RU2830584C1 - Cxcl8 inhibitors for use in treating covid-19 - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmaceutics, namely discloses the use of a CXCL8 inhibitor or a pharmaceutical composition containing a CXCL8 inhibitor and at least one inert pharmaceutically acceptable excipient, in treating a patient with pneumonia caused by COVID-19, wherein said CXCL8 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In general formula (I), where R¹ is selected from linear or branched C1-C6 alkyl, benzoyl, phenoxy and trifluoromethanesulfonyloxy; R² is selected from a hydrogen atom and a linear or branched C1-C3 alkyl; and R³ is a linear or branched C1-C6 alkyl or trifluoromethyl. EFFECT: use of the invention enables the effective treatment of a patient with pneumonia caused by COVID-19.

11 cl, 1 dwg, 2 tbl, 2 ex

Description

FIELD OF INVENTION

The present invention relates to compounds for the treatment of COVID-19, in particular for use in improving respiratory function in patients suffering from pneumonia caused by SARS-CoV-2.

LEVEL OF TECHNOLOGY

Coronaviruses (Covs) are a large family of viruses belonging to the Coronaviridae family and are enveloped positive-sense RNA viruses. The limited number of coronaviruses known to circulate in humans have been considered to cause mild infections and in the past they were regarded as relatively harmless human respiratory pathogens. However, in recent years, the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome virus (MERS) has shown that some coronaviruses can cause severe and sometimes fatal respiratory tract infections in humans (Pereira, H et al., 1989 Coronaviridae. Andrewes' Viruses of Vertebrates, 5 ^th ed.pp. 42-57; Holmes, KV et al., Virology 1996,1: 1075-1093).

In December 2019, cases of SARS, which were identified as being caused by a new coronavirus, emerged in Wuhan, China and then quickly spread around the world. The World Health Organization officially named the new disease "COVID-19," while the International Committee on Taxonomy of Viruses named the new virus "SARS-CoV-2."

Symptoms of human infection with SARS-CoV-2 typically include fever, fatigue, dry cough, and shortness of breath. Studies on the epidemiological, clinical characteristics, and treatment outcomes of patients infected with SARS-CoV-2 have shown that the infection causes pneumonia similar to known SARS-CoV pneumonia with respiratory failure. Notably, a significant percentage of COVID-19 pneumonia cases progress to severe and critical forms of the disease, among which the most common complications are acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), resulting in a large number of hospitalized patients requiring supplemental oxygen, mechanical ventilation, or even extracorporeal membrane oxygenation (ECMO).

In the case of coronaviruses, direct cytopathic effects and viral evasion of the host immune response are thought to play an important role in disease severity (Min et al, Sci Rep 2016; 6: 25359; Channappanavar et al, Semin Immunopathol 2017, 39(5): 529-539).

A recent study (Chuan Qin et al, Clin Infect Dis, 2020, doi: 10.1093/cid/ciaa248), which compared laboratory parameters of severe COVID-19 patients with respiratory distress and low oxygen saturation with those of patients with milder forms, reported that patients with severe COVID-19 had a dysregulated immune response with severe lymphocytopenia. In addition, severe patients also had higher serum levels of proinflammatory cytokines such as TNF-α, IL-1, and IL-6, and chemokines such as IL-8.

From the above data, it can be concluded that patients with severe COVID-19 pneumonia have an impaired immune system, resulting in impaired defense mechanisms against the virus, extensive lung infection and an associated inflammatory response with the formation of a cytokine storm, which aggravates tissue damage caused by the virus.

Another factor that has been suggested to worsen the severity of respiratory distress in COVID-19 patients appears to be exposure to air pollution, particularly particulate matter.

A positive correlation has been demonstrated between exposure to particulate matter, particularly PM ₁₀ levels, and an increased risk of death in patients with SARS-CoV infection (Yan Cui et al, Environmental Health 2003, 2(1):15). Preliminary data suggest that the same correlation also exists for SARS-CoV-2 infections, with severe cases concentrated in areas with high PM ₁₀ levels.

Particulate matter has been shown to cause lung injury and fibrosis and increase susceptibility to various pathogens, including viruses, thereby increasing the risk and severity of respiratory infections (Liyao Yang, 2020, Front Cell Dev Biol 8, 91; I-Yin Cheng et al, Int J Mol. Sci., 2020, 21, 227; Horne et al, Am J Respir Crit Care Med, 2018, 198(6), 759).

Currently, clinical management of COVID-19 pneumonia includes prophylaxis of coinfection and supportive care for respiratory failure, including supplemental oxygen and mechanical ventilation when indicated.

