MX2008003698A - Novel nitrocatechol derivatives having selectin ligand activity - Google Patents

Abstract

Pharmaceutical compositions comprising at least one compound of e.g. the formulas (Ie) 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 is e.g. or the pharmaceutically acceptable salts, esters or amides and prodrugs of the above identified compounds can be applied to modulate the in- vitro and in- vivo binding processes mediated by E-, P- or L-selectin binding.

Description

NEW DERIVATIVES OF NITROCATECOL THAT HAVE ACTIVITY OF THE SELECTINE LIGAND 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 are nitro aromatic compounds, which 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.: 191153 in part, due to the increased surface expression of E-selectin. F. Consequently, excessive migration of leukocytes 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 Pulmy 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, cardiopulmy 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 bound 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-terminal 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 Lewis3 (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 acute as well as chronic inflammatory disorders [eg, asthma, chronic obstructive pulmonary disease (COPD), psoriasis, etc.], an association between infiltration of activated leukocytes into tissue simultaneously with a marked elevation has been demonstrated. of tissue expression of corresponding adhesion molecules, 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 assumed 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. Some nitrocatechols have been developed for the treatment of Morbus Parkinson acting as specific catechol-O-methyl transferase inhibitors (COMT) [J. Axelrod et al., J. Biol. Chem. 1958, 233 (3), 702-705; P.T. Mánnisto et al., Pharmacological Reviews 1999, 51, 593-628], such as tolcapone, nitecapone, and entacapone [EP00426468]. Nitrocatechols have also been described as having cardioprotective function caused by iron-chelating [N. Haramaki et al., Biochemical Pharmacology 1995, 50, 839-843] or reduced levels of plasma homocysteine [E. Nissinen et al., J. Neural Transm. 2005, 112, 1213-1221]. Nitecapone has also been reported to act as a purifying radical [Y. J. Suzuki et al., Free Radical Biology & Medicine, 1992, 13, 517-525; L. Marcocci et al., Biochemistry and Molecular Biology International, 1994, 34, 531-541]. Some observations indicate that entacapone may protect against renal damage induced by angiotensin II [T. Helkamaa et al., J. Hypertens., 2003, 21, 2353-2363]. However, at present, nitrocatechols have not been described as selectin-modulating compounds. 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], heterocycles of 5 substituted elements [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] Appeldoom 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. Structures that carry carbohydrates have additional advantages, such as the high degree of chirality, anus, 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 pyrogallol substructures. 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 Pharmacology, 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 a mimetic of PSGL-1 [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-spheroidal 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 thus , in the oral bioavailability required for the treatment of most inflammatory disorders such as rheumatoid arthritis, septic shock, atherosclerosis, reperfusion injury and many others. EP-A 1 577 289 describes aromatic compounds which are hydroxylated in the phenyl part of the molecule and which can be used for the treatment of inflammatory disorders. In WO 1997/01335, aromatic compounds are described which are linked to a carbohydrate unit. The compounds described herein are inhibitors of selectin and can be used as therapeutic agents, however, they are structurally different from the nitro-substituted aromatic compounds according to this invention. In EP-A 1 481 669, polyhydroxyphenols are described which have P-selectin modulating activities.

BRIEF DESCRIPTION OF THE INVENTION It is an object of the invention to provide novel 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 based on 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 the formulas (la) or (Ib) or (le) or (le) or (le) or (If) and a pharmaceutically acceptable carrier which is employed in a medicine. the Ib where the symbols and substituents have the following meanings -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, 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 configuration (and) (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, C0CH3, CH2OH, 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, 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 should not be NH2 or SH; 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, OCH3, SH, NH2. (or) R independently of R is H, F, Cl, Me, tere-Bu, CN, NH2 (iü) iv) with K = NH, NMe, O, S (v) VII, -W-R "or the pharmaceutically acceptable salts, esters or amides and prodrugs of the compounds identified above of formulas (la), (Ib), (le), (Id), (le) or (If) • In a further embodiment, the invention relates to pharmaceutical compositions comprising at least one compound of the formulas (Ib) or (le) or (le) or (If) and a pharmaceutically acceptable carrier 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, NHArilo, NHAcilo and k = 0.1.

-Y = with s being 0 or 1, R being C02H, C02Alkyl, C02Aryl, C02NH2, C02Aralkyl, S03H, S02NH2, PO (OH) 2, 1-H-tetrazolyl-, CHO, COCH3, CH2OH, 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 being 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; with t being 0, 1, 2 (g) (i) R7 independently of R2 is H, NO2, 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 formulas (Ib) or (le) or (le) or (If). The pharmaceutical compositions comprise compounds of the formulas (lía) or (Ilb) or (líe) or (lid) or (lie) or (Ilf), where -Y is as defined above and where -X'- is X (a), X (b), X (c) and X (d) as defined above. In a further embodiment, the invention relates to compositions comprising compounds of the structures: I have llf where -Y and -X'- as X (a) and X (b), are as defined above. Additional preferred pharmaceutical compositions comprise compounds of formulas (Al) or (A2) or (A3) or (A4) or (A5) or (Bl) or (B2) or (B3) or (B4) or (B5¡ [B6) where -X '- and -Y- are as defined above, and where -X "- is and where -Y 'is where all the indices, symbols and substituents are similar defined above. In a further embodiment, the invention also relates to pharmaceutical compositions comprising compounds of the formula: 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 compositions comprise compounds of formulas (Cl) or (C2) or (C3) or (C4) or (C5) or (C6).

C6 where -X '- and -Y are as defined above. A further preferred group of compounds of the following composition have the following structures: C5 C6 wherein "X" - and -Y "- are as defined above .. Very particularly preferred pharmaceutical compositions comprise compounds of formulas (DI) or (D2) or (D3) or (D4) or (D5) or (D6).

D4 OS D6 where -X "is as defined above and -Y '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 . Also preferred are pharmaceutical compositions, wherein the compounds are defined by the formulas (D2) or (D3) or (D5) or (D6).

