be treated by the modulation of this binding interaction. In addition to being found in some white blood cells, sLea is found in several cancer cells, which include colon and lung cancer cells. It has been suggested that cell adhesion involving sLea may be involved in the metastasis of certain cancers and sLea binding antagonists could be used in the treatment of some forms of cancer. The use of the active ingredients according to the invention or of topical or cosmetic determatological compositions with an effective content of active ingredient according to the invention, surprisingly allows effective treatment, but also the prophylaxis of skin aging caused by extrinsic and intrinsic factors. The invention particularly relates to the use of a compound of formula (I) or a stereoisomeric form thereof, for the preparation of a cosmetic or dermatological composition. The amount used of the active compound or stereoisomeric form thereof corresponds to the amount required to obtain the desired result using the cosmetic or dermatological compositions. An expert in this technique is able to evaluate this effective amount, which depends on the derivative use, the individual in whom it is applied, and the time of this application. To provide an order of magnitude, in the cosmetic or dermatological compositions according to the invention, the compound of formula (I) or a stereoisomeric form thereof, can be administered in an amount representing from 0.001% to 40% by weight, preferentially 0.005% up to 30% by weight and more preferably from 0.01% up to 20% by weight. An additional aspect covers cosmetic compositions comprising a compound of formula (I) or a stereoisomeric form thereof and at least one cosmetically tolerable component, for example, a cosmetically tolerable component for skin applications. The quantities of the various components of the medium The physiological composition of the cosmetic composition according to the invention are those in general, included in the fields under consideration. When the cosmetic composition is an emulsion, the proportion of the fatty phase can vary from 2% to 80% by weight, and preferably from 5% to 50% by weight relative to the total weight of the cosmetic composition. Thus, the cosmetic composition must contain a physiologically acceptable non-toxic medium, which can be applied to human skin. For a topical application to the skin, the cosmetic composition can be in the form of a solution, a suspension or an emulsion or a dispersion of more or less fluid consistency and especially liquid or semi-liquid consistency, obtained by dispersing a fatty phase in an aqueous phase (O / W), or conversely, (W / O), or alternatively, a gel. A cosmetic composition in the form of a mousse or in the form of an atomizer or an aerosol, which then comprises a pressurized propellant, may also be provided. Also, the compositions may be in the form of a hair lotion, a shampoo or hair conditioner, a liquid or solid soap, a masking treatment, or a foaming cream or gel to clean the hair. It can also be in the form of hair dye or hair mask. The cosmetic compositions of the invention, they may also comprise one or more other ingredients usually employed in the fields under consideration, selected from among formulation additives for example, aqueous phase or oily phase thickeners or gelling agents, dyes which are soluble in the medium of the cosmetic composition, particles solids such as fillers or organic or mineral pigments in the form of microparticles or nanoparticles, preservatives, fragrances, hydrotropes or electrolytes, neutralizers (acidifying or basifying agents), propellants, anionic, cationic or amphoteric surfactants, polymers in particular, water-soluble polymers or anionic, nonionic, cationic or amphoteric dispersible in water, which forms film, organic or mineral salts, chelating agents; mixtures thereof. The cosmetic compositions can be used to inhibit the micro-inflammatory cycle. Thus, the present invention also relates to cosmetic compositions comprising a compound of formula (I) or a stereoisomeric form thereof, which is used for the cosmetic treatment or cosmetic prophylaxis of micro-inflammatory conditions. Cosmetic compositions comprising a compound of formula (I) or a stereoisomeric form thereof, which are used for cosmetic treatment or prophylaxis Cosmetics of skin aging caused by intrinsic factors are also the subject of the present invention. The intrinsic factors responsible for the aging of the skin are genetically programmed determinants that include age, hormonal status and psychological factors. In addition to the cosmetically inactive ingredients, the cosmetic compositions of the present invention may also comprise one or more cosmetically active ingredients with beneficial action on the skin. Thus, the present invention relates to cosmetic compositions comprising a compound of formula (I) or a stereoisomeric form thereof and at least one additional cosmetically active ingredient, for example, a UV blocker or proteins. Dermatological compositions comprising a compound of formula (I) or stereoisomeric form thereof and at least one dermatologically tolerable component, for example, a dermatologically tolerable component for skin applications, are also subject of the invention. The dermatologically tolerable components that can be used for the dermatological compositions described herein are identical to the cosmetically tolerable components as defined in this invention. A further embodiment of this invention are dermatological compositions comprising a compound of Formula (I) or a stereoisomeric form thereof which is used for the dermatological treatment, dermatological diagnosis or dermatological prophylaxis of micro-inflammatory conditions. In particular, the invention covers dermatological compositions comprising a compound of formula (I) or a stereoisomeric form thereof, which is used for the dermatological treatment, dermatological diagnosis or dermatological prophylaxis of itching and aging of the skin caused by extrinsic factors. Extrinsic factors include environmental factors in general: more particularly photo-aging due to exposure to the sun, light or any other radiation, atmospheric pollution, wounds, infections, trauma, anoxia, cigarette smoke, hormonal status in response to external factors , neuropeptides, electromagnetic fields, gravity, lifestyles (for example, excessive consumption of alcohol), repetitive facial expressions, sleeping positions, and psychological stress. In addition to the dermatologically inactive ingredients, the dermatological compositions may also comprise dermatologically or pharmaceutically active ingredients. Thus, the present invention also relates to dermatological compositions comprising a compound of formula (I) or a stereoisomeric form thereof, and at least one dermatologically active ingredient or pharmaceutically additional. The dermatologically or pharmaceutically active ingredients that can be used for the dermatological compositions described herein, are defined as cosmetically active ingredients defined above. The dermatologically or pharmaceutically active ingredients can be identical to the cosmetically active ingredients as defined in this invention. Another subject of the present invention are dermatological compositions comprising a compound of formula (I) or a stereoisomeric form thereof and at least one dermatologically or pharmaceutically active ingredient, characterized in that it is used for dermatological treatment, dermatological diagnosis or dermatological prophylaxis. of micro-inflammatory conditions. In particular, the present invention relates to dermatological compositions comprising a compound of formula (I) or a stereoisomeric form thereof and at least one dermatologically or pharmaceutically active ingredient, characterized in that it is used for dermatological treatment, dermatological diagnosis or prophylaxis. dermatological itching and aging of the skin, caused by intrinsic factors. Skin aging can also be caused by a combination of intrinsic factors and extrinsic Therefore, the present invention also relates to dermatological compositions comprising a compound of formula (I) or a stereoisomeric form thereof and at least one pharmaceutically or cosmetically active ingredient, characterized in that it is used for cosmetic or dermatological treatment and prophylaxis dermatological skin aging caused by a combination of intrinsic and extrinsic factors. Another embodiment of this invention is a process for the preparation of a cosmetic composition, by mixing a compound of formula (I) or a stereoisomeric form thereof, at least one cosmetically tolerable component and optionally additional cosmetically active ingredients. In particular, it is the subject of the present invention, a process for the preparation of a cosmetic composition by mixing a compound of formula (I) or a stereoisomeric form thereof, at least one cosmetically tolerable component and additional cosmetically active ingredients, wherein the composition includes from 0.01% to 20% by weight of the compound of formula (I) or a stereoisomeric form thereof, based on the total weight of the composition of this invention. An additional aspect according to a process for the preparation of a dermatological composition by mixing a compound of formula (I) or a stereoisomeric form thereof, and at least one dermatologically tolerable component and optionally, additional pharmaceutically active ingredients. Many of the compounds of the present invention can be synthesized in accordance with the following general synthetic schemes.

