INHIBITORS OF THE INTERACTION OF THE UPAR/FPRS RECEPTORS

Abstract

The compound

##STR00001##

wherein R1 is selected from amongst: H, Me, OH; R2 is selected from amongst: H, OH, Me, t-Bu, Et, OMe, Pr, Allyl; R3 is selected from amongst: H, OH, Me, Cl, F; R4 is selected from amongst: H, Me, Ome, t-Bu, Cl; R5 is selected from amongst: H, OH, Me, OMe; R6 is selected from amongst: H, Me, OH, OMe; R7 is selected from the group consisting of: H, Me, OMe, t-Bu, Cl; R8 is selected from the group consisting of: OH, Me, H, F; R9 is selected from the group consisting of; OH, Me, H, t-Bu, Et, OMe, Pr, Allyl; R10 is selected from the group consisting of: H, Me, OH; and X is either absent or is selected from the group consisting of:

##STR00002##

, CO, CH.sub.2,

##STR00003##

, for use in a method for treating pathologies mediated by the interaction of the uPAR/FPRs receptors.

Claims

1. A method for treating diseases mediated by the interaction of uPAR/FPRs receptors, comprising administering a therapeautically effective dose of the compound of formula (1) ##STR00010## to a patient in need thereof, wherein R1 is selected from the group consisting of: H, Me, OH; R2 is selected from the group consisting of: H, OH, Me, t-Bu, Et, OMe, Pr, Allyl; R3 is selected from the group consisting of: H, OH, Me, Cl, F; R4 is selected from the group consisting of: H, Me, OMe, t-Bu, Cl; R5 is selected from the group consisting of: H, OH, Me, OMe; R6 is selected from the group consisting of: H, Me, OH, OMe; R7 is selected from the group consisting of: H, Me, OMe, t-Bu, Cl; R8 is selected from the group consisting of: OH, Me, H, F; R9 is selected from the group consisting of: OH, Me, H, t-Bu, Et, OMe, Pr, Allyl; R10 is selected from the group consisting of: H, Me, OH; and X is either absent or selected from the group consisting of: ##STR00011## CO, CH2, and ##STR00012## .

2. The method of claim 1, wherein the disease being treated is systemic sclerosis.

3. The method of claim 1, wherein the disease being treated is morphea.

4. The method of claim 1, wherein the disease being treated is eosinophilic fasciitis.

5. The method of claim 1, wherein the disease being treated is idiopathic pulmonary fibrosis.

6. The method of claim 1, wherein the disease being treated is Glomerulonephritis.

7. The method of claim 1, wherein the disease being treated is Sarcoidosis.

8. The method of claim 1, wherein the disease being treated is relapsing polychondritis.

9. The method of claim 1, wherein the disease being treated is rheumatoid arthritis.

10. The method of claim 1, wherein the disease being treated is systemic Lupus erythematosus.

11. The method of claim 1, wherein the disease being treated is Sjogren’s syndrome.

12. The method of claim 1, wherein the disease being treated is Crohn’s disease.

13. The method of claim 1, wherein the disease being treated is ulcerative rectocolitis.

14. The method of claim 1, wherein the disease treated is being treated is atrophic antral gastritis.

15. The method of claim 1, wherein the disease being treated is primary biliary cirrhosis.

16. The method of claim 1, wherein the disease being treated is polymyositis.

17. The method of claim 1, wherein the disease being treated is Dermatomyositis.

18. The method of claim 1, wherin the disease being treated is Psoriasis.

19. The method of claim 1, wherein the disease being treated is psoriatic arthritis.

20. The method of claim 1, wherein the disease being treated is Pemphigus.

21. The method of claim 1, wherein the disease being treated is cutaneous and systemic vasculitis.

22. The method of claim 1, wherein the disease being treated is Uveitis.

23. The method of claim 1, wherein the disease being treated is Behcet’s disease.

24. The method of claim 1, wherein the disease being treated is amyloidosis.

25. The method of claim 1, wherein: X = 0; R1 = H; R2 = Pr; R3 = OH; R4 = 4; R5 = H; R6 =H; R7 = H; R8 = OH; R9 = Pr: R10 = H.