D5 D6 where -X "is as defined above, and -Y 'is where 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, wherein all the indices, symbols and substituents are as are defined above. These chemical compounds (Cl), (C2), (C3), (C4), (C5), (C6), (DI), (D2), (D3), (D4), (D5) and (D6) , they are also new compounds by themselves. Chemical compounds having the general structure of formula (C2) or (C3) or (C5) or (C6) or (D2) or (D3) or (D5) or (D6), are preferred. 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. Compared with bimosiamose, the bread-lead selectin antagonists, the compounds described in this document, show increased biological activity. 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 compounds formulas (la) or (Ib) or (le) or (Id) or (le) or (If) and in a preferred variant of formulas (Ha) or (Hb) or (He) or (lid) or (He) or (Ilf). In a further preferred variant, the invention provides pharmaceutical compositions comprising at least one compound of formula (Al) or (A2) or (A3) or (A4) or (A5) or (A6) or (Bl) or (B2) ) or (B3) or (B4) or (B5) or (B6). In a particularly preferred variant, the invention provides pharmaceutical compositions comprising at least one compound of formula (Cl) or (C2) or (C3) or (C4) or (C5) or (C6). In a very particularly preferred variant, the invention provides pharmaceutical compositions comprising at least one compound of formula (DI) or (D2) or (D3) or (D4) or (D5) or (D6). In a further embodiment of the invention, a compound of formulas (A2), A3, A5, A6, B2, B3, B5, B6, C2, C3, C5, C6, D2, D3, D5 or D6. 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 which has the structure of formulas (la) or (Ib) or (le) or (Id) or (le) or (If) to modulate the binding of P, E or L-selectin to sLex or sLea and tyrosin sulfate. It has been found that compounds having the formulas (la) or (Ib) or (le) or (Id) or (le) or (If) shown above, act to modulate the E, P or L-selectin bond. As used in this document, the term "alkyl", shall mean a monovalent straight chain group of 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, 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, Wherever possible, 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. during the isolation and final purification of the compounds or separately by reacting the purified compounds in their free with an appropriate 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, lauryl sulfonate 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 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 cycloalkyl esters, Ce and C, as well as arylalkyl esters such as, but not limited to, benzyl. Alkyl esters Ci, C2, C3, C4, C5 and e 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 Ce 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 can also be in the form of a 5 or 6 element 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 parent compound of the above formulas (la) or (Ib) or (le ) or (Id) or (le) or (If), for example, by blood hydrolysis or in vivo metabolism. It is also contemplated that the pharmaceutically active compositions 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 formulas (la) or (Ib) or (le) or (Id) or (le) or (If), 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 can include one or more of the compounds having the structure (la) or (Ib) or (le) or (Id) or (le) or (If), formulated together with one or more carriers , physiologically acceptable 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 sterile, physiologically acceptable, aqueous or non-aqueous solutions, stabilizers, antioxidants, preservatives (eg, 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 retard 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 excipient (or carrier), 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 (disintegrating agents, such as, for example, agar, 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, for example, quaternary ammonium, (vii) wetting agents, 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 of the same. 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, metabolized lipid 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 present 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 transplants. organs, traumatic shock, multiple organ failure, autoimmune diseases such as multiple sclerosis, percutaneous transluminal angioplasty, asthma and inflammatory bowel disease. 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 factors. intrinsic The invention particularly relates to the use of a compound of formula (a) (If), particularly (Ib), (le), (le), or (If), 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 (Ib), (le), (le) or (If) 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 (Ib), (le), (le) or (If) or a stereoisomeric form thereof and at least one cosmetically tolerable component, for example, a cosmetically tolerable component for applications to the skin. The amounts of the various components of the physiological medium 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 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 oil phase thickeners or gelling agents, dyes which are soluble in the means of the cosmetic composition, solid particles 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, anionic, nonionic, cationic or amphoteric water soluble or water dispersible polymers, which form 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 (Ib), (le), (le) or (If), or a stereoisomeric form thereof, which is used for cosmetic treatment or cosmetic prophylaxis of micro-inflammatory conditions. Cosmetic compositions comprising a compound of formula (Ib), (le), (le) or (If) or a stereoisomeric form thereof, which are used for the cosmetic treatment or cosmetic prophylaxis of skin aging caused by intrinsic factors , they 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 active 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 (Ib), (le), (le) or (If), or a stereoisomeric form thereof and at least one cosmetically additional active ingredient, for example, a UV blocker or proteins. Dermatological compositions comprising a compound of formula (Ib), (le), (le) or (If) or stereoisomeric form thereof and at least one dermatologically tolerable component, for example, a dermatologically tolerable component for applications to the skin , they 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 (Ib), (le), (le) or (If), or a stereoisomeric form thereof which is used for dermatological treatment, dermatological diagnosis or dermatological prophylaxis. of micro-inflammatory conditions. In particular, the invention covers dermatological compositions comprising a compound of formula (Ib), (le), (le) or (If) 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 (eg, excessive alcohol consumption), repetitive facial expressions, sleeping positions, and psychological stress. In addition to the dermatologically active 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 (Ib), (le), (le) or (If) or a stereoisomeric form thereof, and at least one dermatologically or pharmaceutically active ingredient. 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 (Ib), (le), (le) or (If) or a stereoisomeric form thereof and at least one dermatologically or pharmaceutically active ingredient, characterized in that It is used for the 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 (Ib), (le), (le) or (If) or a stereoisomeric form thereof and at least one dermatologically or pharmaceutically active ingredient, characterized because it is used for the dermatological treatment, dermatological diagnosis or dermatological prophylaxis of itching and aging of the skin, caused by intrinsic factors. Skin aging can also be caused by a combination of intrinsic and extrinsic factors. Therefore, the present invention also relates to dermatological compositions comprising a compound of formula (Ib), (le), (le) or (If) 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 dermatological prophylaxis of 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 (Ib), (le), (le) or (If) 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 (Ib), (le), (le) or (If) 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 (Ib), (le), (le) or (If) or a stereoisomeric form thereof, based on the total weight of the composition. An additional aspect according to a process for the preparation of a dermatological composition by mixing a compound of formula (Ib), (le), (le) or (If) 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-ethyl carbodiimide (EDC), triethylamine, 4-dimethylamino-pyridine (DMAP) ) and carboxylic acid of type (2) in dichloromethane, to give an amide of type (3). Any amide of type (3) is further reacted with boron tribromide in dichloromethane at -78 ° C to obtain the corresponding 2,4,6-trihydroxyphenyl of type (4). The synthesis sequence shown in the SCHEME REACTION 1, which leads to compounds similar to (4) is not only reduced to construction clusters Y-H as (1), but can be generally applied to all other building blocks type Y-H.

REACTION SCHEME 2 In the REACTION SCHEME 2, an acid chloride similar to (5), is reacted with an aniline of the general type (6), under basic conditions (pyridine in dichloromethane), to form the corresponding anuide (7). Alternatively, triethylamine can be used for this reaction step. The ester (7) is hydrolyzed with LiOH in MeCN or THF / MeOH to obtain a carboxylic acid such as (8), which is also reacted with boron tribromide in dichloromethane at -78 ° C, to be obtained after the next lifting aqueous, corresponding demethylated acids of type (9). The synthesis sequence shown in the REACTION SCHEME 2 that leads to the compounds as (9), is not only reduced to the building blocks YH as (6), but can be generally applied to all other building blocks type YH. Similar type (2) or (5) building blocks, shown in the reaction schemes can be synthesized as summarized in the following REACTION SCHEMES 3 to 9: REACTION SCHEME 3 In the REACTION SCHEME 3, guaiacol (10) is selectively nitrated with 70% HNO3 in AcOH to give nitroguayacol (11), which is also methylated with methyl iodide and K2CÜ3 in acetone to give the corresponding veratrol (13). ). Alternatively, (13) is available from veratrol (12) by subsequent reaction with BuLi and N, N, N ', N'-tetramethylethylenediamine (TMEDA) at low temperature, followed by dinitic tetraoxide. Subsequent reaction of (13) with Buli and TMEDA in THF followed by trimethylborate and hydrochloric acid provides boronic acid (14). The boronic acid (14) is reacted under inert conditions with a brominated aromatic or heteroaromatic ester of the general type (15), under basic conditions of the Suzuki type (Pd (PPh3) 4 and aqueous sodium bicarbonate in dimethoxyethane) to a biaryl of type (16). The biaryl (16) is further hydrolyzed with aqueous lithium hydroxide in THF and MeOH or MeCN to give the corresponding carboxylic acid (17), which is converted to a building block of type (18) by reaction with oxalyl chloride in anhydrous dichloromethane.

REACTION SCHEME 4 In the REACTION SCHEME 3, 3-nitroveratrol (13) is subsequently reacted with Buli and TMEDA in THF followed by copper bromide- (I) and ethyl bromoacetic acid ester to obtain the substituted phenylacetic acid ethyl ester (19) , which is also hydrolyzed with aqueous lithium hydroxide in THF and MeOH or MeCN to give the corresponding carboxylic acid (20).