REACTION SCHEME 1 In the REACTION SCHEME 1 an aniline of type (1) is reacted under conditions of inert atmosphere with N '- (3-dimethylaminopropyl) -N-yl carbodiimide (EDC), triethylamine, 4-dimethylaminopyridine (DMAP) and a carboxylic acid of type (2) in dichloromethane to give an amide of type (3). The amide of type (3) is further reacted with boron tribromide in dichloromethane at -78 ° C to obtain 2, 4, 6-t-hydroxy-phenyl corresponding type (4). The synthesis sequence shown in REACTION SCHEME 1 leads to compounds (4) and not only reduces to building blocks Y-H (1) but can be generally applied to all other type Y-H building blocks.

REACTION SCHEME 2 In the REACTION SCHEME 2, a brominated aromatic ester or a heteroaromatic ester of the general type (5) is reacted under inert conditions with 2, 4, 6-t-rimethoxyphenylboronic acid (6) under basic Suzuki-like conditions (Pd (PPh3) 4 and aqueous sodium bicarbonate in dimethoxyethane) to a biaryl of type (7) which is further hydrolyzed with aqueous lithium hydroxide in acetonitrile to give the corresponding carboxylic acid (8), which is converted to a building block of type (9) by reaction with oxalyl chloride in anhydrous dichloromethane.

REACTION SCHEME 3 LiOH THP / MeOH 1 BBr3 CH2CI2 -78 ° C 2 H20 In the REACTION SCHEME 3, an acid chloride (9) is reacted with a general type aniline (10) under basic conditions (pyridine in dichloromethane) to form the corresponding anuide (11). Alternatively, triethylamine can be used for this reaction step. Ester (11) is hydrolysed with LiOH in MeCN or THF / MeOH to obtain a carboxylic acid (12), which is further reacted with boron tribromide in dichloromethane at -78 ° C to obtain an additional aqueous reaction corresponding to demethylated acids of type (13). The synthesis sequence shown in the REACTION SCHEME 3 leads to compounds (13) not only reduced to building blocks Y-H (10) but can be generally applied to all other Y-H type building blocks. The present invention is further illustrated by the following representative examples.

EXAMPLE 1 3- [2- (2,4,6-trihydroxy-phenyl) -acetyl] -benzene acid (18) REACTION SCHEME 4 LiOH H20THF Stage 1: (The following reaction is carried out in an anhydrous atmosphere of N2). Dissolve EDC hydrochloride (122 mg, 0.64 mmol) and triethylamine (89 μl, 0.64 mmol) in anhydrous dichloromethane (3.2 ml) and stir for 5 minutes at room temperature. 2- (2,4,6-Trimethoxyphenyl) -acetic acid (14) (101 mg, 0.45 mmol) and DMAP (8 mg, 0.06 mmol) are added and stirred for 10 minutes. Ethyl ester (15) (70 mg, 0.42 mmol) is added and the reaction solution is stirred overnight at room temperature. The reaction solution is hydrolysed with saturated aqueous NH4C1 followed by Water, the layers are separated, the aqueous layer is extracted with dichloromethane (3 times) and the combined organic layers are washed with water and brine, and dried with Na2SO4. The solvent is removed under reduced pressure. The crude product is purified by preparative radial chromatography (silica gel 60PF, EtOAc / CyH 1 + 1) to obtain 3- [2- (2,4-, 6-trimethoxy-phenyl) -acetylamino] -benzoic acid methyl ester. (16) as a white solid (145mg, 95%). [K. C. Nicolaou; P. S. Baran; Y.-L. Zhong; K. Sugita; J Am. Chem. Soc; 2002; 124; 10; 2212-2220]. 1 H NMR (400MHz, CDC13): 3.68 (s, 2 H); 3.83 (s, 3 H); 3.84 (s, 6 H); 3.87 (s, 3 H); 6.18 (s, 2 H); 7.33 (t, 1 H, J = 8.0 Hz); 7.56 (br.s, 1 H); 7.69 (br.dd, 1 H, J = 7.8 Hz); 7.78 (t, 1 H, J = 1.8 Hz); 7.90 (dd, 1 H, Ji = 8.1Hz, J2 = 1.3Hz).

Step 2: 3- [2- (2,4-, 6-Trimethoxy-phenyl) -acetylamino] -benzoic acid methyl ester (140 mg, 0.39 mmol) is dissolved in THF (25.0 ml) at room temperature and 1 M is added. of aqueous LiOH (2.0 ml, 2.0 mmol). The reaction mixture is stirred 40 hours at room temperature. The reaction mixture turns off (cooling bath) with 2M aqueous HCl. The mixture is extracted with EtOAc (3x), the combined organic layer is wash with brine and dry with Na 2 SO to obtain 3- [2- (2,4,6-trimethoxy-phenyl) -acetylamino] -benzoic acid (17) (134 mg, 99%) as a beige solid -H NMR (400MHz, CD30D): 3.71 (s, 2 H); 3.84 (s, 3 H); 3. 85 (s, 6 H); 6.29 (s, 2 H); 7.43 (t, 1 H, J = 7. 8Hz); 7.76 (d, 1 H, J = 7.8 Hz); 7.83 (d, 1 H, J = 8. 1Hz); 8.19 (br.s, 1 H).

Stage 3: (The next reaction is carried out in an anhydrous atmosphere of N2). 3- [2- (2,4,6-Trimethoxy-phenyl) -acetylamino] -benzoic acid (17) (134 mg, 0.39 mmol) is dissolved in anhydrous DCM (5.3 mL), the solution is cooled to -78 °. C and BBr3 (240 μl, 2.55 mmol) is added dropwise. The reaction mixture is stirred for 30 minutes at -78 ° C and then heated slowly for up to 2 additional hours at room temperature. Ice water is added dropwise, the layers are separated and the aqueous layer is extracted with EtOAc (3 times). The combined organic layer is washed with brine and dried with Na 2 SO 4. The crude product is purified by preparative HPLC RP (gradient, water / CH3CN 95: 5 to 5:95) to obtain 3- [2- (2,4,6-Trihydroxy-phenyl) -acetylamino] -benzoic acid (18) (29 mg, 22%) as a yellowish solid. ? NMR (400MHz, CD3OD): 3.69 (s, 2 H); . 97 (s, 2 H); 7.43 (t, 1 H, J = 8.0 Hz); 7.76 (br.dd, 1 H, Ji = 7.6Hz); 7.84 (br.dd, 1 H, J = 8.1 Hz); 8.17 (t, 1 H, J = 1.8 Hz).