26. The method of claim 1, wherein: X = CH2; R1 = OH; R2 = t-Bu; R3 = H; R4 = Me; R5 = H; R6 = OH; R7 = t-Bu; R8 = H; R9 = Me; R10 = H.

27. The method of claim 1, wherein: X= CH2; R1 = H; R2 = t-Bu; R3 = H; R4 = C1; R5 = OH; R6 = OH; R7 = Cl; R8 = H; R9 = t-Bu; R10 = H.

28. Pharmaceutical composition comprising at least one compound selected from the group consisting of: 6,6′- (propan-2,2-diyl)bis (3-methylphenol); 3,3′-diethyl-5,5′-dimethyl[1,1′-biphenyl]-4,4′-diol; 4,4′-(propane-2,2-diyl)bis(2-methylphenol); 3,3′,5,5′-tetramethoxy[1,1′-biphenyl]-4,4′-diol; [1,1′-biphenyl]-3,3′,4,4′-tetrol; [1,1′-biphenyl]-3,3′,4,4′,5,5′-hexol; 3,3′-dipropyl[1,1′-biphenyl]-4,4′-diol; 6,6′-methylenebis(2-(tert-butyl)-4-methylphenol); 6,6′-methylenebis(2-(tert-butyl)-4-ethylphenol); 2,2″,4,4″-tetramethyl-[1,1′:4′,1″-terphenyl]-2′,5′-diol; 6,6′-methylenebis(4-(tert-butyl)-2-chlorophenol); 3,3′-diallyl[1,1′-biphenyl]-4,4′-diol; 4,4′-methylenebis(2-(tert-butyl)-6-methylphenol); 2′,4,4′,6′-tetramethyl[1,1′-biphenyl]-2,5-diol, and combinations and pharmaceutically acceptable excipients thereof.

29. The pharmaceutical composition according to claim 28,comprising at least one compound selected from the group consisting of: 3,3′-dipropyl[1,1′-biphenyl]-4,4′-diol; 6,6′-methylenebis(2-(tert-butyl)-4-methylphenol); 6,6′-methylenebis(4-(tert-butyl)-2-chlorophenol), or combinations and pharmaceutically acceptable excipients thereof.

30. The pharmaceutical composition according to claim 28 in the form of acceptable solutions, suspensions, powders, granules, tablets, pills, capsules, syrups, suppositories, sprays, aerosols or controlled-release systems, cream, ointment or gel, lubricants, pastes, syrups, vials, drops, eye drops, aerosols.

31. (canceled)

32. A method for treatment of diseases mediated by the interaction of uPAR/FPRs receptors, comprising administering a therapeutically effective dose of the pharmaceutical composition of claim 28 to a patient in need thereof.

33. A method for treatment of diseases selected from: Systemic sclerosis, morphea, eosinophilic fasciitis, idiopathic pulmonary fibrosis, glomerulonephritis, sarcoidosis, recurrent polychondritis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, Crohn’s disease, rectoculitis ulcer, atrophic antral gastritis, primary biliary cirrhosis, polymyositis, dermatomyositis, psoriasis, psoriatic arthritis, pemphigus, cutaneous and systemic vasculitis, uveitis, Behcet’s disease, and amyloidosis, the method comprising administering a therapeutically effective dose of the pharmaceutical composition of claim 28 to a patient in need thereof.

34. The method of claim 33, wherein the pharmaceutical composition is administered orally, transdermally, subcutaneously, intravenously, intramuscularly, rectally, or intranasally.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The invention will be described in detail hereinbelow also with reference to the enclosed figures, in which:

[0019] FIG. 1 shows the general formula that is shared by the 27 selected compounds according to the present invention, for use in the treatment of pathologies tied to uPAR/FPRs interaction.