Therefore, there is an urgent need to identify an effective therapeutic approach to this disease, in particular to improve respiratory function, which is severely impaired in severe patients and is the most critical period of the disease, which can lead to death of patients.

Currently, a large number of drugs are undergoing clinical trials on COVID-19 patients around the world.

In acute lung injury, compounds that act by inhibiting neutrophil recruitment, such as CXCL8 inhibitors, have been proposed as potential therapeutic approaches. In particular, the therapeutic potential of the CXCL8 inhibitor reparixin has been studied in mouse models of LPS-induced lung inflammation and acid-induced ALI (Zambrock et al, Br J Pharmacol 2008;155:357-364).

However, the above work suggests that treatment with reparixin may only be effective in the early, non-bacterial phases of ALI, as neutrophils are the first line of host defense against pathogens and impaired neutrophil recruitment may have deleterious effects in the presence of infection (Zambrock et al, Br J Pharmacol 2008,155:357-364; Moore et al, J Immunol. 2000, 164:908-915). This aspect is particularly important for COVID-19 patients given the observed immune dysregulation.

The biological activity of CXCL8 is mediated by interaction with two receptors, CXCR1 and CXCR2. CXCR1 is selective for CXCL8, whereas CXCR2 is a promiscuous receptor that binds a number of different cytokines and chemokines, such as CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, and CXCL7 (Baggiolini, M., (2000) Immunol. Rev. 177, 5-7).

ESSENCE OF THE INVENTION

The present inventors have now unexpectedly found that administration of a CXCL8 inhibitor, such as reparixin, to patients with COVID-19 pneumonia is able to improve respiratory function measured as the ratio of arterial oxygen partial pressure (PaO ₂ ) to inspiratory O ₂ fraction (FiO ₂ ).

In addition, the present inventors have found that administering a CXCL8 inhibitor, such as reparixin, to patients with severe COVID-19 pneumonia is more effective in preventing progression to more severe respiratory disease compared to standard treatment alone. In fact, these patients have fewer days of oxygen use and shorter duration of mechanical ventilation compared to those treated with standard treatment alone. In addition, treatment with a CXCL8 inhibitor results in a shorter recovery time for patients.

Accordingly, a first object of the present invention is a CXCL8 inhibitor for use in the treatment of patients with COVID-19 pneumonia.

A second object of the invention is a pharmaceutical composition comprising i) a CXCL8 inhibitor and ii) at least one inert pharmaceutically acceptable excipient, for use in the treatment of patients with pneumonia caused by COVID-19.

A third object of the invention is a method for treating pneumonia caused by COVID-19, comprising administering to a patient affected by the disease a CXCL8 inhibitor.

FIGURES

Figure 1 shows the absence of a composite event (at least one of the following events: death, need for supplemental oxygen, use of invasive mechanical ventilation, intensive care unit admission, and use of rescue medications for any reason), measured as a percentage expressed as a decimal, over time for the reparixin group and the control group, as described in Example 1. The numbers at the bottom of the figures corresponding to reparixin and standard of care indicate the number of patients assessed at each time point for the reparixin group and the control group, respectively.

DETAILED DESCRIPTION OF THE INVENTION

The first object of the present invention is a CXCL8 inhibitor for use in the treatment of patients with COVID-19 pneumonia.

According to the present invention, "COVID-19 pneumonia" refers to an inflammatory condition of the lungs associated with SARS-CoV-2 infection. It is a severe complication of COVID-19 that affects a proportion of patients.

Preferably, said CXCL8 inhibitor for use in the treatment of patients with COVID-19 pneumonia is administered in combination with standard treatment for patients with COVID-19.

According to the present invention, “standard treatment for patients with COVID-19” means a pharmacological treatment that includes one or more drugs that have been approved by regulatory authorities i) as a treatment for COVID-19 or ii) as a treatment for other pathological conditions and their symptoms and that are used in clinical practice to treat symptoms and complications associated with COVID-19.

Preferably, said standard of treatment comprises treating the patient with at least one drug selected from:

i) antiviral drugs, preferably remdesivir;

ii) antipyretic, analgesic and anti-inflammatory drugs, preferably non-steroidal anti-inflammatory drugs, corticosteroids, cytokine, chemokine and interleukin inhibitors, more preferably selected from dexamethasone, paracetamol, anakinra, celecoxib, prednisone, prednisolone, methylprednisolone, pyrirone and tramadol;

iii) antibiotics, preferably selected from piperacillin, in combination with tazobactam, azithromycin and ceftriaxone; and

iv) anticoagulants and antithrombotic drugs, preferably selected from enoxaparin and acetylsalicylic acid.

Preferably, said CXCL8 inhibitor is intended for use to improve respiratory function in said patients, where said respiratory function is measured as the ratio of partial oxygen tension in arterial blood ( _PaO2 ) to fractional inspired _O2 ( _FiO2 ).