REACTION SCHEME 5 In the REACTION SCHEME 5, veratrol (12) is selectively nitrated with 70% HN03, in AcOH to give 4-nitroveratrol (21). Subsequent reaction of (21) with Buli and TMEDA in THF, followed by trimethyl borate and hydrochloric acid, provides boronic acid (22). The boronic acid (22) is reacted under inert conditions with a brominated aromatic or heteroaromatic ester of the general type (15), under basic Suzuki-type conditions (Pd (PPh3) 4) and aqueous sodium bicarbonate in dimethoxyethane) to a biaryl ester. type (23). The biaryl (23) is further hydrolyzed with aqueous lithium hydroxide in THF and MeOH or MeCN to give the corresponding carboxylic acid (24) which is converted to a building block of type (25) by reaction with oxalyl chloride in dichloromethane anhydrous. 2 REACTION ELEMENT 6 In the REACTION SCHEME 6, the generation of the acid building block (27) is summarized. The synthesis of (27) is analogous to that described in the REACTION SCHEME 4.

REACTION SCHEME Pd (PPh3) 4 DME In the REACTION SCHEME 7, 4-bromoguayacol (28) is selectively nitrated with 70% HN03 in AcOH to give 4-bromo-6-nitroguayacol (29), which is further methylated with methyl iodide and K2C03 in acetone for give the corresponding 5-bromo-3-nitroveratrol (30). The 5-bromo-3-nitroveratrol (30) is reacted under inert conditions with a boronic acid of the general type (31) under basic Suzuki-type conditions (Pd (PPh3) 4 and aqueous sodium bicarbonate in dimethoxyethane), to a biaryl of type (32). The biaryl (32) is further hydrolysed with aqueous lithium hydroxide in THF and MeOH or MeCN to give the corresponding carboxylic acid (33), which is converted to a building block of type (34) by reaction with oxalyl chloride in anhydrous dichloromethane.

REACTION SCHEME 8 The summarized acid building block (35), in the REACTION SCHEME 8, is generated from 5-bromo-3-nitroveratrol (30), in accordance with REACTION SCHEMES 4 and 6.

REACTION SCHEME 9 Pd (PP 3) 4, DME In the REACTION SCHEME 9, 3, 4-dimethoxyphenol (36) is selectively nitrated with 70% HN03 in AcOH to give 4,5-dimethoxy-2-nitrophenol (37), which is further converted to the corresponding triflate (38). ) with trifluoromethylsulfonic anhydride (Tf20) and pyridine in dichloromethane. The triflate (38) is reacted under inert conditions with a boronic acid of the general type (31), under basic conditions of Suzuki type (Pd (PPh3) 4 and aqueous potassium phosphate in toluene) to a biaryl of type (39) . The biaryl (39) is further hydrolyzed with aqueous lithium hydroxide in THF and MeOH or MeCN to give the corresponding carboxylic acid (40), which is converted to a building block of type (41) by reaction with oxalyl chloride in anhydrous dichloromethane.

Example A Preparation of [5- (2-Amino-phenyl) thiophen-2-yl] -acetic acid methyl ester (87) REACTION SCHEME 11 Step 1: (The following reaction was carried out in an anhydrous atmosphere of N2). Thiofen-2-yl-acetic acid methyl ester (85) (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 rt. 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 (86) as a yellow oil (2.46 g, 81% ), which is 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).

Stage 2: (The following reaction was performed in an atmosphere of N2). 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), are subsequently added to an acid solution hydrochloric 2-amino-benzeneboronic acid (910 mg, 5.25 mmol) in toluene (52 ml). The reaction mixture is degassed carefully (5 times) and flushed with N2 again. A solution of (5-bromo-thiophen-2-yl) -acetic acid methyl ester (1.17 g, 5.0 mmol) in toluene (4.5 ml) is added. The mixture is degassed again (5 times) and stirred for 22 hours at 100 ° C. The reaction solution is partitioned between EtOAc and brine and the aqueous layer is separated with EtOAc (3 times). The combined organic layer is washed with water and brine and dried with Na 2 SO. The crude product is purified by preparative radial chromatography (CyH / EtOAc 5 + 1) to obtain [5- (2-amino-phenyl) -thiophen-2-yl] -acetic acid methyl ester (87) as a brown oil ( 634 mg, 51%). 1 H 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, Ji = 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, Ji = 7.6 Hz, J2 = 1.5 Hz), 7.23 (dd, 14 H, Jx = 1.6 Hz, J2 = 1.5 Hz).

Example B Preparation of 5- (2-amino-phenyl) thiophene-2-carboxylic acid methyl ester (90) REACTION SCHEME 12 Step 1: LE23 is dissolved 5-bromo-thiophene-2-carboxylic acid (88) (1.50 g, 7.24 mmol) in methanol (10 m) and concentrated sulfuric acid (0.39 ml, 7.24 mmol) is added. The reaction mixture is stirred for 20 hours at 75 ° C. The mixture is cooled to rt, the solvent is removed under reduced pressure and the residue is resolved in EtOAc. This organic layer is washed 3 times with 5% aqueous Na 2 CO 3 and the combined aqueous layer is extracted with EtOAc. The combined organic layers are 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 pump oil to obtain ester (89) as a white solid (1.48 g, 92%). X H NMR (400 MHz, CDC13): 3.88 (s, 3 H); 4.00 (br.s, 2 H); 6.73-6.82 (m, 2 H); 7.13-7.21 (m, 2 H); 7.26 (dd, ° H, Jj. = 7.6 Hz, J2 = 1.0 Hz); 7.78 (d, 1 H, J = 3.8).

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 889) (1.97 g, 8.91 mmol) are dissolved in DMF (16 ml), the reaction mixture is degassed carefully (5 times) and flushes with N2. Add 2- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxoborolan-2-yl) -phenylamine (2.15 g, 9.80 mmol) and 1 M aqueous NaHC03 solution (27.0 mL, 27.0 mmol) , the reaction mixture is degassed again carefully (5 times) and flushed with N2. The mixture is stirred for 18 hours at 95 ° 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 is purified by flash chromatography (silica gel, CyH / EtOAc 5 + 1) to obtain 5- (2-amino-phenyl) -thiophene-2-carboxylic acid methyl ester (90) as a yellow solid (1.41 g, 67%). 1 H NMR (400 MHz, CDC13): 3.88 (s, 3 H); 4.00 (br.s, 2 H); 6.73-6.82 (m, 2 H); 7.13-7.21 (m, 2 H), 7.26 (dd, 1 H, J? = 7.6 Hz, J2 = 1.0 Hz), 7.78 (d, 1 H, J = 3.8).

Example C Preparation of 4 ', 5'-Dimethoxy-2'-nitro-biphenyl-3-carbonyl chloride (95) REACTION SCHEME 13 Stage 1: DK006 (The following reaction was carried out in an atmosphere of N2). Tetrakis (triphenylphosphine) -palladium (0) (200 mg, 0.17 mmol) and methyl 3-bromobenzoate (91) (1.25 mg, 5.81 mmol) were dissolved in DME (12 mL), the reaction mixture was degassed carefully ( 5 times) and flushed with N2. 3,4-Dimethoxyphenylboronic acid (1.25 g, 6.85 mmol) and a 1M aqueous solution of NaHCO 3 (17.7 mL, 17.7 mmol) were added, the reaction mixture was degassed again carefully (5 times) and flushed with N 2. The mixture was stirred for 2 h at 95 ° C. The reaction solution was partitioned between EtOAc and water and the separated aqueous layer was extracted with EtOAc (4 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, CyH / EtOAc 5 + 1) to obtain biphenyl (92) as a yellow solid (1.27 g, 80%). XH NMR (400 MHz, CDC13): 3.92 ( s, 3 H), 3.93 (s, 3 H), 3.95 (s, 3 H), 6.94 (d, 1 H, J = 8.3 Hz), 7.11 (d, 1 H, J = 1.8 Hz), 7.16 ( dd, 1 H, J = 8.3 Hz, J2 = 1.8 Hz), 7.47 (t, 1 H, J = 7.7 Hz), 7.73 (dt, 1 H, Ji = 7.6 Hz, J2 = 0.9 Hz), 7.96 (d , 1 H, J = 7.8 Hz), 8.22 (s, 1H).