[0020] FIG. 2 shows the results detected for evaluating the inhibitory activity of the 27 selected compounds on the bond of purified uPAR to the VN in ELISA assays (FIG. 2(A)) and in cell adhesion assays to the VN on BJ cells (FIG. (2B). Specifically, FIG. 2(A) shows the percentage of bond to the VN of uPAR, biotinylated in the presence of the compounds at the concentration of 50 .Math.M (black column) or of only the vehicle DMSO (white column), as control. The quantity of uPAR which is bonded to VN in the absence of compounds has been established at 100%. The values represent the mean (± S.D.) of three experiments executed in triplicate (.sup.∗p<0.05). FIG. 2(B) instead shows the percentage of adhesion to the VN of BJ cells treated with the compounds at the concentration of 50 .Math.M (black column) or with only the vehicle DMSO (white column). The data represents the mean (±DS) of three independent experiments, each executed in triplicate. The asterisks indicate the statistical significance of the cell adhesion to the VN in the presence of the compounds with respect to the adhesion in the presence of only DMSO, considered equal to 100%, determined by the test t of Student (.sup.∗p<0.05).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] In order to identify possible compounds that are structurally and functionally adapted for the inhibition of specific activities mediated by the interaction of the uPAR/FPRs receptors, a silico screening was carried out (similarity searching based on 2D fingerprint and scaffold analysis) in the National Cancer Institute (NCI) Open Database, freely accessible and containing the three-dimensional coordinates of over a quarter million small bio-active drug-like molecules. All this for identifying new analogous structures of the lead compound, 4,4′-dimethyl[1,1′-biphenyl]-2,2′,5,5′-tetraol, object of a previous study performed by the same research team involved in the definition of the present invention, but provided with an improved inhibitory activity and capable of interfering with the protein-protein interactions of the uPAR-VN or uPAR-FPRs complexes.

[0022] It is therefore of interest to specify that the similarity searching in general aims to detect small molecules with similar biological activity, and provides important insight on the structure-activity relations (SAR), thus becoming essential for conducting structural optimization studies .sup.(7).

[0023] Since it is essential to estimate the requirements of the drug-likeness in the initial drug design step (8), the pre-processing of the NCI Open Database was conducted by using the FILTER which reduced the initial database to a subgroup of 164,085 compounds based on the chemical-physical properties and on the functional groups. Then, the subset of drug-like compounds obtained was subjected to a similarity searching based on 2D-fingerprint with the Canvas software (Schrodinger software), using the structure of the lead compound, 4,4′-dimethyl[1,1′-biphenyl]-2,2′,5,5′-tetraol as query. In the successive passage, a scaffold analysis allowed selecting only the compounds which had the same molecular scaffold of said compound. In addition, with the objective of expanding the number of chemotypes considered, structurally correlated scaffolds were also included, which maintained the key pharmacophore of 4,4′-dimethyl[1,1′-biphenyl]-2,2′,5,5′-tetraol.

[0024] The computational strategy employed in the course of defining the object of the invention led to the identification of 27 small molecules (Table 1), which were evaluated for their capacity to inhibit: the bond of uPAR to VN, the cell adhesion mediated by uPAR to VN and the cell migration mediated by uPAR.