It is preferable that the above patients have impaired respiratory function.

In one embodiment of the invention, it is preferred that in said patients the values of the partial pressure of oxygen in arterial blood (PaO ₂ ) to the fractional O ₂ on inspiration (FiO ₂ ) before the treatment according to the invention are below 400 mmHg, more preferably below 300 mmHg, below 200 mmHg or below 100 mmHg (where 1 mmHg = 0.133 kPa). More preferably, in said patients the values of the ratio of the partial pressure of oxygen in arterial blood (PaO ₂ ) to the fractional O ₂ on inspiration (FiO ₂ ) are in the range between 100 and 300 mmHg.

In another embodiment of the invention, also in combination with the previous embodiment, patients experience respiratory distress with a respiratory rate of about 30 or more breaths/min or higher without oxygen support.

Preferably, said improvement in respiratory function in said patients comprises an increase in the partial pressure of oxygen in arterial blood ( _PaO2 ) to fractional inspired _O2 ( _FiO2 ) by at least 20%, 50%, 80%, 100%, 120%, 150%, 200% or 250% compared to the ratio before treatment.

Preferably, said improvement in respiratory function in said patients includes an increase in the ratio of partial oxygen tension in arterial blood ( _PaO2 ) to fractional inspired _O2 ( _FiO2 ) to a value greater than 400 mmHg.

It is preferable for these patients with COVID-19 pneumonia to have lymphopenia.

According to a preferred embodiment of the invention, said patients with lymphocytopenia are adult patients (14 years of age and older) and have a blood lymphocyte concentration of below 1000, below 900, below 850, below 800, or below 750 cells/microliter.

According to another preferred embodiment of the invention, said patients with lymphocytopenia are children (under 14 years of age) and have a blood lymphocyte concentration of below 3000, below 2800, below 2500, below 2300, or below 2000 cells/microliter.

In one embodiment of the invention, said improvement in respiratory function in said patients means reducing, delaying or preventing the need for supplemental oxygen, the use of mechanical ventilation or hospitalization in an intensive care unit.

Preferably, said patients with COVID-19 pneumonia are exposed to PM ₁₀ at levels above 50 μg/ ^m3 for more than 20 days, preferably more than 30 days, even more preferably for 35 days during the year preceding infection with SARS-CoV-2. According to the present invention, the term PM ₁₀ refers to the mass of particles present in the air having a 50% threshold for particles with an aerodynamic diameter of 10 microns.

Preferably, said CXCL8 inhibitor is intended for use to shorten the time of clinical recovery of said patients. According to the present invention, the time of "clinical recovery" is understood to mean the period of time from the onset to the disappearance of symptoms.

The term "CXCL8 inhibitor" according to the present application refers to a compound capable of inhibiting, partially or completely, the biological activity of CXCL8. Such a compound may act by reducing the expression of CXCL8 or its receptor(s) or by inhibiting the initiation of intracellular signaling activated by the CXCL8 receptor(s). Preferably, said inhibitor of CXCL8 activity is capable of inhibiting at least 60%, preferably at least 70%, more preferably at least 80%, even more preferably at least 90% of the PMN chemotaxis induced by the optimal concentration of CXCL8 (1 nM) at a concentration equal to or below 500 nM, preferably below 100 nM.

According to a preferred embodiment of the invention, the CXCL8 inhibitor of the present invention inhibits CXCL8 activity mediated by the CXCR1 receptor or mediated by both CXCR1 and CXCR2 receptors. Preferably, according to this embodiment, said CXCL8 inhibitor is an inhibitor of CXCL8 receptor(s) that inhibits the binding of CXCL8 to its receptor(s) and/or the intracellular signaling activated by the binding of CXCL8 to its receptor(s). Preferably, said CXCL8 receptor inhibitor is either an allosteric inhibitor or an orthosteric antagonist of the CXCR1 receptor or of both CXCR1 and CXCR2 receptors.

More preferably, the CXCL8 receptor(s) inhibitor of the invention has an IC ₅₀ value for the CXCR1 receptor in the low nanomolar range, preferably in the range of 0.02-5 nanomolar.

Preferably, said CXCL8 inhibitor is selected from low molecular weight molecules, peptides and antibodies, more preferably, it is a low molecular weight molecule.

CXCL8 inhibitors as defined above, capable of inhibiting CXCL8 activity mediated by the CXCR1 receptor or mediated by both the CXCR1 receptor and the CXCR2 receptor, are well known to those skilled in the art.