Step 2: DK010 Biphenyl (92) (653 mg, 2.39 mmol) was dissolved in glacial acetic acid (32 ml), 70% nitric acid (1.18 ml, 26.30 mmol) was added and the mixture was stirred for 30 minutes at room temperature. Water (12 ml) was slowly added to the cooled reaction solution (01C), the precipitate was filtered and the filter paste was washed carefully with water. The filter cake was dried without further purification in a vacuum pump in oil, followed by desiccator to obtain the biphenyl (93) nitrated as a yellow solid (644 mg, 98%). 2 H NMR (400MHz, CDC13) 3.91 (s, 3 H); 3.94 (s, 3 H); 3.90 (s, 3 H); 6.75 (s, 1 H) 7.42-7.51 (m, 2 H); 7.60 (s, 1 H); 7.97 (t, IH, J = 1.6 Hz) 8.05 (dt, 1 H, Jx = 7.1 Hz, J2 = 1.6 Hz).

Step 3: DK011 The nitrated biphenyl (93) (1.28 g, 4.70 mmol) was dissolved in MeCN (46 mL) and aqueous LiOH was added. 1M (23.5 ml, 23.5 mmol). The reaction mixture was stirred by hours at room temperature. The reaction mixture was quenched (cooling bath) with 1M aqueous HCl (to give pH about 3). The mixture was extracted with EtOAc (3x), the combined organic layer was washed with brine and dried with Na2S0. The solvent was removed and the residue was dried without further purification in a vacuum pump in oil to obtain carboxylic acid (94) as a yellow solid (1.14 g, 80%). X H NMR (400MHz, DMS0-d 6): 3.89 (s, 3 H); 3.90 (s, 3 H); 7.01 (s, 1 H); 7.53-7.59 (m, 2 H); 7.64 (s, 1 H); 7.84 (br.s, 1H); 7.93-7.98 (m, 1 H).

Step 4: DK012 (The following reaction was carried out in an anhydrous N2 atmosphere). Carboxylic acid (94) (550 mg, 1.81 mmol) was dissolved in anhydrous dichloromethane (13 ml) and anhydrous DMF (1 ml) was added. Oxalyl chloride (237 μl, 2.72 mmol) was added slowly while maintaining the temperature at about 20 ° C with a water bath and stirred for an additional 3 hours at room temperature. The solvent was removed and the residue dried in vacuo to obtain 4 ', 5'-dimethoxy-2'-nitrobiphenyl-3-carbonyl chloride (95) as a yellow solid. Without additional purification.

Example D Preparation of 2 ', 3'-dimethoxy-5'-nitrobiphenyl-3-carbonyl chloride (99) REACTION SCHEME 14 Stage 1: FR631 (The following reaction was carried out in an atmosphere of N2). Tetrakis (triphenylphosphine) -palladium (0) (217 mg, 0.19 mmol) and methyl 3-bromobenzoate (91) (1.35 mg, 6.28 mmol) were dissolved in DME (12 mL), the reaction mixture was degassed carefully ( 5 times) and flushed with N2. 2,3-Dimethoxyphenylboronic acid (1.33 g, 7.28 mmol) and a 1 M aqueous solution of NaHCO3 (19 mL, 19 mmol) were added, the reaction mixture degassed again carefully (5 times) and flushed with 2 • The mixture was stirred for 22 h at 100 ° C. The reaction solution was partitioned between EtOAc and water and the aqueous layer was separated with EtOAc (4 times). The combined organic layer was washed with brine and dried with Na 2 SO 4. The crude product was purified by preparative radial chromatography (silica gel, CyH / EtOAc 10 + 1) to obtain biphenyl (96) as a white solid (1.50 g, 87%). XH NMR (400 MHz, CDC13): 3.57 (s, 3 H), 3.90 (s, 3 H), 3.91 (s, 3 H), 6.91-6.96 (m, 2 H), 7.11 (t, H, J = 8.0 Hz), 7.46 (t, 1) H, J = 7.8 Hz), 7.75 (dt, 1 H, Ji = 7.8 Hz, J2 = 1.5 Hz), 8.00 (dt, 1 H, Ji = 7.8 Hz, J2 = 1.4 Hz), 8.19 (t, 1 H) , J = 1.5 Hz) Step 2: FR632 Biphenyl (96) (1.49 g, 5.47 mmol) was dissolved in glacial acetic acid (30 ml), 70% nitric acid (0.76 ml, 6.04 mmol) was added and the The mixture was stirred for 22 h at 0. The reaction solution was poured into ice water, the precipitate was filtered and the filter cake was carefully washed with water.The filter cake was dried without further purification in a vacuum pump in oil. , followed by desiccator to obtain the nitrated biphenyl (97) as a yellow solid (1.29 g, 74%).? H NMR (400 MHz, CDCl 3): 3.71 (s, 3 H); 3.93 (s, 3 H); 3.99 (s, 3 H); 7.52 (t, 1 H, J = 7.7 Hz); 7.71 (d, 1 H, J = 7.8 Hz); 7.80 (d, 1 H, J = 2.3 Hz); 7.91 (br.d, 1 H, J = 2.3 Hz); 8.07 (br.d, 1 H, J = 7.8 Hz); 8.18 (br.s, 1 H).

Step 3: FR634 The nitrated biphenyl (97) (1.29 g, 4.07 mmol) was dissolved in MeCN (100 mL) and 1M aqueous LiPH (41 mL, 41 mmol) was added. The reaction mixture was stirred for 22 hours at room temperature. The reaction mixture was quenched (cooling bath) with 2M aqueous HCl (to give pH about 3). The precipitate was filtered and the filter cake washed carefully with water and once with EtOAc. The filter cake was dried without further purification in a pump-in-oil vacuum followed by desiccant to obtain carboxylic acid (98) as a beige solid (1.06 g, 86%). 1 H NMR (400 MHz, DMSO-d 6): 3.71 (s, 3 H); 3.99 (s, 3 H); 7.61 (t, 1 H, J = 7.7 Hz); 7.77 (br.d, 1 H, J = 7.6 Hz); 7.83 (d, 1 H, J = 2.8 Hz); 7.89 (d, 1 H, J = 2.8 Hz); 7.99 (br.d, 1 H, J = 7.6 Hz); 8.05 (t, 1 H, J = 1.6 Hz); 13.14 (br.s, 1 H). Stage 4: FR637 (The following reaction was carried out in an anhydrous N2 atmosphere). The carboxylic acid (98) was dissolved (500 mg, 1.65 mmol) in anhydrous dichloromethane (11 ml) and anhydrous DMF (5 ml) was added. Oxalyl chloride (220 μl, 2.47 mmol) was added slowly maintaining the temperature at about 20 ° C with a water bath and stirred for an additional 4 hours at room temperature. The solvent was removed and the residue was dried in vacuo to obtain crude 2 ', 3'-dimethoxy-5'-nitrobiphenyl-3-carbonyl chloride (99), as a yellow solid. Without additional purification. - (4-Amino-phenyl) -2-methyl-furan-3-carboxylic acid methyl ester (102) REACTION SCHEME 15 Stage 1: (The following reaction was performed under exclusion of light). 2-Methyl-furan-3-carboxylic methyl ester (100) (3.60 mL, 28.5 mmol) was dissolved in chloroform (20 mL) and glacial acetic acid (20 mL) and NBS (6.90 g, 38.8 mmol) was added in portions between a period of 95 minutes. 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 Na2SO4 to obtain methyl ester of the same. 5-bromo-2-methyl-furan-3-carboxylic acid (101) (4.90 g, 78%) as a brown oil. Without additional purification. 1 H NMR (400 MHz, CDC13): 2.54 (s, 3H); 3.80 s, 3H); 6.53 (s, 1H). Stage 2: (The following reaction was performed in an atmosphere of N2). Pd (PPh3) 4 (1.26 g, 1.09 mmol) and 5-bromo-2-methyl-furan-3-carboxylic acid methyl ester (101) (4.77 g, 21.77 mol) in DME (116 ml) were dissolved and stirred for 15 minutes at room temperature. 4- (4, 5,5-tetramethyl- [1, 3, 2] dioxoborolan-2-yl) -phenylamine (5.25 g, 23.96 mmol) was added, followed by an aqueous solution of 1M sodium bicarbonate (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 Na 2 SO 4. The obtained crude product was purified by flash chromatography (silica gel), EtOAc / CyH 1 + 2) to obtain 5- (4-amino-phenyl) -2-methyl-furan-3-carboxylic acid methyl ester (102 (2.35 g) , 46%) as a yellow-brown solid XH NMR (400MHz, 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, J, = 8.8 Hz, J2 = 2.3 Hz).