EXAMPLE 2 2-Methyl-5- Acid. { 4- [2- (2,4,6-trihydroxy-phenyl) -acetylamino] -phenyl} -furan-3-carboxyl (19) REACTION SCHEME 5 In accordance with the procedure described in EXAMPLE 1, 2-Methyl-5-acid is obtained. { 4- [2- (2, 4, 6-trihydroxy-phenyl) -acetylamino] -phenyl} -furan-3-carboxylic acid (19) as a beige solid. 1 H NMR (400MHz, CD 3 OD): 2.66 (s, 3 H); 3.68 (s, 2 H); 5.97 (s, 2 H); 6.89 (s, 1 H); 7.60 (dd, 2 U, Ji = 9.1Hz, J2 = 2.3Hz); 7.64 (dd, 2 H, Jx = 9.1Hz, J2 = 2.3Hz). In the following, the preparation of intermediaries is described. [5- (2-Amino-phenyl) -thiophen-2-yl] -acetic acid methyl ester (44) REACTION SCHEME 7 Step 1: (The following reaction was carried out in an anhydrous atmosphere of N2). Thiofen-2-yl-acetic acid methyl ester (42) (2.0 g, 12.8 mmol) was dissolved in anhydrous chloroform (9.0 ml) and glacial acetic acid (9.0 ml), N-bromosuccinimide (2.3 g, 13.0 mmol) was added. ) in portions and the mixture was stirred for 3 days at room temperature. Water was added to the reaction mixture, the layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed several times with 1M aqueous NaOH and water and once with brine and dried with Na2SO4. The crude product was purified by preparative radial chromatography (CyH / EtOAc 5 + 1) to obtain (5-bromo-thiophen-2-yl) -acetic acid methyl ester (43) as a yellow oil (2.46 g, 81%). , which was used without any additional purification. 1 H NMR (400 MHz, CDC13): 3.71 (s, 3 H); 3.75 (s, 2 H); 6.67 (d, 1 H, J = 3.8 Hz); 6.88 (d, 1 H, J = 3.8 Hz).

Step 2: (The following reaction was carried out in an anhydrous atmosphere of N2). Subsequently, ethanol (3.7 ml), tetrakis- (triphenylphosphine) -palladium (0) (289 mg, 0.25 mmol) and Na2C03 decahydrate (4.0 g, 14.0 mmol) dissolved in water (5.2 ml) were added to a solution of hydrochloride. 2-amino-benzeneboronic acid (910 mg, 5.25 mmol) in toluene (52 ml). The reaction mixture was degassed carefully (5 times) and flushed with N2 again. A solution of (5-bromo-thiophen-2-yl) -acetic acid methyl ester (43) (1.17 g, 5.0 mmol) in toluene (4.5 ml) was added. The mixture was degassed again (5 times) and stirred for 22 hours at 100 ° C. The reaction solution was partitioned between EtOAc and brine and the separated aqueous layer was extracted with EtOAc (3 times). The combined organic layer was washed with water and brine and dried with Na2SO4. The crude product was purified by preparative radial chromatography (CyH / EtOAc 5 + 1) to obtain [5- (2-amino-phenyl) -thiophen-2-yl] -acetic acid methyl ester (44) as a brown oil ( 634 mg, 51%). 1H NMR (400 MHz, CDC13): 3.73 (s, 3 H); 3.83 (s, 2 H); 3.92-4.07 (br.s, 2 H); 6.74 (d, 1 H); 6.76 (td, 1 H, J, = 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, J, = 7.6 Hz, J2 = 1.5 Hz); 7.23 (dd, 14 H, Ji = 7.6 Hz, J2 = 1.5 Hz). - (2-Amino-phenyl) -thiophene-2-carboxylic acid methyl ester (47) REACTION SCHEME 8 Step 1: LE23 5-Bromo-thiophene-2-carboxylic acid (1.50 g, 7.24 mmol) was dissolved in MeOH (10 mL) and concentrated sulfuric acid (0.39 mL, 7.24 mmol) was added. The reaction mixture was stirred for 20 hours at 75 ° C. The mixture was cooled to room temperature, the solvent was removed under reduced pressure and the residue was resolved in EtOAc. This organic layer was washed 3 times with 5% aqueous NaCl3 and the combined aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried with Na 2 SO 4. The solvent was removed under reduced pressure and the residue was dried without further purification in vacuum pumped oil to obtain (46) as a white solid (1.48 g, 92%). X H NMR (400 MHz, CDC13): 3.85 (s, 3 H); 7.05 (d, 1 H, J = 4.0 Hz); 7.53 (d, 1 H, J = 4.0 Hz).

Stage 2: LE29 (The following was carried out reaction in an atmosphere of N2). Tetrakis (triphenylphosphine) -palladium (0) (510 mg, 0.45 mmol) and ester (46) (1.97 g, 8.91 mmol) were dissolved in DME (16 mL), the reaction mixture was degassed carefully (5 times) and it was flushed with N2. 2- (4, 5, 5-tetramethyl- [1, 3, 2] dioxoborolan-2-yl) -phenylamine (2.15 g, 9.80 mmol) and an aqueous solution of 1 M NaHCO 3 (27.0 mL, 27.0 mmol) were added. , the reaction mixture was degassed again carefully (5 times) and flushed with N2. The mixture was stirred for 18 hours at 95 ° C. The reaction solution was partitioned between EtOAc and water, and the separated aqueous layer was extracted with EtOAc (3 times). The combined organic layer was washed with brine and dried with Na2SO4. The crude product was purified by flash chromatography (silica gel 60, CyH / EtOAc 5 + 1), to obtain 5- (2-amino-phenyl) -thiophene-2-carboxylic acid methyl ester (47) as a yellow solid. (1.41 g, 67%) XH NMR (400 MHz, CDC13): 3.88 (s, 3 H); 4.00 (s, 2 H); 6.73-6.82 (m, 2 H); 7.13-7.21 (m, 2) H), 7.26 (dd, 1 H, Ji = 7.6 Hz, J2 = 1.0 Hz), 7.78 (d, 1 H, J = 3.8 Hz).