To date, several CXCL8 inhibitors have been described, such as small molecules, peptides, and antibodies, many of which are currently in clinical trials or used in therapy (Jie Jack, Expert Opinion Ther. Patents, 2001, 11(12), Chao J. et al., Bioorganic & Medicinal Chemistry Letters 17, 2007, p. 3778-3783, Busch-Petersen J. Current Topics in Medicinal Chemistry, 2006, 6, p. 1345-135, Allegretti et al, Immunology Letters 2012, Vol. 145, p. 68-78).

Preferred CXCL8 inhibitors according to the present invention are described in WO2000/024710A1 and WO2005/090295, which also describe their method of synthesis, their activity as CXCL8 inhibitors, as well as their use as inhibitors of CXCL8-induced neutrophil chemotaxis and degranulation and in the treatment of CXCL8-dependent pathologies.

Among them, particularly preferred CXCL8 inhibitors of the present invention are inhibitors of the following formula (I):

Where

R ¹ is selected from a linear or branched C ₁ -C ₆ alkyl, benzoyl, phenoxy and trifluoromethanesulfonyloxy;

R ² is selected from a hydrogen atom and a linear or branched C ₁ -C ₃ alkyl; and

R ³ is a linear or branched C ₁ -C ₆ alkyl or trifluoromethyl,

or a pharmaceutically acceptable salt thereof.

Preferably, R ¹ is selected from benzoyl, isobutyl and trifluoromethanesulfonyloxy. More preferably, R ¹ is preferably bonded to the phenyl ring at the 3- or 4-position. According to a most preferred embodiment, R ¹ is 3-benzoyl, 4-isobutyl or 4-trifluoromethanesulfonyloxy.

Preferably, R ² is selected from a hydrogen atom or methyl.

Preferably, R ³ is selected from linear or branched C ₁ -C ₆ alkyl, more preferably from linear or branched C ₁ -C ₃ alkyl. According to a most preferred embodiment, R ³ is methyl.

Preferably, the chiral carbon of the compounds of formula (I) has the RS- or R-configuration, more preferably it has the R-configuration.

Particularly preferred of the said CXCL8 inhibitors of formula (I) are:

- 2-(4-isobutylphenyl)propionyl methanesulfonamide, preferably R-(-)-2-(4-isobutylphenyl)propionyl methanesulfonamide and its pharmaceutically acceptable salts, preferably its lysine salt (also known as reparixin), and 2-(4-trifluoromethanesulfonyloxy)phenyl]-N-methanesulfonyl propionamide, preferably R(-)-2-(4-trifluoromethanesulfonyloxy)phenyl]-N-methanesulfonyl propionamide (and its pharmaceutically acceptable salts, in particular the sodium salt (also known as ladarixin).

Furthermore, other preferred CXCL8 inhibitors according to the present invention are those described in WO2010/031835, which also describes their method of synthesis, their activity as CXCL8 inhibitors, as well as their use as inhibitors of CXCL8-induced neutrophil chemotaxis and degranulation and in the treatment of CXCL8-dependent pathologies.

Among them, CXCL8 inhibitors particularly preferred in the present invention are inhibitors of the following formula (II):

and their pharmaceutically acceptable salts, where:

R1 represents hydrogen;

X represents OH;

R2 is hydrogen or linear C ₁ -C ₄ alkyl,

Y is a heteroatom selected from S, O and N,

Z is selected from linear or branched _C1 - _C4 alkyl, linear or branched _C1 - _C4 alkoxy, halogen _C1 - _C3 alkyl and halogen _C1 - _C3 alkoxy.

Preferably, the chiral carbon in the compounds of formula (II) has the RS- or S-configuration, more preferably the S-configuration.

Particularly preferred of the said CXCL8 inhibitors of formula (II) is 2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid, preferably (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid and its pharmaceutically acceptable salts, preferably its sodium salt.

According to an alternative embodiment of the invention, the CXCL8 inhibitor of the present invention inhibits CXCL8 activity mediated by the CXCR2 receptor. Preferably, according to this embodiment, said CXCL8 inhibitor is an inhibitor of the CXCL8 receptor(s) that inhibits the binding of CXCL8 to the CXCR2 receptor and/or the intracellular signaling activated by the binding of CXCL8 to the CXCR2 receptor. Preferably, said CXCL8 receptor inhibitor is either an allosteric inhibitor or an orthosteric antagonist of the CXCR2 receptor.

More preferably, the CXCL8 receptor(s) inhibitor according to the present invention has an IC ₅₀ value with respect to the CXCR2 receptor in the low nanomolar range, preferably in the range of 0.02-5 nanomolar.

Preferred CXCL8 inhibitors according to this embodiment of the invention are those described in WO2007135080.