EXAMPLE F (3,4-Dimethoxy-5-nitro-phenyl) -acetic acid (107) REACTION SCHEME 16 103 104 105 106 107 Stage 1: (The following reaction was performed under exclusion of light). The aldehyde was dissolved (103) (877 mg, 4.15 mmol) in MeOH (30 mL), the solution was cooled to 0 ° C and sodium borohydrate was added in portions (548 mg, 14.49 mol) over a period of 40 minutes . The reaction solution was stirred for an additional 70 minutes at room temperature. The mixture was cooled to 0 ° C, 1M HCl (20 ml) was added slowly and the solvent was removed. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3 times), the combined organic layer was washed with brine and dried with Na 2 SO 4. The solvent was removed to obtain the benzyl alcohol (104) (876 mg, 99%) as a brown solid. Without additional purification. X H NMR (400 MHz, CDC13): 3.92 (s, 3 H); 3.95 (s, 3 H); 4.68 (s, 2 H); 7.14 (d, 1 H, J = 1.8 Hz); 7.29 (d, 1 H, J = 1.8 Hz).

Step 2: (The following reaction was carried out in a 3-necked flask, equipped with a reflux condenser and a dropping funnel under an anhydrous N2 atmosphere). Phosphorus tribromide (800 μl, 8.52 mmol) was dissolved in anhydrous toluene (90 ml) and the solution was heated to 80 ° C. A suspension of benzyl alcohol (104) (1.82 g, 8.52 mmol) in anhydrous toluene (80 ml) was added slowly and the reaction mixture was stirred for an additional 2 hours at 80 ° C. The mixture was cooled down with an ice bath and ice water was slowly added to the reaction solution. The mixture 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 Na 2 SO 4. The solvent was removed to obtain benzyl bromide (105) (2.23 g, 95%) as a brown solid. Without additional purification. 1 H NMR (400 MHz, CDCl 3): 3.92 (s, 3 H); 3.96 (s, 3 H); 4.42 (s, 2 H); 7.10 (d, 1 H, J = 2.0 Hz); 7.34 (d, I H, J = 2.0 Hz).

Step 3: Benzyl bromide (105) (2.22 g, 8.06 mmol) was dissolved in MeOH (44.0 mL) and water (9.0 mL), and potassium cyanide (787 mg, 12.09 mmol) and the reaction mixture was stirred by 90 additional minutes at 75 ° C (reflux). The mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3 times), the combined organic layer was washed with a saturated solution of sodium bicarbonate (3 times) and brine, and dried with Na 2 SO 4. The crude product was purified by preparative radial chromatography (silica gel, CyH / EtOAc 2 + 1) to obtain the nitrile (106) as a yellow solid (1.35 g, 75%). XH NMR (3.74 (s, 2 H) 3.94 (s, 3 H), 3.96 (s, 3 H), 7.06 (d, 1 H, J = 2.0 Hz), 7.26 (d, 1 H, J = 2.0 Hz).

Step 4: Nitrile (106) (1.35 g, 6.07 mmol) was suspended in glacial acetic acid (53 ml) and water (65 ml), concentrated sulfuric acid (22 ml) was added slowly and the reaction mixture was stirred for 18 hours Additional under reflux The cooled reaction mixture was extracted with EtOAc (5 times), the combined organic layer was washed with water (5 times) and brine and dried with Na 2 SO 4. The solvent was removed to (3,4-dimethoxy-5-nitro-phenyl) -acetic acid (107) (1.46 g, 99%) as a yellow solid. Without additional purification. 1 HOUR NMR (400 MHz, DMS0-d6): 3.64 (s, 2 H); 3.83 (s, 3 H); 3.87 (s, 3 H); 7.30 (s, 2 H); 12.45 (br.s, 1 H).

EXAMPLE 1 Acid (5- {2- (2- (4,5-dihydroxy-2-nitro-phenyl) -acetylamino] phenyl} -thiophen-2-yl) -acetic acid (110) REACTION SCHEME 17 Step 1 (The following reaction was made in an anhydrous atmosphere of N2). EDC hydrochloride (58 mg, 0.30 mmol) was suspended in anhydrous dichloromethane (1.0 ml), triethylamine (0.042 ml, 0.30 mmol) was added and stirred for 10 minutes at room temperature. (4,5-dimethoxy-2-nitro-phenyl) -acetic acid (54 mg, 0.22 mol) and DMAP (8 mg, 0.06 mmol) was added and stirred for 15 minutes. Aniline (87) (50 mg, 0.20 mmol) was added and the reaction solution was stirred 22 h at 40 ° C. The reaction solution was partitioned between dichloromethane and water (1 + 1), the layers were separated and the aqueous layer was extracted with dichloromethane (3 times). The combined organic layer was washed with brine and dried with Na 2 SO 4. The crude product was purified by preparative radial chromatography (silica gel 60PF, CyH / EtOAc 3 + 1) to obtain product (108) as a yellow-white solid (28 mg, 30%). 1 H NMR (400MHz, CDC13): 3.75 (s, 3 H); 3.82 (s, 2 H); 3.92 (s, 2 H); 3.94 (s, 3 H); 3.96 (s, 3 H); 6.75 (d, 1 H, J = 3.3 Hz); 6.80-6.84 (m, 2 H); 7.09 (t, 1 H, J = 7.5 Hz); 7.27-7.35 (m, 2 H); 7.63 (s, 1 H); 7.89 (s, 1 H), 8.27 (d, 1 H, J = 7.8 Hz).

Step 2: Ester (108) (49 mg, 0.10 mmol) was dissolved in methanol (1.3 ml) and THF (3.8 ml), a 1M aqueous solution of LiOH (0.52 ml, 0.52 mmol) was added and stirred for 20 hours at 40 ° C. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and 1M HCl (1 + 1). The aqueous layer was separated and extracted 3 times with EtOAc. The combined organic layer was 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 a pump-in-oil vacuum to obtain the crude product (109) as a light brown solid (48 mg, amount). ? H NMR (400MHz, CDC13): 3.87 (s, 2 H); 3.92 (s, 2 H); 3.94 (s, 3 H); 3.96 (s, 3 H); 6.76 (d, 1 H, J = 3.3 Hz); 6.82 (s, 1 H); 6.85 (d, 1 H, J = 3.3 Hz); 7.09 (t, 1 H, J = 7.7 Hz); 7.26-7.35 (m, 2 H); 7.63 (s, 1 H); 7. 88 (br.s, 1 H), 8.28 (d, 1 H, J = 8.1 Hz).

