WO2014170706A1

WO2014170706A1 - Galloyl benzamide-based compounds as jnk modulators

Info

Publication number: WO2014170706A1
Application number: PCT/IB2013/000679
Authority: WO
Inventors: Saverio CELLAMARE; Angelo Carotti; Angela STEFANACHI; Francesco LEONETTI; Orazio NICOLOTTI; Marco CATTO; Leonardo PISANI; Piero TARDIA; Antonellina INTROCASO; Valentina LEO; Francesco Addabbo; Monica MONTAGNANI; Carmela NACCI
Original assignee: Università Degli Studi Di Bari
Priority date: 2013-04-15
Filing date: 2013-04-15
Publication date: 2014-10-23
Also published as: EP2986286A1

Abstract

The present invention relates to the use of compounds having a galloyl benzamide structure in the treatment and/or prevention of medical conditions mediated through c-Jun N-terminal kinases (JNKs) and to pharmaceutical compositions comprising said compounds.

Description

"Galloyl benzamide-based compounds as JNK modulators"

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Summary of the invention

Technical background

Mitogen-activated protein kinases (MAPK) family is a complex system of signalling components acting as major regulators of multiple physiological processes. Within MAPK families, Erk, p38 MAPKs, and the c-Jun N-terminal kinases (JNKs) have been extensively studied for their role in cell growth, differentiation, apoptosis, and survival.

JNKs, also termed stress-activated protein kinases (SAPKs), are activated in response to a variety of external stresses such as ultraviolet (UV) irradiation, hyperosmolarity or heat shock cytokines such as tumour necrosis factor-a (TNF-a), interleukin-1 (IL-1), IL-3 or colony-stimulating factors (CSF) or growth factors such as epidermal growth factor (EGF) or platelet-derived growth factor (PDGF). In addition, activation of G-protein coupled receptors and the noncanonical Wnt pathway can lead to JNK activation.

JNK activation requires a dual phosphorylation on threonine 183 and tyrosine 185 in the enzyme regulatory loop. MKK4 and MKK7 are among upstream MAPK kinases able to phosphorylate JNKs on these activating residues. As their name implies, JNKs are the predominant protein kinase family that phosphorylates c-Jun, a component of the activator protein- 1 (Ap-1) transcription factor complex. Phosphorylation on serine 63 and serine 73 within the transactivation domain potentiates c-Jun transcriptional activity through the loss of repression mediated by histone deacetylase 3, resulting in activation of the AP-1 complex and subsequent genomic response.

The importance of JNK in the control of cell proliferation and apoptosis makes JNK signalling an interesting target for conditions characterized by abnormal cell growth

l and survival. Moreover, because J Ks play a central role in the inflarnmatory signalling network, hyperactivation of JNK signalling is a very common finding in a number of disease states, including inflammatory, metabolic, cardiovascular and neurodegenerative syndromes. In fact, JNK activity has been implicated in the development of arthritis, obesity, diabetes, atherosclerosis, abdominal aortic aneurysm, cardiac diseases, liver diseases and tumorigenesis. The use of JNK gene knockout animals is continuing to reveal in vivo functions for these kinases, with tissue-specific roles now being dissected with tissue-specific knockouts. Consequently, JNK inhibitors have been discovered and characterized in the hope that therapeutic inhibition of JNK may provide clinical benefit in many diseases.

Some small molecules have been reported to act as ATP-competitive JNK inhibitors. However, many of them exhibit poor kinase selectivity and/or do not inhibit the phosphorylation of well-characterized substrates of JNK in cells.

Thus, the screening of novel kinase inhibitors, including not only optimization of in vitro potency and selectivity by biochemical assays, but also cell-based evaluation of biological effects, is needed.

