Treatment of acute respiratory distress syndrome (ARDS) with gpbp1 inhibitors

Abstract

The present invention relates to compounds for use in the treatment of acute respiratory distress syndrome (ARDS). The present invention also relates to a composition, a pharmaceutical composition and / or a drug for use in the treatment of ARDS. Furthermore, the present invention relates to a kit, or a unit dosage form, for use in the treatment of ARDS.

Description

[0001] DESCRIPTION

[0002] Treatment of Acute Respiratory Distress Syndrome (ARDS) with GPBP1 inhibitors

[0003] TECHNICAL SECTOR

[0004] The present invention relates to compounds for use in the treatment of acute respiratory distress syndrome (ARDS). The present invention also relates to a composition, a pharmaceutical composition, and a medicament for use in the treatment of ARDS. Furthermore, the present invention relates to a kit or a unit dosage for use in the treatment of ARDS.

[0005] BACKGROUND OF THE INVENTION

[0006] GPBP or GPBP1 inhibitors are related to the treatment of various medical conditions. In this context, WO 2011 / 054530 addresses, among other topics, pharmaceutical compositions comprising GPBP inhibitors and their application in the treatment of diseases such as antibody-mediated disorders, drug-resistant cancer, inflammation, disorders related to protein misfolding, and endoplasmic reticulum stress-mediated disorders and aberrant apoptosis. WO 2015 / 044352 addresses, among other topics, compounds containing a GPBP inhibitor for the treatment or diagnosis of diabetes or prediabetes. WO 2016 / 107906 addresses, among other topics, the use of GPBP1 inhibitor compounds for the inhibition of the mesenchymal phenotype following epithelial-mesenchymal transition and the treatment of invasive tumors. WO 2014 / 006020 addresses, among other topics, compounds containing a GPBP inhibitor and an antitumor drug.WO 2017 / 134146 refers to GPBP1 inhibitor compounds and their use for the treatment of invasive tumors and for the inhibition of the mesenchymal phenotype following the epithelial-mesenchymal transition.

[0007] Normally, pneumocytes, the alveolar basement membrane (ABM), and endothelial cells form the alveolar-capillary barrier, a structural requirement for proper blood oxygenation in the lungs. The human ABM contains a KRGDS motif for anchoring pneumocytes to the alveolar wall. Additionally, the ABM contains COL4A3, the α3 chain of collagen IV, which also contains the KRGDS motif. The ABM results from the fusion of two basement membranes during development: one produced by pneumocytes (the epithelial component of the ABM) and the other by endothelial cells (the endothelial component). The epithelial and endothelial components are maintained by a network of triple-helical molecules of α chains: COL4A3 / A4 / A5 or α345 (hereafter referred to as COL4A3) and COL4A1 / A2 / A1 or α121 (hereafter referred to as COL4A1), respectively. Regarding COL4A3, it is normally GPBP1 (Goodpasture antigen-binding protein 1 also known as GPBP) that phosphorylates and reorganizes it.Specifically, GPBP1 phosphorylates the KRGDS motif on the COL4A3 chain, to which integrins bind when not phosphorylated by GPBP1. Integrins are receptors on epithelial cells (e.g., pneumocytes) that bind to basement membranes (e.g., BMBs). COL4A3BP, the human gene encoding GPBP1, is expressed from a promoter that responds to inflammatory signals (TNF and NF-κB).

[0008] BRIEF EXPLANATION OF THE INVENTION

[0009] The present invention describes a novel therapeutic use of GPBP1 inhibitors. Specifically, the present invention provides GPBP1 inhibitors for use in the treatment of acute respiratory distress syndrome (ARDS).

[0010] The technical problem is solved by the embodiments reflected in the claims, in the description and illustrated in the figures and examples.

[0011] In this context, the inventors found, in COVID-19 patients with severe ARDS and short-term diffuse alveolar damage (DAD), a dissociation of the epithelial (COL4A3) and endothelial (COL4A1) components of the alveolar membrane barrier (AMB) in alveolar lesions where pneumocytes were still anchored. In more advanced alveolar wall lesions, already devoid of pneumocytes, the inventors found large linear deposits of GPBP1 replacing the epithelial (COL4A3) component and a highly expanded endothelial (COL4A1) component trapping the pneumocytes that had not detached. The detached pneumocytes expressed more GPBP1 than the pneumocytes that remained trapped in the alveolar wall. In these more advanced lesions, COL4A3 accumulated within the detached pneumocytes, forming a dense intracellular mesh of collagenous nature that masked the cellular structures, including the nucleus.The inventors also found that detached pneumocytes secreted this mesh into the alveolar lumen, where it concealed them within obliterative alveolar lesions that eventually filled the entire alveolar lumen. They further found that the desquamated pneumocytes, which successively increased the size of the obliterative lesions, expressed the SARS-CoV-2 nucleoprotein (N), and that this protein recognized and bound with high affinity to GPBP1. Finally, the inventors found that administering a GPBP1 inhibitor induced reabsorption of the collagenous mesh and re-epithelialization of the alveolar wall with reconstruction of the alveolar membrane. Overall, the inventors discovered that SARS-CoV-2 activates GPBP1, causing it to detach and position infected pneumocytes in a niche conducive to efficient viral replication.

[0012] The compounds of the invention as described herein can be used for the treatment of mild, moderate, or severe ARDS. The present invention also relates to a composition, pharmaceutical composition, or medicament comprising the compounds of the invention, or salts thereof, as described herein, for use in the treatment of ARDS.

[0013] Furthermore, the present invention relates to a kit or a unit dosage, containing the compounds of the invention, or salts thereof, as described herein, for use in the treatment of ARDS.

[0014] DESCRIPTION OF THE FIGURES

[0015] Figure 1: Confocal immunofluorescence (IFC) analysis of the alveolar wall in a COVID-19 patient with severe ARDS of short duration. COL4A3 accumulated in pneumocytes detached from or trapped by an expanded and ringed COL4A1. On the right, the fluorescence distribution along the lines indicated in the image is shown: the COL4A3 (epithelial) chain and the COL4A1 (endothelial) chains are shown. Pneumocytes are found attached to the alveolar wall in the control lung and within the alveolar lumen in the COVID-19 patient. Colocalization of the fluorescence in fine structures identifies a well-structured alveolar membrane in the control. The distribution and intensity of fluorescence in the patient reveals the lack of COL4A3 expression in the alveolar wall (epithelial component of the MBA) and a thickening of the endothelial component (COL4A1) that organizes into coarse structures lacking COL4A3 that eventually trap pneumocytes in the alveolar wall.The large amount of COL4A3 that accumulates inside the cell masks the nucleus. The antibodies used to stain COL4A3 and COL4A1 in this figure and in the following ones unless otherwise indicated were a monoclonal antibody (Mab) M3 / 1A that recognizes the human COL4A3-specific KRGDS motif (Raya et al, 1999 J Biol. Chem 274: 12642-49; Borza et al., 2000, J Biol Chem. 275;.

[0016] 6030-37) and anti-COL4, a commercial polyclonal antibody against human placental collagen IV (COL4A1A2A1) made in goats (Millipore AB769). DAPI was used to stain the nuclei.

[0017] Figure 2: GPBP1 was expressed more in detached pneumocytes than in those trapped by COL4A1, but even more so in walls devoid of pneumocytes (arrows). In a COVID-19 patient with severe ARDS of short duration, linear deposits of GPBP1 were commonly found on the epithelial side of desquamated alveolar walls. GPBP1 and COL4A1 are shown in gray, and cell nuclei in white. The fluorescence distribution along the lines drawn in the image is shown on the left. The inset shows the maximum and minimum intensity values ​​for each fluorescence in the image. An alveolar wall is shown in its entirety and thickness. On the epithelial side facing right, linear deposits of GPBP1 are observed (arrows), reminiscent of the distribution of the epithelial component (COL4A3) of the alveolar membrane.Newly shed pneumocytes on the left-facing epithelial side express abundant GPBP1, revealing that these were the cells that formed the GPBP1 deposits in the alveolar wall before desquamation. The fluorescence distribution shows that the two proteins (COL4A1 and GPBP1) are in close proximity, although not fused, suggesting that the large GPBP1 aggregates lining the epithelial side of the alveolar membrane participate in pneumocyte desquamation.

[0018] Figure 3: Immunohistochemical (IHC) characterization of desquamative lesions in a COVID-19 patient with severe ARDS of short duration. COL4A3 and GPBP1 are intensely expressed in the detached pneumocytes. We analyzed the expression of COL4A3 (top) and GPBP1 (bottom) in control (left) and COVID-19 (right) lung specimens. To detect COL4A3 we used Mab3, a Mab extensively characterized by the inventors that recognizes a conformational epitope overlapping with the Goodpasture epitope(s) (Saus et al., 1988 J Biol Chem. 263: 13374-80; Borza et al., 2000, J Biol Chem. 275; 6030-37), and to detect GPBP1 we used Mab e11-2 that recognizes the pathogenesis-associated isoform of GPBP1 (Revert et al. 2018. Oncotarget. 9:11020-45). In lung samples representing normal parenchyma, Mab3 stained the MBA, cytoplasm, and nuclei of pneumocytes with type 2 morphology.In lung samples from the COVID-19 patient, detached pneumocytes showed high and dense Mab3 reactivity that often masked the nuclei and cytoplasmic structures, resulting in pneumocyte cords with diffuse staining resembling hyaline membranes. Mab e11-2 showed slight reactivity in pneumocytes and the alveolar matrix of normal lung parenchyma, but intensely stained detached pneumocytes in the patient sample, replicating the Mab3 staining pattern. It also diffusely stained the matrix occupying the alveolar lumen. Original magnification 400X.

[0019] Figure 4: Histochemical and IHC characterization of obliterative lesions in a COVID-19 patient. A dense collagenous matrix obscures intracellular structures and desquamated pneumocytes in lesions that obliterate the alveolar lumen. Staining with Masson's reagent and anti-CK7 (cytokeratin 7) confirms the IFC and IHC studies by revealing the presence of a dense collagenous material that stains intensely with the aniline blue of Masson's reagent and obscures intracellular structures and the pneumocytes themselves in lesions that obliterate the alveolar lumen. Images of strings of detached pneumocytes lining a lesion suggest that these lesions increase in size as pneumocytes detach and synthesize the matrix that envelops and obscures them. Original magnification: x 400. Arrow: detached pneumocytes; star: alveolar wall; double star: obliterative lesion.

[0020] Figure 5: Basement membrane (BMM) dissociation and pneumocyte desquamation are associated processes in COVID-19 patients with severe ARDS. Top left, electron micrograph shows a desquamating pneumocyte with the arrow pointing to the BMM epithelial component dissociated from the endothelial component, but still attached to the pneumocyte that is about to detach. Right, the same region is shown at higher magnification to reveal a gap (star) between the endothelial component (line 1) and the epithelial component (line 2) of the BMM. The pneumocyte plasma membrane (N) (line 3) remains attached to the basement membrane (basal pole), so the pneumocyte still shows polarization: note the microvilli at the apical pole (particulate cloud). The endothelial cell nucleus (E), capillary lumen (C), and alveolar lumen (L) are also visible. Original magnification 13k (left) and 26k (right).Below, in the electron micrograph, a capillary is circled within an alveolar wall devoid of pneumocytes because these have already been sloughed off. A large gap (star) is visible between the dissociated epithelial and endothelial components. Original magnification: 2.6k (left); 11k (right). It should be noted that these and the following electron micrographs were taken from autopsy material fixed in formalin, not glutaraldehyde, and therefore their quality is not optimal.

[0021] Figure 6: Electron microscopy (EM) analysis shows that in a COVID-19 patient with severe ARDS, the extracellular matrix (ECM) of an obliterative lesion is produced, at least in part, by desquamated pneumocytes. Desquamated pneumocytes synthesize an electron-dense mesh that occupies both the intracellular and extracellular compartments. The micrograph on the left (original magnification: 26k) shows an obliterative lesion lined with desquamated pneumocytes.In the micrograph on the right (original magnification: 88k) the region framed with a circle is enlarged to show that the intracellular material that accumulates in the cytoplasm of the pneumocyte (elephant trunk-shaped extension) shows the same structure and electron density (star, surrounded by a circle to facilitate its visualization) as the extracellular material (double star, surrounded by a circle to facilitate its visualization) thus confirming that the pneumocyte produces the matrix that hides them in the obliterative alveolar lesion.

[0022] Figure 7: A very dense matrix obscures pneumocytes within the obliterative lesions present in the lung of COVID-19 patients with ARDS. The electron-dense mesh obscures pneumocytes within the alveolar obliterative lesions. From left to right and top to bottom, an incipient obliterative lesion is visualized, within which the magnified region is framed to show cells (star) hidden in a highly interlocked mesh (double star). Original magnification (xK): 4.4; 62; 62; 118. The image at the top right has been reduced in the composite to show a wider region.

[0023] Figure 8: Pneumocytes lining the obliterative lesions express the SARS-CoV-2 nucleoprotein (N) and accumulate COL4A3 and COL4A5. Pneumocytes shed into the alveolar lumen are infected with SARS-CoV-2. Although we confirmed the presence of SARS-CoV-2 in paraffin-embedded samples using RT-qPCR procedures (not shown), all attempts to identify viral particles by electron microscopy in deparaffinized samples were unsuccessful. However, using standard double IHC staining (Agilent, USA) on paraffin-embedded samples, we identified the expression of the SARS-CoV-2 nucleoprotein (N) in pneumocytes lining the lesions obliterating the alveolar lumen.Pneumocytes identified by CK7 expression (light gray) stained intensely with anti-SARS-CoV-2 nucleoprotein, anti-COL4A3, or anti-COL4A5 (dark gray), but not with anti-COL4A1A2, suggesting that SARS-CoV-2 recruits GPBP1 to enhance pneumocyte detachment. It should be noted that in the COL4A1A2 staining, the light gray coloration appears without interference from the dark gray stain because pneumocytes express cytokeratin, but not these two collagen IV chains, which are characteristic of endothelial cells. In the remaining cases, the light gray color combines with the dark gray to produce a dark stain that indicates co-expression of cytokeratin and the protein under investigation.Most of the desquamated, shed, and lining or embedded pneumocytes in the obliterative lesions expressed abundant viral protein N, as well as abundant collagen IV of composition COL4A3 and COL4A5, revealing their infected condition and suggesting that infected pneumocytes are hidden within the obliterative lesions. Original magnification x 400. Star: Alveolar wall; Double star: Obliterative lesion. Antibodies used: anti-CK7 mouse (Agilent, USA); anti-N-SARS-CoV-2 rabbit (Sino Biological Catalog No.: 40143-019); anti-COL4A3 mouse (Mab3); anti-COL4A5 rabbit (LSBio Cat: LS-C119458); anti-COL4A1A2 mouse (Agilent, USA).

[0024] Figure 9: In a recombinant in vitro system, GPBP1 specifically interacts with the SARS-CoV-2 nucleoprotein (N). Similar quantities of the indicated proteins were analyzed by non-reducing SDS-PAGE and, once separated, were stained with Coomassie blue or transferred to a nitrocellulose membrane (Western blot) stained with Ponceau red. Subsequently, the membrane was decolorized and incubated either with recombinant GPBP1 and N27-HRP, Mab N27 conjugated to HRP or horseradish peroxidase (far western, FLAG-GPBP+N27-HRP), or with antibodies against the FLAG sequence conjugated to HRP (a-Flag). Under experimental conditions in which GPBP1 did not bind to the SARS-CoV-2 spike protein (S), it bound to the nucleoprotein (N) of this virus. Of particular interest was the observation that GPBP1 bound more efficiently to the viral N protein than to the NCI3 polypeptide, which represents its natural ligand.In the figure: BSA, bovine serum albumin; NCI3, NC1 domain of COL4A3 containing KRGDS labeled with the sequence FLAG (DYKDDDDK); ACE2, angiotensin-converting enzyme 2; N, SARS-CoV-2 nucleoprotein; S, SARS-CoV-2 spike protein; MW, molecular weight standards of 180, 130, 100, 70, 55, 40, 35, 25, 15, 10 kDa. N27-HRP, identifies the Mab N27 antibody conjugated to horseradish peroxidase.

