Treatment of symptomatic viral illness

Abstract

Compositions comprising phenylpyrrole aminoguanidine derivatives are provided for use in methods of treating viral disorders and diseases, including symptomatic viral disorders and diseases, including symptomatic COVID-19.

Description

Technical Field

[0001] The present invention relates to compositions comprising a compound of formula (I) or (II) or a pharmaceutically acceptable derivative thereof for use in methods for treating viral diseases and disorders, including symptomatic COVID-19. Background of the Invention

[0003] Historically, infectious diseases, especially those caused by viruses, have been among the most important causes of morbidity and mortality in humans. They account for a large proportion of deaths and disability worldwide and remain the most important cause of ill health in some regions. The recent outbreak of coronavirus disease 2019 (COVID-19) illustrates the burden of viral diseases and conditions.

[0004] COVID-19 is an infectious disease caused by the recently discovered coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), often referred to as the COVID-19 virus. The viral airway infection COVID-19 is also known as 2019-nCoV acute respiratory disease (2019-nCoV ARD) and novel coronavirus pneumonia (NCP).

[0005] Most people infected with the COVID-19 virus experience mild to moderate respiratory illness similar to mild pneumonia and recover without specific treatment. Older adults and those with underlying medical problems such as cardiovascular disease, diabetes, chronic respiratory disease, and cancer are more likely to develop severe illness. Common symptoms include fever, tiredness, and a dry cough. Other symptoms include shortness of breath, aches and pains, and sore throat.

[0006] The clinical spectrum of COVID-19 ranges from asymptomatic or paucisymptomatic forms to clinical conditions characterized by respiratory failure requiring mechanical ventilation and intensive care unit support, to multi-organ and systemic manifestations with sepsis, septic shock, and multiple organ dysfunction syndrome.

[0007] Severe disease is manifested by dyspnea, increased respiratory rate, decreased oxygen saturation, and / or pulmonary infiltrates. Critical disease is manifested by respiratory failure, septic shock, and / or multiple organ dysfunction (MOD) or failure (MOF).

[0008] The upper and lower respiratory tract infections caused by the COVID-19 virus can lead to mild or severe acute respiratory syndrome, followed by the release of proinflammatory cytokines, including interleukins IL-6 and IL-1β. The SARS-CoV-2 virus causes an increase in IL-6 and IL-1β, and elevated cytokine levels have been found to predict the severity of COVID-19.

[0009] Initially, there are no specific vaccines or treatments for COVID-19. To date, some treatments have shown some efficacy. Typically, treatment is symptomatic, with oxygen therapy representing the mainstay of therapeutic intervention for patients with severe infection. Strategies to address respiratory failure include protective mechanical ventilation and high-flow nasal oxygen (HFNO) or noninvasive ventilation (NIV).

[0010] Virus-induced ARDS (acute respiratory distress syndrome) is characterized by capillary damage and leakage of plasma into the alveolar sacs, which disrupts the blood-gas barrier and severely impairs blood oxygenation. This can occur directly as a result of viral damage, or indirectly through overactivation of the immune system triggering infiltration of immune cells such as neutrophils and macrophages into the lungs and a "cytokine storm" (excessive or uncontrolled production of cytokines such as TNF, interleukin (IL)-1b, IL-6, IL-12 and IFNc, and chemokines such as IL-8, MCP-1 and IP-10). In principle, this is a protective response to limit viral spread, but it ultimately does more harm than good. Although some details may vary, cytokine storms are common complications of respiratory infections caused by influenza A, SARS-CoV, MERS-CoV and SARS-CoV-2 viruses.

[0011] The melanocortin system is a group of neuropeptide-ergic and immunoendocrine signaling pathways that play an integral role in a variety of physiological functions, including melanogenesis, stress response, inflammation, immune regulation, and homeostatic control of adrenocortical steroidogenesis. It consists of multiple components, including five G protein-coupled melanocortin receptors: melanocortin receptor 1 (MC1R) to MC5R; peptide ligands: α, β, γ-melanocyte stimulating hormone (α, β, γ-MSH) and adrenocorticotropic hormone (ACTH) secreted by the anterior pituitary; and endogenous antagonists. The biological functions of the melanocortin system are mediated by five melanocortin receptors (MCRs), which have different tissue distributions in different organ systems, transmit different signals, and exert different biological activities.