Description of the invention

According to one of its aspects, the present invention relates to a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

^■ X is -CO- and Y is -NH- or X is -NH- and Y is -CO-;

^■ Ri R₂ and R₃ are, each independently, -H, -OH or O-alkyl;

^■ R4 is H, -O-alkyl, -halogen, -NH₂, -NH-alkyl, -N(alkyl)₂, -NH-acyl, -N0₂, - CN, -COOH, -COOAlkyl, -CONH₂, -CONH-alkyl or -CF₃,

^■ Ar is an aryl or a heteroaryl group selected from phenyl, benzo[l,3]dioxolyl, pyrrolyl, thienyl, furanyl, pyridinyl, pyridinyl and pyrimidin-5-yl; wherein the phenyl group is optionally substituted with one or two halogens, a nitro group, one or two alkoxy groups, an acetyl group, a cyano group and one or two alkyl groups;

for their use as inhibitors of c-Jun N-terminal kinases (JNKs).

According to preferred embodiments of the invention, Ar is selected from phenyl-3- or 4-yl, 3'-halophenyl-3- or 4-yl, 4'-halophenyl-3- or 4-yl, 3',4'-dihalophenyl-3- or 4-yl, 3',5'-dihalophenyl-3- or 4-yl, 3'-nitrophenyl-3- or 4-yl, 4'-nitrophenyl-3- or 4- yl, 3'-alkoxyphenyl-3- or 4-yl, 4'-alkoxyphenyl-3- or 4-yl, 3',4'-dialkoxyphenyl-3- or 4-yl, 3',5'-dialkoxyphenyl-3- or 4-yl, 3 '-acetylphenyl-3- or 4-yl, 4'-acetylphenyl- 3- or 4-yl, 3'-cyanophenyl-3- or 4-yl, 4'-cyanophenyl-3- or 4-yl; benzo[l,3]dioxol-4- yl; benzo[l,3]dioxol-5-yl; benzo[l,3]dioxol-4-yl; 5-benzo[l,3]dioxol-5-yl; pyrrol-1- yl, lH-pyrrol-2-yl, lH-pyrrol-3-yl, 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, thien-2-yl, thien- 3-yl, furan-2-yl, furan-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl andpyrimidin-5- yi-

According to another preferred embodiment of the invention, X is -CH- and Y is - NH-.

According to anotherpreferred embodiment of the invention, ¾ R₂ and R₃ are O- alkyl, wherein alkyl is methyl. Advantageously, all R_\ R₂ and R₃ are O-alkyl, especially O-methyl, or at least two of R_\ R₂ and R₃ are O-alkyl, especially O-methyl and the other is hydrogen.

According to anotherpreferred embodiment of the invention, Ar is phenyl, optionally substituted as defined above.

According to another preferred embodiment of the invention, Ar is selected from thien-2-yl, benzo[l,3]dioxol-5-yl and pyridin-3-yl.

According to another preferred embodiment of the invention, the compound of formula (I) is selected from N-(4-benzo[l,3]dioxol-5-yl-2-nitro-phenyl)-3,4,5- trimethoxybenzamide, N-(3-fluoro-biphenyl-4-yl)-3,4,5-trimethoxybenzamide, 3,4,5- trimethoxy-N-(3-nitro-biphenyl-4-yl)benzamide, N-(3-amino-biphenyl-4-yl)-3,4,5- trimethoxybenzamide, N-(3-acetylamino-biphenyl-4-yl)-3,4,5-trimemoxybenzamide, 3,5-dimethoxy-N-(3-nitro-biphenyl-4-yl)benzamide, 3,4-dimethoxy-N-(3-nitro- biphenyl-4-yl)benzamide, 3 ,4-dimethoxy-N-(3 -nitro-biphenyl-4-yl)benzamide, 3 ,4,5- trirnethoxy-N-(4-nitro-biphenyl-3-yl)-benzamide, 3,4,5-trimethoxy-N-(2-nitro-4- thiophen-2-ylphenyl)benzamide, 3 ,4,5-trimethoxy-N-(2-nitro-4-pyridin-3 - ylphenyl)benzamide, N-(3',5'-difluoro-3-nitro-biphenyl-4-yl)-3,4,5- trimethoxybenzamide N-(3'-acetyl-3-nitro-biphenyl-4-yl)-3,4,5- trimethoxybenzamide, 3,4,5-trimethoxy-N-(3'-nitro-biphenyl-4-yl)-benzamide and 3- nitro-biphenyl-4-carboxylic acid (3,4,5-trimethoxy-phenyl)amide.

For purposes of the present invention, as described and claimed herein, the following terms are defined as follows.