Chloride 2 ', 4', 6 '-trimethoxy-biphenyl-3-carbonyl (51) REACTION SCHEME 9 Stage 1: KM03 1, 3, 5-trimethoxybenzene is dissolved (10.0 g, 59.46 mmol) in anhydrous dichloromethane (100 mL), the reaction mixture is cooled to -78 ° C, bromide (3.0 mL, 59.44 mmol) is added dropwise, the mixture is stirred for 1 hour between -70 ° C and -40 ° C. The solution is warmed to 0 ° C and water is added. The layers are separated, and the aqueous layer is extracted with EtAOc (3 times). The combined organic layer is washed with water and brine, and dried with Na 2 SO 4. The solvent is removed and the crude product is purified by recrystallization from hot EtOAc and cyclohexane to obtain 2-bromo-1,3,5-trimethoxy-benzene (48) as a white solid (8.84 g, 60%). X H NMR (400 MHz, CDC13): 3.80 (s, 3 H); 3.86 (s, 6 H); 6.15 (s, 2 H). Stage 2: FR542 (The next reaction is carried out in an atmosphere of N2). Dissolve Pd (PPh3) 4 (342 mg, 0.30 mmol) and 2-bromo-1,3,5-trimethoxy-benzene (48) (2.44 g, 9.87 mmol) in DME (20 mL) and stirred for 15 minutes at room temperature. Ethyl 3- (4, 4,5,5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzoic acid ester (3.16 g, 11.45 mmol) is added followed by a 1M sodium bicarbonate solution. aqueous (29.6 ml, 29.6 mmol). The reaction mixture is degassed carefully, flushed with N2 (5 times) and stirred for 20 hours at 100 ° C (reflux). The reaction mixture is cooled to room temperature, the organic solvent is removed under reduced pressure and the residue is partitioned between water and EtOAc. The aqueous layer is extracted with EtOAc (3 times), the combined organic layer is washed with water and brine, and dried with Na2SO4. The crude product obtained is purified by preparative radial chromatography (silica gel, EtOAc / CyH 1 + 3) to obtain the biphenyl (49) (2.41 g, 77%). Like a brown oil. XH NMR (400MHz, CDC13): 1.35 (t, 3 H, J = 7.1Hz); 3.70 (s, 6 H); 3.85 (s, 3 H); 4.35 (q, 2 H, J = 7.8 Hz); 6.21 (s, 2 H); 7.42 (t, 1 H, J = 7.6 Hz); 7.95 (br.d, 1 H, J = 7.8Hz); 7.99 (br.s, 1 H). Step 3: FR543 Dissolve the biphenyl (49) (2.41 g, 7. 62 mmol) in MeCN (76 ml) and 1M aqueous LiOH (38.0 ml, 38.0 mmol) is added. The reaction mixture is stirred for 4 hours under reflux. The cooled reaction mixture is quenched (cooling bath) with 1M aqueous HCl (to obtain pH about 3). The mixture is extracted with EtOAc (3x), the The combined organic layer is washed with water and brine, and dried with Na2SO4. The solvent is removed and the residue is dried without further purification in vacuum pumped oil to obtain carboxylic acid (50) as a yellow solid (2.25 g, amount). X H NMR (400 MHz, CDC13): 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 (br.d, 1 H, J = 7.8 Hz); 8.00 (br.d, 1 H, J = 7.6 Hz); 8.06 (br. S, 1 H) - Stage 4: DU011 (The next reaction is carried out in an anhydrous atmosphere of N2). Dissolve carboxylic acid (50) (1.00 g, 3.50 mmol) in anhydrous dichloromethane (23 mL) and add anhydrous DMF (5 drops). Oxalyl chloride (460 μl, 5.25 mmol) is slowly added maintaining the temperature at about 20 ° C with a water bath and stirring for an additional 2 hours. The solvent is removed and the residue is dried under vacuum to obtain 2 ', 4', 6'-trimethoxy-biphenyl-3-carbonyl chloride (51) (1.10 g, amount) as a yellow solid. Without additional purification. - (4-Amino-phenyl) -2-methyl-furan-3-carboxylic acid methyl ester (54) REACTION SCHEME 10 Stage 1: DK001 (The following reaction was performed under exclusion of light). Acid methyl ester was dissolved 2-methyl-furan-3-carboxylic acid (52) (3.60 mg, 28.5 mmol) in chloroform (20 ml) and glacial acetic acid (200 ml) and NBS (6.90 g, 38.8 mmol) was added in portions. 95 minute period. The reaction suspension was stirred for an additional 19 hours at room temperature. Water was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (2 times), the combined organic layer was washed with 2M aqueous NaOH, water (3 times) and brine and dried with water.

Na2SO4 to obtain 5-bromo-2-methyl-furan-3-carboxylic acid methyl ester (53) (4.90 g, 78%) as a red brown oil. Without additional purification. (XH NMR (400 MHz, CDC13): 2. 54 (s, 3 H); 3.80 (s, 3 H); 6.53 (s, 1 H).

Stage 2: DK002 + 003 (The following reaction was performed in an atmosphere of N2). Pd (PPh3) was dissolved (1.26 g, 1.09 mmol) and 5-bromo-2-methyl-furan-3-carobxylic acid methyl ester (46) (4.77 g, 21.77 mmol) in DME (116 ml) and stirred for 15 minutes at room temperature. 4- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxoborolan-2-yl) -phenylamine (5.25 g, 23.96 mmol) was added followed by 1M aqueous sodium bicarbonate solution (65.4 ml, 65.3 mmol). The reaction mixture was carefully degassed, flushed with N2 (5 times), and stirred for 4 hours at 95 ° C (reflux). The reaction mixture was cooled to room temperature, the organic solvent was removed under reduced pressure and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3 times), the combined organic layer was washed with water and brine and dried with Na2SO4. The obtained crude product was purified by flash chromatography (silica gel 60, EtOAc / CyH 1 + 2) to obtain 5- (4-amino-phenyl) -2-methyl-furan-3-carboxylic acid methyl ester (54) (2.35 g, 46%) as a yellow-brown solid. 1 H NMR (400 MHz, CDC13): 2.60 (s, 3 H); 3.74 (br.s, 2 H); 3.82 (s, 3 H); 6.64 (s, 1 H); 6.67 (dt, 1 H, Ji = 8.6 Hz, J2 = 2.3 Hz); 7.42 (dt, 2 H, Ji = 8.8 Hz, J2 = 2.3 Hz). 2-Thiophene-2-yl-phenylamine (55) REACTION SCHEME 11 Stage 1: AB427 (The following reaction was performed in an atmosphere of N2). Tetrakis (triphenylphosphine) -palladium (0) (297 mg, 0.26 mmol) and 2-bromo-thiophene (837 mg, 5.13 mmol) were dissolved in DME (42 mL), the reaction mixture was carefully degassed (5 times) and flushed with N2. After 10 minutes of stirring, 2- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxoborolan-2-yl) -phenylamine (1.24 g, 5.64 mmol) and a 1M aqueous solution of NaHC03 (15.4 mi, 15.4 mmol), the reaction mixture was degassed again carefully (5 times) and flushed with N. The reaction mixture was stirred for 3 hours at 95 ° C. The mixture was cooled to room temperature, the solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The separated aqueous layer was extracted with EtOAc (3 times). The combined organic layer was washed with brine and dried with Na 2 SO 4. The crude product was purified by flash chromatography (silica gel 60, CyH / EtOAc 15 + 1) to obtain 2-thiophen-2-yl-phenylamine (55) as a solid. brown (825 mg, 92%). 1 H NMR (400 MHz, CDC13): 4.40-6.00 (m, 2 H); 6.88 (td, 1 H, Jx = 7.6 Hz, J2 = 1.0 Hz); 6.93 (dd, 1 H, Ji = 8.0 Hz, J2 = 1.0 Hz); 7.07 (dd, 1 H, J, = 5.3 Hz, J2 = 3.5 Hz); 7.17 (td, 1 H, J, = 8.0 Hz, J2 = 1.5 Hz) 7.22 (dd, 1 H, Ji = 3.5 Hz, J2 = 1.3 Hz); 7.30 (dd, 1 H, Ji = 7.6 Hz, J2 = 1.5 Hz); 7.33 (dd, 1 H, Ji = 5.3 Hz, J2 = 1.3 Hz). [5- (3-Amino-phenyl) -thiophen-2-yl] acetic acid methyl ester (50) REACTION SCHEME 12 Stage 1: FR544 (The next reaction is carried out in an atmosphere of N2). Dissolve Tetrakis- (triphenylphosphine) -palladium (O) (1.12 g, 0.97 mmol) and ester (43) (4.57 g, 19.44 mmol) in toluene (20 mL) and EtOH (20.0 mL), the reaction mixture degasses carefully (5 times) and flushed with N2. 3-Nitrophenylboronic acid (3.57 g, 21.38 mmol) and 3 M aqueous Na 2 CO 3 solution (18.1 ml, 54.3 mmol) are added, the reaction mixture is degassed again carefully (5 times) and flushed with N 2. Mix stir for 18 hours at 100 ° C. The reaction solution is partitioned between EtOAc and water and the separated aqueous layer is extracted with EtOAc (3 times). The combined organic layer is washed with brine and dried with Na 2 SO 4. The crude product obtained is purified by preparative radial chromatography (silica gel, EtOAc / CyH 1 + 5) to obtain [5- (3-nitro-phenyl) -thiophen-2-yl] -acetic acid methyl ester (56) as a yellow solid (3.15 g, 58%). X H NMR (400 MHz, CDC13): 3.75 (s, 3 H); 3.85 (s, 2 H); 6.94 (br.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); 7.84 (ddd, 1 H, Ji = 7.8 Hz, J2 = 1.5 Hz, J3 = 0.8 Hz); 8.08 (ddd, 1 H, Ji = 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 N2). [5- (3-Nitro-phenyl) -thiophen-2-yl] -acetic acid methyl ester (56) (3.15 g, 11.35 mmol) is dissolved in MeOH (225 mL) and Pd is added to carbon (10%). (w / w) Pd content, 1.20 g, 1.13 mmol) followed by NH4C02H (7.15 g, 113.4 mmol) at room temperature. The reaction mixture is degassed carefully (flushed with N2) and stirred for 22 hours at room temperature. The reaction mixture is filtered through a short pad of celite and the solvent is removed. The crude product obtained is purified by preparative radial chromatography (silica gel, EtOAc / CyH 1 + 3) to obtain [5- (3-Amino-phenyl) -thiophen-2-yl] -acetic acid methyl ester (57) (2.08 g, 74%) as a yellow solid. 1ti NMR (400 MHz, CDC13): 3.73 (s, 3 H); 3.81 (s, 2 H); 6.59 (dd, 1 H, Jx = 7.8 Hz, J2 - 2.0 Hz); 6.86 (br.d, 1 H, J = 3.5 Hz); 6.88 (t, 1 H, J = 1.9 Hz); 6.97 (br.d, 1 H, J = 7.6 Hz); 7.09 (d, 1 H, J = 3.5 Hz); 7.13 (t, 1 H, J = 7.7 Hz).