[0025] Figure 10: The SARS-CoV-2 nucleoprotein (N) interacts with high affinity with GPBP1. Subsequently, biolayer interferometry (BLI) was used to determine the affinity constant (KD) of the interaction of interest. A KD of 2.79E-08 M was estimated for the binding of the recombinant counterparts of the SARS-CoV-2 N protein and GPBP1, a value slightly below the nM range commonly found for antigen-antibody binding. Kon: association constant (M -1 s -1 ). Koff: dissociation constant (s -1KD = Koff / Kon (M). Figure 11: Treatment with compound formula (IX) of a COVID-19 patient with long-standing ARDS. To understand the pharmacological effects, specimens from the treated patient and a COVID-19 patient with ARDS and a similar clinical course who had not received treatment were analyzed in parallel. The combined comparative analysis of hematoxylin and eosin (H&E), Masson's trichrome, and cytokeratin (CK7) staining on serial sections revealed that treatment with compound formula (IX) in Table 1 was associated with a strong reduction in the hyaline-appearing collagenous material (dark gray in Masson's stain) that masked the pneumocytes in the obliterative alveolar lesions.In both specimens, pneumocytes appeared to be re-epithelializing the alveolar walls, but in the untreated patient they exhibited a cuboidal shape, while in the treated patient the pneumocytes showed a flatter, more physiological morphology, suggesting that the treatment induced more effective repair compared to the inoperative repair observed in the untreated patient. Original magnification x630.

[0026] Figure 12: IFC analysis of lung specimens from a control COVID-19 patient and a patient treated with compound formula (IX). Treatment with compound formula (IX) was associated with a complete absence of COL4A3 in re-epithelialized pneumocytes and an alveolar membrane composed of fine, intimately fused COL4A3 and COL4A1 structures. A scan of the lung parenchyma is shown on the left, and the region shown in magnification in the images on the right is outlined in a box. Re-epithelialized pneumocytes are identified with arrows, and the alveolar lumen with asterisks. The distribution of COL4A3 and COL4A1 fluorescence along the lines drawn on the magnified images is shown on the right. Detailed analysis revealed significant differences in the expression pattern between patients.Thus, in the patient who had not received the compound of formula (IX), COL4A3 was intracellular, whereas in the patient who received the COL4A3 treatment, it was found outside the cell, occupying the alveolar lumen. In general, the flatter the re-epithelialized pneumocyte, the less COL4A3 it accumulated, while the more cuboidal it was, the more COL4A3 it accumulated inside, obscuring the intracellular structures, including the nucleus. In the preserved alveolar structures, a coarse alveolar membrane (ABM) of endothelial origin (COL4A1) in the untreated patient contrasted with a fine ABM containing both COL4A3 and COL4A1 in the treated patient (see fluorescence distribution on the right). Of particular interest was the large number of autofluorescent erythrocytes occupying a significant number of alveolar spaces (white dots) in the treated patient.

[0027] Figure 13: IFC analysis of lung specimens from a control COVID-19 patient and a patient treated with compound formula (IX). Treatment with compound formula (IX) induced COL4A5 expression in the MBA but not its release into the alveolar lumen. The fluorescence distribution diagrams show COL4A5, the partner chain of COL4A3 in the COL4A3 / A4 / A5 molecule, which is physiologically synthesized and produced by pneumocytes. The antibody used was a commercially available rabbit polyclonal antibody against COL4A5 (LSBio Cat: LS-C119458).

[0028] Figure 14: Treatment with the compound of formula (IX) was associated with a reduction in plasma levels of inflammatory and alveolar damage markers. SAA, serum amyloid A protein (acute phase reactant); CRP, C-reactive protein (acute phase reactant); IL-6 and IL-10, inflammatory interleukins 6 and 10; CC16, a 16 kDa protein derived from Clara cells, also known as Club cells, a marker of alveolar damage. Acute phase reactants are a group of proteins of hepatic origin that are synthesized and secreted in response to inflammatory stimuli. In the case of CRP, the changes observed were between days 54 and 55 (before treatment) and between days 55 and 56 (after treatment).

[0029] Figure 15: Increased circulating GPBP1 levels are associated with MBA dissociation in patients with sepsis and ARDS. On the left, the arrow points to MBA dissociation in a septic patient with ARDS on an electron micrograph. On the right, circulating GPBP1 levels are shown in a cohort of patients with ARDS compared to a control group that includes patients with sepsis without ARDS (circle). Each point represents one patient (p<0.0001). Blood GPBP1 levels were determined using a sandwich ELISA. Fluorescence intensity is indicated in arbitrary units.

[0030] Figure 16: Patients with ARDS of non-COVID-19 septic origin showed GPBP1 overexpression in the alveoli and bronchoalveolar membrane (BAM) dissociation. In sepsis, respiratory distress was associated with GPBP1 overexpression and COL4-dependent epithelial-endothelial BAM dissociation. Specimens from normal lung parenchyma (Control) and from patients with sepsis and ARDS were analyzed by IFC to investigate the presence of GPBP1-dependent BAM structure alterations. Thickened and dissociated BAMs were observed in both patients. The three fluorescence peaks (COL4A3, GPBP1, and COL4A1) were sharp and aligned in the BAM of the Control, while in the patients with sepsis and ARDS, the fluorescence peaks were broad and not aligned. Specifically, the GPBP1 peak either aligned with COL4A3 (very frequently) or was found between the COL4A3 and COL4A1 peaks.To the right of the images are the individual fluorescence distributions (COL4A3 at the top, GPBP1 in the middle, and COL4A1 / A2 at the bottom) in the regions indicated by the arrows in the images. The antibodies used were: Mab3 for mouse COL4A3 (Saus et al., 1988 J Biol Chem. 263: 13374-80; Borza et al., 2000, J Biol Chem. 275; 6030-37), immunopurified chicken polyclonal antibodies against the characteristic 26-residues of GPBP1 (Raya et al., 2000 J Biol Chem. 275: 40392-99), and goat anti-COL4A1A2 (Millipore AB769) following the procedure detailed in Revert et al., 2007 Am J Pathol 171: 1419-30). DETAILED DESCRIPTION OF THE INVENTION AND ITS PREFERRED EMBODIMENTS.

[0031] The present invention relates therefore to GPBP1 inhibitor compounds for use in the treatment of acute respiratory distress syndrome (ARDS), represented by formula (I), or by salts thereof;

[0032]

[0033] where R is selected from N and CRs;

[0034] Ri is hydrogen; halogen; hydroxy; Ci-Ce alkyl; halo(Ci-Ce alkyl); Ci-Ce alkoxy; halo(Ci-Ce alkoxy); hydroxy(Ci-C6 alkyl); (Ci-Ce alkoxy)Ci-Ce alkyl; amino(Ci-Ce alkyl); sulfanyl(Ci-Ce alkyl); or (Ci-Ce alkyl)sulfanyl(Ci-Ce alkyl);

[0035] R2 is C1-C6 alkyl; cyano; (Ci-Ce alkyl)thio(Ci-Ce alkyl); halo(Ci-Ce alkyl); C1-C6 alkoxy; halo(Ci-Ce alkoxy); hydroxy(Ci-Ce alkyl); (Ci-Ce alkoxy)Ci-Ce alkyl; formyl(Ci-Ce alkyl); amino(Ci-C6 alkyl); sulfanyl(Ci-Ce alkyl); (Ci-Ce alkyl)sulfanyl(Ci-Ce alkyl); -(CH2)I-5-C(O)OH; -(CH2)I-5-C(O)O-; -(CH2)I-5-C(O)(Ci-C6 alkoxy); -(CH2)I-5-C(O)NH2; (aryl)Ci-C6 alkyl; (Co-Ce)carbonyl; -CH=CH-C(O)(CI-C6 alkoxy); or (heteroaryl)Ci-C6 alkyl;

[0036] R3 is C1–C6 alkyl; halo(Ci-Ce alkyl); Ci-Ce alkoxy; halo(Ci-Ce alkoxy); hydroxy(Ci-Ce alkyl); (C1–C6 alkoxy)Ci–Ce alkyl; formyl(Co-Ce alkyl); amino(Ci-Ce alkyl); sulfanyl(Ci-Ce alkyl); -(Ci-C6alkyl)sulfanyl(Ci-C e rent); -C(O)OH, -C(O)O'; -(CH2)I-5-C(O)OH; -(CH2)i-5-C(O)O'; -C(O)(Ci-C6alkoxy); -(CH2)I-5-C(O)(CI-C6alkoxy); -C(O)NH2, -(CH2)I-5-C(O)NH2; -C(O)NH(CI-C6alkyl); -(CH2)I-5-C(O)NH(CI-C6alkyl); -C(O)N(CI-C6alkyl)2; -(CH2)I-5-C(O)N(CI-C6alkyl)2; -CH=CH-C(O)OH; CH=CH-C(O)O'; -CH=CH-C(O)(Ci-C e alkoxy); (aryl) Cy-C6alkyl or (heteroaryl) Oi-Ce alkyl;

[0037] R4 is hydroxy; halogen; Ci-Ce alkyl; Ci-Ce alkoxy; halo(Ci-C6 alkoxy); benzyloxy; -C(O)OH, -0(0)0′; -(CH2)I-5-C(O)OH; -(CH2)I-5-C(O)O'; -(CH2)I-5-C(O)(CI-C6alkoxy); -(CH2)i-5-C(O)NH2; -(CH2)I-5-C(O)NH(CI-C6alkyl); -(CH2)i-5-C(O)N(Ci-C6alkyl)2; -CH=CH-C(O)OH; -CH=CH-0(0)0-; -CH=CH-C(O)(Ci-C ealkoxy); -O(CH2)I-5-C(O)OH; -O(CH2)i-5-C(O)O'; -O(CH2)I-5-C(O)(Ci-C6 alkoxy); (aryl)Ci-C6 alkyl or (heteroaryl)Ci-C6 alkyl and

[0038] Rs is selected from the group consisting of: hydrogen; halogen; cyano; nitro; hydroxy; C2-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; halo(C2-C6 alkyl); C2-C6 alkoxy; halo(C2-C6 alkoxy); amino; (C2-C6 alkyl)amino; di(C2-C6 alkyl)amino; hydroxy(C2-C6 alkyl); (C2-C6 alkoxy)C2-C6 alkyl; amino(C2-C6 alkyl); sulfanyl(C2-C6 alkyl); (C2-C6 alkyl)sulfanyl(C2-C6 alkyl); -(CH2)I-5-C(O)(C2-C6 alkoxy); -(CH2)ISC(O)NH2; (aryl)C2-C6 alkyl; (Co-Ce)carbonyl and (heteroaryl)Ci-C6 alkyl.

[0039] The present invention further relates to the use of any compound or salt of the invention to manufacture a medicament for the treatment of acute respiratory distress syndrome.

[0040] Additionally, the present invention also relates to a method of treating acute respiratory distress syndrome in a subject, comprising administering to said subject an effective amount of any compound or salt of the invention.

[0041] Preferred compounds for use with the invention are those represented by formula (II), or by salts thereof:

[0042]

[0043] where R, Ri, R2, R3 and R4 are defined as in formula (I).

[0044] Compounds also preferred for use with the invention are those represented by formula (III) or by salts thereof:

[0045]

[0046] where R1, R2, R3 and R4 are defined as in formulas (I) and (II).

[0047] Another preferred embodiment is the compounds for use according to the invention represented by formula (IV) or salts thereof:

[0048]

[0049] where Ri, R2, R3, R4 and Rs are defined as in formulas (I), (II) and (III).

[0050] Another preferred embodiment is the compounds for use according to the invention represented by formula (I), (II), (III) or (IV) or salts thereof, wherein:

[0051] R is selected from N and CRs;

[0052] R1 is hydrogen, halogen, hydroxy, Ci-Ce alkyl, halo(Ci-Ce alkyl), Ci-Ce alkoxy, halo(Ci-Ce alkoxy), hydroxy(Ci-Ce alkyl), (Ci-Ce alkoxy)Ci-Ce alkyl, amino(Ci-Ce alkyl), sulfanyl(Ci-Ce alkyl), (Co-Ce)carbonyl or (Ci-C6alkyl)sulfanyl(Ci-C6 alkyl);

[0053] R2 is C1-C6 alkyl, cyano, (Cy-Ce alkyl)thio(Cy-Ce alkyl), halo(Cy-Ce alkyl), Cy-Ce alkoxy, halo(Cy-Ce alkoxy), hydroxy(Cy-Ce)alkyl, (Cy-Ce alkyl(Cy-Ce)alkyl, (Cy-Ce alkyl(Cy-Ce),forme amino(Ci-C6 alkyl), sulfanyl(Ci-Ce alkyl), (Ci-Ce alkyl)sulfanyl(Ci-Ce alkyl), -(CH2)ISC(O)OH, -(CH2)I-5-C(O)O-, -(CH2)I-5-C(C(O)O)(CI)car, (Co6-C6 -CH=CH-C(O)(CI-C6alkoxy) or -(CH2)I-5-C(O)NH2;

[0054] R3 is C1-C6 alkyl, halo(Cy-Ce alkyl), Ci-Ce alkoxy, halo(Cy-Ce alkyl), hydroxy(Cy-Ce alkyl), (Cy-Cealcoxy)Cy-C6 alkyl, formyl(Co-C6 alkyl), amino(Cy-Ce alkyl), sulfur(Cy-Ce alkyl (C1-C6alkyl)sulfanyl(Ci-C6alkyl), -C(O)OH, -C(O)O; -(CH2)I-5-C(O)OH, -(CH2)I-5-C(O)O,-C(O)(C1-C6alkoxy), -(CH2)I-5-C(O)(CI-C6alkoxy), -C(O)NH2),-(CH2)I-5-CN(H(O)CIH(2) -(CH2)I-5-C(O)NH(CI-C6alkyl), -C(O)N(CI-C6alkyl)2, -(CH2)I-5-C(O)N(CI-C6alkyl)2, -CH=CH-C(O)OH, -CH=CH-C(O)O; or -CH=CH-C(O)(Ci-C e alkoxy);

[0055] R4 is hydroxy, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, halo(Ci-C6 alkoxy), benzyloxy, -C(O)OH, -0(0)0; -(CH2)I-5-C(O)OH, -(CH2)I-5-C(O)O; -(CH2)I-5-C(O)(CI-C6alkoxy), -(CH2)I-5-C(O)NH2, -(CH2)I-5-C(O)NH(CI-C6alkyl), -(CH2)I-5-C(O)N(CI-C6alkyl)2,(C-()=CH)= -CH=CH-C(O)(Ci-C e alkoxy), -O(CH2)I-5-C(O)OH, -O(CH2)I-5-C(O)O; or -O(CH2)I-5-C(O)(Ci-C6 alkoxy);

[0056] Rs is selected from the group consisting of: hydrogen, halogen, cyano, nitro, hydroxy, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(Ci-C6 alkyl), Ci-Ce alkoxy, halo(Ci-C6.alkylcyl(alkyl)- amino, (Cy-C6 alkyl(alkyl)- amino, alkyl)amino, hydroxy(Ci-Ce alkyl), (Ci-Ce alkoxy)Ci-C6 alkyl, amino(Ci-C6 alkyl), sulphanyl(Ci-C6 alkyl), (Ci-C6alkyl)sulfan¡l(Ci-C6 alkyl), -(5C-i-C6(C6)I- (Co-C6)carbonyl y -(CH2)I-5-C(O)NH2.