Among them, CXCL8 inhibitors particularly preferred in the present invention are inhibitors of the following formula (III):

and their pharmaceutically acceptable salts, where:

R is selected from

H, OH, C ₁ -C ₅ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₂ -C ₅ -alkenyl, C ₁ -C ₅ -alkoxy and phenyl,

a heteroaryl group selected from unsubstituted pyrrole, thiophene, furan, indole, imidazole, thiazole, oxazole, pyridine and pyrimidine,

a residue of the formula CH ₂ CH ₂ O(CH ₂ CH ₂ ) _n Rʺ, where Rʺ is H or C ₁ -C ₅ alkyl and n is an integer from 0 to 2;

R is selected from

- linear or branched C ₁ -C ₅ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₂ -C ₅ -alkenyl and trifluoromethyl;

- phenyl, unsubstituted or substituted by a group selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl;

- unsubstituted benzyl;

- a heteroaryl group selected from unsubstituted pyridine, pyrimidine, pyrrole, thiophene, furan, indole, thiazole and oxazole.

Particularly preferred of the said CXCL8 inhibitors of formula (III) is 2-{4[(isopropylsulfonyl)amino]phenyl}propanamide, preferably (2R)-2-{4[(isopropylsulfonyl)amino]phenyl}propanamide, and its pharmaceutically acceptable salts, preferably its sodium salt.

The most preferred CXCL8 inhibitors according to the present invention are 2-(4-isobutylphenyl)propionyl methanesulfonamide, preferably R-(-)-2-(4-isobutylphenyl)propionyl methanesulfonamide and its pharmaceutically acceptable salts, preferably its lysine salt.

According to a preferred embodiment of the invention, when the CXCL8 inhibitor is R-(-)-2-(4-isobutylphenyl)propionyl methanesulfonamide, it is administered to said patient intravenously at a dose of 2 to 3 mg/kg body weight/hour, preferably 2.772 mg/kg body weight/hour, for 5 days.

According to an alternative preferred embodiment of the invention, when the CXCL8 inhibitor is R-(-)-2-(4-isobutylphenyl)propionyl methanesulfonamide, it is administered to said patient orally at a dose of 1200 mg three times a day.

The CXCL8 inhibitor compounds of the present invention may form stable pharmaceutically acceptable acid or base salts with pharmaceutically acceptable organic or inorganic acids or bases, and in such cases it may be appropriate to administer the compound as a salt.

Examples of acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexylsulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate and undecanoate.

Examples of base addition salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as aluminum, calcium and magnesium salts; salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine salts; and salts with amino acids such as arginine, lysine, ornithine, etc. Furthermore, the basic nitrogen-containing groups can be quaternized with agents such as: lower alkyl halides such as methyl, ethyl, propyl and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide and the like. Non-toxic physiologically acceptable salts are preferred, although other salts may be used, for example, in the isolation or purification of the product.

Salts may be formed by conventional means, such as reacting the free form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble, such as, for example, water or ethanol, which is removed in vacuo or by freeze drying.

The present invention also includes prodrugs, isotopically labeled stereoisomers, such as deuterated ones, derivatives and enantiomers of the CXCL8 inhibitor compounds described above.

As used herein, the term "prodrug" refers to an agent that is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug is converted into the desired dosage form when brought to physiological pH). Prodrugs are often effective because they are easier to administer than the parent drug in some situations. For example, they may be orally bioavailable, whereas the parent drug is not. A prodrug may also have improved solubility in pharmacological compositions compared to the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention that is administered as an ester (the "prodrug") to facilitate penetration through a cell membrane where aqueous solubility is not beneficial, but then undergoes metabolic hydrolysis once inside the cell where aqueous solubility is beneficial.

Prodrugs have many useful properties. For example, a prodrug may be more water soluble than the final drug, making the drug easier to administer intravenously. A prodrug may also have a higher level of oral bioavailability than the final drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the final drug into the blood or tissue.

In particular, ester prodrugs of the CXCL8 inhibitor compounds disclosed herein are contemplated. Without limitation, the ester can be an alkyl ester, an aryl ester, or a heteroaryl ester. The term "alkyl" has the meaning generally understood by those skilled in the art and refers to straight-chain, branched, or cyclic alkyl moieties. Particularly useful are C _1-6 alkyl esters, wherein the alkyl portion of the ester has from 1 to 6 carbon atoms and include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and combinations thereof containing from 1 to 6 carbon atoms.

Certain CXCL8 inhibitor compounds may exist in tautomeric forms, and the present invention includes all such tautomeric forms of these compounds unless otherwise indicated.

Unless otherwise indicated, the structures depicted herein also include all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Thus, individual stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Thus, this invention encompasses each diastereomer or enantiomer substantially free of other isomers (>90% and preferably >95% free of other stereoisomers on a molar basis), as well as a mixture of such isomers.