EXAMPLE 3 2-Methyl-5-Acid. { 4- [(2 ', 4', 6 '-trihydroxy-biphenyl-3-carbonyl) -amino] -phenyl} -furan-3-carboxylic (60) REV968 REACTION SCHEME 13 Stage 1: AB438 (The following reaction is performed in an anhydrous atmosphere of N). Aniline (54) (150 mg, 0.65 mmol) is dissolved in anhydrous dichloromethane (10.0 ml), anhydrous pyridine (1.7 ml) and carboxylic acid chloride (51) (218 mg, 0.71 mmol) are added. The reaction mixture is stirred for 20 hours at room temperature. The reaction mixture is poured into ice-cold 1M aqueous HCl extract with EtOAc (3x), the combined organic layer is washed with water and brine and dried with Na2SO4. Purification of the product obtained by preparative radial chromatography (silica gel, EtOAc / CyH 1 + 5, last 1 + 3, last 1 + 1) to obtain the amide (58) as a yellow solid (95 mg, 29%). XH NMR (400 MHz, CDC13): 2.63 (s, 3 H); 3.72 (s, 6 H); 3.83 (s, 3 H); 3.86 (s, 3 H); 6.23 (s, 2 H); 6.81 (s, 1 H); 7.46-7.53 (m, 2 H); 7.61 (d, 2 H, J = 8.5 Hz); 7.66 (d, 2 H, J- 8.6 Hz); 7.76-7.82 (m, 3 H). Step 2: AB439 Ester (58) (71 mg, 0.14 mmol) is dissolved in THF (2.4 mL) and MeOH (0.6 mL) and 1M aqueous LiOH (710 μL, 0.71 mmol) is added. The reaction mixture is stirred for 24 hours at room temperature. The solvent is removed under reduced pressure and the residue is partitioned between EtOAc and 1M HCl. The aqueous layer is separated and extracted 3 times with EtOAc. The combined organic layer is washed with water and brine, and dried with Na 2 SO 4. The solvent is removed under reduced pressure and the residue is dried without further purification in vacuum pumped oil to obtain product crude (59) as a beige solid (68 mg, 99%). X H NMR (400 MHz, DMSO-d 6): 2.59 (s, 3 H); 3.67 (s, 6 H); 3.83 (s, 3 H); 6.34 (s, 2 H); 6.99 (s, 1 H); 7.38 (br.d, 1 H, J = 7.6 Hz); 7.48 (t, 1 H, 7.7 Hz); 7.67 (d, 2 H, J = 8.8 Hz); 7.77 (br.s, 1 H); 7.81-7.87 (m, 3 H); 10.29 (s, 1 H); 12.60 (br.s, 1 H). Stage 3: AB440 (The following reaction is carried out in anhydrous atmosphere of N2). Carboxylic acid (59) (65 mg, 0.13 mmol) is suspended in anhydrous dichloromethane (2.7 ml) and anhydrous 1,2-dichloroethane (2.0 ml), the solution is cooled to -78 ° C and a 1 M solution is added dropwise. of BBr 3 in dichloromethane (800 μl, 0.80 mmol). The reaction mixture is stirred for 10 minutes at -78 ° C and then slowly heated for an additional 4 hours at room temperature. The reaction mixture is cooled to 0 ° C, water and dichloromethane are added dropwise followed by EtOAc. The aqueous layer is separated and extracted 3 times with EtOAC. The combined organic layer is washed with brine and dried with Na 2 SO 4. The solvent is removed under reduced pressure and the product is purified by preparative HPLC RP (gradient, water / CH3CN 95: 5 to 5:95) to obtain 2-Methyl-5- acid. { 4- [(2 ', 4', 6 '-trihydroxy-biphenyl-3-carbonyl) -amino] -phenyl} -furan-3-carboxylic acid (60) (11 mg, 19%) as a yellow solid. 1 H NMR (400 MHz, CD30D): 2.68 (s, 3 H); 6.03 (s, 2 H); 6.95 (s, 1 H); 7.52 (t, 1 H, J = 7.7 Hz); 7.61 (dt, 1 H, Ji = 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, Ji = 8.1 Hz, J2 = 1.4 Hz), 7.95 (t, 1 H, J = 1.5 Hz).