[0057] Another preferred embodiment is the compounds for use according to the invention represented by formula (I), (II), (III) or (IV) or salts thereof, wherein:

[0058] R is selected from N and CRs;

[0059] Ri is hydrogen; halogen; hydroxy; Ci-Ce alkyl; halo(Ci-Ce alkyl); Ci-Ce alkoxy or halo(Ci-Ce alkoxy);

[0060] R2 is C1-C6 alkyl; (Ci-Ce alkyl)thio(Ci-Ce alkyl); halo(Ci-Ce alkyl); hydroxy(Ci-Ce alkyl); (C1-C6 alkoxy)Ci-Ce alkyl; formyl(C o -C6 alkyl); amino(Ci-Ce alkyl), -CH=CH-C(O)(CI-C6 alkoxy), -(CH2)I-5-C(O)OH; -(CH2)I-5-C(O)O' O sulfanyl(Ci-C6alkyl);

[0061] R3 is Ci-C6alkyl, -(CH2)I-5-C(O)OH; -(CH2)i-5-C(O)O'; -C(O)OH; -0(0)0'; -(CH2)I-5-C(O)(CI-C6alkoxy); -(CH2)I-5-C(O)NH2; -(CH2)I-5-C(O)NH(CI-C6alkyl); -(CH2)I-5-C(O)N(CI-C6alkyl)2; -CH=CH-C(O)OH; -CH=CH-C(O)O'; -CH=CH-C(O)(Ci-C ealkoxy); R4is hydroxy; Ci-C6alkoxy; halo(Ci-C6alkoxy); -O(CH2)I-5-C(O)OH; -O(CH2)I-5-C(O)O'; -O(CH2)I-5-C(O)(CI-C6alkoxy)o phenoxy;

[0062] Rs, is selected from the group consisting of: hydrogen; halogen; cyano; nitro; hydroxy; C2-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; halo(C2-C6 alkyl); C2-C6 alkoxy; halo(C2-C6 alkoxy); amino; (C2-C6 alkyl)amino; di(C2-C6 alkyl)amino; hydroxy(C2-C6 alkyl); (C2-C6 alkoxy)C2-C6 alkyl; (C2-C6)carbonyl and amino(C2-C6 alkyl).

[0063] The present invention preferably includes compounds in which in the formulas (l)-(IV), R1 is hydrogen or Ci-Ce alkoxy, preferably hydrogen.

[0064] The present invention preferably comprises compounds in which, in formulas (I)-(IV), R2 is: C1-C6 alkyl; Ci-Ce alkoxy; halo(Ci-Ce alkyl); hydroxy(Ci-Ce alkyl); formyl(C o-C6 alkyl); -(CH2)I-5-C(O)OH; -(CH2)i-5-C(O)O; amino(Ci-C6 alkyl); (Ci-Ce)carbonyl or sulfanyl(Ci-Ce alkyl). Preferably R2 can be Ci-Ce alkyl; Ci-Ce alkoxy; halo(Ci-Ce alkyl); hydroxy(Ci-Ce alkyl); formyl(C o -C6 alkyl); -(CH2)I-5-C(O)OH or -(CH2)I-5-C(O)O'. More preferably R2 can be Ci-Ce alkyl; formyl(C o -C6 alkyl); Ci-Ce alkoxy; halo(Ci-Ce alkyl) or hydroxy(Ci-Ce alkyl).

[0065] The present invention preferably covers compounds in which, in formulas (I)-(IV), R3 is: Ci-C6 alkyl; -(CH2)I-5-C(O)OH; -(CH2)I-5-C(O)O'; -C(O)OH; -C(O)O'; -(CH2)I-5-C(O)(CI-C6 alkoxy); -CH=CH-C(O)OH; -CH=CH-C(O)O'; or -CH=CH-C(O)(CI-C6 alkoxy). Preferably, R3 can be Ci-C6 alkyl; -(CH2)I-5-C(O)OH; -(CH2)I-5-C(O)O'; -CH=CH-C(O)(CI-C6 alkoxy); or -(CH2)I-5-C(O)(CI-C6 alkoxy). The present invention is preferably directed to compounds in which, in formulas (I)-(IV), R4 is: hydroxy; halogen; C1-C6 alkyl; C1-C6 alkoxy; halo(C1-C6 alkoxy); -O(CH2)ISC(O)OH; -O(CH2)I-5-C(O)O _ ; -O(CH2)I-5-C(O)(CI-C6alkoxy) or benzyloxy. Preferably R4 can be hydroxy; -O(CH2)i-5-C(O)OH; -O(CH2)i-5-C(O)O'; -O(CH2)I-5-C(O)(CI-C6alkoxy) or Ci-C6alkoxy. More preferably R4 may be hydroxy or C1-C6 alkoxy.

[0066] The present invention is preferably directed to compounds in which, in formulas (I)-(IV), Rs is: C1-C6 alkyl; halo(CiCe alkyl); C1-C6 alkoxy; (Co-Ce)carbonyl; or halo(Ci-Ce alkoxy). Preferably, Rs may be Ci-Ce alkyl; halo(CiCe alkyl); or formyl(Co-Ce).

[0067] The present invention preferably encompasses compounds having the following residues in formulas (l)-(IV):

[0068] R is selected from N and CRs;

[0069] R1 is hydrogen;

[0070] R2 is C1-C6 alkyl; halo(Ci-Ce alkyl); hydroxy(Ci-Ce alkyl) or formyl(Co-Ce alkyl);

[0071] R3 is Ci-C6alkyl; -(CH2)ISC(O)OH; -(CH2)i-5-C(O)O'; -C(O)OH; -0(0)0'; or -(CH2)I-5-C(O)(CI-Ce alkoxy); -CH=CH-C(O)OH; -CH=CH-C(O)O _ ; -(CH2)I-2-C(O)NH2; preferably R3 can be: Ci-C6alkyl; -(CH2)ISC(O)OH; -(CH2)I-5-C(O)O'; -C(O)OH; -O(O)O'; -(CH2)I.5-C(O)(CI-C6alkoxy); -CH=CH-C(O)OH or -CH=CH-C(O)O';

[0072] R4 is hydroxy or Ci-Ce alkoxy;

[0073] Rs is C1-C6 alkyl; halo(Ci-C6 alkyl); C1-C6 alkoxy; (Co-C6)carbonyl; or halo(Ci-C6 alkoxy); preferably R4 can be: C1-C6 alkyl; halo(Ci-C6 alkyl); C1-C6 alkoxy; or (Co-C6)carbonyl.

[0074] The present invention is also preferably directed to compounds having the following residues in formulas (l)-(IV):

[0075] R is selected from N and CRs;

[0076] R1 is hydrogen;

[0077] R2 is C1-C6 alkyl;

[0078] R3es -(CH2)I-5-C(O)OH; -(CH2)I-5-C(O)O'; -C(O)OH; -0(0)0'; -CH=CH-C(O)OH; or -CH=CH-0(0)0';

[0079] R4 is C1-C6 alkoxy;

[0080] Rs is selected from the group consisting of: hydrogen; halogen; cyano; nitro; hydroxy; C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; halo(C1-C6 alkyl); C1-C6 alkoxy; halo(C1-C6 alkoxy); amino; (C1-C6 alkyl)amino; di(C1-C6 alkyl)amino; hydroxy(C1-C6 alkyl); (C1-C6 alkoxy)C1-C6 alkyl; (C1-C6)carbonyl and amino(C1-C6 alkyl); preferably Rs is selected from hydrogen and C1-C6 alkyl;

[0081] The present invention also preferably relates to compounds having the following residues in the formulas (l)-(IV) described herein:

[0082] R is selected from N and CRs; Ri is hydrogen;

[0083] R2 is methyl;

[0084] R3es -(CH2)I-5-C(O)OH; -(CH2)I-5-C(O)O'; -C(O)OH; -0(0)0'; -CH=CH-C(O)OH; or -CH=CH-0(0)0';

[0085] R4 is methoxy;

[0086] Rs is selected from the group consisting of: hydrogen; halogen; cyano; nitro; hydroxy; C2-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; halo(C2-C6 alkyl); C2-C6 alkoxy; halo(C2-C6 alkoxy); amino; (C2-C6 alkyl)amino; di(C2-C6 alkyl)amino; hydroxy(C2-C6 alkyl); (C2-C6 alkoxy)C2-C6 alkyl; (C2-C6)carbonyl and amino(C2-C6 alkyl); preferably Rs is selected from hydrogen and C2-C6 alkyl.

[0087] The present invention preferably encompasses compounds having the following residues in formula (I), (II), (III) and (IV):

[0088] R is CR50 N;

[0089] R1 is hydrogen or (Ci-Ce) alkoxy, preferably (C1-C3) alkoxy;

[0090] R2 is Oi-Ce alkyl, preferably C1-C3 alkyl; halo(Ci-Ce alkyl), preferably halo(Ci-C3 alkyl); hydroxy(Ci-Ce alkyl), preferably hydroxy(Ci-C3 alkyl); (Co-Ce)carbonyl, preferably (Co-C3)carbonyl; (Ci-Ce)alkoxy; preferably: (Ci-C3)alkoxy, -C(O)OH, -C(O)O_ ; -CH2=CH2-C(0)(Ci-C6)alcox¡, preferably: -CH=CH-C(0)(Ci-C3)alcox¡, -(CH2)I-6-C(O)OH, -(CH2)I-3-C(O)OH; O -(CH2)I-6-C(O)O', preferably -(CH2)i-3-C(O)O';

[0091] R3 is (Ci-Ce) alkyl, preferably (Ci-Ce) alkyl; -(CH2)I-6-C(O)OH, preferably -(CH2)I-3-C(O)OH; -(CH2)I-5-C(O)O-; preferably: -(CH2)I-3-C(O)O', -C(O)OH; -CABBAGE'; -(CH2)I-2-C(O)(CI-C6 alkoxy), preferably: -(CH2)I-2-C(O)(CI-C3 alkoxy) or -CH=CH-C(O)(Ci-Ce)alkoxy¡, preferably: -CH=CH-C(0)(C2)alkoxy; (Ci–Ce) alkoses, preferably: (C1–C3) alkoses; -CH=CH-C(O)OH; -CH=CH-C(O)Q-;

[0092] R4 is hydroxy, (Ci–Ce) alkoxy, preferably (C1–C3) alkoxy; phenosis; -O(CH2)ISC(O)OH, preferably -O(CH2)I-3-C(O)OH; -O(CH2)I-5-C(O)O _ ; -O(CH2)ISC(O)(CI-C6 alkoxy), preferably -O(CH2)I-3-C(O)(CI-C3 alkoxy);

[0093] Rs is (Ci-Cs) alkyl, preferably -(C1-C3) alkyl; halogen, preferably Cl or F; halo(Ci-C6 alkyl), preferably halo(Ci-C3 alkyl); or (Co-C6)carbonyl, preferably (Co-C3)carbonyl.

[0094] The present invention preferably encompasses compounds having the following residues in formula (I), (II) and (III):

[0095] R is N;

[0096] R1 is hydrogen;

[0097] R2 is (Ci-Cs) alkyl, preferably -CH3; halo(Ci-C6 alkyl), preferably -CH2F or CHF2; hydroxy(Ci-C6 alkyl), preferably -CH2-OH; (Co-C6)carbonyl, preferably formyl(Co-C6 alkyl); -CH=O; -C(O)OH; -C(O)O'; -(CH2)I-6-C(O)O', preferably -(CH2)i-3-C(O)O';

[0098] R3is -(CH2)I-2-C(O)OH, -CH2-CH2-COOH; -(CH2)ISC(O)O', preferably -CH2-CH2-COC>-; - C(O)OH; -C(O)O _; -(CH2)i-2-C(O)(Ci-Ce alkoxy), preferably -(CH2)I-2-C(O)(C2 alkoxy); -CH=CH-C(0)(Ci-C6)alkoxy, preferably -CH=CH-C(0)(C2)alkoxy;

[0099] R4 is hydroxy, phenoxy or (Ci-Ce) alkoxy, preferably -O-CH3.

[0100] The present invention preferably encompasses compounds having the following residues in formula (I), (II) and (IV):

[0101] R is CRs;

[0102] R1 is hydrogen or Ci-Ce alkoxy, preferably -O-CH3;

[0103] R2 is C1-C6 alkyl, preferably -CH3; halo(C1-C6 alkyl), preferably -CH2F or CHF2; hydroxy(C1-C6 alkyl), preferably -CH2-OH; (C1-C6)carbonyl, preferably -CHO; (C1-C6)alkoxy, preferably -OCH3, -C(O)OH; -C(O)O _ ; -CH2=CH2-C(0)(Ci-C6)alkoxy¡, preferably -CH=CH-C(0)(C2)alkoxy¡ or -(CH2)I-5-C(O)OH; -CH2-CH2-COOH;

[0104] R3 is C1-C6 alkyl, preferably -CH3 or -CH-(CH3)2; -(CH2)I-5-C(O)OH, preferably -CH2-CH2-COOH; -(CH2)I-5-C(O)O-, preferably: CH2-CH2-COO-, -C(O)OH, -C(O)Q-; -(CH2)I-2-C(O)(Ci-Ce alkoxy), preferably -(CH2)I-2-C(O)(C2 alkoxy); -CH=CH-C(0)(Ci-C6)alkoxy¡, preferably -CH=CH-C(0)(C2)alkoxy¡; Ci-Ce alkoxy; -O-CH2-CH2-CH3; -CH=CH-C(O)OH or -CH=CH-C(O)O-;

[0105] R4 is hydroxy; (Ci-Ce)alkoxy; -O-CH2-CH2-CH3; -O-CH3; phenoxy; -O(CH2)I-5-C(O)OH, preferably -O-CH2-COOH; -O(CH2)I-5-C(O)O _ , preferably -O-CH2-COO-; -O(CH2)ISC(O)(Ci-Ce alkoxy), preferably -O-CH2-CH2-C(O)(C2 alkoxy);

[0106] Rs is (Ci-Ce) alkyl; -CH3; halogen, preferably Cl or F; halo(Ci-Ce alkyl), preferably -CH2F or CHF2; (Co-Ce)carbonyl, preferably -CHO.

[0107] The present invention is also preferably directed to the compounds listed in Table 1 below, or to a salt thereof.

[0108] Table 1

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117] The synthesis of these compounds, except for compounds T55, T109a, and T109b, is described in WO 2011 / 054530. The synthesis of compound T55 is described in WO 2014 / 006020. The synthesis of compounds T109a and T109b is described in WO 2017 / 134146. The synthesis of compounds T109a and T109b is within the normal capabilities of someone skilled in the art. One possible synthesis of compounds T109a and T109b is analogous to the synthesis of compound 22a in Table 1. Instead of preparing the -CC-COOH chain of the R3 residue, the -C=C-COOH chain of the R3 residue is prepared. Someone skilled in the art knows how to prepare this alternative R3 residue by unsaturating a hydrocarbon chain.