TABLE-US-00001 List of the substituents for the 27 selected compounds and relative access codes to the NCI Open Database Cp d NCI X R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 R.sub.6 R.sub.7 R.sub.8 R.sub.9 R.sub.10 1 1267 0 H H H H H H H OH OH H 2 4187 0 H Me OH H H H H OH Me H 3 9773 [00004] H H Me H OH OH H Me H H 4 11167 CO H H Cl H H H Me OH H H 5 11186 CH.sub.2 H Me OH H H H H H H H 6 29020 [00005] Me Me Me H Me Me H OH Me Me 7 36395 CH.sub.2 H H H H OH H H OH H H 8 37068 0 OH H H H H H H H H OH 9 60666 0 H t-Bu OH Me H H Me OH t-Bu H 10 12839 9 0 H Me OH Me H H Me OH Me H 11 13541 4 0 H Et OH Me H H Me OH Et H 12 40798 8 0 H H H H H OH H H OH H 13 40848 9 [00006] H Me OH H H H Me OH H H 14 65069 0 OH H OH H OH H OH H OH H 15 66167 0 H H OH H OH OH H OH H H 16 83599 0 H OMe OH OMe H H OMe OH OMe H 17 13336 9 0 H OH OH H H H H OH OH H 18 14354 1 0 H OH OH OH H H OH OH OH H 19 2817 0 H Pr OH H H H H OH Pr H 20 7781 CH.sub.2 OH t-Bu H Me H OH t-Bu H Me H 21 7782 CH.sub.2 H Et H t-Bu OH OH t-Bu H Et H 22 29013 [00007] H H Me H Me Me H Me H H 23 35255 CH.sub.2 H t-Bu H Cl OH OH Cl H t-Bu H 24 57617 0 H Allyl O H H H H H OH Allyl H 25 67513 CH.sub.2 H t-Bu O H Me H H t-Bu OH Me H 26 21251 1 0 Me H Me H Me OH H Me OH H 27 10369 0 H H F H OMe OMe H F H H

TABLE-US-00002 Nomenclature of the 27 selected compounds Cpd Chemical name 1 [1,1′-biphenyl] -3,4-diol 2 3,3′-dimethyl[1,1′-biphenyl]-4,4′-diol 3 6,6′-(propan-2,2-diyl)bis(3-methylphenol) 4 (4-chlorophenyl)(4-hydroxy-3-methylphenyl)methanone 5 4-benzyl-2-methylphenol 6 2,2″,3,3″,4″,6,6″-heptamethyl-[1,1′:4′,1″-terphenyl]-2′,4,5′-triol 7 o-(p-hydroxybenzyl)phenol 8 [1,1′-biphenyl]-2,2′-diol 9 3,3′-ditert-butyl-5,5′-dimethyl[1,1′-biphenyl]-4,4′-diol 10 3,3′,5,5′-tetramethyl[1,1′-biphenyl]-4,4′-diol 11 3,3′-diethyl-5,5′-dimethyl[1,1′-biphenyl]-4,4′-diol 12 [1,1′-biphenyl]-2,5-diol 13 4,4′-(propan-2,2-diyl)bis(2-methylphenol) 14 [1,1′-biphenyl]-2,3′,4,5′,6-pentol 15 [1,1′-biphenyl]-2,2’,4,4′-tetrol 16 3,3′,5,5′-tetramethoxy[1,1′-biphenyl]-4,4′-diol 17 [1,1′-biphenyl]-3,3′,4,4′-tetrol 18 [1,1′-biphenyl]-3,3′,4,4′,5,5′-hexol 19 3,3′-dipropyl[1,1′-biphenyl]-4,4′-diol 20 6,6′-methylenebis(2-(tert-butyl)-4-methylphenol) 21 6,6′-methylenebis(2-(tert-butyl)-4-ethylphenol) 22 2,2″,4,4″-tetramethyl-[1,1′:4′,1″-terphenyl]-2′,5′-diol 23 6,6′-methylenebis(4-(tert-butyl)-2-chlorophenol) 24 3,3′-diallyl[1,1′-biphenyl]-4,4′-diol 25 4,4′-methylenebis(2-(tert-butyl)-6-methylphenol) 26 2′,4,4′,6′-tetramethyl[1,1′-biphenyl]-2,5-diol 27 4,4-difluoro-2,2′-dimethoxy-1,1′-biphenyl

[0025] According to the present invention, a compound of general formula was therefore identified like that indicated in FIG. 1, i.e. compound of formula 1, in which different possible substituents present therein, suitably identified, confer to said compound the aforesaid searched inhibitory activity.

[0026] Specifically the possible substituents are such that for R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10, these are selected in the group consisting of: H, Me, OH, t-Bu, Et, OMe, Pr, Allyl, Cl, F.