The terms "halo'Or "halogen", unless otherwise indicated, means fluoro, chloro or bromo.

The term "alkyl", as used herein, unless otherwise indicated includes saturated, partially unsaturated, or unsaturated hydrocarbon radicals having straight or branched moieties C1-C4. A preferred "alkyl" is methyl.

The term "alkoxy", as used herein, unless otherwise indicated includes O-alkyl groups wherein alkyl is as defined above.

The expression "pharmaceutically acceptable salt(s)", as used herein includes salts of acid or basic groups that may be present in the compounds of formula (I). The acids that may be used to prepare pharmaceutically acceptable acid addition salts are those that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, such as acetate, bicarbonate, bisulfate, bitartrate, hydrobromide, hydrochloride, citrate, phosphate salts.

Certain compounds of formula (I) may have asymmetric centres and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula (I), and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of formula (I), the invention includes the use of racemates, one or more enantiomeric forms, one or more diastereomeric forms, or mixture thereof. The compounds of formula (I) may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.

The compounds of formula (I) showed an interesting inhibitory activity on c-Jun N- terminal kinases (JNKs). As it is known, the central role of JNK in many physiological processes makes it an interesting target, thus providing multiple opportunities for the design of small molecule inhibitors that might modulate specific components of JNK signalling. As a consequence the compounds of formula (I) may be used in the treatment and/or prevention of several severe human disorders and pathologies, including inflammatory diseases, such as inflammatory bowel disease (IBD), psoriasis, rheumatoid arthritis; diabetes, obesity, atherosclerosis,abdominal aortic aneurysm, liver diseases, CNS disorders, such as Alzheimer's disease, neurodegeneration,cerebral ischemia, retinopathy and acute organ failure such as hepatic failure, pain and cancer.

Also, the compounds of formula (I) may be used to improve successful engraftments. Additionally, corticosteroids and JNK inhibitors both inhibit many common proinflammatory genes including TNF-R, IL-4, and IL-13, suggesting a common mechanism that may provide therapeutic opportunities that are complementary to existing treatments of respiratory diseases.

According to another of its aspects, the present invention relates to a combination of at least a compound of formula (I) or one of its salts and a corticosteroid, and to the use of such a combination in the treatment and/or prevention of respiratory diseases, such as asthma, chronic obstructive pulmonary disorder or acute respiratory distress syndrome.

According to another of its aspects, the present invention relates to a method for inhibiting c-Jun N-terminal kinases (JNKs), which comprises administering to a mammal in need thereof an effective amount of at least one compound of formula(I) or a pharmaceutically acceptable salt thereof.

According to another of its aspects, the present invention relates to a method for the treatment and/or prevention of the above mentioned disorders and pathologies, which comprises administering to a mammal in need thereof an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

Most of the compounds of formula (I) and their chemical synthesis were disclosed in J Med Chem. 2012, 55, 424-36. The other compounds may be synthesized in a similar way, according to the general processes given in the above publication. The present invention further relates to the pharmaceutical compositions in which the compound of formula (I) and its pharmaceutically acceptable salts are present as the active principle, especially in admixture with one or more pharmaceutical acceptable carrier.

For its use in therapeutics, the product of formula (I), either pure or in association with any other pharmaceutically compatible substance, can be used in appropriate pharmaceutical forms intended for oral, parenteral, sublingual, rectal, transdermal and topical administration.

For oral administration, it is possible for example to use tablets, coated tablets, granules or liquid compositions such as syrups, elixirs, emulsions or solutions.

It is possible to use aqueous or non-aqueous injectable sterile compositions for parenteral administration, suppositories for rectal administration and patches for transdermal administration; if appropriate, it is possible to prepare delayed-release forms or forms in which the active principle of formula (I) is included in liposomes or in cyclodextrins.

These pharmaceutical forms are prepared by the conventional methods, the active principle of formula (I) being mixed with the excipients and additives normally employed in the art of pharmaceutics, such as starch, lactose, talc, magnesium stearate, sucrose, paraffin oil, wetting products, flavorings, stabilizers, etc.