[0118] In embodiments of the compound for use of the invention, the compound is selected from the group consisting of: 7a, 13a, 1a, 14a, 21a, 1b, 1c, 2a, 7b, 7c, 11a, 11b, 12a, 12b, 13b, 13b, 13b, 14b, 4c 15a, 15b, 15c, 18a, 18b, 18c, 19a, 19b, 19c, 20a, 20b, 20c, 21b, 21c, 21d, 21e, 21f, 21g, 21h, 21, 21, 21, 21, k 22a, 22b, 22b', 22c, 22d, 22e, 22f, 22g, 22h, 22¡, 22j, 22k, 221, 23a, 23b, 23c, 24a, 24b, 24c, 23, 23, 38, 38 T55, T109a, T109b, or a salt thereof:

[0119] (E)-3-[4"-(benzyloxy)-2'-form¡l-3-met¡l-(1,1';4',1") terphenyl-2"-yl]ethyl acrylate (7a);

[0120] 3-[4"-hydroxy-2'-(hydroxymethyl)-3-methyl-(1,1';4',1") terphenyl-2"-yl]ethyl propionate (13a);

[0121] (E)-3-[4"-(benzyloxy)-2'-form¡l-3-met¡l-(1,1';4',1") terphenyl-2"-yl]ethyl acrylate (1a);

[0122] 3-[2'-(fluoromethyl)-4"-hydroxy¡-3-met¡l-(1,1';4',1")terphenyl-2"-yl]ethyl prop¡onate (14a);

[0123] 3-[2'-(hydroxymethyl)-4"-methoxy-3-methyl-(1,1';4',1"terphenyl-2"-yl]ethylprop¡onate (21a); ​​acid 3-[4"-hydroxy-2'-(hydroxymethyl)-3-(trifluoromethyl)-(4',1';(4',1')- ")terphenyl-2"-yl]propionic acid (1b) 3-[4-h id roxi-3'-(h id roxymethyl)-4'-(pyrid in-3-yl) bife n il-2-yl] propionic (1 c);

[0124] 3-[4"-hydroxy-2"-isopropyl-3-methyl-(1,1';4',1") terphenyl-2'-yl]propionic acid (2a);

[0125] (E)-3-[4"-(benzyloxy)-2'-formyl-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-yl]ethyl acrylate (7b); (E)-3-[4-(benzyloxy)-3'-formyl-4'-2-la-ethylphenyl]-3 (7c);

[0126] 3-[4"-hydroxy-2',3-d¡met¡l-(1,1';4',1")terphenyl-2"-yl]ethyl prop¡onate (11a);

[0127] 3-[4"-hydroxy-2'-methyl-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-yl]ethyl prop¡onate (11b); acid 3-[4"-hydroxy-2',3-d¡methal-(1,propion);

[0128] 3-[4"-hydroxy-2'-methyl-3-(trifluoromethyl)-(1,1';4',1") terphenyl-2"-yl]propionic acid (12b);

[0129] ethyl 3-[4"-hydroxy-2'-(hydroxymethyl)-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-yl]propionate (13b);

[0130] ethyl 3-[4-hydroxy-3'-(hydroxymethyl)-4'-(pyridin-3-yl)biphenyl-2-yl]propionate (13c);

[0131] ethyl 3-[2'-(fluoromethyl)-4"-hydroxy-3-(trifluoromethyl)-(1,1';4',1") terphenyl-2"yl]propionate (14b);

[0132] ethyl 3-[3'-(fluoromethyl)-4-hydroxy-4'-(pyridin-3-yl)biphenyl-2-yl]propionate (14c);

[0133] 3-[2'-(fluoromethyl)-4"-hydroxy-3-methyl-(1,1';4',1")terphenyl-2"-yl]propionic acid (15a); 3-[2'-(fluoromethyl)-4"-hydroxy-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-yl]propionic acid (15b); 3-[3'-(fluoromethyl)-4-hydroxy-4'-(pyridine-3-yl)biphenyl-2-yl]propionic acid (15c);

[0134] (E)-3-[4"-(bencyloxy)-2'-(difluoromethyl)-3-methyl-(1,1';4',1")terfenyl-2"-yl]ethyl acrylate (18a); (E)-3-[4"-(bencyloxy)-2'-(difluoromethyl)-3-(trifluoromethyl)-(1,1';4',1")terfenyl-2"-yl]ethyl acrylate (18b);

[0135] (E)-3-[4-(bencyloxy)-3'-(d ifluoromethyl)-4'-(pyrid yn-3-ylo) biphenyl-2-ylo]ethyl acrylate (18c);

[0136] 3-[2'-(difluoromethyl)-4"-hidroxy-3-methyl-(1,1';4',1")terphenyl-2"-ilo]propionate ethyl (19a); ethyl(19b);

[0137] 3-[3'-(difluoromethyl)-4-hidroxi-4'-(pyridin-3-ilo)biphenyl-2-ilo]acido 3-[2'-(difluoromethyl)-4"-hidroxi-3-methyl-(1,1';4',1"terphenyl-2"-ilo]propionato de etilo (19c);

[0138] ácido 3-[2'-(difluorometil)-4"-hidroxi-3-metil-(1,1';4',1"terfenil-2"-¡lo]propión¡co (20a); ácido 3-[2'-(difluorometil)-4"-hidroxi-3-(trifluorometil)-(1,1';4',1")terfenil-2"-¡l]propión¡co (20b); 3-[3'-(difluorometil)-4-hydroxy-4'-(pyridin-3-ilo)bifenil-2-ilo]propionico (20c);

[0139] 3-[4"-methoxy-3,2'-dimethyl-(1,1';4',1")terphenyl-2"-yl]ethyl propionate (21b);

[0140] 3-[2'-(fluoromethyl)-4"-methoxy-3-methyl-(1,1';4',1"terphenyl-2"-yl]ethyl propionate (21c);

[0141] 3-[2'-(difluoromethyl)-4"-methoxy-3-methyl-(1,1';4',1") terphenyl-2"-yl]propionate of ethyl (21d); 3-[2'-(hydroxymethyl)-4"-methoxy-3-(trifluoromethyl)-(1,1';4',1") terphenyl-2"-yl]propionate of ethyl (21 e);

[0142] 3-[2'-methyl-4"-methoxy-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-yl]propionate of ethyl (21 f); 3-[2'-(fluoromethyl)-4"-methoxy-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-yl]propionate of ethyl (21g);

[0143] 3-[2'-(difluorometil)-4"-methoxy-3-(trifluorometil)-(1,1';4',1")terfenil-2"ilo]propionato de etilo (21 h);

[0144] 3-[3'-(hydroxymethyl)-4-methoxy-4'-(pyridin-3-yl)biphenyl-2-yl]ethyl propionate (21 i);

[0145] 3-[4-methoxy-3'-methyl-4'-(pyridin-3-yl)biphenyl-2-yl]ethyl propionate (21 j);

[0146] 3-[3'-(fluoromethyl)-4-methoxy-4'-(pyridin-3-yl)biphenyl-2-yl]ethyl propionate (21k);

[0147] 3-[3'-(difluoromethyl)-4-methoxy-4'-(pyridin-3-yl)biphenyl-2-yl]ethyl propionate (211);

[0148] acid 3-[2'-(hydroxymethyl)-4"-methoxy-3-methyl-(1,1';4',1"terphenyl-2"-yl]prop¡on¡co (22a); acid 3-[4"-methoxy-3,2'-dimethyl-(1,1'-(cophenyl];¡prop2b2"ter formula (V)); anion 3-[4"-methoxy-3,2'-dimethyl-(1,1';4',1"terphenyl-2"-yl]propionate (22b', formula (VI)); acid. 3-[2'-(fluoromethyl)-4"-methoxy-3-methyl-(1,1';4',1"terphenyl-2"-yl]prop¡oneco (22c); acid 3-[2'-(difluoromethyl)-4"-methoxy-3-methyl-pro-(1,2"1"onylco];4'' (22d); acid 3-[2'-(hydroxymethyl)-4"-methoxy-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-ylo]propon¡co (22e); 3-[2'-methyl-4"-methoxy-3-(trifluoromethyl)-(1,1';4',1"terphenyl-2"-yl]prop¡onco (22f); acid 3-[2'-(fluoromethyl)-4"-methoxy-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-yl]prop¡onco (22g); acid 3-[2'-(difluoromethyl)-4"-methoxy-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-ylo]prop¡onco (22h);

[0149] 3-[3'-(hydroxymethyl)-4-methoxy-4'-(pyridin-3-yl)-biphenyl-2-yl]propionic acid (22¡);

[0150] 3-[4-methoxy-3'-methyl-4'-(pyridin-3-yl)biphenyl-2-yl]propionic acid (22j);

[0151] 3-[3'-(fluoromethyl)-4-methoxy-4'-(pyridin-3-yl)-biphenyl-2-yl]propionic acid (22k);

[0152] 3-[3'-(difluoromethyl)-4-methoxy-4'-(pyridin-3-yl)-biphenyl-2-yl]propionic acid (22I);

[0153] 3-[3,2'-dimethyl-4"-propox¡-(1,1';4',1")terphenyl-2"-yl]ethyl prop¡onate (23a);

[0154] 3-[4"-(etoxiccarbonylmethoxy)-3,2'-dimethyl-(1,1';4',1")terphenyl-2"-yl]ethyl prop¡onate (23b); of ethyl (23c); acid 3-[3,2'-dimethyl-4"-propox¡-(1,1';4',1"terphenyl-2"-ylo]prop¡on¡co (24a);

[0155] acid 3-[4"-(carboxymethoxy)-3,2'-d¡l-(1,1';4',1")terphenyl-2"-yl]prop¡oneco (24b); acid 3-[2'-methyl-4"-propox¡-3-(tnfluoromethyl)-(1,1';4',1"terphenyl-2"-ilo]prop¡on¡co (24c);

[0156] ethyl 3-[3'-formyl-4-methoxy-4'-(pyridin-3-yl)biphenyl-2-yl]propionate (28);

[0157] ethyl 3-[4,4"-dimethoxy-3,2'-d¡met¡l-(1,1';4',1")terphenyl-2"-yl]proponate (31);

[0158] 3-[4,4"-dimethoxy-3,2'-d¡met¡l-(1,1';4',1")terphenyl-2"-ilo]prop¡ón¡co acid (32);

[0159] (E)-3-[4"-(benciloxy)-3-formyl-2"-isopropyl-(1,1';4',1")terphenyl-2'-yl]ethyl acrylate (38);

[0160] 3-[4"-hydroxy-2"-isopropyl-3-methyl-(1,1';4',1") terphenyl-2'-yl]ethylpropionate (39);

[0161] 3-[3-chloro-2'-methyl-4,4"-dimethox¡-(1,1';4',1")terphenyl-2"-ilo]prop¡ón¡co acid (T55);

[0162] (E)-3-[2'-(hidroximethyl)-4"-methoxi-3-methyl-(1,1';4',1")terphenyl-2"-¡l]acrylic acid (T109a, formula (Vil)); y

[0163] anión (E)-3-[2'-(hidroximethyl)-4"-methoxi-3-methyl-(1,1';4',1")terphenyl-2"-yl]acrylate (T109b, formula (VIII)).

[0164] The present invention is also preferably directed to a compound having the formula (V), or a salt thereof:

[0165]

[0166] and / or a compound having the formula (VI), or a salt thereof:

[0167]

[0168] (VI).

[0169] The present invention is also preferably directed to a compound having the formula (Vil), or a salt thereof:

[0170]

[0171] (Vile) and / or

[0172] to a compound having the formula (VIII), or a salt thereof:

[0173]

[0174] The present invention also preferably encompasses that the compounds whose use is described herein are salts of the GPBP1 inhibitor compounds of formulas (I) to (VIII). Notably, the salts described herein are not produced for purely pharmaceutical reasons. That is, the salts described herein are prepared solely for their therapeutic effect in the treatment of ARDS. The preparation of the salts is not intended to improve their pharmaceutical properties (stability, solubility, etc.).

[0175] The choice of the sodium salt of T12 as the preferred formulation stems from a not-so-obvious observation. T12 is transported in plasma bound to albumin as if it were a fatty acid. Indeed, its structure includes a hydrophobic pole with two methyl and two phenyl groups, and a hydrophilic pole with the third phenyl ring and two substituents: a carboxylate (propionate) and a methoxy group. For this reason, it was decided to saponify the fat with caustic soda to obtain a soap that would allow the active ingredient to be distributed to any cell or tissue via biological membranes.

[0176] The term “salts” refers to the non-toxic, inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. Generally, those skilled in the art know how to obtain salts from a compound. For example, Gupta et al. (2018) “Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations” Molecules 23, 1719 describes which counterions may be an option for preparing a salt from a compound. The publication Sadeque Hossain Mithu et al. (2021) “Advance Methodologies for Pharmaceutical Salt Synthesis” Cryst. Growth Des. 2021, 21, 2, 1358-1374 explains which techniques a person skilled in the art can use to prepare a salt from a compound.For example, a subject matter expert can prepare a salt of a compound via solvent evaporation, solution crystallization, pure milling, liquid-assisted milling, slurrying, comelting, and steam digestion. Other methods include sonication, sublimation, steam digestion, and the use of supercritical carbon dioxide. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free-base form with a suitable organic or inorganic acid and isolating the salt thus formed.

[0177] A salt of the compound of formula (V) described herein may be prepared by suspending the solid of the compound of formula (V) in 1 equivalent of 0.2 M NaOH solution and stirring at room temperature until the mixture became clear. The solution was then freeze-dried and the resulting powder stored in a desiccator to obtain the sodium salt of compound (V) (compound of formula (VI)). Other similar salts may be prepared analogously.

[0178] However, preparing a salt does not guarantee that the salt of the compound will have a therapeutic effect. The therapeutic effect of a salt must be tested separately. Figures 11, 12, 13, and 14, along with the corresponding examples, illustrate how a compound's therapeutic effect can be verified.

[0179] The present invention comprises compounds described herein in the form of a salt, wherein the compound of formula (I) to (VIII) is the anion of the salt and the cation of the salt is selected from the group consisting of: aluminum, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethylamine, copper, and zinc. The present invention also comprises compounds described herein as a salt, wherein the compound is the anion and the cation of the salt is selected from the group consisting of: calcium, magnesium, lithium, potassium, sodium, triethylamine, and zinc. Preferably, the salts of the compounds described herein are a combination of the compound of the invention of formula (I) to (VIII) with an alkali or alkaline earth metal.

[0180] The present invention encompasses compounds described herein in salt form wherein the compound of formula (I) to (VIII) is the anion of the salt and the cation of the salt is selected from the group consisting of: copper, calcium, lithium, potassium, sodium and zinc; preferably sodium, copper and zinc.

[0181] Preferably, the present invention relates to a sodium salt of formula (IX):

[0182]

[0183] Preferably, the present invention also relates to a sodium salt of formula (X):

[0184]

[0185] (X) Treatment of a COVID-19 patient with ARDS using a GPBP1 inhibitor, specifically the compound of the invention of formula (IX), is associated with a rapid reduction of the collagen matrix and re-epithelialization of the alveolar walls. Furthermore, treatment with the compound of formula (IX) is associated with a complete absence of COL4A3 in the re-epithelialized pneumocytes and an alveolar membrane (ABM) composed of fine, intimately fused structures of COL4A3 and COL4A1. Thus, while in the patient who did not receive the compound of formula (IX), COL4A3 is intracellular, in the patient who received the treatment, COL4A3 is assembled within the ABM and also occupies the alveolar lumen.

[0186] In preserved alveolar structures, a coarse alveolar membrane (ABM) of endothelial origin (COL4A1) in the untreated patient contrasts with a fine ABM containing COL4A3 and COL4A1 in the treated patient. Treatment with the compound of the invention of formula (IX) induces the expression of COL4A5 in the ABM, but not its release into the alveolar lumen. Treatment with the compound of the invention of formula (IX) is also associated with a reduction in plasma levels of inflammatory markers and alveolar damage.