[0027] Preferably possible substituents for R1 are selected in the group consisting of: H, Me, OH; for R2 are selected in the group consisting of: H, OH, Me, t-Bu, Et, OMe, Pr, Allyl; for R3 are selected in the group consisting of: H, OH, Me, Cl, F; for R4 are selected in the group consisting of: H, Me, OMe, t-Bu, Cl; for R5 are selected in the group consisting of: H, OH, Me, OMe, for R6 are selected in the group consisting of: H, Me, OH, OMe; for R7 are selected in the group consisting of: H, Me, OMe, t-Bu, Cl, for R8 are selected in the group consisting of: OH, Me, H, F; per R9 are selected in the group consisting of; OH, Me, H, t-Bu, Et, OMe, Pr, Allyl; for R10 are selected in the group consisting of: H, Me, OH; and in X said substituent is: either absent or is selected from the group consisting of:

##STR00008##

, CO, CH.sub.2,

##STR00009##

[0028] Still more preferably, the following combination and selection of the substituents have led to the definition of 27 selected compounds corresponding to the 27 compounds listed in table 1. Specifically the preferred compounds are those having formula 1 and in which specific substituents are assigned via R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, while for X a substituent can be selected from among those listed above or said substituent may be absent (indication corresponding to X = 0 in table 1).

[0029] With reference to FIG. 2 and to tables 1 and 2, the compounds identified as more suitable in the treatment of the pathologies that follow events mediated by the uPAR/FPRs interaction, are the following: the compounds 3, 11, 13, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 indicated in the tables 1 and 2, i.e. the compounds: [0030] 6,6′-(propan-2,2-diyl)bis(3-methylphenol); [0031] 3,3′-diethyl-5,5′-dimethyl[1,1′-biphenyl]-4,4′-diol; [0032] 4,4′-(propan-2,2-diyl)bis(2-methylphenol); [0033] 3,3′,5,5′-tetramethoxy[1,1′-biphenyl]-4,4′-diol; [0034] [1,1′-biphenyl]-3,3′,4,4′-tetrol; [0035] [1,1′-biphenyl]-3,3′4,4′,5,5′-hexol; [0036] 3,3′-dipropyl[1,1′-biphenyl]-4,4′-diol; [0037] 6,6′-methylenebis(2-(tert-butyl)-4-methylphenol); [0038] 6,6′-methylenebis(2-(tert-butyl)-4-ethylphenol); [0039] 2,2″,4,4″-tetramethyl-[1,1′:4′,1″-terphenyl]-2′,5′-diol; [0040] 6,6′-methylenebis(4-(tert-butyl)-2-chlorophenol); [0041] 3,3′-diallyl[1,1′-biphenyl]-4,4′-diol; [0042] 4,4′-methylenebis(2-(tert-butyl)-6-methylphenol); [0043] 2′,4,4′,6′-tetramethyl[1,1′-biphenyl]-2,5-diol.

[0044] It is of interest to specify that most of said selected compounds are commercially available or in any case can be synthesized with procedures and methods that are known to the man skilled in the art.

[0045] Still with reference to FIG. 2, the conducted experiments have indicated that, among said compounds, those which showed greater inhibitory activity against the interaction of the uPAR with the VN in vitro and against its cell adhesion to the VN, are the compounds 3, 19, 20, 23 indicated in said tables 1 and 2. In particular those most promising are the compounds 19, 20 and 23, for which a considerable contribution was encountered to the aforesaid inhibition of the cell adhesion.

[0046] Said compounds are specifically 3,3′-dipropyl[1,1′-biphenyl]-4,4′-diol; 6,6′-methylenebis(2-(tert-butyl)-4-methylphenol); 6,6′-methylenebis(4-(tert-butyl)-2-chlorophenol).

[0047] Still more specifically the structure of said compounds corresponds to that of the compound of formula 1 [0048] in which: X = 0; R1 = H; R2 = Pr; R3 = OH; R4 = 4; R5 = H; R6 =H; R7 = H; R8 = OH; R9 = Pr: R10 = H; or [0049] X = CH.sub.2; R1 = OH R2 = t-Bu R3 = H; R4 = Me; R5 = H; R6 = OH; R7 = t-Bu; R8 = H R9 = Me; R10 = H; or [0050] X = CH.sub.2; R1 = H; R2 = t-Bu; R3 = H; R4 = Cl; R5 = OH; R6 = OH; R7 = Cl; R8 =H; R9 = t-Bu; R10 = H.