The pharmaceutical compositions according to the invention advantageously contain, as the active principle, from 0.01 to 20 mg of the compound of formula (I) or one of its pharmaceutically acceptable salts. Other dosage are anyway possible.

The appropriate dosage in the therapeutic use of these compositions has to be evaluated in each individual case by considering the characteristics of the subjects to be treated, namely the age, the body weight and the severity of the complaints to be treated. In general, the therapeutic use of the compound of formula (I) provides for the administration of a dosage between 0.01 and 60 mg/day (preferably between 20- 40 mg/day), optionally subdivided into doses to be administered several times a day, the preferred dose regimen being one to three times a day. The invention will now be described in reference to the following examples. These examples are not to be regarded as limiting the scope of the present invention, but shall only serve in an illustrative manner.

Experimental section

In Table 1, the structure, name and spectroscopic data of some representative compounds of formula (I) are given.

Table 1

3,4,5-Trimethoxy-N-(3-nitro-biphenyl-4- yl)benzamide. Crystallized from ethyl acetate. Yield: 57%. mp 198-200 °C. 1H NMR (DMSO- d₆) δ: 10.78 (s, 1H), 8.23 (d, J = 2.2 Hz, 1H), lc 8.08 (dd, J = 2.2, 8.5 Hz, 1H), 7.83 (d, J = 8.5

Hz, 1H), 7.77 (d, J = 7.4 Hz, 2H), 7.50 (t, J = 7.4 Hz, 2H), 7.43 (d, J = 7.4 Hz, 1H), 7.32 (s, 2H), 3.87 (s, 6H), 3.73 (s, 3H). LRMS (ESI) m/z 407 [M-H]^".

N-(3-Amino-biphenyl-4-yl)-3,4,5- trimethoxybenzamide. Crystallized from absolute ethanol. Yield: 79%. mp 190-192. °C. 1H NMR (DMSO-4 δ: 9.69 (s, 1H), 7.58 (d, J

Id = 7.4 Hz, 2H), 7.43 (t, J= 7.4 Hz, 2H), 7.26 (m,

3H), 7.21 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 1.7 Hz, 1H), 6.89 (dd, J = 1.7, 8.0 Hz, 1H), 5.01 (s, 2H), 3.85 (s, 6H), 3.71 (s, 3H). LRMS (ESI) m/z 377 [M-H]^".

N-(3-Acetylamino-biphenyl-4-yl)-3,4,5- trimethoxybenzamide.

Yield: 54%. mp 233-236 °C. 1H NMR (DMSO- d₆) δ: 9.91 (s, 1H), 9.85 (s, 1H), 7.80 (m, 2H), le

7.64 (d, J = 7.4 Hz, 2H), 7.52 (d, J = 10.5 Hz, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.37 (d, J = 7.4 Hz, 1H), 7.28 (s, 2H), 3.86 (s, 6H), 3.72 (s, 3H), 2.12 (s, 3H). LRMS (ESI) m/z 419 [M-H]^~.

3,5-Dimethq:sy-jV-(3-nitro-bipheiiyl-4- yl)benzamide.

If

A Crystallized from ethyl acetate. Yield: 30%. mp

215-218 °C. 1H NMR (DMSO-c ₆) δ: 10.71 (s,

BIOLOGICAL ACTIVITY METHODS

Reagents - Tumor necrosis factor-a (TNFa) was from R&D System Europe (Lille, France). Pharmacological inhibitor SP600125 was purchased Sigma- Aldrich (St. Louis, MO). Monoclonal antibody infliximab (Remicade) was from Janssen Biologies B.V. (Leiden, Holland).

Cell cultures - Human umbilical vein endothelial cells EA.hy926 and murine fibroblasts NIH-3T3 (ATCC, Rockville, MD) were grown in Dulbecco's modified Eagle's medium with 4 mM L-glutamine containing 10% FBS and 1% Pen/Strep (Euroclone, Milan, Italy). All cell lines were maintained in a humidified atmosphere at 37°C/5% C0₂. At confluence, cells were stimulated with TNFa (10 ng ml) for 10 minutes in the absence and in the presence of the SP600125 (20 μΜ) and 6d (Table 6) at various concentrations (50 μΜ, 20 μΜ, 1 μΜ).