[0187] In summary, the administration of a compound according to the invention, of formula (IX), is associated with a reversal of the inflammatory process, revealing that it is the first specific treatment against diffuse alveolar damage (DAD) caused by inflammation in an ARDS of infectious origin (e.g. SARS-CoV-2), thus displacing the existing generic therapies in the state of the art based on antibiotics and corticosteroids, not without toxicity, which are administered to these patients to control the state of hyper-inflammation and who present a compromised general condition.

[0188] The inventors found similar reactions regarding GPBP1 expression and MBA components in patients with sepsis and ARDS. Specifically, there is an increase in circulating GPBP1 levels associated with MBA dissociation in patients with sepsis and ARDS. Patients with non-COVID-19 septic ARDS also showed GPBP1 overexpression in the alveoli and MBA dissociation.

[0189] Therefore, the mechanisms observed in patients with COVID-19 and ARDS are the same as those observed in patients with sepsis and ARDS. This means that these observed mechanisms are common to ARDS and are not due to underlying conditions such as COVID-19 or sepsis. Consequently, the use of the compounds, as described herein, particularly the compound of the invention of formula (IX), is effective in the treatment of ARDS, regardless of the underlying disease or its origin.

[0190] As used herein, “treat” or “treatment” means administering a compound of the invention, as described herein, preferably as a medicament, to a subject suffering from a disease and in need of relief or improvement of the symptoms of that disease. Similarly, it includes the administration of one or more compounds of the invention, as described herein, preferably as medicaments, to a patient suffering from ARDS, to relieve and improve the symptoms of such disease.

[0191] Acute respiratory distress syndrome (ARDS) is a type of respiratory (pulmonary) failure with dangerously low blood oxygen levels caused by diffuse alveolar damage (DAD). ARDS is divided into three categories: mild, moderate, and severe. The characteristics of these categories are listed in Table 2.

[0192] Table 2

[0193]

[0194] PaO2 in mm Hg; FIO2 in decimal fraction (e.g., 0.5).

[0195] ARDS = acute respiratory distress syndrome; CPAP = continuous positive airway pressure; FiO2 = fraction of inspired oxygen; PaC>2 = partial pressure of arterial oxygen; PEEP = positive end-expiratory pressure.

[0196] The expert in the field knows how to measure oxygen levels. For example, blood oxygen levels can be measured using a sensor placed on a finger or earlobe, a method called oximetry. The concentration of oxygen (along with carbon dioxide) in the blood can also be measured by analyzing a blood sample taken from an artery (arterial blood gas analysis).

[0197] The expert is familiar with and applies other clinical criteria to diagnose ARDS. These clinical criteria include, for example, (a) onset within 1 week of a known injury or new or worsening respiratory symptoms, (b) bilateral opacities not fully explained by effusions, lobar or pulmonary collapse, or nodules (CT scan or chest X-ray), or (c) edema origin such as respiratory failure not fully explained by heart failure or fluid overload.

[0198] ARDS, as described herein, is known to be a consequence of other pathologies. These pathologies are recognized by experts and are described, among other things, in the Merck Manual under the term “ARDS.” Therefore, ARDS, as described herein, can result from: massive blood transfusion (e.g., > 15 units), bone marrow transplantation, burns, cardiopulmonary bypass, drug overdose, or drug toxicity (e.g.,The invention describes ARDS as developing, preferably as a consequence of acid aspiration, pneumonia, sepsis, trauma with shock, or infection with SARS-CoV-2 (COVID-19). (Aspirin, cocaine, opiates, phenothiazines, tricyclic antidepressants), neurogenic pulmonary edema due to stroke, seizures, head trauma, anoxia, preeclampsia, septic abortion, radiographic contrast (rare), inhalation of irritant gases, amniotic fluid embolism, sepsis, trauma with prolonged hypovolemic shock, pancreatitis, acid aspiration, pneumonia, diffuse alveolar hemorrhage, pulmonary contusion, drowning, lung transplantation, or fat embolism. Preferably, ARDS develops as a consequence of infection with SARS-CoV-2 (COVID-19), pneumonia, or sepsis.

[0199] In embodiments of the compound or salt for use of the invention, acute respiratory distress syndrome results from sepsis; pneumonia; COVID-19 pneumonia; aspiration or inhalation of acidic stomach contents into the lungs; burns; pregnancy complications such as amniotic fluid embolism, preeclampsia, infection of the uterine tissues before, during, or after a spontaneous or septic abortion; chest injury such as a pulmonary contusion; coronary artery bypass surgery; drowning; inflammation of the pancreas or pancreatitis; inhalation of smoke or toxic gases; lung injury due to inhalation of high concentrations of oxygen; overdose of drugs such as heroin, methadone, propoxyphene, or aspirin; prolonged or severe low blood pressure; shock; pulmonary embolism; stroke or seizure; and transfusions of more than approximately 15 units of blood in a short period of time.

[0200] In embodiments of the compound for use of the invention, acute respiratory distress syndrome is a consequence of sepsis, pneumonia, or pneumonia caused by SARS-CoV-2.

[0201] The present invention also relates to a pharmaceutical composition for use in the treatment of acute respiratory distress syndrome comprising the compound or salt of the invention.

[0202] Additionally, the present invention relates to a medicament for use in the treatment of acute respiratory distress syndrome comprising the compound of the invention or a salt thereof. In another aspect, the present invention relates to the use of the compound or salt of the invention to manufacture a medicament for the treatment of acute respiratory distress syndrome.

[0203] Additionally, the present invention also relates to a kit for use in the treatment of acute respiratory distress syndrome containing the compound or salt of the invention.

[0204] In another aspect, the present invention relates to a unit dosage for use in the treatment of acute respiratory distress syndrome comprising the compound or salt of the invention.

[0205] ARDS can be of short duration (in which the desquamative and exudative phases of DAD predominate) or of long duration (in which the reparative phase of DAD predominates). It is predominantly of long duration.

[0206] Diffuse alveolar damage (DAD) is a histological hallmark of ARDS. DAD is well-known to experts and was described in the publication Katzenstein et al. (1976) “Diffuse Alveolar Damage—The Role of Oxygen, Shock, and Related Factors” American Journal of Pathology, vol. 85, no. 1, pp. 210–228. Typically, DAD involves endothelial and alveolar lining cell (pneumocyte) injury, with detachment of the alveolar wall forming characteristic hyaline membranes that accumulate in obliterative exudative lesions and, in some cases, progress to extensive interstitial fibrosis. Methods for detecting DAD are also described in the figures and examples.

[0207] Treatment for ARDS can also include improving a patient's health status compared to their health status before treatment began. In the case of ARDS, this could mean the patient experiences improved oxygenation, as shown in Table 2 above.

[0208] The present invention encompasses that treatment with the compounds of the invention, as described herein, results in a reduction of the collagen matrix in the airways compared to the collagen matrix present in the airways before treatment. Those skilled in the art are familiar with methods for studying the collagen matrix. Some of these methods are described in the figures and examples herein.

[0209] The present invention encompasses that treatment with the compounds of the invention, as described herein, results in re-epithelialization of the alveolar walls compared to the epithelialization present before treatment. Methods for studying the re-epithelialization of alveolar walls are known to the practitioner. Some of these methods are described in the figures and examples herein. The present invention also encompasses that treatment with the compounds of the invention, as described herein, results in the absence or reduction of COL4A3 expression in the re-epithelialized pneumocytes compared to the COL4A3 expression in the pneumocytes present before treatment. Methods for measuring COL4A3 expression are known to the practitioner. Some of these methods are described in the figures and examples herein.

[0210] The present invention includes that treatment with the compounds of the invention, as described herein, results in a thin basal membrane composed of COL4A3 and COL4A1, compared to a coarse, thick basal membrane of predominantly endothelial nature (COL4A1) present before treatment. Methods for studying the expression of COL4A3 and COL4A1 are known to those skilled in the art. Some of these methods are described in the figures and examples herein.

[0211] The present invention comprises that treatment with the compounds of the invention, as described herein, results in COL4A3 expression in the MBA and alveolar lumen (extracellular), compared to COL4A3 expression being more intracellular before the start of treatment.

[0212] The present invention relates to the fact that treatment with the compounds of the invention, as described herein, increases the extracellular expression of COL4A5 in the MBA compared to the intracellular expression of COL4A5 present in pneumocytes before the start of treatment. Methods for studying COL4A5 expression are known to those skilled in the art. Some of these methods are described in the figures and examples herein.

[0213] The present invention encompasses that treatment with the compounds of the invention, as described herein, reduces plasma levels of inflammatory and alveolar damage markers in the airways compared to the plasma levels of these markers prior to the start of treatment. For example, inflammatory markers may include interleukins 6 and 10 (IL-6 and IL-10). An alveolar damage marker, for example, may be the 16 kDa Club cell-derived protein (CC16). Methods for measuring plasma levels of inflammatory and alveolar damage markers in the airways are known to those skilled in the art. Some of these methods are disclosed in the examples and figures herein.

[0214] Notably, the compounds of the invention, as described herein, are GPBP1 inhibitors. These GPBP1 inhibitors are described, among others, in documents WO 2011 / 054530, WO 2014 / 006020, WO 2015 / 044352, WO 2016 / 107906, and WO 2017 / 134146. These documents, and in particular WO 2011 / 054530, WO 2014 / 006020, US 9066938, and WO 2017 / 134146, also describe the synthesis of these GPBP1 inhibitor compounds and methods for determining whether a given compound is a GPBP1 inhibitor.

[0215] A GPBP1 inhibitor, as defined herein, is a compound that reduces the kinase activity of GPBP1. The inhibitor can achieve this effect by reducing the effectiveness of GPBP1 in performing its pathogenic cellular function. An inhibitor can reduce or decrease the pathogenic function / activity of the GPBP1 protein by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to the pathogenic function / activity of GPBP1 without the addition of the inhibitor. Blockage of the pathogenic function / activity of the GPBP1 protein occurs when the pathogenic function / activity of GPBP1 is inhibited by 100% compared to the pathogenic function / activity of GPBP1 without the addition of the inhibitor.

[0216] The term “halo” or “halogen” as used here means -Cl, -Br, -I or -F. Preferably the halogen is Cl or F.

[0217] The term “alkyl,” as used herein, means a straight-chain or branched hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an “alkyl” group is a linking group between two other moieties, it may also be a straight or branched chain. Examples include, but are not limited to -CH2-, -CH2CH2-, -CH2CH2CHC(CH3)-, or -CH2CH(CH2CH3)CH2-.

[0218] It is described here that the -CCC chain includes hydrogens and thus can alternatively appear as -CH2-CH2-CH3. Similarly, -C=C- chains mean -CH=CH-. The expert knows that these carbon chains contain hydrogens and thus recognizes / understands their presence even when they are not explicitly stated.

[0219] The term “alkenyl,” as used herein, means a straight-chain or branched hydrocarbon containing from 2 to 10 carbon atoms, unless otherwise specified, and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and 3,7-dimethyl-2,6-dienyl.

[0220] The term “alkylene” refers to a divalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH₂)ₙ-, where n is a positive integer, preferably from one to six, one to four, one to three, one to two, or two to three. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for a substituted aliphatic group. An alkylene chain may also be substituted at one or more positions with an aliphatic group or a substituted aliphatic group.

[0221] The term “alkynyl,” as used herein, means a straight-chain or branched hydrocarbon group containing from 2 to 10 carbon atoms and at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylene, 1-propynyl, 2-propynyl, 3-butyl, 2-pentyl, and 1-butyl.

[0222] The terms “haloalkyl,” “haloalkenyl,” and “haloalkoxy” refer to an alkyl, alkenyl, or alkoxy group, as the case may be, that is substituted with one or more halogen atoms. The halogen is preferably located at the end of the carbon chain. For example, a haloalkyl group can be a C1-C2 alkyl chain, preferably C1-C2 alkyl, with one or two halogens, preferably F. Therefore, the invention encompasses the haloalkyl groups -CH2-F and -CF3.

[0223] The term “alkoxy,” as used herein, means an alkyl group, as defined herein, attached to the parent molecule through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. Examples of alkoxy include -OCC-CH2, -OC-CH2, and -OCH3.

[0224] The term “aryl,” as used herein, means a phenyl (e.g., monocyclic aryl), or a bicyclic ring system containing at least one phenyl ring, or an aromatic bicyclic ring containing only carbon atoms in the aromatic bicyclic ring system. The bicyclic aryl may be azulenyl naphthyl, or a phenyl group fused to a monocyclic cycloalkyl, monocyclic cycloalkenyl, or monocyclic heterocyclyl. The bicyclic aryl is attached to the parent molecule through any carbon atom contained in the phenyl portion of the bicyclic system, or any carbon atom with the naphthyl or azulenyl ring. The fused monocyclic cycloalkyl or monocyclic heterocyclic portions of the bicyclic aryl are optionally substituted with one or two oxo and / or thio groups. Representative examples of bicyclic aryls include, but are not limited to, azulenyl, naphthyl, dihydroinden-1-yl,dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl, inden- 3-yl, indene-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1 -yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, benzo[d] [1,3 ]dioxol-4-yl, benzo[d] [1,3 ]dioxol-5-yl, 2H-chromium-2-on-5-yl, 2H-chromium-2-on-6-yl, 2H-chromium-2-on-7-yl, 2H-chromium-2-on-8-yl, isoindolin-1,3-dion-4-yl, isoindolin-1,3-dion-5-yl, ¡nden-1-on-4-¡lo, 1-on-5-lo, 1-on-6-lo, 1-on-7-lo, 2,3-dihydrobenzo[b][1,4 ]dioxan-5-yl, 2,3-dihydrobenzo[b][1,4 ]dioxan-6-yl, 2Hbenzo[b][1,4]oxazin3(4H)-on-5-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-6-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-7-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-8-yl,benzo[d]oxazin-2(3H)-on-5-yl, benzo[d]oxazin-2(3H)-on-6-yl, benzo[d]oxazin-2(3H)-on-7-yl, benzo[d]oxazin-2(3H)-on-8-yl, quinazolín-4(3H)-on-5-yl, quinazolin-4(3H)-on-6-yl,quinazolin-4(3H)-on-7-yl, quinazolin-4(3H)-on-8-yl, quinoxalin-2(1 H)-on-5-yl, quinoxalin-2(1 H)-on-6-yl, quinoxalin-2(1 H)-on-7-yl, quinoxalin-2(1 H)-on-8-yl, benzo[d]thiazol-2(3H)-on-4-yl, benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and benzo[d]thiazol-2(3H)-on-7-yl. In certain embodiments, the bicyclic aryl is (i) naphthyl or (ii) a phenyl ring fused to a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, or a 5- or 6-membered monocyclic heterocyclyl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl are optionally substituted with one or two groups that are independently oxo or thio.

[0225] The term “heteroaryl,” as used herein, means a monocyclic heteroaryl or a bicyclic ring system containing at least one heteroaromatic ring. The monocyclic heteroaryl may be a 5- or 6-membered ring. The 5-membered ring consists of two double bonds and one, two, three, or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6-membered ring consists of three double bonds and one, two, three, or four nitrogen atoms. The 5- or 6-membered heteroaryl is connected to the parent molecule through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridynyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl.A bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclyl, or monocyclic heteroaryl group. The fused cycloalkyl or heterocyclyl group of the bicyclic heteroaryl is optionally substituted with one or two groups that are either oxo or thio. When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclyl ring, the bicyclic heteroaryl group is connected to the parent molecule through any carbon or nitrogen atom contained in the monocyclic heteroaryl portion of the bicyclic ring system. When the bicyclic heteroaryl is a monocyclic heteroaryl fused to a benzoic ring, then the bicyclic heteroaryl group is connected to the parent molecule through any carbon atom or nitrogen atom within the bicyclic ring system.Representative examples of heteroaryl heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1 -¡lo, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, 5, 6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,1. 6,7,8-tetrahydroisoquinolin-1 -yl, thienopyridinyl, 4, 5, 6, 7- tetrahydrobenzo[ c ][1,2,5]oxadiazolyl, and 6, 7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl.In certain embodiments, the fused bicyclic heteroaryl is a 5- or 6-membered monocyclic heteroaryl ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 6-membered ring, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heterocyclyl, where the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups that are independently oxo or thio.