[0012] Phenylpyrrole aminoguanidine derivatives active at melanocortin receptors are disclosed in WO 2007 / 141343. An example of such a compound is the anti-inflammatory compound AP1189 ((E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate), which was first shown to bind to MC1R (WO 2007 / 141343) and was later identified as a biased dual agonist of the receptors MC1R and MC3R without causing classical cAMP production. The mechanism of action of AP1189 is through direct activation of melanocortin receptors on macrophages, thereby reducing the pro-inflammatory activity of macrophages and stimulating macrophage efferocytosis, a specific ability to clear inflammatory cells, to promote the resolution of inflammation (Montero-Melendez et al. 2015). This effect has been demonstrated to be effective in disease models of inflammatory and autoimmune diseases, and the clinical potential of the approach is currently being tested in a Phase 2 clinical study in patients with active rheumatoid arthritis. Summary of the invention

[0013] The inventors have found that the phenylpyrrole aminoguanidine derivative AP1189 ((E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate) reduces the levels of proinflammatory cytokines IL-1 and IL-1β and reduces the accumulation of neutrophils compared to the vehicle. This means that AP1189 and related compounds are candidate drugs for the treatment of symptomatic COVID-19.

[0014] Samples from patients with COVID-19 pneumonia showed that macrophages make up 80% of the total cells in the alveoli and play a key role in the hyperinflammation associated with the damaging effects of COVID-19 infection.

[0015] Clinical trial data have now demonstrated that among patients with COVID-19-induced pulmonary insufficiency who were receiving AP1189, none developed the need for more intensive lung support and patients were discharged from the hospital between days 3 and 9 of treatment.

[0016] Therefore, AP1189 and related compounds are promising candidates for the treatment of viral diseases and conditions through their ability to control or suppress inflammation (including inappropriate overactivation of the immune system and resulting excessive inflammation) while leaving the immune system fully capable of fighting the underlying viral infection, and in some cases even stimulating the immune system. This is called resolution therapy.

[0017] One aspect of the present disclosure is to provide a composition comprising a compound of formula (I):

[0018]

[0019] including tautomeric and stereoisomeric forms thereof;

[0020] wherein n is 1; and R1 is CF3, CCl3, F, Cl, NO2 or CN, and R2, R3, R4, R5, R6 and R7 are hydrogen; or a pharmaceutically acceptable derivative thereof,

[0021] It is useful for treating viral diseases and disorders, such as symptomatic viral diseases and disorders, such as symptomatic viral diseases and disorders with respiratory symptoms including respiratory failure and ARDS.

[0022] One aspect of the present disclosure is to provide a composition comprising a compound of formula (I):

[0023]

[0024] including tautomeric and stereoisomeric forms thereof;

[0025] wherein n is 1; and R1 is CF3, CCl3, F, Cl, NO2 or CN, and R2, R3, R4, R5, R6 and R7 are hydrogen; or a pharmaceutically acceptable derivative thereof,

[0026] It is used to treat symptomatic COVID-19, such as symptomatic COVID-19 associated with respiratory symptoms including respiratory failure and ARDS.

[0027] In one embodiment, the compound is (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine and pharmaceutically acceptable salts thereof.

[0028] In one embodiment, the compound is (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate (AP1189). BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Test item A = AP1189(E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate.

[0030] Figure 1 : Pretreatment with AP1189 reduced the level of the proinflammatory cytokine IL-1β by 37% compared with pretreatment with vehicle.

[0031] Figure 2 : Pretreatment with AP1189 reduced the level of the proinflammatory cytokine IL-6 by 59% compared with pretreatment with vehicle.

[0032] Figure 3 : Pretreatment with AP1189 reduced neutrophil accumulation by 70% compared with pretreatment with vehicle.

[0033] definition

[0034] In this article, the term "pharmaceutically acceptable derivative" includes pharmaceutically acceptable salts, which means salts that are harmless to patients. Such salts include pharmaceutically acceptable base or acid addition salts and pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. Pharmaceutically acceptable derivatives also include esters and prodrugs, or other precursors of the compound that can be biologically metabolized into active compounds, or crystalline forms of the compound. In one embodiment, the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt.

[0035] The term "acid addition salt" is intended to include "pharmaceutically acceptable acid addition salts", which means salts that are harmless to patients. Acid addition salts include salts of inorganic acids and organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bimethylene salicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include pharmaceutically acceptable salts listed in J. Pharm. Sci. 66, 2, (1977), which is incorporated herein by reference.

[0036] The term "therapeutically effective amount" of a compound as used herein refers to an amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially prevent the clinical manifestations of a given disease or condition and its complications. An amount sufficient to achieve this is defined as a "therapeutically effective amount". The effective amount for each purpose will depend on the severity of the disease or injury and the weight and overall condition of the subject. It will be understood that routine experimentation can be used to determine the appropriate dosage by constructing a numerical matrix and testing different points in the matrix, which is within the ordinary skill of a trained physician or veterinarian.