Western Blot Analysis - Activation of JNK, p38 MAPK, and NF-κΒ pathways was assessed using prototypical proinflammatory cytokine TNFa as positive control. Phosphorylation at Thrl 83/Tyrl 85 of JNK as well as phosphorylation at Ser63/Ser73 of c-jun were assumed as indicators for JNK activation. Phosphorylation at Thr202/Tyr204 and at Thrl80/Tyrl82 were considered indicators of activation for p42/44 and p38 MAPK, respectively. Phosphorylation of p65 subunit at Ser536 as well as degradation of flcBcc were assumed as indicators for NF-kB activation. Cell lysates were prepared using 130 μΐ of lysis buffer (100 mM NaCl, ,40 mM Hepes, pH 7.5, 1% Triton X-100, lmM Na₃V0₄, 4 mM Na₄P₂O_v, 10 mM EDTA, 1 mM PMSF, 10 mM NaF, 2 μg/ml aprotinin and 2 μg/ml leupeptin). Equal amounts of protein (30 μg) were separated by 10% SDS-PAGE and subjected to immunoblotting with the following primary antibodies (dilution 1: 1000): ph-c-Jun (Ser 63) and ph-p65 (Ser 536) (Santa Cruz Biotecnology Inc., CA); JNK, ph-JNK, c-Jun, ph-c-Jun (Ser73), DcBa, ph-ERKl/2 (Thr 202/Tyr 204), p38 MAPK and ph-p38 MAPK (Thr 180/Tyr 182) (Cell Signaling Technology, MA). The β-actin antibody was from Sigma. Incubation with horseradish peroxidase-linked anti-mouse, anti-rabbit, and anti-goat secondary antibodies (Santa Cruz Biotecnology) (1: 3,000) was performed for 1 h at room temperature. Immunoblotting results were visualized by Molecular Imager ChemiDoc XRS System (Bio-Rad Laboratories). Images were captured with QuantityOne Software (Bio-Rad Laboratories) and blots quantified by scanning densitometry (Image J; National Institutes of Health, Bethesda, MD).

Ototoxicity Analysis - Evaluation of cell viability was performed with the tetrazolium compound 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay. The MTT is reduced by metabolically active cells to insoluble formazan dye crystals. The rate of tetrazolium reduction is proportional to the rate of cell proliferation.The data is analysed by plotting cell number versus absorbance, allowing quantitation of changes in cell proliferation. Human EA.hy926 cells and murine NIH-3T3 fibroblasts were seeded in 96-well culture plate and treated with lm at various concentration (50μΜ, 20μΜ, ΙμΜ) for lh. Cells were then incubated with MTT (200 μΐ from a 5mg/ml solution, Sigma-Aldrich, St. Louis, MO) for 3h al 37°C, supernatant removed, and optical density measured at 570 nm wavelength with spectrophotometer Microplate Reader (Biorad). ICs₀ was calculated by GraphPad Prism extrapolation from plotted data.

Statistical Analysis - Two way ANOVA for repeated measures followed by post- hoc Student's t test for paired or unpaired data were used as appropriate. Values of P < 0.05 were considered to indicate statistical significance. Results are expressed as mean ± SEM of at least 3 independent experiments for each condition, repeated as duplicates or triplicates.

Biological activity - In order to measure the cellular effects of lm on JNK signaling cascade, we first evaluated specificity, efficacy and potency of selective ATP- competitive JNK inhibitor SP600125 on NIH-3T3 cells. When compared to basal levels (Figure 1, line 1), phosphorylation of JNK, p42/44 MAPK, p38 MAPK, p65 and IkBa/NF-kB proteins, were significantly increased in NIH-3T3 fibroblasts treated acutely with TNFa (lOng/ml, 10 min) (Figure 1, line 2).

As expected, SP600125 pretreatment (1, 20, 50 μΜ, 1 h) dose-dependently inhibited TNFa-mediated phosphorylation of JNK, with a significant effect at 20 μΜ concentration (Figure 1, line 4). Conversely, phosphorylation of p42/44, p38 MAPK and NF-kB signaling pathways by TNFa were not significantly reduced by SP600125 pretreatment at any of the concentration used. Thus, in this cell line, SP600125 effectively and specifically inhibits JNK signaling activated in response to TNFa. Moreover, no significant effect on cell viability was observed after 1 h pretreatment with lm.