[0226] The term (Co-Ce)carbonyl refers to a group in which the carbon atom is double-bonded to an oxygen atom. It is common to several classes of organic compounds (aldehydes, ketones, etc.). Therefore, the carbonyl group can have the formula RCH=O or RR'C=O. The invention encompasses that (Co-Ce)carbonyl is a carbonyl group in which the oxygen is at the end of the carbohydrate (aldehyde) chain. For example, (Ci-Ce)carbonyl can have the formula -C=O or -CC=O. Therefore, the term (Co-Ce)carbonyl in some embodiments may refer to formyl(Co-Ce). If the carbonyl or formyl group is Co, this means that the carbonyl / formyl group is directly bonded to the ring system.

[0227] The term benzyloxy as used herein preferentially refers to a phenoxy group.

[0228] The present invention also relates to a composition for use in the treatment of acute respiratory distress syndrome, comprising one, two, three, four or more compounds of the invention, as described herein.

[0229] A treatment such as that described herein refers to the administration of at least one compound of the invention, as described herein. Notably, the compounds of the invention described herein for administration include salts, zwitterionic forms, esters, amides, and pharmaceutically acceptable prodrugs thereof that are, to the extent of sound medical judgment, suitable for use in contact with patient tissues, without undue toxicity, irritation, allergic response, or the like, and that are proportionate to a reasonable benefit / risk ratio, as well as effective for the intended use.

[0230] Examples of pharmaceutically acceptable and non-toxic esters of the compounds of the invention include: C1-C2 alkyl esters, wherein the alkyl group is straight or branched, substituted or unsubstituted; C5-C7 cycloalkyl esters; and arylalkyl esters, such as benzyl and triphenylmethyl. C1-C4 alkyl esters, such as methyl, ethyl, 2,2,2-trichloroethyl, and terebutyl, are preferred. Esters of the compounds of the present invention can be prepared by conventional methods.

[0231] Examples of pharmaceutically acceptable and non-toxic amides include ammonia-derived amides, C1-C3 primary alkyl amines, and C1-C2 secondary dialkyl amines, in which the alkyl groups are linear or branched. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing a nitrogen atom. Ammonia-derived amides, C1-C3 alkyls, and C1-C2 secondary dialkyl amines are the preferred amides according to the invention. The amides of the compounds of the invention can be prepared by conventional methods.

[0232] The term “prodrug” refers to compounds that are rapidly transformed in vivo to produce the original compound from the previous formulations, for example, through hydrolysis in blood. The publication Markovic et al. (2020) “Prodrugs for Improved Drug Delivery: Lessons Learned from Recently Developed and Marketed Products” Pharmaceutics. 2020;12(11):1031 presents a brief overview of the prodrug concept, classifications, recent developments, and clinical applications.

[0233] The present invention also includes a pharmaceutical composition for use in the treatment of acute respiratory distress syndrome, comprising one, two, three, four or more compounds according to the invention, as described herein.

[0234] Preferred pharmaceutical compositions are those comprising one or more compounds of the invention, as described herein, and at least one pharmaceutically acceptable carrier, solvent, adjuvant, and / or diluent.

[0235] For administration, the compounds of the invention are normally combined with one or more adjuvants appropriate for the indicated route of administration. The compounds may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and / or polyvinyl alcohol, and tableted or encapsulated for conventional administration.

[0236] Additionally or alternatively, the compounds of the invention may be administered as the sole active pharmaceutical agent, or they may be used in combination with one or more compounds useful for carrying out the methods / uses of the invention. When administered as a combination, the therapeutic agents may be formulated as separate compositions that are administered simultaneously or at different times, or they may also be administered as a single composition.

[0237] The compounds may be in solid form (including granules, powders, or suppositories) or in liquid form (e.g., solutions, suspensions, or emulsions). The compounds of the invention may be applied in a variety of solutions and may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, humectants, emulsifiers, buffers, etc.

[0238] The compounds of the invention can be administered orally, topically, parenterally, by inhalation or spray, or rectally. Therefore, the compounds of the invention can be administered orally, topically, parenterally, by inhalation or spray, or rectally in dosage unit formulations containing pharmaceutically non-toxic carriers, adjuvants, and vehicles. Thus, the compounds of the present invention can be administered orally.

[0239] The term “parenteral”, as used herein, includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal routes.

[0240] Furthermore, a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable carrier is provided. One or more compounds of the invention may be present in association with one or more non-toxic, pharmaceutically acceptable carriers and / or diluents and / or adjuvants, and, if desired, other active ingredients.

[0241] Pharmaceutical compositions containing compounds of the invention may be presented in a form suitable for oral use, for example, as tablets, lozenges, pastilles, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0242] Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preservatives in order to provide palatable preparations.

[0243] The tablets contain the active ingredient mixed with pharmaceutically acceptable, non-toxic excipients suitable for tablet manufacture. These excipients may include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as maize starch or alginic acid; binding agents such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or coated using known techniques. In some cases, such coatings may be prepared using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, a retardant such as glyceryl monostearate or glyceryl distearate may be used.Aqueous suspensions contain the active materials mixed with excipients suitable for the manufacture of aqueous suspensions.These excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; dispersing or wetting agents may be a natural phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as polyoxyethylenated sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydride hexitol, for example polyethyleneilated sorbitan monooleate.Aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavorings, and one or more sweeteners such as sucrose or saccharin.

[0244] Oil suspensions can be formulated by suspending the active ingredients in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oil suspensions may contain a thickening agent, for example, beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings may be added to obtain palatable oral preparations. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

[0245] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing, wetting, or suspending agents include those mentioned above. Additional excipients, such as sweeteners, flavorings, and colorings, may also be present.

[0246] The pharmaceutical compositions of the invention may also be presented as oil-in-water emulsions. The oil phase may be a vegetable oil or a mineral oil, or mixtures thereof. Suitable emulsifying agents may be natural gums, for example, acacia gum or tragacanth gum, natural phosphatides, for example, soybean oil, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example, sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, for example, polyoxyethylenated sorbitan monooleate. The emulsions may also contain sweeteners and flavorings.

[0247] Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol, glucose, or sucrose. They may also contain a demulcent, a preservative, and flavoring and coloring agents.

[0248] Pharmaceutical compositions may be presented as a sterile aqueous or oily suspension for injection. This suspension may be formulated according to known technique, using suitable dispersing or wetting agents and suspending agents that have been shown to be effective in dispersion or wetting. The sterile injectable preparation may also be a sterile solution or suspension for injection in a non-toxic diluent or solvent acceptable for injectable use (parenteral administration), for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and sodium chloride isotonic solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. Any soft fixed oil, including synthetic mono- or diglycerides, may be used for this purpose.In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0249] The pharmaceutical compounds and compositions of the present invention can also be administered in the form of suppositories, for example, for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

[0250] The pharmaceutical compounds and compositions of the present invention can be administered parenterally in a sterile environment. Depending on the vehicle and concentration used, the drug may be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives, and sealing agents can be dissolved.

[0251] The present invention also relates to a medicament for use in the treatment of acute respiratory distress syndrome comprising one, two, three, four or more compounds according to the invention and as described herein.

[0252] The present invention also encompasses a method for treating acute respiratory distress syndrome, wherein the method comprises administering to a subject in need a therapeutically effective amount of one, two, three, four or more compounds according to the invention, as described herein.

[0253] The therapeutically effective amount of the compound or pharmaceutical composition as disclosed herein may vary due to several factors, including, but not limited to, the compound's activity: the compound's stability within the body of the subjects / patients; the severity of the pathological conditions being treated; weight; age, etc., as will be evident to a person skilled in the art. The amount of the compound of the invention to be administered may be adjusted as the various factors change over time.

[0254] The pharmaceutical compounds or compositions disclosed in this document may be administered at a dose of 0.01 mg to 50 mg per kilogram of body weight per day. More preferably, doses between 0.1 mg and approximately 50 mg per kilogram of body weight per day are useful in the treatment of the conditions indicated herein. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the subject / patient being treated and the particular route of administration.

[0255] A daily oral dose of 0.1 mg / kg / day to 20 mg / kg / day, 0.5 mg / kg / day to 10 mg / kg / day, 0.5 mg / kg / day to 5 mg / kg / day, and 0.2 mg / kg / day to 3 mg / kg / day as 2 mg / kg / day is also foreseen.

[0256] The pharmaceutical compounds or compositions containing the compounds of the invention, described herein, are administered to a subject or individual in need. The term "subject" may mean a human being or an animal. The subject may be a vertebrate, more preferably a mammal, and even more preferably a human being.

[0257] The subject may also be a human with a massive blood transfusion (e.g., > 15 units), bone marrow transplant, burns, cardiopulmonary bypass, drug overdose or toxicity (e.g., aspirin, cocaine, opiates, phenothiazines, tricyclic antidepressants), neurogenic pulmonary edema due to stroke, seizures, head trauma, anoxia, preeclampsia, septic abortion, radiographic contrast (rare), inhalation of irritant gases, amniotic fluid embolism, sepsis, trauma with prolonged hypovolemic shock, pancreatitis, acid aspiration, pneumonia, diffuse alveolar hemorrhage, pulmonary contusion, drowning, lung transplant, SARS-CoV-2 (COVID-19) infection, or fat embolism. Therefore, the patient to be treated may preferably be a subject with acid aspiration, pneumonia, sepsis, trauma with shock, or SARS-CoV-2 (COVID-19) infection.The subject may be a subject with sepsis or SARS-CoV-2 (COVID-19) infection.

[0258] The present invention also relates to the use of one, two, three, four or more compounds of the invention, as described herein, for treating acute respiratory distress syndrome.

[0259] The present invention also relates to a kit for treating acute respiratory distress syndrome, a kit comprising one, two, three, four or more compounds of the invention, as described herein.

[0260] The present invention also relates to a unit dosage for treating acute respiratory distress syndrome, comprising the use of one, two, three, four or more compounds or salts according to the invention, as described herein.

[0261] The unit dose generally contains between 0.5 mg and 500 mg of the active ingredient. A daily oral dose of 0.1 mg / kg / day to 20 mg / kg / day, 0.5 mg / kg / day to 10 mg / kg / day, 0.5 mg / kg / day to 5 mg / kg / day, and 0.2 mg / kg / day to 3 mg / kg / day or 2 mg / kg / day is also provided.

[0262] In this document, the singular forms “un”, “una”, “el”, and “la” include plural referents unless the context clearly indicates otherwise. “Y”, as used here, is used interchangeably with “o” unless expressly stated otherwise.

[0263] All terms common to different aspects and embodiments of the invention have the same meaning, unless the context clearly indicates otherwise. Unless the context clearly indicates otherwise, embodiments disclosed for one embodiment of the invention may also be used for other aspects of the invention, and in combination with embodiments disclosed for other aspects of the invention.

[0264] The present invention is also described by the following examples.

[0265] EXAMPLES

[0266] Example 1. Confocal immunofluorescence (IFC) analysis of the alveolar wall in a COVID-19 patient with short-term ARDS

[0267] The distribution and intensity of fluorescence in the patient reveals a lack of COL4A3 expression in the alveolar wall (epithelial component of the alveolar membrane) and thickening of the endothelial component (COL4A1), which organizes into coarse, COL4A3-deficient structures that eventually trap pneumocytes in the alveolar wall. The large amount of COL4A3 that accumulates within the cell masks the nucleus, which appears white (Figure 1).

[0268] In a COVID-19 patient with short-term ARDS, linear deposits of GPBP1 were commonly found on the epithelial side of desquamated alveolar walls. GPBP1 was more highly expressed on detached pneumocytes than on those trapped by COL4A1, but even more so on walls devoid of pneumocytes (arrows in Figure 2). The fluorescence distribution reveals that the two proteins (COL4A1 and GPBP1) are in close proximity, although not fused, suggesting that the large GPBP1 aggregates lining the epithelial side of the alveolar membrane participate in pneumocyte desquamation (Figure 2). The production and characterization of Mab e11-2 are described in Revert et al. 2018 Oncotarget. 9:11020-45.

[0269] In general, for the confocal immunofluorescence studies described here in Examples 1–3, a Leica TCS SP8X white light laser confocal microscope and an HC PL APO CS2 40x / 1.30 OIL objective were used, and images were captured sequentially with (nm) Ex: 495 ZEm: 500–600 and Ex: 595 / Em: 600–770 for FITO and Texas Red, respectively. The production and characterization of Mab e11-2 are described in WO 2010 / 009856.

[0270] Example 2. Immunohistochemical (IHC) characterization of desquamative lesions in a COVID-19 patient with ARDS

[0271] COL4A3 and GPBP1 are intensely expressed in shed pneumocytes (Figure 3). To detect COL4A3 we used Mab3, a Mab extensively characterized by us that recognizes a conformational epitope overlapping with the Goodpasture epitope(s) (Saus et al., 1988 J Biol Chem. 263: 13374-80; Borza et al., 2000, J Biol Chem. 275; 6030-37), and to detect GPBP1 we used Mab e11-2 that recognizes the pathogenesis-associated isoform of GPBP1 (Revert et al. 2018 Oncotarget. 9:11020-45) using conventional IHC procedures. In lung samples representing normal parenchyma, Mab3 stained the MBA, cytoplasm, and nuclei of pneumocytes with type 2 morphology. In lung samples from the COVID-19 patient, detached pneumocytes showed high and dense Mab3 reactivity that often masked the nuclei and cytoplasmic structures, resulting in cords of pneumocytes with diffuse staining resembling hyaline membranes.Mab e11 -2 showed slight reactivity in pneumocytes and the MBA of normal lung parenchyma, but intensely stained the detached pneumocytes in the patient sample replicating the staining pattern of Mab3, but also diffusely stained the matrix that occupied the alveolar lumen (Figure 3).

[0272] Example 3. Histochemical and IHC characterization of obliterative lesions in a COVID-19 patient

[0273] A dense collagenous matrix obscures intracellular structures and desquamated pneumocytes in lesions that obliterate the alveolar lumen. Images of strings of pneumocytes lining a lesion suggest that these lesions increase in size as pneumocytes detach and synthesize the matrix that envelops and obscures them (Figure 4).

[0274] The pneumocytes lining the obliterative lesions express the SARS-CoV-2 nucleoprotein (N) and accumulate COL4A3 and COL4A5, revealing that the pneumocytes shed into the alveolar lumen are infected with SARS-CoV-2 (Figure 8). Although we confirmed the presence of SARS-CoV-2 in the paraffin-embedded samples using RT-qPCR procedures (not shown), all attempts to identify viral particles by electron microscopy in the deparaffinized samples were unsuccessful. However, using a standard double IHC stain (Agilent, USA) on the paraffin-embedded samples, we identified the expression of the SARS-CoV-2 nucleoprotein (N) in the pneumocytes lining the lesions that obliterated the alveolar lumen.Most of the desquamated, shed pneumocytes lining the obliterative lesions expressed abundant viral protein N, as well as abundant collagen IV of composition COL4A3 and COL4A5, revealing their infected condition and suggesting that infected pneumocytes are hidden within the obliterative lesions (Figure 8). The antibodies used were: anti-CK7 mouse (Agilent, USA); anti-N-SARS-CoV-2 rabbit (Sino Biological Catalog No.: 40143-019); anti-COL4A3 mouse (Mab3); anti-COL4A5 rabbit (LSBio Cat: LS-C119458); and anti-COL4A1A2 mouse (Agilent, USA).