Materials and Methods

Computational Chemistry

Preparation of the Ligand Database

[0051] The NCI Open Database, containing 265, 242 ligands, was processed with the Filter software (release 3.1.1.2, OpenEye Scientific Software Inc., Santa Fe, USA, http://www.eyesopen.com/) in order to remove molecules with undesired chemical-physical properties such as poor oral bioavailability, non-standard chemical elements, excessively reactive functional groups. The resulting database consisted of 164,085 structures with drug-like characteristics.

[0052] Similarity searching based on 2D fingerprint and scaffold analysis

[0053] The fingerprint MACCS.sup.(9), implemented in the Canvas software (Schrödinger Release 2019-3: Canvas, Schrödinger, LLC, New York, NY, 2019.) was employed for coding the structural characteristics of the compounds contained in the database. The fingerprint MACCS consists of a dictionary of predefined structural fragments. The Tanimoto coefficient (Tc), which is widely used in the scope of similarity searching.sup.(10), was selected for quantifying the similarity between the lead compound, 4,4′-dimethyl[1,1′-biphenyl]-2,2′,5,5′-tetraol, and the compounds present in the database, assigning a score comprised between 0 (if the compounds do not have fragments in common) and 1 (if the compounds have identical fragments). Subsequently, the compounds of the database were ordered in decreasing order with reference to the score and the first 1640 compounds (which represent 1% of the entire database) were selected for further research. Indeed, it was reported in preceding studies that the pre-selection of a subset of structures of such order of magnitude (~ 1%) from a database allows on average recovering 25% of the scaffolds and hence obtaining a greater number of structurally different hits.sup.(11). Subsequently, the hits were analyzed by means of the scaffold decomposition module implemented in Canvas. 100 compounds were collected that contain the biphenyl scaffold of the lead compound 4,4′-dimethyl[1,1′-biphenyl]-2,2′,5,5′-tetraol, also including several congeners which contained this structural motif. Finally, based on the chemical intuition and on the availability of the compounds, we selected and ordered 27 molecules for the biological tests.

Preparation of the Protein

[0054] The coordinates of the crystalline structure of the ternary complex between the receptor uPAR, the N-terminal (ATF) fragment of urokinase (uPA) and the somatomedin B (SMB) domain of vitronectin were downloaded from the Protein Data Bank (PDB code: 3BT1).sup.(12). The unresolved segment comprised between the residues 82-85 was constructed by means of the graphical interface of the MODELLER software in Chimera 1.6.1.sup.(13). The structure of the protein was then prepared by means of the module “Protein Preparation” of the graphical interface of Maestro. The hydrogen atoms were added to the protein, considering the physiological pH (7.0). The obtained structure was then energetically minimized by means of 2500 iterations by using the method of the Polak-Ribiere conjugate gradient and the force field OPLS3, implemented in Macromodel, in order to eliminate possible inconsistencies in the bond geometries.

[0055] The compounds, identified by means of the similarity searching and the subsequent biological assays, were constructed with the Molecular Builder module in Maestro and prepared for docking by means of the LigPrep software (LigPrep, Schrödinger, LLC, New York, NY, 2019). The resulting structures were optimized with Macromodel (Schrödinger, LLC, New York, NY, 2019), by using the force field MMFF with the steepest descent method (1000 steps) followed by 500 steps with the conjugate gradient method of truncated-Newton type. The partial atomic loads were assigned with the force field OPLS-AA.