Next, we evaluated the kinase inhibitory ability of lm by comparing its effects with those elicited by 20 μΜ SP600125. lm pretreatment (1, 20, 50 μΜ, 1 h) did not significantly affect TNFa-mediated phosphorylation of p38 MAPK and NF-kB signaling pathways at any concentration used. As far as JNK signaling, a slight inhibition of JNK phosphorylation was observed in NIH-3T3 pretreated with the highest dose of lm used (50 μΜ) (Figure 1, line 4). Nevertheless, a significant inhibition of was observed for phosphorylated c-jun at both Ser65 and Ser75 in lysates of cells pre-treated with lm 20 and 50 μΜ (Figure 2, lines 4-5). Thus, lm seems able to efficiently inhibit JNK activity on the specific JNK substrate c-jun. Representative blot shows in Figure 3 show protein levels of phosphorylated JNK, c-Jun and p38 MAPK in NIH-3T3 treated for 10 min with 10 ng/ml TNFa alone and in NIH-3T3 pre-treated with 20 μΜ SP600125 or 50 μΜ lm. Bar graphs indicate the mean ± SEM of densitometric analysis for phosphorylated proteins normalized to β- actin expression * p < 0.05, ** p < 0.01 vs. indicated group.

We then assessed whether the observed inhibitory activity of lm on TNFoc- dependent JNK activity and its signaling specificity were conserved among cell types. For this aim, experiments were carried out on human endothelial cells EA.hy926. Effects of lm pretreatment on JNK signaling were compared to those obtained in cells pre-treated with JNK inhibitors SP600125. Inhibitory effects on all signaling pathways explored were compared to those obtained in cells pretreated with TNFa monoclonal antibody infliximab.

As expected, TNFa significantly activated JNK, p38 MAPK and NF-kB signaling in endothelial cells (Figure 4, line 2). Infliximab was able to completely inhibit TNFa- dependent activation of JNK, p38 MAPK and NF-kB signaling pathways (Figure 4, line 4). SP600125 significantly inhibited JNK phosphorylation and activation (Figure 4, line 3). However, a significant inhibitory effect was also noted for SP600125 on TNFa-dependent activation of p38 MAPK, whereas no inhibitory effect was detected on NF-kB signaling pathways (Figure 4, line 3). lm was able to reduce phosphorylated levels of JNK and c-Jun (Figure 4, line 5); as for SP 600125, however, this effect was not pathway specific, since reduced phosphorylation was also detectable on p38 MAPK. In addition, in contrast to SP600125, a significant inhibition of TNFa-mediated degradation of NF-kB signaling components was noted in cells pre-treated with lm (Figure 4, line 5).

Ototoxicity - At all doses tested, lm did not significantly alter cell viability and proliferation in NIH 3T3 murine fibroblasts (IC50= 7119 μΜ). Moreover, no significant citotoxic effect was detected in human EAhy endothelial cells (IC50= 855.1 μΜ).

Claims

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

■ X is -CO- and Y is -NH- or X is -NH- and Y is -CO-;

^■ Ri R₂ and R₃ are, each independently, -H, -OH or O-alkyl;

^■ Ar is an aryl or a heteroaryl group selected from phenyl, benzo[l,3]dioxolyl, pyrrolyl, thienyl, furanyl, pyridinyl, and pyrimidin-5-yl; wherein the phenyl group is optionally substituted with one or two halogens, a nitro group, one or two alkoxy groups, an acetyl group, a cyano group and one or two alkyl groups;

for its use as inhibitor of c-Jun N-terminal kinases (JNKs).

The compound for its use according to claim 1, for its use in the treatment and/or prevention of inflammatory diseases, such as inflammatory bowel disease (IBD), psoriasis, rheumatoid arthritis; diabetes, obesity, atherosclerosis,abdominal aortic aneurysm, liver diseases, CNS disorders, such as Alzheimer's disease, neurodegeneration, cerebral ischemia, retinopathy and acute organ failure such as hepatic failure, pain and cancer.