EXAMPLE 4 Acid (5- {2 - [(2 ', 4', 6 '-Trihydroxy-biphenyl-3-carbonyl) -amino] phenyl.}. -thiophen-2-yl) -acetic REACTION SCHEME 14 Stage 1: FR600 (The next reaction is carried out in an anhydrous atmosphere of N2). Aniline (44) (823 mg, 3.33 mmol) is dissolved in anhydrous dichloromethane (17.0 ml), anhydrous pyridine (680 μl, 8.33 mmol) and carboxylic acid chloride (51), (1.67 mg, 4.32 mmol) are added. The reaction mixture is stirred for 20 hours at room temperature. The reaction mixture is poured into 1 M aqueous HCl extract cooled in ice, extract with EtOAc (3x), the combined organic layer is washed with brine and dried with Na2SO4. The crude product is purified by preparative radial chromatography (silica gel 60PF, CyH / EtOAc 3 + 1) to obtain the amide (61) as a yellow solid (722 mg, 41%). 1 H NMR (400 MHz, CDC13): 3.69 (s, 6 H); 3.72 (s, 3 H); 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 Hi J = 3.5 Hz); 7.14 (t, 1 H, J = 7.3 Hz); 7.36-7.42 (m, 2 H); 7.44 (d, 1 H, J = 7.8 Hz); 7.48 (br.d, 1 H, J = 7.6 Hz); 7.61 (br.d, 1 H, 7.3 Hz); 7.78 (br.s, 1 H); 8.35 (br.s, 1 H); 8.50 (d, 1 H, J = 8.3 Hz). Step 2: FR60 The ester (61) (722 mg, 1.39 mmol) is dissolved in MeCN (14.0 mL) and 1M aqueous LiOH (7.0 mL, 7.00 mmol) is added. The reaction mixture is stirred for 20 hours at room temperature. The solvent is removed under reduced pressure and the residue is partitioned between EtOAc and 1M HCl (1 + 1). The aqueous layer is separated and extracted 3 times with EtOAc. The combined organic layer is washed with brine and dried with Na 2 SO 4. The solvent is removed under reduced pressure and the residue is dried without further purification in vacuum pumped oil to obtain the crude product (62) as a yellow solid (714 mg, amount). X H NMR (400 MHz, CD 3 CN): 3.69 (s, 6 H); 3.80 (s, 2 H); 3.85 (s, 3 H); 6.30 (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, Ji = 7.6 Hz, J2 = 1.3 Hz); 7.39 (td, 1 H, Ji = 7.8 Hz, J2 = 1.3 Hz); 7.42-7.49 (m, 2 H); 7.54 (dd, 1 H, Jx = 7.8 Hz, J2 = 1.3 Hz); 7.69 (br.s, 1 H); 7.73 (dt, 1 H, J, = 7.3 Hz, J2 = 1.8 Hz); 7.89 (d, 1 H, J = 7.6 Hz); 8.53 (br. S, 1 H). Step 3: FR602 (The following reaction is carried out in anhydrous atmosphere N2) Dissolve carboxylic acid (62) (700 mg, 1.39 mmol) in anhydrous dichloromethane (28.0 ml), the solution is cooled to -78 ° C and added by drip a 1M solution of BBr3 in dichloromethane (8.5 ml8.50 mmol). The reaction mixture is stirred for 10 minutes at -78 ° C and then heated slowly for an additional 4 hours at room temperature. The reaction mixture is cooled to 0 ° C, water and dichloromethane are added dropwise followed by EtOAc. The aqueous layer is separated and extracted 3 times with EtOAc. The combined organic layer is washed with brine and dried with Na 2 SO 4. The solvent is removed under reduced pressure and the crude product is purified by preparative HPLC RP (gradient, water / CH 3 CN 95: 5 to 95: 5) to obtain (5-. {2- [(2 ', 4') acid. 6 '-Trihydroxy-biphenyl-3-carbonyl) -amino] -phenyl.}. -thiophen-2-yl) -acetic acid (63) (146 mg, 22%) as a beige solid. XH NMR (400 MHz, CD3OD) 3.85 (s, 2 H); 6.02 (s, 2 H); 6.97 (d, 1 H, J = 3.5 Hz); 7.18 (d, 1 H, J = 3.5 Hz); 7.35 (td, 1 H, J, = 7.6 Hz, J2 = 1.3 Hz); 7.42 (td, 1 H, Jx = 7.6 Hz, J2 = 1.5 Hz); 7.50 (t, 1 H, J = 7.7 Hz); 7.61 (br.d, 2 H, J = 7.6 Hz); 7.79 (br.d, 2 H, J = 7.6 Hz); 7.93 (br.s, 1 H).

EXAMPLE 5 (5- {2- [2- (2,4,6-Trihydroxy-phenyl) -acetylamino] -phenyl} thiophen-2-yl) -acetic acid REACTION SCHEME 15 (5- {2- [2- (2,4,6-Trihydroxy-phenyl) -acetylamino] -phenyl} -thiophen-2-yl) -acetic acid (25) is prepared starting from the amine ( 44) and carboxylic acid chloride (14) according to the procedure described in steps 1 to 3 of EXAMPLE 1 to obtain (5- {2- [2- (2,4,6-Trihydroxy-phenyl)) -acetylamino] -phenyl.}. -thiophen-2-yl) -acetic acid (25) (25 mg, 16% over 3 steps) as a brown solid. 1 H NMR (400 MHz, CD30D): 3.58 (s, 2 H); 3.88 (s, 2 H); 5.88 (s, 2 H); 6.67 (d, 1 H, J = 3.3 Hz); 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); 8.26 (d, 1 H, J = 8.6 Hz).

EXAMPLE 6 Acid 5-. { 2 - [(2 ', 4', 6 '-trihydroxy-biphenyl-3-carbonyl) -amino] phenyl} -thiophene-2-carboxylic acid (26) REV971, LE37 REACTION SCHEME 16 Acid is prepared 5-. { 2- [(2 ', 4', 6 '-trihydroxy-biphenyl-3-carbonyl) -amino] -phenyl} -thiophen-2-carboxylic acid (26) starting from amine (47) and carboxylic acid chloride (51) according to the procedure described above in steps 1 to 3 of EXAMPLE 4 to obtain 5- acid. { 2- [(2 ', 4', 6 '-trihydroxy-biphenyl-3-carbonyl) -amino] -phenyl} -thiophene-2-carboxylic acid (26) (44 mg, 22% over 3 steps) as a white solid. H NMR (400 MHz, CD3OD): 6.02 (s, 2 H); 7.32-7.36 (m, 1 H); 7.41 (t, 1 H, J = 7.6 Hz); 7.46-7.53 (m, 2 H); 7.62 (dt, 1 H, Jx = 7.6 Hz, J2 = 1.3 Hz); 7.65-7.73 (m, 3 H); 7.80 (dt, 1 H, Jx = 8.1 Hz, J2 = 1.4 Hz); 7.96 (br.s, 1 H).