Molecular Docking

[0056] The docking simulations of the compounds identified via similarity in the bond site of the VN on uPAR were carried out with the genetic algorithm implemented in GOLD 5.5 (CCDC Software Limited, Cambridge, UK, 2008).sup.(14). For the docking simulations, a grid was calculated, centered on the residues involved in the bond with the VN within a range of 10 Å, employing the default parameters of the program. The chemotactic sequence SRSRY (comprised between the residues 88-92), situated on the mobile loop that connects the domains DI and DII of uPAR, was considered flexible. The mobility of such residues was set by means of a specific option in GOLD, which implements the Lovell library of rotamers.sup.(15). The poses obtained were classified based on the scoring functions ChemPLP and ChemScore.sup.(16). The ligand-final receptor complex for each compound was selected by selecting the pose with the best score, consistent with the experimentally-derived information.

[0057] Based on the obtained results, pharmaceutical compositions and their possible formulations were designed and prepared, comprising the compounds selected for use in the treatment of pathologies related to the uPAR/FPRs interaction, as a non-limiting example for use in the treatment of pathologies such as: Systemic sclerosis, Morphea, Eosinophilic fasciitis, Idiopathic pulmonary fibrosis, Glomerulonephritis, Sarcoidosis, Relapsing polychondritis, Rheumatoid arthritis, Systemic Lupus erythematosus, Sjogren’s syndrome, Crohn’s disease, ulcerative rectocolitis, Atrophic antral gastritis, Primary biliary cirrhosis, Polymyositis, Dermatomyositis, Psoriasis, Psoriatic arthritis, Pemphigus, Cutaneous and systemic vasculitis, Uveitis, Behcet’s disease, Amyloidosis, and especially for use in the treatment of systemic sclerosis.

[0058] Object of the present description, in accordance with that indicated in the enclosed claims, is also a pharmaceutical composition comprising at least one of the following compounds selected from among: [0059] 6,6′-(propan-2,2-diyl)bis(3-methylphenol); [0060] 3,3′-diethyl-5,5′-dimethyl[1,1′-biphenyl]-4,4′-diol; [0061] 4,4′-(propan-2,2-diyl)bis(2-methylphenol); [0062] 3,3′,5,5′-tetramethoxy[1,1′-biphenyl]-4,4′-diol; [0063] [1,1′-biphenyl]-3,3′,4,4′-tetrol; [0064] [1,1′-biphenyl]-3,3′,4,4′,5,5′-hexol; [0065] 3,3′-dipropyl[1,1′-biphenyl]-4,4′-diol; [0066] 6,6′-methylenebis(2-(tert-butyl)-4-methylphenol); [0067] 6,6′-methylenebis(2-(tert-butyl)-4-ethylphenol); [0068] 2,2″,4,4″-tetramethyl-[1,1′:4′,1″-terphenyl]-2′,5′-diol; [0069] 6,6′-methylenebis(4-(tert-butyl)-2-chlorophenol); [0070] 3,3′-diallyl[1,1′-biphenyl]-4,4′-diol; [0071] 4,4′-methylenebis(2-(tert-butyl)-6-methylphenol); [0072] 2′,4,4′,6′-tetramethyl[1,1′-biphenyl]-2,5-diol; [0073] or combinations thereof, and its use in medicine and in particular in the treatment of said pathologies, as a non-limiting example: Systemic sclerosis, Morphea, Eosinophilic fasciitis, Idiopathic pulmonary fibrosis, Glomerulonephritis, Sarcoidosis, Relapsing polychondritis, Rheumatoid arthritis, Systemic Lupus erythematosus, Sjogren’s syndrome, Crohn’s disease, ulcerative rectocolitis, Atrophic antral gastritis, Primary biliary cirrhosis, Polymyositis, Dermatomyositis, Psoriasis, Psoriatic arthritis, Pemphigus, Cutaneous and systemic vasculitis, Uveitis, Behcet’s disease, Amyloidosis and, typically, but not limited thereto, in the treatment of systemic sclerosis. Preferably said composition comprises a selection of the following: 3,3′-dipropyl[1,1′-biphenyl]-4,4′-diol; 6,6′-methylenebis(2-(tert-butyl)-4-methylphenol); 6,6′-methylenebis(4-(tert-butyl)-2-chlorophenol), or combinations thereof, and pharmaceutically acceptable excipients, as a non-limiting example solvents such as alcohols or organic solvents, possibly in combination, light liquid paraffin dispersed in an aqueous medium by means of surfactants, mineral oil, wax. Said composition can be formulated as: solutions, suspensions, powders, granules, tablets, pills, capsules, syrups, suppositories, sprays, aerosols or controlled-release systems, cream, ointment or gel, lubricants, pastes, syrups, vials, drops, eye drops, aerosols that are acceptable for medical use. The compositions can be administered through different pathways, in particular orally, transdermally, subcutaneously, intravenously, intramuscularly, rectally and intranasally.