The compound for its use according to claim 1 or 2, wherein Ar is selected from phenyl-3- or 4-yl, 3'-halophenyl-3- or 4-yl, 4'-halophenyl-3- or 4-yl, 3',4'- dihalophenyl-3- or 4-yl, 3',5'-dihalophenyl-3- or 4-yl, 3'-nitrophenyl-3- or 4-yl, 4'-nitrophenyl-3- or 4-yl, 3'-alkoxyphenyl-3- or 4-yl, 4'-alkoxyphenyl-3- or 4- yl, 3',4'-dialkoxyphenyl-3- or 4-yl, 3',5'-dialkoxyphenyl-3- or 4-yl, 3'- acetylphenyl-3- or 4-yl, 4'-acetylphenyl-3- or 4-yl, 3'-cyanophenyl-3- or 4-yl, 4'-cyanophenyl-3- or 4-yl; benzo[l,3]dioxol-4-yl; benzo[l,3]dioxol-5-yl; benzo[l ,3]dioxol-4-yl; 5-benzo[l,3]dioxol-5-yl; pyrrol-l-yl, lH-pyrrol-2-yl, 1H- pyrrol-3-yl, 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl.

3. The compound for its use according to anyone of claims 1 to 3, wherein X is - CH- and Y is -NH-.

4. The compound for its use according to anyone of claims 1 to 4, wherein all ¾ R₂ and R₃ are O-alkyl or at least two of Ri R₂ and R₃ are O-alkyl and the other one is hydrogen.

5. The compound for its use according to claim 5, whereinalkyl is methyl.

6. The compound for its use according to anyone of claims 1 to 6, wherein Ar is phenyl, optionally substituted as defined in claims 1 or 2.

7. The compound for its use according to anyone of claims 1 to 6, wherein Ar is selected from thien-2-yl, benzo[l,3]dioxol-5-yl and pyridin-3-yl.

8. The compound for its use according to claim 1 or two which selected from N-(4- berizo[l ,3]dioxol-5-yl-2-nitro-phenyl)-3,4,5-trimethoxybenzamide, N-(3-fiuoro- biphenyl-4-yl)-3 ,4,5-trimethoxybenzamide, 3 ,4,5-trimethoxy-N-(3 -nitro- biphenyl-4-yl)benzamide, N-(3 -amino-biphenyl-4-yl)-3 ,4,5- trimethoxybenzamide, 7V-(3-acetylamino-biphenyl-4-yl)-3,4,5- trimethoxybenzamide, 3 ,5-dimethoxy-N-(3 -nitro-biphenyl-4-yl)benzamide, 3 ,4- dimethoxy-N-(3 -nitro-biphenyl-4-yl)benzamide, 3 ,4-dimethoxy-N-(3 -nitro- biphenyl-4-yl)benzamide, 3,4,5-trimethoxy-N-(4-nitro-biphenyl-3-yl)- benzamide, 3 ,4,5-trimemoxy-N-(2-nitro-4-miophen-2-ylphenyl)benzamide, 3 ,4, 5-trimethoxy-N-(2 -mtro-4-pyridin-3 -ylphenyl)benzarmde N-(3 ', 5 '-difluoro-

3- mtro-biphenyl-4-yl)-3 ,4,5-trimethoxybenzamide N-(3 '-acetyl-3 -nitro-biphenyl-

4- yl)-3 ,4,5-trimethoxybenzamide 3 ,4,5-trimethoxy-N-(3 '-nitro-biphenyl-4-yl)- benzamide and 3-nitro-biphenyl-4-carboxylic acid (3,4,5-trimethoxy- phenyl)amide.

9. A pharmaceutical composition which comprises, as the active ingredient, at least a compound of formula (I) or a pharmaceutical acceptable salt thereof, as defined in any one of claims 1 to 9, in admixture with one or more pharmaceutical acceptable carrier.

10. A combination of at least a compound of formula (I) or one of its salts as defined in any one of claims 1 to 9, and a corticosteroid.

11. The combination of claim 11 for its use of such a combination in the treatment and/or prevention of respiratory diseases.