EXAMPLE 7 Acid (5- { 3 - [(2 ', 4', 6 '-trihydroxy-biphenyl-3-carbonyl) -amino] phenyl} -thiophen-2-yl) -acetic (64) REV996 , KM7 REACTION SCHEME 17 Acid is prepared 5-. { 3- [(2 ', 4', 6 '-trihydroxy-biphenyl-3-carbonyl) -amino] -phenyl} -thiophen-2-yl) -acetic (64) starting from the amine (57) and carboxylic acid chloride (51) according to the procedure described above in steps 1 to 3 of EXAMPLE 4 to obtain (5-) acid. {3 - [(2 ', 4', 6 '-trihydroxy-biphenyl-3-carbonyl) -amino] -phenyl} -thiophen-2-yl) -acetic acid (64) (3 mg, 4% during 3 stages) as a brown solid. X H NMR (400 MHz, CD 3 OD): 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); 7.36-7.44 (m, 2 H) 7.53 (t, 1 H, J = 7.7 Hz); 7.61 (dt, 1 H, Ji = 7.6 Hz, J2 = 1.4 Hz); 7.66 (dt, 1 H, Jx = 7.3 Hz, J2 = 1.8 Hz), 7.85 (dt, 1 H, Jx = 7.8 Hz, J2 = 1.5 Hz); 7.96 (t, 1 H, J = 1.5 Hz); 8.05 (br.s, 1 H).

EXAMPLE 8 2 ', 4', 6 '-Trihydroxy-biphenyl-3-carboxylic acid (2-thiophen-2-yl-phenyl) -amide (65) REV965, AB437 REACTION SCHEME 18 2 ', 4', 6 '-Trihydroxy-biphenyl-3-carboxylic acid (2-thiophen-2-yl-phenyl) -amide (65) is prepared starting from the amine (55) and carboxylic acid chloride (51). ) according to the procedure described above in steps 1 and 3 of EXAMPLE 4 to obtain (2-thiophene-2-yl-phenyl) -amide of 2 ', 4', 6'-Triachydroxy-biphenyl-3-carboxylic acid (65) (12 mg, 9% over 2 steps) as a beige solid. X H NMR (400 MHz, CD 3 OD): 6.02 (s, 2 H); 7.13 (dd, 1 H, Ji = 5.1 Hz, J2 = 3.8 Hz); 7.35 (dd, 1 H, Ji = 3.5 Hz, J2 = 1. 0 Hz); 7.38 (dd, 1 H, Jx = 7.6 Hz, J2 = 1.3 Hz); 7.41-7.48 (m, 2 H); 7.50 (d, 1 H, J = 7.6 Hz); 7.61 (dt, 1 H, Jx = 7.8 Hz, J2 = 1.4 Hz); 7.64 (dd, 1 H, Jx = 7.6 Hz, J2 = 1.5 Hz); 7.73 (dd, 1 H, J? = 7.8 Hz, J2 = 1.3 Hz); 7.77 (dt, 1 H, Jx = 8. 1 Hz, J2 = 1.4 Hz); 7.92 (t, 1 H, J = 1.5 Hz).

EXAMPLE 9 2 ', 4', 6 '-Trihydroxy-biphenyl-3-carboxylic acid (3-trifluoromethyl-phenyl) -amide (66) REV961, DU15 REACTION SCHEME 19 Acid (3-trifluoromethyl-phenyl) -amide is made 2 ', 4', '-Trihydroxy-biphenyl-3-carboxylic acid (66) starting from 3-trifluoromethyl-phenylamine and carboxylic acid chloride (51) according to the procedure described above in steps 1 and 3 of EXAMPLE 4 for obtain (2-trifluoromethyl-phenyl) -amide of the 2 ', 4', 6'-Tri- hydroxy-biphenyl-3-carboxylic acid (66) (54 mg, 54% over 2 steps) as a beige solid. l H NMR (400 MHz, CD30D): 6.02 (s, 2 H); 7.45 (br.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); 7.62 (dt, 1 H, Ji = 7.8 Hz, J2 = 1.4 Hz); 7.85 (ddd, 1 H, Ji = 7.8 Hz, J2 = 1.8 Hz, J3 = 1.3 Hz); 7.95-7.99 (m, 2 H); 8.21 (br.s, 1 H).

EXAMPLE 10 3- [(2 ', 4', 6 '-Trihydroxy-biphenyl-3-carbonyl) -amino] benzoic acid (67) REV1007, LE80 REACTION SCHEME 20 3- [(2 ', 4', 6 '-Trihydroxy-biphenyl-3-carbonyl) -amino] -benzoic acid (67) is prepared starting from 3-Amino-benzoic acid methyl ester and carboxylic acid chloride (51) ) according to the procedure described above in steps 1 to 3 of EXAMPLE 3 to obtain 3- [(2 ', 4', 6 '-Trihydroxy-biphenyl-3-carbonyl) -amino] -benzoic acid (67) ( 22 mg, 14% over 3 steps) as a whitish solid. X H NMR (400 MHz, CD30D): 6.02 (s, 2 H); 7.48 (t, 1 H, J = 8.0 Hz); 7.52 (t, 1 H, J = 7.8 Hz); 7.61 (br.d, 1 H, J = 7.8 Hz); 7.84 (t, 2 H, J = 7.2 Hz); 7.96 (br.s, 1 H); 8.01 (br.d, 1 H, J = 8.3 Hz); 8.34 (br.s, 1 H). All of the compounds referred to in the following REACTION SCHEME 6 are those compounds referred to as the particularly preferred compounds herein.

REACTION SCHEME 6 Sialyl Lewis Tyrosine Sulfate Assay (sLexTSA): The compounds of the present invention are tested at a molecular level for their ability to inhibit the binding of chimeric P-, L- or E-selectin molecules to sLex and bound tyrosin sulfate residues to a polymer matrix as a PSGL-1 substitute. Selected IC50 values are determined. The microtiter plates are coated overnight in carbonate buffer pH 9.6, with goat anti human mAB Fc (10 μg / ml). After washing in assay buffer (25 mM 4- (2-hydroxyethyl) -1-piperazine-ta-sulphonic acid (HEPES), 150 mM NaCl, 1 mM CaCl2 pH 7.4) and blocking plates (bovine alb. 3% (BSA) in assay buffer) are incubated for 2 hours at 37 ° C with P-selectin-IgG-human chimera (0.61 nM respectively 150 ng / ml) or L-selectin-IgG-human chimera (0.61 nM respectively 89 ng / ml) or E-selectin-human IgG-chimera (0.61 nM respectively 131 ng / ml). 5 μl of sLex-tyrosine sulfate polyacrylamide (1 mg / ml) carrying 15% sLex, 10% tyrosine sulfate and 5% biotin is complexed with 20 μl of Streptavidin-Peroxidase solution (1 mg / ml) ) and 25 μl of assay buffer without CaCl2. For use in the assay, the ligand complex is diluted 1: 10000 in assay buffer and further diluted 1: 1 with varying amounts of the compounds in test cushion incl. DMSO at 20%. This mixture is added to the cavities pre-coated with E or P selectin. After incubation for 2 hours at 37 ° C, the cavities are washed six times with assay buffer incl. Polyoxyethylene sorbitan monolaurate at 0.005% (TWEEN 20), developed for 10-15 minutes with 20 μl of 3,3 ', 5,' -tetramethylbenzidine (TMB) / H202 substrate solution and stopped with 20 μl 1M H2S04. The binding of the sLex-Tyrosine sulfate ligand complex is determined by measuring the optical density at 450 nm against 620 nm in an alpha-FP fusion reader (sold by Packard Bioscience, Dreieich, Germany).