[0275] In general, histopathological autopsy tissue blocks were fixed in 4% formaldehyde and embedded in paraffin; 3 pm thick sections were stained with hematoxylin-eosin, Masson's trichrome, or used for immunohistochemistry using the automated Autostainer Link 48 system (Agilent, USA).

[0276] Example 4. Ultrastructural characterization of alveolar lesions in COVID-19 patients with severe ARDS

[0277] The EM (electron microscopy) analysis reveals that epithelial-endothelial dissociation of the BAM and type 2 pneumocyte desquamation are processes associated with ARDS in COVID-19 (Figure 5).

[0278] Electron microscopy also shows that in a COVID-19 patient with severe ARDS, the extracellular matrix (ECM) of an obliterative lesion is produced, at least in part, by desquamated pneumocytes. Desquamated pneumocytes synthesize an electron-dense mesh that occupies both the intracellular and extracellular compartments (Figure 6).

[0279] The electron-dense mesh obscures pneumocytes within the obliterative alveolar lesions present in the COVID-19 lung with ARDS (Figure 7).

[0280] In general, the ultrastructural studies described here were performed using the paraffin-embedded specimen. A fragment was extracted from the area of ​​interest for deparaffinization with successive xylene baths followed by hydration. It was fixed in 2.5% glutaraldehyde and 1% osmium tetroxide and embedded in EPON resin blocks. The ultrathin sections were stained with uranyl acetate and Reynolds solution and examined using a Hitachi HT7700 transmission electron microscope.

[0281] Example 5. Recombinant nucleoprotein counterparts of SARS-CoV-2 and GPBP1 interact specifically

[0282] To investigate the recruitment of GPBP1 by SARS-CoV-2, we first looked for N-terminal sequence homologies between the SARS-CoV-2 and GPBP1 proteins, as these sequences typically determine the subcellular fate of newly synthesized polypeptides in ribosomes. Interestingly, we found that the SARS-CoV-2 N protein and GPBP1 share the N-terminal tetrapeptide with the sequence MSDN, suggesting that in vivo, the SARS-CoV-2 N protein and GPBP1 may eventually share a subcellular fate and, therefore, could interact. This was first explored using an in vitro recombinant approach with far-Western blot procedures (Figure 9). Under experimental conditions where GPBP1 did not bind to the SARS-CoV-2 spike (S) protein, it bound to the nucleoprotein (N) of this virus.Of particular interest was the observation that GPBP1 bound more efficiently to the viral N protein than to the NCI3 polypeptide that represents its natural ligand, that is, the human NC1 domain of the COL4A3 chain containing the KRGDS motif for GPBP1 binding in its N-terminal region.

[0283] Similar amounts of protein (500 ng) were analyzed by electrophoresis on 12% polyacrylamide gels in the presence of sodium dodecyl sulfate (SDS-PAGE) under non-reducing conditions. Proteins separated on the gel were visualized by Coomassie blue staining or transferred to a nitrocellulose membrane and stained with Ponceau red to assess the level of transfer. After stain removal, the membranes were blocked with 3% BSA in Tris-buffered saline (TBS) and incubated with GPBP1 (50 pg / ml) in TBS containing 0.05% Tween-20 (TBS-T). The membranes were then washed with TBS-T and incubated with N27-HRP. Alternatively, the blocked membranes were incubated with anti-Flag (M2)-HRP, a commercial mouse Mab that recognizes the FLAG (Sigma) protein conjugated to an HRP (a-Flag). Specific membrane-bound antibodies were detected using ECL reagent (Bio-Rad), and capture was performed on an Amersham Imager 680 UV (Cytiva).The production and characterization of Mab N27 is described in WO 2010 / 009856; FLAG-GPBP in Revert et al. 2018 Oncotarget 9:11020-45 and NCI3 in Gozalbo-Rovira et al. 2013 Kidney Int. 83, 438-45. Molecular weight standards were PageRuler™ Prestained Protein Ladder, Thermo Fisher, USA.

[0284] Example 6. The SARS-CoV-2 nucleoprotein (N) interacts with high affinity with GPBP1

[0285] Subsequently, biolayer interferometry or BLI was used to determine the affinity constant (KD) of the interaction of interest. A KD of 2.79E-08 M was estimated for the SARS-CoV-2 recombinant protein N-GPBP1 binding, a value slightly below the nM range commonly found for antigen-antibody binding (Figure).

[0286] Binding kinetics assays were performed using Octet K2 (ForteBio) in 0.005% Tween-20 TBS at 28°C with a stirring speed of 1,000 rpm. Briefly, Ni-NTA biosensors were loaded with N protein (Certest) at 0.01 mg / mL for 240 seconds (s), producing a typical ~2 nm signal. The biosensors were then equilibrated for 240 s to obtain a stable baseline. Association was performed for 80 s with intracellular BM40-FLAG-GPBP (Revert et al. 2018 Oncotarget 9:11020-45) serially diluted from 1 to 0.125 pM in 1:2 steps. Finally, dissociation was also performed for 240 s. A loaded sensor operated solely in test buffer was used as a drift control. The resulting curves were analyzed using Data Analysis HT software (ForteBio) with a 1:1 model for global fitting.

[0287] Example 7. Treatment with the compound of formula (IX) is associated with a rapid reduction of the collagenous matrix and re-epithelialization of the alveolar walls

[0288] A combined comparative analysis of hematoxylin and eosin (H&E), Masson's trichrome, and cytokeratin (CK7) staining on serial sections reveals that treatment with the compound of formula (IX) is associated with a significant reduction in the hyaline-appearing collagenous material that masked the pneumocytes in the obliterative alveolar lesions. In both specimens, the pneumocytes appeared to be re-epithelializing the alveolar walls, but in the untreated patient, they exhibited a cuboidal shape, while in the treated patient, the pneumocytes displayed a more physiological, flattened morphology, suggesting that the treatment induced more effective repair compared to the inoperative repair observed in long-standing ARDS patients with COVID-19 (Figure 11).

[0289] Example 8. IFC analysis of lung specimens from the COVID-19 patient control and treated with the compound of formula (IX)

[0290] Treatment with compound formula (IX) is associated with a complete absence of COL4A3 in re-epithelialized pneumocytes and an alveolar membrane (AM) composed of fine, tightly fused structures of COL4A3 and COL4A1. Detailed analysis reveals significant differences in the expression pattern between patients. Thus, while in patients who did not receive compound formula (IX), COL4A3 was intracellular, in patients who received the treatment, COL4A3 was located externally, assembled within the AM and occupying the alveolar lumen. In general, the flatter the re-epithelialized pneumocyte, the less COL4A3 it accumulated, while the more cuboidal it was, the more COL4A3 it accumulated internally, obscuring intracellular structures, including the nucleus. In the preserved alveolar structures, a coarse MBA of endothelial nature (COL4A1) in the untreated patient contrasted with a fine MBA with COL4A3 and COL4A1 in the patient who had received the treatment.Of particular interest was the finding of a large number of autofluorescent erythrocytes occupying a good number of alveolar spaces in the treated patient (Figure 12).

[0291] Treatment with the compound of formula (IX) induces COL4A5 expression in the MBA but not its release into the alveolar lumen (Figure 13). Example 9. Treatment with the compound of formula (IX) is associated with a reduction in plasma levels of inflammatory markers and alveolar damage (Figure 14).

[0292] Summary of examples 1-9

[0293] At a dose of 2 mg / kg / day, the compound of formula (IX) has demonstrated the expected efficacy (re-epithelialization) in lung tissue with diffuse alveolar damage (DAD) that still retained some alveolar structure in a patient with long-standing severe COVID-19. Accordingly, administration of the compound of formula (IX) was associated with a reversal of the inflammatory process, revealing it to be the first specific treatment against the origin of DAD that causes inflammation in ARDS of infectious origin (e.g., SARS-CoV-2), thus replacing current generic therapies (antibiotics and corticosteroids), which are not without toxicity, currently administered to these patients to control the hyperinflammatory state and in those with a compromised general condition.

[0294] Example 10. An increase in circulating GPBP1 levels is associated with MBA dissociation in patients with sepsis and ARDS

[0295] The inventors found elevated circulating levels of GPBP1 and MBA dissociation in patients with sepsis and ARDS (Figure 15). MBA dissociation was observed by EM, and blood levels of GPBP1 were determined by sandwich ELISA using rabbit polyclonal antibodies generated against the N-terminal region of GPBP1 as capture antibodies (Raya et al., 1999 J Biol Chem. 274:12642-49) and immunopurified chicken polyclonal antibodies against the characteristic 26-residues of GPBP1 for detection antibodies (Raya et al., 2000 J Biol Chem. 275: 40392-99).

[0296] Example 11. Patients with ARDS of non-COVID-19 septic origin showed GPBP1 overexpression in the alveolus and BAM dissociation

[0297] In sepsis, respiratory distress was associated with GPBP1 overexpression and epithelial-endothelial dissociation of the COL4-dependent basement membrane (BM). Thickened and dissociated BMs were observed in patients. The fluorescence peaks of COL4A3, GPBP1, and COL4A1 were sharp and aligned in the BM of the control group, whereas in patients with sepsis and ARDS, the fluorescence peaks were broad and not aligned. Specifically, the GPBP1 peak either aligned with COL4A3 (very frequently) or was located between the COL4A3 and COL4A1 peaks (Figure 16). The antibodies used were: Mab3 for COL4A3 (Saus et al., 1988 J Biol Chem. 263: 13374-80; Borza et al., 2000, J Biol Chem. 275; 6030-37), immunopurified chicken polyclonal antibodies against the characteristic 26-residues of GPB (Raya et al., 2000 J Biol Chem. 275: 40392-99) and goat anti-COL4A1 A2 (Millipore AB769) following the procedure detailed in Revert et al. 2007 Am J Pathol 171: 1419-30).Taken together, the findings reveal that sepsis-associated ARDS depends on a pathogenic mechanism that the compound of the invention of formula (IX) specifically inhibits.

[0298] The use of the compound of formula (IX) is intended to cover the lack of specific treatments for ARDS associated with sepsis that causes severe COVID-19 and by extension to ARDS of other etiologies.

[0299] REFERENCES

[0300] Borza et al., (2000) “The Goodpasture Autoantigen”, J Biol Chem. 275; 6030-37

[0301] Goza I bo-Ro vira et al. (2013) “Precise mapping of the Goodpasture epitope(s) using phage display, site-directed mutagenesis, and surface plasmon resonance” Kidney Int. 83, 438-45. Gupta et al. (2018) “Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations” Molecules 23, 1719

[0302] Katzenstein et al. (1976) “Diffuse Alveolar Damage-The Role of Oxygen, Shock, and Related Factors” American Journal of Pathology, vol. 85, no. 1, pp. 210-228

[0303] Markovic et al. (2020) “Prodrugs for Improved Drug Delivery: Lessons Learned from Recently Developed and Marketed Products” Pharmaceutics. 2020 Oct 29;12(11):1031

[0304] Raya et al., (1999) “Characterization of a novel type of serine / threonine kinase that specifically phosphorylates the human goodpasture antigen” J Biol Chem. 274:12642-49

[0305] Raya et al., (2000) “Goodpasture antigen-binding protein, the kinase that phosphorylates the goodpasture antigen, is an alternatively spliced variant implicated in autoimmune pathogenesis” J Biol Chem. 275: 40392-99

[0306] Revert et al., (2007) Increased Goodpasture antigen-binding protein expression induces type IV collagen disorganization and deposit of immunoglobulin A in glomerular basement membrane” Am J Pathol 171: 1419-30

[0307] Revert et al. (2018) “Selective targeting of collagen IV in the cancer cell microenvironment reduces tumor burden.” Oncotarget. 9:11020-45

[0308] Sadeque Hossain Mithu et al. (2021) “Advance Methodologies for Pharmaceutical Salt Synthesis” Cry st. Growth Des. 2021, 21, 2, 1358-1374

[0309] Saus et al., (1988) “Identification of the Goodpasture antigen as the alpha 3(IV) chain of collagen IV” J Biol Chem. 263: 13374-80

[0310] WO 2010 / 009856

[0311] WO 2011 / 054530

[0312] WO 2014 / 006020 WO 2015 / 044352 US 9066938 WO 2017 / 134146

Claims

CLAIMS 1. A compound for use in the treatment of acute respiratory distress syndrome wherein the compound is of formula (I), or a salt thereof: in which: R is selected from N and CRs; Rs is selected from the group consisting of: hydrogen; halogen; cyano; nitro; hydroxy; C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; halo(Ci-Ce alkyl); Ci-Ce alkoxy; halo(Ci-Ce alkoxy); amino; (C1-C6 alkyl)amino; di(Ci-Ce alkyl)amino; hydroxy(Ci-Ce alkyl); (C1-C6 alkoxy)Ci-Ce alkyl; amino(Ci-Ce alkyl); sulfanyl(Ci-Ce alkyl); (C1-C6 alkyl)sulfanyl(Ci-Ce alkyl); -(CH2)I-5-C(O)(Ci-C6 alkoxy); -(CH2)I-5-C(O)NH2; (aryl)C2-Ce alkyl; (Co-Ce)carbonyl and (heteroaryl)Ci-C6 alkyl; R1 is hydrogen; halogen; hydroxy; C1-C6 alkyl; halo(Ci-Ce alkyl); C1-C6 alkoxy; halo(Ci-Ce alkoxy; hydroxy(Ci-Ce alkyl); (C1-C6 alkoxy)Ci-Ce alkyl; amino(Ci-Ce alkyl); sulfanyl(Ci-Ce alkyl) or (C1-C6 alkyl)sulfanyl(Ci-Ce alkyl); R2 is C1-C6 alkyl; cyan; (Ci-Ce alkyl)thio(Ci-Ce alkyl); halo(Ci-Ce alkyl); C1-C6 alkoxy; halo(Ci-Ce alkoxy); hydroxy(Ci-Ce alkyl); (Ci-Ce alkoxy)Ci-Ce alkyl; formyl(Co-Ce alkyl); amino(Ci-C6 alkyl); sulfanyl(Ci-Ce alkyl); (Ci-Ce alkyl)sulfanyl(Ci-Ce alkyl); -(CH2)I-5- C(O)OH; -(CH2)I-5-C(O)O-;-(CH2)I-5-C(O)(CI-C6alkoxy); -(CH2)I-5-C(O)NH2; -CH=CH- C(O)(Ci-Ce alkoxy); (aryl) C1-C6 alkyl; (Co-Ce)carbonyl or (heteroaryl)Ci-Ce alkyl; R3 is C1–C6 alkyl; halo(Ci-Ce alkyl); Ci-Ce alkoxy; halo(Ci-Ce alkoxy); hydroxy(Ci-Ce alkyl); (Ci-Ce alkoxy)Ci-Ce alkyl; formyl(Co-Ce alkyl); amino(Ci-Ce alkyl); sulfanyl(Ci-Ce alkyl); -(Cy-C6alkyl)sulfanyl(Cy-C6alkyl); -C(O)OH; -C(O)Q-; -(CH2)I-5-C(O)OH; -(CH2)I- 5-C(O)O'; -C(O)(Ci-C6alkoxy); -(CH2)I-5-C(O)(CI-C6alkoxy); -C(O)NH2; -(CH2)I-5-C(O)NH2; - C(O)NH(CI-C6 alkyl); -(CH2)I-5-C(O)NH(CI-C6alkyl); -C(O)N(CI-C6alkyl)2; -(CH2)I-5- C(O)N(CI-C6alkyl)2; -CH=CH-C(O)OH; -CH=CH-C(O)O'; -CH=CH-C(O)(Ci-C e alkoxy); (aryl) Oí-Ce alkyl or (heteroaryl) Ci-Ce alkyl; y R4 is hydroxy; halogen; Ci-Ce alkyl; Ci-Ce alkoxy; halo(Ci-C6 alkoxy); benzyloxy; -C(O)OH; - 0(0)0'; -(CH2)I-5-C(O)OH; -(CH2)I-5-C(O)O-; -(CH2)I-5-C(O)(CI-C6alkoxy); -(CH2)I-5-C(O)NH2; -(CH2)I-5-C(O)NH(CI-C6alkyl); -(CH2)I-5-C(O)N(CI-C6alkyl)2-CH=CH-C(O)OH; - CH=CH-C(O)O-; -CH=CH-C(O)(Ci-C ealkoxy); -O(CH2)I-5-C(O)OH; -O(CH2)I-5-C(O)O-; - O(CH2)I-5-C(O)(CI-C6alkoxy); (aryl)Ci-C6 alkyl or (heteroaryl)Ci-C6 alkyl.