Chemical Inhibitors

[0074] The selected compounds were obtained from the Open Chemical Repository of the Developmental Therapeutics Program (DTP) at the National Cancer Institute (NCI) (http://dtp.cancer.gov). Subsequently, the lyophilized compounds were resuspended in dimethyl sulfoxide (DMSO) at a concentration of 0.01 mol/L and preserved at -20° C.

Cell Cultures

[0075] The cell line BJ (ATCC CRL2522) was used as model of human skin fibroblasts. The cells were cultivated in Dulbecco’s Modified Eagle Medium (DMEM) containing fetal bovine serum at 10% (FBS) at 37° C. with CO.sub.2 at 5%.

[0076] Biotinylation of uPAR

[0077] Soluble recombinant uPAR (suPAR; R&D System, Minneapolis, MN, USA) was biotinylated and purified with the biotinylation module of the proteins ECL Amersham according to the producer’s instructions (GE Healthcare, Buckinghamshire, UK).

Bond of Soluble uPAR to Immobilized VN

[0078] The (high-binding) plates with 96 wells (Corning, New York, USA) were covered with 0.5 .Math.g/well of VN (Becton Dickinson Biosciences, Franklin Lakes, NJ, USA) diluted in PBS (0.08 M NaCl, 0.002 M KCl, 0.0115 M Na.sub.2HPO.sub.4, 0.002 M KH.sub.2PO.sub.4, pH 7.2) or bovine serum albumin (BSA), as negative control, and incubated at 4° C. for the entire night. After a washing in PBS, the residual bond sites were blocked with 200 .Math.L of BSA at 1% in PBS, for 1 hour at ambient temperature. 25 nmol/L of biotinylated s-uPAR (diluted in PBS, 1 mg/mL of BSA), on its own or in the presence of selected compounds, were placed in the covered wells. The plates were maintained at 4° C. for 1 hour, washed with PBS containing 0.1% Tween 20 and then avidin marked with peroxidase (Amersham), diluted 1:1.500 in PBS containing 10 mg/mL of BSA. After further washings, the substrate of peroxidase o-phenylenediamine (Sigma, St. Louis, MO, USA) was added and left to react for 3 minutes. The reactions were stopped with 1 mol/L H.sub.2SO.sub.4 and the product was measured at 492 nm by using an automated plate reader (Bio-Rad, Munich, Germany).

Assay of Cell Adhesion

[0079] The plates with 96 wells (Nunc, Roskilde, Denmark) were covered with VN (1 .Math.g) or with 100 .Math.l of 1% BSA deactivated with heat in PBS, as negative control, and incubated during the entire night at 4° C. The plates were then blocked 1 hour at ambient temperature with 1% BSA deactivated with heat in 1% PBS. The cells were detached with PBS containing 2 mM of EDTA and washed with DMEM lacking serum, they were counted, plated in the wells with a density of 10.sup.5 cells/well and incubated for 1 hour at 37° C. in the presence of or in the absence of the selected compounds. The cells were then fixed with paraformaldehyde at 3% in PBS for 10 minutes and then incubated with methanol at 2% for 10 minutes. The cells were finally colored for 10 minutes with 0.5% crystal violet in 20% methanol, eluted with 0.1 mol/l of sodium citrate in 50% ethanol (pH 4.2) and the absorbance was measured at 540 nm with a spectrophotometer.

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