Results of sLexTSA: In vitro inhibition data for E / P / L selectin Results of sLexTSA: IC50 data for Selectina E / P / L Cell Flow / Cell Adhesion and Rollback Test under Flow Conditions To assess the ability of the compounds to inhibit cell binding under dynamic conditions similar to the flow in a blood vessel, direct flow chamber tests are carried out. HL-60 cells / cell lines varied for chimeric molecules P-selectin, L-selectin and E-selectin. Cell binding is determined under flow conditions using parallel flow chamber system. A 35 mm polystyrene culture dish is coated for 1 hour at room temperature with a wash buffer (50 mM). of tris- (hydroxymethyl) aminomethane (Tris) buffer, 150 mM NaCl, 2 mM CaCl 2; pH 7.4) containing chimera selectin E or P-IgG at concentrations of 2.5 μg / ml or 10 μg / ml, respectively. After removing non-specific binding sites from the coating solution, they are blocked for an additional hour with 1% BSA in coating buffer at room temperature. After washing with assay buffer ("Roswell Park Memorial Institute 1640" (RPMI 1640) + 10 mM HEPES) the disk is fixed in a parallel plate laminar flow chamber (sold by Glycotech, Rockville, MD) and mounts in an inverted phase contrast microscope (sold by Olympus, Hamburg, Germany) equipped with a CCD camera (JVC) that connects to a CP. Using a peristatic pump (sold by Ismatec, Wertheim-Mondfeld, Germany) the recirculation system is equilibrated with a test buffer containing 125 μM of the compound or control vehicle (DMSO). The cells (1 million / ml) are added to the chamber and allowed to distribute for 2 minutes at a high flow rate. The flow rate then decreases, resulting in a calculated flow cutoff of 1 din / cm2. The video sequences of 10 flow energy fields are recorded digitally after 5 minutes of continuous flow. The percent inhibition is calculated from the average number of cells per field that binds to the surface of the coated disc in the presence against the absence of the compound of independent experiments.

Data from the Flow Chamber Test for Selectin E Values are given as normalized proportions of% inhibition of compound x divided by% inhibition of bimosiamosa It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (12)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1 . Pharmaceutical composition, characterized in that it comprises at least one compound of the formula (I) and a pharmaceutically acceptable carrier which is used in a medicine. where the symbols and substituents have the following meanings -X- = (a) with m = 0, 1; n = an integer from 1 to 3 where "ring" is and with R1 being H, N02, CF3, F, Cl, Br, I, CN, CH3, NH2, NHA alkyl, NHArilo, NHAcilo and k = 0.1. (c) T being 0, S or [H, H]; p = 0, 1, 2 -Y = (a; with s being 0 or 1, R2 being C02H, C02Alkyl, C02Aryl, C02NH2, C02Aralkyl, S03H, S02NH2, PO (OH) 2, 1-H-tetrazolyl-, CHO, C0CH3, CH20H, NH2, NHAalkyl, N (Alkyl) Alkyl ', 0CH3, CH2OCH3, SH, F, Cl, Br, I, CH3, CH2CH3, CN, CF3. R3 independently of R2 is H, CH3, CH2CH3, CF3, F, Cl, Br, I, CN, N02 and R4 independently of R2 and R3 is H, CH, CH2CH3, CF3, F, Cl, Br, I, CN, N02, R

2. R5 is H, N02, CF3, F, Cl, Br, I, CN, CH3, OCH3, SH, NH2. and -w- = -. { CH2) v. cis-CH = CH- or trans-CH = CH-, and v being 0, 1, 2; in case -W- is cis-CH = CH- or trans-CH = CH, R2 should not be NH2 or SH; (b) R6 is independently of R2 being H, F, Cl, Me, tert-Bu, CN, NH2 (c) (and) with t being 0, 1, 2 -2 (i) R7 independently of R2 is H, N02, CF3, F, Cl, Br, I, CN, CH3, OCH3, SH, NH2. (iv) with K = NH, NMe, O, S (v) or the pharmaceutically acceptable salts, esters or amides and prodrugs of the compounds identified above of formula (I). 2. Pharmaceutical compositions according to claim 1, characterized in that the compounds are defined by the formula (II), wherein "X" is X (a) or X (b) and Y is as defined in claim 1.

3. Pharmaceutical compositions according to claim 2, characterized in that the compounds are defined by the formulas (A) or (B). B where -X'- and -Y- are as defined in claim 2, and wherein -X "- is and where -Y 'is wherein all the indices, symbols and substituents are as defined in accordance with claim 1.

4. Pharmaceutical compositions according to claim 3, characterized in that the compounds are defined by the formula (C). wherein "X" - and -Y "are as defined in claim 3. Pharmaceutical compositions according to claim 4, characterized in that the compounds are defined by the formula (D). where -X "is as defined in the claim 3 and -Y 'is wherein R is C02H, C02alkyl, C02aryl, C02NH2, C02aralkyl, CH2S03H, CH2S02NH2, CH2PO (OH) 2, 1H-tetrazolyl, CHO, COCH3, CH2OH, CH2NH2, CH2NHalkyl, CH2N (alkyl) alkyl, CH2OCH3, CH2SH , wherein all indices, symbols and substituents are as defined in accordance with claim 1. 6. Chemical compounds, characterized in that they have the general structure of formula (C) O (D) in accordance with claim 4 or

5. 7. Use of compounds having the structure of formula (I) as defined in accordance with claim 1, for the preparation of a medicine for the treatment of Chronic Obstructive Pulmonary Disease (COPD), acute lung injury (ALI). , cardiopulmonary bypass, respiratory distress syndrome (ARDS), Crohn's disease, septic shock, sepsis, chronic inflammatory diseases such as psoriasis, atopic dermatitis and rheumatoid arthritis, and reperfusion injury, which occurs after ataxia cardiac events, strokes, atherosclerosis, and organ transplants, traumatic shock, multiple organ failure, autoimmune diseases such as multiple sclerosis, percutaneous transluminal angioplasty, asthma and inflammatory bowel disease. 8. Use of compounds having the structure of formula (I) as defined in accordance with claim 1, for the preparation of a medicine for the treatment, diagnosis or prophylaxis of inflammatory disorders. 9. Use of compounds having the structure of formula (I) as defined in accordance with claim 1, for the preparation of a vehicle for directing diagnostic or therapeutic drugs. 10. Use of compounds having the structure of formula (I) as defined in accordance with claim 1, for the preparation of dermatological and cosmetic compositions. 11. Cosmetic compositions, characterized in that they comprise at least one compound of the formula (I) according to claim 1 and at least one cosmetically tolerable component. 12. Dermatological compositions, characterized in that they comprise at least one compound of formula (I) according to claim 1 and at least one dermatologically tolerable component.