Specific optical isomers can be obtained by separating racemic mixtures according to conventional methods, for example, by forming diastereomeric salts, treating with an optically active acid or base. Examples of suitable acids are tartaric, diacetyl tartaric, dibenzoyl tartaric, ditoluoyl tartaric and camphorsulfonic acid, and then separating the mixture of diastereomers by crystallization, followed by liberation of the optically active bases from these salts. Another process for separating optical isomers involves using a chiral chromatographic column optimally selected for maximum separation of enantiomers. Yet another method involves the synthesis of covalent diastereomers by reacting the compounds of the invention with an optically pure acid in activated form or an optically pure isocyanate. The synthesized diastereomers can be separated by conventional methods, such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to yield an enantiomerically pure compound. The optically active compounds of the invention can be prepared using active starting materials. These isomers can be in the form of a free acid, a free base, an ester or a salt.

The inhibitor for use in accordance with the first aspect of the invention is administered in the form of a pharmaceutical composition formed by mixing the compound with one or more pharmaceutically acceptable excipients.

Typically, the CXCL8 inhibitor for use according to the first aspect of the invention is administered in the form of a pharmaceutical composition.

Accordingly, a second aspect of the present invention relates to a pharmaceutical composition comprising a CXCL8 inhibitor as defined above and at least one inert pharmaceutically acceptable excipient, for use in the treatment of patients with COVID-19 pneumonia as defined above.

Preferably, the pharmaceutical composition of the present invention is prepared in suitable dosage forms containing an effective amount of a CXCL8 inhibitor, its salt with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof, and at least one inert pharmaceutically acceptable excipient.

Administration of the pharmaceutical composition of the present invention to a patient is carried out according to known methods and may include one to several oral doses per day (e.g., twice daily (BID) or four times daily (QID)), parenteral administrations (including intravenous, intraperitoneal, intracerebral, intrathecal, intracranial, intramuscular, intra-articular, intrasynovial, intrasternal, intraocular, intraarterial, subcutaneous, intradermal or intralesional injection or infusion), topical, buccal and suppository administration, or prolonged release administration, among other routes of administration.

Preferably, the pharmaceutical composition is intended for intravenous or oral administration.

In the present description and in the following claims, the expression "effective amount" means an amount of the compounds or composition that is sufficient to significantly and positively alter the symptoms and/or conditions being treated (e.g., to provide a positive clinical response). An effective amount of an active ingredient for use in a pharmaceutical composition will vary depending on the particular condition being treated, the severity of the condition, the duration of treatment, the nature of concomitant therapy, the particular active ingredient(s) used, the particular pharmaceutically acceptable excipient(s)/carrier(s), and similar factors within the knowledge and experience of the attending physician.

As described herein, the pharmaceutical composition of the present invention comprises a CXCL8 inhibitor together with a pharmaceutically acceptable excipient, which as used herein includes any solvents, diluents or other carriers, dispersing or suspension aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like suitable for the particular dosage form desired.

Some examples of substances which can serve as pharmaceutically acceptable excipients include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; sterilized water; Ringer's solution; buffered saline; dextrose solution; maltodextrin solution; ethyl alcohol and phosphate buffer solutions.

Moreover, the composition of the present invention can be prepared into inhalation or injection dosage forms such as solutions, suspensions and emulsions by further adding diluents, dispersants and surfactants.

In addition, the composition of the present invention can be suitably prepared using appropriate methods known in the art or by the method described in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton Pa.

The terms "pharmaceutically acceptable" and "physiologically acceptable" are intended to define, without any specific limitation, any substance suitable for the manufacture of a pharmaceutical composition for administration to a living being.

Dosage forms may also contain other traditional ingredients such as preservatives, stabilizers, surfactants, buffers, salts for regulating osmotic pressure, emulsifiers, sweeteners, colorants, flavorings, and the like.

In addition, specific doses and treatment regimens for each individual patient will depend on a variety of factors including, for example, the potency and half-life of the particular compound used, age, body weight, general health, gender, diet, and the severity and progression of the disease.

The amount of CXCL8 inhibitor or pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention may vary widely depending on factors known to those skilled in the art, such as the compound used, the severity of the disease, the patient's body weight, the dosage form, the chosen route of administration, and the number of administrations per day. However, the skilled artisan can determine the optimal amount in a simple and routine manner.

Specific doses and treatment regimens for a particular patient will depend on a variety of factors including the activity of the particular compound used, age, body weight, general health, gender, diet, time of administration, rate of elimination, drug combination, severity and course of the disease, the patient's predisposition to the disease, and the judgment of the treating physician.