Stage 3: (The following reaction was made in an anhydrous atmosphere of N2). Carboxylic acid (109) (48 mg, 0.10 mmol) was dissolved in anhydrous dichloromethane (3.0 mL), cooled to -78 ° C (acetone / dry ice) and a 1M solution of BBr3 in dichloromethane (0.42 mL, 0.42 mmol). The reaction mixture was stirred for an additional 30 minutes at -78 ° C. The cooling bath was removed and the reaction mixture was stirred for 1.5 hours at 0 ° C and further 2 hours at room temperature. The reaction mixture was cooled to 0 ° C, water (1.00 ml) was slowly added under vigorous stirring. The reaction mixture was partitioned between EtOAc and water (1 + 1). The separated aqueous layer was extracted with EtOAc (2 times) and the combined organic layer was washed with brine and dried with Na 2 SO 4. The solvent was removed under reduced pressure and the crude product was purified by RP CLAR (gradient, water / CH3CN 95: 5 to 5:95) to obtain (5- {2- [2- (5-dihydroxy) acid. 2-nitro-phenyl) -acetylamino] -phenyl.}. -thiophen-2-yl) -acetic acid (110) as a yellow-brown solid (10 mg, 23%). XH NMR (400MHz, CD30D): 3.88 (s, 2 H); 3.96 (s, 2 H); 6.83 (s, 1 H); 6.91 (d, 1 H, J = 3.3 Hz); 6.93 (d, 1 H, J = 3.5 Hz); 7.23 (t, 1 H, J = 7.5 Hz); 7.35 (t, 1 H, J = 7.8 Hz); 7.45 (d, 1 H, J = 7.8 Hz); 7.66 (s, 1 H); 7.85 (d, 1 H, J = 8.1 Hz).

EXAMPLE 2 2-Methyl-5-acid. { 4- [(2'-nitro-4 ', 5'-dihydroxy-biphenyl-3-carbonyl) -amino] -phenyl} -furan-3-carboxylic (113) REACTION SCHEME 18 Stage 1: (The following reaction was made in an anhydrous atmosphere of N2). The aniline (102) (25 mg, 0.11 mmol) was dissolved in anhydrous dichloromethane (700 μL), anhydrous pyridine (22 μL, 0.27 mmol) and the carboxylic acid chloride (95) (45 mg, 0.14 mmol) were added. The reaction mixture was stirred for 3.5 hours at room temperature. The reaction mixture was poured into ice-cold 1M aqueous HCl, extracted with dichloromethane (3x), the organic layer was washed with brine and dried with Na2SO4. The solvent was removed to obtain the amide (111) as a yellow solid (51 mg, 91%).

Without additional purification. * H NMR (400MHz, CDC13): 2.64 (s, 3 H); 3.84 (s, 3 H); 3.96 (s, 3 H); 3.99 (s, 3 H); 6.78 (s, 1 H); 6.83 (s, 1 H); 7.44 (dt, 1 H, Ji = 8.1 Hz, J2 = 1.4 Hz); 7.53 (t, 1 H, J = 7.7 Hz); 7.60-7.69 (m, 5 H); 7.79-7.83 (m, 2 H); 7.85 (dt, 1 H, Ji = 7.8 Hz, J2 = 1.4 Hz).

Step 2: Ester (111) (51 mg, 0.10 mmol) was dissolved in THF (2.0 mL) and MeOH (0.4 mL) and 1M aqueous LiOH (495 μL, 0.49 mmol) was added. The reaction mixture was stirred for 40 hours at 40 ° C. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and 1M HCl (1 + 1). The aqueous layer was separated and extracted 3 times with EtOAc. The combined organic layer was 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 a vacuum pump in oil to obtain the crude product (112) as a yellow solid. (35 mg, 70%). X H NMR (400MHz, DMSO-d 6): 2.58 (s, 3 H); 3.91 (s, 3 H); 3.92 (s, 3 H); 6.99 (br.s, 1 H); 7.06 (s, 1 H); 7. 53 (br.d, 1 H, J = 7.6 Hz); 7.59 (t, 1 H, J = 7.7 Hz); 7.67 (s, 1 H); 7.68 (d, 2 H, J = 8.6 Hz); 7.84 (d, 2 H, J = 8.6 Hz); 7.93 (br.s, 1 H,); 7.98 (br.d, 1 H, J = 7.8 Hz); 10.38 (br.s, 1 H).

Stage 3: (The following reaction was made in an anhydrous atmosphere of N2). Carboxylic acid (112) (35 mg, 0.07 mmol) was dissolved in anhydrous dichloromethane (1.3 ml), the solution was cooled to -78 ° C and a 1M solution of BBr3 in dichloromethane (280 μl, 0.28 mmol) was added dropwise. . The reaction mixture was stirred for 10 minutes at -78 ° C, then slowly warmed by an additional 2.5 hours at room temperature. The reaction mixture was cooled to 0 ° C, water was added dropwise and dichloromethane followed by EtOAc. The aqueous layer was separated and extracted 3 times with EtOAc. The combined organic layer was washed with brine and dried with Na 2 SO 4. The solvent was removed under reduced pressure and the crude product was purified by preparative RP CLAR (gradient, water / CH3C 95: 5 to 5:95) to obtain 2-methyl-5- acid. { [(2'-nitro- ', 5'-dihydroxy-biphenyl-3-carbonyl) -amino] -phenyl} -furan-3-carboxylic acid (113) (8 mg, 24%) as a yellow solid. 1 H NMR (400 MHz, CD 3 OD): 2.65 (s, 3 H); 6.82 (s, 1 H); 6.92 (s, 1 H); 7.48 (dt, 1 H, Jx = 7.8 Hz, J2 = 1.4 Hz); 7.57 (t, 1 H, J = 7.7 Hz); 7.57 (s, 1 H); 7.69 (d, 2 H, J = 8.8 Hz); 7.78 (d, 2 H, J = 8.8 Hz); 7.89 (t, 1 H, J = 1.6 Hz); 7.97 (dt, 1 H, Jj. = 8.1 Hz, J2 = 1.4 Hz).

EXAMPLE 3 Acid (3- {2- [(2 ', 3' -dihydroxy-5 '-nitro-biphenyl-3-carbonyl) amino] -phenyl} -thiophen-2-yl) -acetic SCHEME REACTION 19 Stage 1: (The following reaction was done in an anhydrous atmosphere of N2). The aniline (87) (100 mg, 0.40 mmol) was dissolved in anhydrous dichloromethane (3.0 ml), anhydrous pyridine (80 μl, 1.01 mmol) and the carboxylic acid chloride (99) (169 mg, 0.53 mmol) were added. The reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was poured into ice-cold 1M aqueous HCl, extracted with dichloromethane (3x), the combined organic layer was washed with brine and dried with Na2SO4. The crude product was purified by preparative radial chromatography (silica gel 60PF, CyH / EtOAc 3 + 1) to obtain the amide (114) as a yellow solid (184 mg, 85%). X H NMR (400 MHz, CDC13): 3.69 (s, 3 H); 3.71 (s, 3 H); 3.86 (s, 2 H); 4.00 (s, 3 H); 6.98 (d, 1 H, J = 3.3 Hz); 7.03 (d, 1 H, J = 3.5 Hz); 7.17 (td, 1 H, Ji = 7.6 Hz, J2 = 1.0 Hz); 7.38-7.44 (m 2 H); 7.53 (t, 1 H, J = 7.7 Hz); 7.68 (dt, 1 H, J, = 7.8 Hz, J = 1.3 Hz); 7.78 (dt, 1 H, Jx = 7.8 Hz, J2 = 1.3 Hz); 7.80 (d, 1 H, J = 2.5 Hz); 7.88 (d, 1 H, J = 2.5 Hz); 7.91 (t, 1 H, J = 3.0 Hz); 8.43 (br.s, 1 H); 8.51 (d, 1 H, J = 8.6 Hz).