2. A compound for use according to claim 1, wherein the compound has formula (II), or a salt thereof: and in which R, Ri, R2, R3 and R4 are defined as in formula (I).

3. A compound for use according to any of claim 1 or 2, wherein the compound having the formula, or a salt thereof: and in which R1, R2, R3, R4 and Rs are defined as in formula (I).

4. A compound for use according to any of claims 1 to 3, wherein: R is selected from N and CRs; R1 is hydrogen; halogen; hydroxy; C1-C6 alkyl; halo(Ci-Ce alkyl); C1-C6 alkoxy or halo(Ci-Ce alkoxy); R2 is C1–C6 alkyl; (Oi-Ce alkyl)thio(Ci-Ce alkyl); halo(Ci-Ce alkyl); hydroxy(Ci-Ce alkyl); (OI-Ce alkoxy)Ci-Ce alkyl; formyl(C). o -C6 alkyl); amino(Ci-Ce alkyl), -CH=CH- C(O)(Ci-C6alkoxy); -(CH2)I-5-C(O)OH; -(CH2)I-5-C(O)O-; or sulfanyl(Cy-C6alkyl); Ci-C6alkyl R3es; -(CH2)I-5-C(O)OH; -(CH2)I-5-C(O)O-; -C(O)OH; -C(O)O'; -(CH2)I-5- C(O)(C1-C6alkoxy); -(CH2)I-5-C(O)NH2; -(CH2)I-5-C(O)NH(CI-C6alkyl); -(CH2)I-5-C(O)N(CI- 06 alkyl)2; -CH=CH-C(O)OH; -CH=CH-C(O)O'; -CH=CH-C(O)(Ci-C e alkoxy); R4 is hydroxy; Hearing-Ce alkoxy; halo(Ci-C6 alkoxy); -O(CH2)I-5-C(O)OH; -O(CH2)I-5-C(O)O'; - O(CH2)I-5-C(O)(CI-C6alcose); or phenosis; Rs, is selected from the group consisting of: hydrogen; halogen; cyano; nitro; hydroxy; C1-Ce alkyl; C2-C6 alkenyl; C2-C6 alkynyl; halo(Ci-C6 alkyl); Oi-Ce alkoxy; halo(Ci-C6 alkoxy); amino; (C1-C6 alkyl)amino; di(Ci-Ce alkyl)amino; hydroxy(Ci-Ce alkyl); (C1-C6 alkoxy)Ci-C6 alkyl; (Ci-C6)carbonyl and amino(Ci-C6 alkyl).

5. A compound for use according to any one of claims 1 to 4, wherein the compound is selected from the group consisting of: 7a, 13a, 1a, 14a, 21a, 1b, 1c, 2a, 7b, 7c, 11a, 11b, 12a, 12b, 13b, 13c, 14b, 14c, 15a, 15b, 15c, 18a, 18b, 18c, 19a, 19b, 19c, 20a, 20b, 20c, 21b, 21c, 21d, 21e, 21f, 21g, 21h, 21i, 21j, 21k, 211, 22a, 22b, 22b', 22c, 22d, 22e, 22f, 22g, 22h, 22i, 22j, 22k, 221, 23a, 23b, 23c, 24a, 24b, 24c, 28, 31, 32, 38, 39, T55, T109a, T109b, or a salt thereof: (E) Ethyl-3-[4"-(benzyloxy)-2'-formíl-3-methyl-(1,1';4',1") terphenyl-2"-yl]acrylate (7a); 3-[4"-hydroxy-2'-(hydroxymethyl)-3-methyl-(1,1';4',1") terphenyl-2"-yl]ethyl propionate (13a); (E)-3-[4"-(benzyloxy)-2'-form¡l-3-met¡l-(1,1';4',1") terphenyl-2"-yl]ethyl acrylate (1a); 3-[2'-(fluoromethyl)-4"-hydrox¡-3-met¡l-(1,1';4',1")terphenyl-2"-yl]ethyl prop¡onate (14a); 3-[2'-(hydroxymethyl)-4"-methoxy-3-methyl-(1,1';4',1"terphenyl-2"-yl]ethylprop¡onate (21a); ​​acid 3-[4"-hydroxy-2'-(hydroxymethyl)-3-(trifluoromethyl)-(4',1';(4',1')- ")terphenyl-2"-yl]propionic acid (1b) 3-[4-h id roxi-3'-(h id roxymethyl)-4'-(pyrid in-3-yl) bife n il-2-yl] propionic (1 c); 3-[4"-hydroxy-2"-isopropyl-3-methyl-(1,1';4',1") terphenyl-2'-yl]propionic acid (2a); (E)-3-[4"-(benzyloxy)-2'-formyl-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-yl]ethyl acrylate (7b); (E)-3-[4-(benzyloxy)-3'-formyl-4'-2-la-ethylphenyl]-3 (7c); 3-[4"-hydroxy-2',3-d¡met¡l-(1,1';4',1")terphenyl-2"-yl]ethyl prop¡onate (11a); 3-[4"-hidroxi-2'-methyl-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-yl]propionic acid (11b); 3-[4"-hidroxi-2'-methyl-3-(trifluoromethyl)-(1,1';4',1") terphenyl-2"-yl]propionic acid (12b); 3-[4"-hidroxi-2'-(hidroximethyl)-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-yl]ethylproponate (13b); Ethyl 3-[4-hidroxi-3'-(hidroximethyl)-4'-(pyridin-3-yl)biphenyl-2-yl]propionate (13c); 3-[2'-(fluoromethyl)-4"-hidroxy-3-(trifluoromethyl)-(1,1';4',1") ethyl terphenyl-2"yl]propionate (14b); 3-[3'-(fluoromethyl)-4-hydroxy-4'-(pyridin-3-yl)biphenyl-2-yl]ethyl propionate (14c); acid 3-[2'-(fluoromethyl)-4"-hidrox¡-3-met¡l-(1,1';4',1")terphenyl-2"-ilo]prop¡ón¡co (15a); acid 3-[2'-(fluoromethyl)-4"-hidroxy-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-ilo]prop¡ón¡co (15b); 3-[3'-(fl uoromethyl)-4-h id roxi-4'-(pyridyl-3-yl)biphenyl-2-yl] propión ic acid (15c); (E)-3-[4"-(bencyloxy)-2'-(difluoromethyl)-3-methyl-(1,1';4',1")terfenyl-2"-yl]ethyl acrylate (18a); (E)-3-[4"-(bencyloxy)-2'-(difluoromethyl)-3-(trifluoromethyl)-(1,1';4',1")terfenyl-2"-yl]ethyl acrylate (18b); (E)-3-[4-(bencyloxy)-3'-(d ifluoromethyl)-4'-(pyrid yn-3-ylo) biphenyl-2-ylo]ethyl acrylate (18c); Ethyl 3-[2'-(difluoromethyl)-4"-hidroxy-3-methyl-(1,1';4',1")terphenyl-2"-ilo]proponate (19a); ethyl(19b); 3-[3'-(difluoromethyl)-4-hydroxy-4'-(pyridin-3-yl)biphenyl-2-yl] acid 3-[2'-(difluoromethyl)-4"-hydroxy-3-methyl-(1,1';4',1"terphenyl-2"-yl]propionate of ethyl (19c); 3-[2'-(difluoromethyl)-4"-hydroxy-3-methyl-(1,1';4',1"terphenyl-2"-yl]prop¡ón¡co acid (20a); 3-[2'-(difluoromethyl)-4"-hydroxy-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-yl]propionic acid (20b); 3-[3'-(difluoromethyl)-4-hydroxy-4'-(pyridin-3-yl)biphenyl-2-yl]propionic acid (20c); Ethyl 3-[4"-methoxy-3,2'-dimethyl-(1,1';4',1")terphenyl-2"-yl]prop¡onate (21b); Ethyl 3-[2'-(fluoromethyl)-4"-methoxy-3-methyl-(1,1';4',1"terphenyl-2"-yl]propionate (21c); Ethyl 3-[2'-(difluoromethyl)-4"-methoxy-3-methyl-(1,1';4',1") terphenyl-2"-yl]propionate (21d); Ethyl 3-[2'-(hydroxymethyl)-4"-methoxy-3-(trifluoromethyl)-(1,1';4',1") terphenyl-2"-yl]propionate (21e); Ethyl 3-[2'-methyl-4"-methoxy-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-yl]propionate (21 f); Ethyl 3-[2'-(fluoromethyl)-4"-methoxy-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-yl]propionate (21 g); Ethyl 3-[2'-(difluoromethyl)-4"-methoxy-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"yl]propionate (21 h); Ethyl 3-[3'-(hydroxymethyl)-4-methoxy-4'-(pyridin-3-yl)biphenyl-2-yl]propionate (21 i); Ethyl 3-[4-methoxy-3'-methyl-4'-(pyridin-3-yl)biphenyl-2-yl]propionate (21 j); Ethyl 3-[3'-(fluoromethyl)-4-methoxy-4'-(pyridin-3-yl)biphenyl-2-yl]propionate (21 k); Ethyl 3-[3'-(difluoromethyl)-4-methoxy-4'-(pyridin-3-yl)biphenyl-2-yl]propionate (211); acid 3-[2'-(hydroxymethyl)-4"-methoxy-3-methyl-(1,1';4',1"terphenyl-2"-yl]prop¡on¡co (22a); acid 3-[4"-methoxy-3,2'-dimethonel-(1,1'-cophenyl]prop2"terp2"ter Formula (V)); anion 3-[4"-methoxy-3,2'-dimet¡l-(1,1';4',1"terphenyl-2"-yl]prop¡onate (22b', Formula (VI)); acid. 3-[2'-(fluoromethyl)-4"-methoxy-3-met¡l-(1,1';4',1"terphenyl-2"-yl]prop¡on¡co (22c); acid 3-[2'-(difluoromethyl)-4"-methox¡-3-methoxyl cophenol-4-prop¡on-'1,1"-ter (22d); acid 3-[2'-(hydroxymethyl)-4"-methoxy-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-ylo]propon¡co (22e); 3-[2'-methyl-4"-methox¡-3-(tnfluoromethyl)-(1,1';4',1"terphenyl-2"-yl]prop¡on¡co (22f); acid 3-[2'-(fluoromethyl)-4"-methox¡--3-(tnfluoromethyl)-(1,1';4',1")terphenyl-2"-yl]prop¡oneco (22g); acid 3-[2'-(difluoromethyl)-4"-methoxy-3-(trifluoromethyl)-(1,1';4',1")terphenyl-2"-ylo]prop¡onco (22h); 3-[3'-(hydroxymethyl)-4-methoxy-4'-(pyridin-3-yl)-biphenyl-2-yl]propionic acid (22¡); 3-[4-methoxy-3'-methyl-4'-(pyridin-3-yl)biphenyl-2-yl]propionic acid (22j); 3-[3'-(fluoromethyl)-4-methoxy-4'-(pyridin-3-yl)-biphenyl-2-yl]propionic acid (22k); 3-[3'-(difluoromethyl)-4-methoxy-4'-(pyridin-3-yl)-biphenyl-2-yl]propionic acid (22I); 3-[3,2'-dimethyl-4"-propox¡-(1,1';4',1")terphenyl-2"-yl]ethyl prop¡onate (23a); 3-[4"-(etoxiccarbonylmethoxy)-3,2'-dimethyl-(1,1';4',1")terphenyl-2"-yl]ethyl prop¡onate (23b); of ethyl (23c); acid 3-[3,2'-dimethyl-4"-propox¡-(1,1';4',1"terphenyl-2"-ylo]prop¡on¡co (24a); acid 3-[4"-(carboxymethoxy)-3,2'-d¡l-(1,1';4',1")terphenyl-2"-yl]prop¡onco (24b); acid 3-[2'-methyl-4"-propox¡--3-(tnfluoromethyl)-(1,1';4',1"terphenyl-2"-ilo]prop¡onco (24c); 3-[3'-formyl-4-methoxy-4'-(pyridin-3-yl)biphenyl-2-yl]ethyl propionate (28); ethyl 3-[4,4"-dimethoxy-3,2'-dimethyl-(1,1';4',1")terphenyl-2"-yl]propionate (31); 3-[4,4"-dimethoxy-3,2'-dimethyl-(1,1';4',1")terphenyl-2"-yl]propionic acid (32); (E) Ethyl-3-[4"-(benzyloxy)-3-formyl-2"-isopropyl-(1,1';4',1")terphenyl-2'-yl]acrylate (38); ethyl 3-[4"-hydroxy-2"-isopropyl-3-methyl-(1,1';4',1") terphenyl-2'-yl]propionate (39); 3-[3-chloro-2'-methyl-4,4"-dimethoxy-(1,1';4',1")terphenyl-2"-yl]propionic acid (T55); (E)-3-[2'-(hydroxymethyl)-4"-methoxy-3-methyl-(1,1';4',1")terphenyl-2"-¡l]acrylic acid (T109a, Formula (Vil)); and anion (E)-3-[2'-(hydroxymethyl)-4"-methoxy-3-methyl-(1,1';4',1")terphenyl-2"-yl]acrylate (T109b, Formula (VIII)).

6. A compound for use according to any of claims 1 to 5, wherein the compound has formula (V) or (VI), or a salt thereof:

7. A compound for use according to any of claims 1 to 5, wherein the compound has formula (Vil) or (VIII), or a salt thereof: (HIV).

8. A compound for use according to any one of claims 1 to 7, wherein the compound is a salt in which the anion is the compound of formula (I) to (VIII); and the cation of the salt is selected from the group consisting of: aluminum, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethylamine, copper, and zinc.

9. A compound for use according to any of claims 1 to 8, wherein the salt of the compound is a combination of the compound of formula (I) to (VIII), with an alkali or alkaline earth metal.

10. A compound for use according to any of claims 1 to 6, wherein the compound is a sodium salt of formula (IX):

11. A compound for use according to any of claims 1 to 5 or 7, wherein the compound is a sodium salt of formula (X): (X).

12. A pharmaceutical composition for use in the treatment of acute respiratory distress syndrome comprising the compound or salt of any of claims 1 to 11.

13. A medicament for use in the treatment of acute respiratory distress syndrome comprising the compound or salt of any of claims 1 to 11.

14. Use of the compound or salt of any one of claims 1 to 11 to manufacture a medicament for the treatment of acute respiratory distress syndrome.

15. Kit for use in the treatment of acute respiratory distress syndrome containing the compound or salt of any one of claims 1 to 11.

16. Unit dosage for use in the treatment of acute respiratory distress syndrome comprising the compound or salt of any one of claims 1 to 11.

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