The dosage forms of the pharmaceutical composition of the present invention can be prepared by methods familiar to a pharmaceutical chemist and include mixing, granulating, pressing, dissolving, sterilizing, and the like.

In a third aspect, the present invention relates to a method of treating a patient with COVID-19 pneumonia, comprising administering to the patient a CXCL8 inhibitor as defined above.

The above method preferably comprises the steps of i) identifying a patient suffering from COVID-19 pneumonia, and ii) administering to said patient a composition comprising a CXCL8 inhibitor, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof.

EXAMPLES

Example 1

A phase 2 clinical trial was conducted to evaluate the efficacy and safety of reparixin in patients with severe COVID-19 pneumonia.

Patients participating in the study met the following inclusion criteria:

a) at least one of the following:

- respiratory failure, RR ≥30 breaths/min without oxygen;

- partial pressure of oxygen in arterial blood (PaO ₂ )/fraction of O ₂ during inspiration (FiO ₂ ) >100<300 mmHg (1 mmHg = 0.133 kPa).

b) chest imaging confirming lung involvement and inflammation;

c) inflammatory status confirmed by at least one of the following indicators: lactate dehydrogenase (LDH) >normal range, C-reactive protein (CRP) ≥100 mg/L or IL-6 ≥40 pg/mL, serum ferritin ≥900 ng/mL, XDP >20 μg/mL.

All patients received standard treatment, including at least one of the drugs listed in Table 1 below:

Table 1 Standard of treatment Categories of medicinal products Remdesivir Antiviral Enoxaparin Anticoagulant Dexamethasone Anti-inflammatory (corticosteroid) agent Piperacillin+tazobactam Antibiotic Anakinra Anti-inflammatory agent (IL-1 receptor antagonist) Celecoxib Anti-inflammatory drug (NSAID) Paracetamol Antipyretic Warfarin Anticoagulant Acetylsalicylic acid Antithrombotic Prednisolone Anti-inflammatory (corticosteroid) agent Methylprednisolone Anti-inflammatory (corticosteroid) agent Prednisolone Anti-inflammatory (corticosteroid) agent Dipyrone Anti-inflammatory and analgesic agent Azithromycin Antibiotic Ceftriaxone Antibiotic Tramadol Painkiller

Fourteen patients received standard treatment only (control group).

Thirty-two patients received reparixin tablets orally 1200 mg daily in addition to standard treatment (reparixin group) for a maximum of 21 days.

In both groups, where necessary due to the presence of concomitant pathologies (diabetes, hypertension, cancer, etc.), patients also continued to receive special treatment for these pathologies.

The first occurrence of the composite primary endpoint (at least one of the following events: death, need for supplemental oxygen, use of invasive mechanical ventilation, intensive care unit admission, and use of rescue therapy for any reason) was assessed in all patients and the data are presented in Table 2 below.

Table 2 Time Parameter Reparixin (n/% of patients) Standard of care (n/% of patients) All patients (n/% of patients) Initial level Patients assessed 32 14 46 Day 1 Patients assessed 32 14 46 Composite endpoint 3/9.4% 8/57.1% 11/23.9% Day 2 Patients assessed 27 6 33 Composite endpoint 2/7.4% 0 2/6.1% Until the 7th day Patients assessed 15 3 18 Until the 14th day Patients assessed 1 0 1

The data collected from the clinical trial were analysed using the Kaplan–Meier method, and the log-rank test was used to test for differences between treatment groups. The Kaplan–Meier method is a well-established method for analysing patterns of events over time to estimate the probability of event freedom. The shape of the estimated 'survival curves' is a step function, with downward steps occurring at time points when events occur. As patients experience events or are censored (patients who are lost to analysis for reasons unrelated to events), the number of patients remaining evaluable in the study in each treatment group decreases. As a consequence, event freedom probabilities are estimated from fewer and fewer patients over time. To provide information in this regard, the number of patients at risk at different time points is provided: this is the number of patients still at risk of the first occurrence of the composite endpoint.

Figure 1 shows the results of the analysis, where the probability of freedom from events, measured as the percentage of patients who did not experience the primary endpoint events, expressed as a decimal, is plotted over time. As can be seen in the figure, there is a statistically significantly higher freedom from events compared to the control group with a p-value of 0.0031, measured using the log-rank test.

The study results also demonstrate that treatment with reparixin prevents progression to more severe respiratory disease, as measured by the incidence of the composite endpoints, and improved respiratory function in patients in the reparixin group. Treatment with reparixin is associated with fewer days of oxygen use and a shorter subsequent duration of mechanical ventilation.

In addition, it was observed that the recovery time of patients was significantly reduced in the reparixin group compared to the control group.