Step 2: These (114) (184 mg, 0.34 mmol) was dissolved in MeCN (5.0 mL) and MeOH (2.0 mL) and 1M aqueous LiOH (1.7 mL, 1.7 mmol) was added. The reaction mixture was stirred for 20 hours at room temperature. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and 1M HCl (1 + 1). The aqueous layer was separated and extracted 3 times with EtAOc. The combined organic layer was 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 a vacuum pump in oil to obtain the crude product (115) as a light yellow solid (183 mg, amount). 1 H NMR (400 MHz, CD 3 OD): 3.78 (s, 3 H); 3.85 (s, 2 H); 4.07 (s, 3 H); 6.98 (d, 1 H, J = 3.5 Hz); 7.19 (d, 1 H, J = 3.5 Hz); 7.38 (td, 1 H, Ji = 7.5 Hz, J2 = 1.3 Hz); 7.44 (td, 1 H, J? = 7.7 Hz, J2 = 1.5 Hz); 7.61-7.68 (m, 2 H); 7.73 (d, 1 H, J = 8.1 Hz); 7.80 (dd, 1 H, Jx = 7.6 Hz, J2 = 1.3 Hz); 7.94-8.02 (m, 3 H); 8.10 (br.s, 1 H).

Stage 3: (The following reaction is made in an anhydrous atmosphere of N2). Carboxylic acid (115) (70 mg, 0.14 mmol) was dissolved in anhydrous dichloromethane (1.4 mL), the solution was cooled to -78 ° C and a 1M solution of BBr3 in dichloromethane (810 μL, 0.81 mmol) was added dropwise. . The reaction mixture was stirred for 10 minutes at -78 ° C and then slowly heated for an additional 2 hours at room temperature. The reaction mixture was cooled to 0 ° C, water was added dropwise and dichloromethane followed by EtOAc. The aqueous layer was separated and extracted 3 times with EtOAc. The combined organic layer was washed with brine and dried with Na2SO4. The solvnete was removed under reduced pressure and the crude product was purified by preparative RP CLAR (gradient, water / CH3CN 95: 5 to 5:95) to obtain acid (5-. {2- [(2 ', 3' - dihydroxy-5'-nitro-phenyl-3-carbonyl) -amino] -phenyl.}. -thiophen-2-yl) -acetic acid (116) (12 mg, 18%) as a brown solid. X H NMR (400 MHz, CD 3 OD): 3.84 (s, 2 H); 6.99 (d, 1 H, J = 2.8 Hz); 7.19 (d, 1 H, J = 3.5 Hz); 7.37 (td, 1 H, Ji = 7.8 Hz, J2 = 1.5 Hz) 7.44 (td, 1 H, Ji = 7.7 Hz, J2 = 1.5 Hz); 7.58-7.65 (m, 2 H); 7.72- 7.76 (m, 2 H); 7.86-7.97 (m, 3 H); 8.16 (br.s, 1 H).

EXAMPLE 4 5'-Dihydroxy-2'-nitro-biphenyl-3-carboxylic acid phenylamide (117) REACTION SCHEME 20 4 ', 5'-Dihydroxy-2'-nitro-biphenyl-3-carboxylic acid phenylamide (117) was made starting from the aniline and carboxylic acid chloride (95) according to the procedure described in step 1 above and 3 of EJEKPLO 3 to obtain 4 ', 5'-dihydroxy-2'-nitro-biphenyl-3-carboxylic acid phenylamine (117) (2.4 mg, 10% over 2 steps) as a brown solid. H NMR (400 MHz, CD3OD): 6.84 (s, 1 H); 7.19 (br.t, 1 H, J = 7.5 Hz); 7.39 (br.d, 1 H, J = 8.1 Hz); 7.41 (br.d, 1 H; J = 7.6 Hz); 7.48 (dt, 1 H, Ji = 7.6 Hz, J2 = 1.3 Hz); 7.57 (t, 1 H, J = 7.7 Hz); 7.57 (s, 1 H); 7.70-7.75 (m, 2 H); 7.88 (t, 1 H, J = 1.5 Hz); 7.97 (br.d, 1 H, J = 7.8 Hz).

EXAMPLE 5 Acid (5- {2 - [(4 ', 5' -dihydroxy-2'-nitro-bipheni-3-carbonyl) amino] -phenyl} -thiophen-2-yl) -acetic acid (118 ) REACTION SCHEME 1 It was made (5- {2- [(4 ', 5' -dihydroxy-2'-nitro-bipheni-3-carbonyl) -amino] -phenyl} -thiophen-2-yl) -acetic acid ( 118) starting from aniline (87) and carboxylic acid chloride (95) according to the procedure described above in steps 1 to 3 of EXAMPLE 3 to obtain acid (5-. {2 - '[(4', 5 '-dihydroxy-2'-nitro-biphenyl-3-carbonyl) -amino] -phenyl.}. -thiophen-2-yl) -acetic acid (118) (14 mg, 29% over 3 steps) as a yellow solid. X H NMR (400 MHz, CD 3 OD): 3.85 (s, 2 H); 6.83 (s, 1 H); 6.97 (d, 1 H, J = 3.5 Hz); 7.17 (d, 1 H, J = 3.5 Hz); 7.37 (td, 1 H, Ji = 7.6 Hz, J2 = 1.5 Hz) 7.43 (td, 1 H, Ji = 7.6 Hz, J2 = 1.8 Hz); 7.47 (br.d, 1 H, J = 7.6 Hz); 7.55 (t, 1 H, J = 7.6 Hz), 7.56 (s, 1 H), 7.64 (dd, 1 H, Ji = 7.3 Hz, J2 = 1.0 Hz); 7.69 (d, 1 H, J = 7.6 Hz); 7.83 (br.s, 1 H); 7.93 (br.d, 1 H, J = 7.6 Hz), EXAMPLE 6 Acid 5-. { 2- [(4 ', 5' -dihydroxy-2'-nitro-biphenyl-3-carbonyl) amino] -phenyl} -thiophene-2-carboxylic acid (119) REACTION SCHEME 22 It became 5- acid. { 2- [(4 ', 5' -dihydroxy-2 '-nitro-bipheni-3-carbonyl) -amino] -phenyl} -thiophen-2-carboxylic acid (119) starting from amine (90) and carboxylic acid chloride (95) according to the procedure described above in steps 1 to 3 of EXAMPLE 3 to obtain acid (5-. {2- [(4 ', 5'-dihydroxy-2'-nitro-biphenyl-3-carbonyl) -amino] -phenyl] -thiophene-2-carboxylic acid (119) (6 mg, 8% over 2 steps) as a solid yellow, XH NMR (400 MHz, CD3OD): 6.84 (s, 1 H), 7.35 (d, 1 H, J = 3.8 Hz), 7.41-7.63 (m, 6 H), 7.71 (dd, 1 H, Ji = 7.8 Hz, J2 = 1.3 Hz), 7.75 (d, 1 H, J = 3.8 Hz), 7.86 (br.s, 1 H); 7.93 (br.d, 1 H, J = 7.6 Hz).