Claims (29)

1. Use of a CXCL8 inhibitor in the treatment of a patient with COVID-19 pneumonia, wherein said CXCL8 inhibitor is a compound of formula (I): Where R ¹ is selected from linear or branched C ₁ -C ₆ alkyl, benzoyl, phenoxy and trifluoromethanesulfonyloxy; R ² is selected from a hydrogen atom and a linear or branched C ₁ -C ₃ alkyl; and R ³ is a linear or branched C ₁ -C ₆ alkyl or trifluoromethyl, or a pharmaceutically acceptable salt thereof. 2. The use according to claim 1, wherein said treatment comprises improving the respiratory function in said patient, wherein said respiratory function is defined as the ratio of the partial pressure of oxygen in arterial blood ( _PaO2 ) to the fraction of _O2 on inspiration ( _FiO2 ). 3. Use according to claim 1 or 2, wherein said patient has a value of partial oxygen pressure in arterial blood ( _PaO2 ) to fractional _O2 on inspiration ( _FiO2 ) before treatment according to the invention of below 400 mmHg, more preferably between 100 and 300 mmHg (where 1 mmHg = 0.133 kPa) and/or a respiratory rate of at least 30 breaths/min without oxygen support. 4. The use according to any one of claims 1 to 3, wherein said improvement in respiratory function comprises an increase in the ratio of partial oxygen tension in arterial blood ( _PaO2 ) to fractional _O2 on inspiration ( _FiO2 ) by at least 20%, 50%, 80%, 100%, 120% 150%, 200% or 250% compared to the ratio before treatment. 5. Use according to any of paragraphs 1-4, wherein said patient has lymphocytopenia. 6. Use according to claim 4, wherein said patient is an adult patient (aged 14 years and older) and has a blood lymphocyte concentration below 1000, below 900, below 850, below 800 or below 750 cells/microliter, or said patient is a child (aged less than 14 years) and has a blood lymphocyte concentration below 3000, below 2800, below 2500, below 2300 or below 2000 cells/microliter. 7. The use according to any one of claims 1 to 6, wherein said CXCL8 inhibitor is administered in combination with treatment with at least one medicinal product selected from the following: i) antiviral drugs, preferably remdesivir; ii) antipyretic; analgesic and anti-inflammatory drugs, preferably non-steroidal anti-inflammatory drugs, corticosteroids, cytokine, chemokine and interleukin inhibitors, more preferably selected from dexamethasone, paracetamol, anakinra, celecoxib, prednisolone, prednisolone, methylprednisolone, pyrirone and tramadol; iii) antibiotics, preferably selected from piperacillin in combination with tazobactam, azithromycin and ceftriaxone; and iv) anticoagulants and antithrombotic drugs, preferably selected from enoxaparin and acetylsalicylic acid. 8. The use as claimed in any one of claims 1 to 7, wherein said CXCL8 inhibitor inhibits CXCL8 activity mediated by the CXCR1 receptor or mediated by both CXCR1 and CXCR2 receptors. 9. The use as claimed in any one of claims 1 to 8, wherein said CXCL8 inhibitor is selected from: - 2-(4-isobutylphenyl)propionyl methanesulfonamide, preferably R-(-)-2-(4-isobutylphenyl)propionyl methanesulfonamide and its pharmaceutically acceptable salts, preferably its lysine salt, and - 2-(4-trifluoromethanesulfonyloxy)phenyl]-N-methanesulfonyl propionamide, preferably R(-)-2-(4-trifluoromethanesulfonyloxy)phenyl]-N-methanesulfonyl propionamide and its pharmaceutically acceptable salts, in particular its sodium salt. 10. The use as claimed in any one of claims 1 to 9, wherein said CXCL8 inhibitor is R-(-)-2-(4-isobutylphenyl)propionyl methanesulfonamide, wherein said inhibitor is administered to said patient intravenously at a dose of 2 to 3 mg/kg body weight/hour, preferably 2.772 mg/kg body weight/hour, for 5 days. 11. Use of a pharmaceutical composition comprising (i) a CXCL8 inhibitor, and (ii) at least one inert pharmaceutically acceptable excipient, in the treatment of a patient with COVID-19 pneumonia, wherein said CXCL8 inhibitor is a compound of formula (I): Where R ¹ is selected from linear or branched C ₁ -C ₆ alkyl, benzoyl, phenoxy and trifluoromethanesulfonyloxy; R ² is selected from a hydrogen atom and a linear or branched C ₁ -C ₃ alkyl; and R ³ is a linear or branched C ₁ -C ₆ alkyl or trifluoromethyl, or a pharmaceutically acceptable salt thereof.

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