EXAMPLE 7 Acid 5-. { 2 - [(2 ', 3' -dihydroxy-5 '-nitro-bipheni-3-carbonyl] amino] -phenyl] -thiophene-2-carboxylic acid (120) REACTION SCHEME 23 It became 5- acid. { 2- [(2 ', 3' -dihydroxy-5 '-nitro-biphenyl-3-carbonyl) -amino] -phenyl} -thiophen-2-carboxylic acid (120) starting from amine (90) and carboxylic acid chloride (99) according to the procedure described above in steps 1 to 3 of EXAMPLE 3 to obtain acid (5-. {2- [(2 ', 3' -dihydroxy-5 '-nitro-bipheni-3-carbonyl) -amino] -phenyl] -thiophene-2-carboxylic acid (120) (17 mg, 15% over 3 steps) as a solid yellow XH NMR (400 MHz, CD3OD): 7.36 (d, 1 H, J = 4.0 Hz), 7.44 (td, 1 H, Jj. = 7.6 Hz, J2 = 1.5 Hz); 7.51 (td, 1 H , J, = 7.6 Hz, J2 = 1.5 Hz), 7.59-7.67 (m, 2 H), 7.69-7.75 (m, 3 H), 7.86-7.97 (m, 3 H), 8.21 (br.s, 1 H).

EXAMPLE 8 Acid 5-. { 2- [2- (3, -dihydroxy-5-nitro-phenyl) -acetylamino] phenyl} -thiophen-2-yl) -acetic (121) REACTION SCHEME 24 It became 5- acid. { 2- [2- (3, -dihydroxy-5-nitro-phenyl) -acetylamino] -phenyl} -thiophen-2-yl) -acetic (121) starting from amine (87) and carboxylic acid chloride (107) according to the procedure described above in steps 1 to 3 of EXAMPLE 3 to obtain 5- acid. { 2- [2- (3, 4-dihydroxy-5-nitro-phenyl) -acetylamino] -phenyl} -thiophen-2-yl) -acetic (121) (8 mg, 10% over 3 steps) as a yellow solid. X H NMR (400 MHz, CD 3 OD): 3.65 (s, 2 H); 3.81 (s, 2 H); 6.83-6.89 (m, 2 H); 7.17 (br.s, 1 H); 7.27 (td, 1 H, Jx = 7.6 Hz, J2 = 1.5 Hz); 7.36 (td, 1 H, J, = 7.7 Hz, J2 = 1.5 Hz); 7.48 (dd, 1 H, Ji = 7.8 Hz, J2 = 1.5 Hz); 7.55 (s, 1 H); 7.69 (br.d, 1 H, J = 8. 1 Hz).

SLexTSA results: IC50 data for E / P / L selectin Flow Chamber Test Data for Selectin E and P The values are given as normalized ratios of% inhibition of compound x divided by% inhibition of bimosiamosa.

The compounds referred to in the following REACTION SCHEME 10 are those compounds referred to as the particularly preferred compounds herein. REACTION SCHEME 10 Sialil Le Isx Tyrosine Sulfate (sLexTSA) Assay: The compounds of the present invention are tested at a molecular level for their ability to inhibit binding of chimeric P-, L- or E-selectin molecules to sLex and bound tyrosine 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-piperazinetansulfonic acid (HEPES), 150 M NaCl, 1 mM CaCl2 pH 7. 4) and blocking plates (3% bovine serum albumin (BSA) in assay buffer) are incubated for 2 hours at 37 ° C with P-selectin-human IgG-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 trial, the ligand complex is diluted 1: 10000 in assay buffer and further diluted 1: 1 with varying amounts of the compounds in assay buffer 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. Polyoxyeene sorbitan monolaurate at 0.005% (TWEEN 20), developed for 10-15 minutes with 20 μl of 3, 3 ', 5,' -tetramebenzidine (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).

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 selectin p, selectin L and selectin E. Cell binding is determined under flow conditions using parallel flow chamber system. A 35 mm polystyrene culture dish was coated for 1 hour at room temperature with a wash buffer (50 mM tris- (hydroxymethyl) amino ethane buffer (Tris), 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 ("Ros ell 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 it is mounted on an inverted phase contrast microscope (sold by Olympus, Hamburg, Germany) equipped with a CCD camera (JVC) that is connected to a CP. Using a peristatic pump (sold by Ismatec, ertheim-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. 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 from independent experiments. 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 formulas (Ib) or (le) or (le) or (If) and a pharmaceutically acceptable carrier which is used in a drug. where the symbols and substituents have the following meanings -X- = a) with m = 0, 1; n = an integer from 1 to (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. -? = with s being 0 or 1, R2 being C02H, C02Alkyl, C02Aryl, C02NH2, C02Aralkyl, S03H, S02NH2, P0 (OH) 2, 1-H-tetrazolyl-, CHO, COCH3, CH2OH, NH2, NHAalkyl, N (Alkyl) Alkyl ', OCH3, 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, 0CH3, 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; with t being 0, 1, 2 (f) (g) -2 (i) R7 independently of R2 is H, NO2, 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 formulas (Ib) or (le) or (le) or (If). 2. Pharmaceutical compositions according to claim 1, characterized in that the compounds are defined by the formulas (Ilb) or (lie) or (lie) or (Ilf), wherein -Y and -X'- as X (a) and X (b) are in accordance with claim 1.

3. Pharmaceutical compositions according to claim 2, characterized in that the compounds are defined by the formulas (A2) or (A3) or (A5) or (A6) or (B2) or (B3) or (B5) or (B6). where -X'- and -Y- are in accordance with 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 formulas (C2) or (C3) or (C5) ) or (C6). C5 C6 wherein -X "- and -Y 'are in accordance with claim 3. Pharmaceutical compositions according to claim 1, characterized in that the compounds are defined by the formulas (D2) or (D3) or (D5) ) or (D6). wherein "X" is in accordance with claim 3 and -Y "is wherein R9 is C02H, C02alkyl, C02aryl, C02NH2, C02aralkyl, CH2S03H, CH2S0 NH2, CH2P0 (0H) 2, 1 -H-tetrazolyl, CHO, COCH3, CH2OH, CH2NH2, CH2NHalkyl, CH2N (alkyl) alkyl ', CH2OCH3, CH2SH, wherein all the indices, symbols and substituents are as defined in accordance with claim 1. 6. Chemical compounds, characterized in that they have the general structure of the formulas (C2) or (C3) or (C5) or (C6) or (D2) or (D3) or (D5) or (D6), according to claim 4 or

5. 7. Use of compounds having the structure of formulas (Ib), (le), ( le) or (If) as defined in accordance with claim 1, for the preparation of a drug 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 heart attacks, strokes, atherosclerosis, and organ transplants, traumatic shock, inadequacy of or multiple organs, autoimmune diseases such as multiple sclerosis, percutaneous transluminal angioplasty, asthma and inflammatory bowel disease. 8. Use of compounds having the structure of formulas (Ib) or (le) or (le) or (If) as defined in accordance with claim 1, for the preparation of a drug for the treatment, diagnosis or prophylaxis of inflammatory disorders. 9. Use of compounds having the structure of formulas (Ib) or (le) or (le) or (If) 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 formulas (Ib) or (le) or (le) or (If) as defined in accordance with claim 1, for the preparation of dermatological and cosmetic compositions. Cosmetic compositions, characterized in that they comprise at least one compound of the formulas (Ib) or (le) or (le) or (If) according to claim 1 and at least one cosmetically tolerable component. 12. Dermatological compositions, characterized in that they comprise at least one compound of formulas (Ib) or (le) or (le) or (If) according to claim 1 and at least one dermatologically tolerable component.