[0037] The terms "treatment" and "treating" as used herein refer to the management and care of a patient for the purpose of combating a condition, disease or illness. The term is intended to include all types of treatments for a given condition suffered by a patient. The patient to be treated is preferably a mammal, particularly a human being. However, treatment of animals such as mice, rats, dogs, cats, horses, cattle, sheep and pigs is also within the scope of this invention. The patient to be treated can be of various ages. DETAILED DESCRIPTION OF THE INVENTION

[0039] Melanocortin (MC) receptors (MC1R-MC5R) are a family of class A G protein-coupled receptors (GPCRs) that are attractive therapeutic targets for many conditions due to their widespread distribution and the diversity of physiological processes they regulate. MC1R regulates UV light-induced skin tanning and other immune responses due to its expression on leukocytes. MC2R regulates cortisol production on the adrenal glands, while MC5R plays a role in exocrine gland secretion. In addition to specific anti-inflammatory effects, MC3R and MC4R also play non-redundant functions on energy homeostasis; while MC3R activation is particularly protective against joint inflammation such as arthritis, MC4R provides neuroprotection in brain inflammation. Therefore, a variety of pathological conditions can be targeted with MCR drugs, including skin conditions, cardiovascular pathologies, joint inflammation, obesity and cachexia.

[0040] Peripheral MC1R and MC3R can be pharmacologically activated to induce anti-inflammatory effects. Like other protective mediators, the endogenous agonist α-melanocyte stimulating hormone (αMSH) is released by immune cells to counteract pro-inflammatory signals, thereby preventing excessive tissue damage. In line with the concept of resolution of inflammation, therapies targeting MC1R and MC3R act by mimicking the body's own protective resources and may be characterized by a lower burden of side effects.

[0041] The use of corticotropin or adrenocorticotropin (ACTH), which has been shown to be effective for rheumatic diseases since the early 1950s, has decreased when synthetic glucocorticoids became available. However, the discovery that another anti-inflammatory mechanism of ACTH involves activation of peripheral MC receptors on immune cells has rekindled interest in developing novel ACTH-like molecules for the treatment of joint diseases such as gout or RA (rheumatoid arthritis) without steroidogenic effects. However, the lack of currently achieved receptor selectivity has limited the translational delivery of novel MC drugs other than commercially available ACTH preparations.

[0042] Innovative approaches in GPCR drug discovery may help overcome this limitation. Allosteric modulation consists in the ability of a molecule to enhance (positive modulation) or reduce (negative modulation) the effects of an endogenous ligand by binding to a unique site on the receptor protein, known as the allosteric site. Due to the low conservation of the allosteric region among the five MCRs, a higher degree of selectivity is expected, and in fact, allosteric modulators of the MC4R are currently being developed for the treatment of obesity.

[0043] Another emerging concept that has generated significant therapeutic interest is that of biased agonism. The outdated notion that receptors can exist in two unique conformations, one active and one inactive, has been replaced by the idea that multiple active conformations can exist, each producing a different signal and thus a variety of functional outcomes. Rather than being linear and static, receptor activation is emerging as a highly dynamic and multidimensional process in which different molecules can induce different active conformations and thus produce different effects.

[0044] The small molecule AP1189 ((E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate) has been characterized as a biased agonist of the receptors MC1R and MC3R that does not induce classical cAMP production but leads to ERK1 / 2 phosphorylation, a signaling responsible for the proefferocytic effect induced in mouse primary macrophages. AP1189 was shown to reduce cytokine release in macrophages, while AP1189 did not induce melanogenesis in melanocytes. In vivo, oral administration of AP1189 induced an anti-inflammatory effect and accelerated the resolution phase in peritonitis, and significantly reduced macroscopic and histological parameters of joint destruction in experimental inflammatory arthritis. Therefore, AP1189 is a biased dual agonist of MC1R and MC3R that has anti-inflammatory properties but has no effect on melanogenesis.

[0045] Dysregulated release of cytokines has been identified as one of the key factors for poor outcomes in respiratory viral infections. This "cytokine storm" generates excessive inflammatory and immune responses, especially in the lungs, leading to acute respiratory distress syndrome (ARDS), pulmonary edema, and multi-organ failure. Alleviating this inflammatory state is critical to improving outcomes.

[0046] Patients with respiratory symptoms requiring mechanical ventilation, such as pneumonia and ARDS, often experience local inflammation that can spread to life-threatening systemic inflammation. Controlling inflammation in these patients to suppress inflammation (e.g., overactivated inflammatory cascades) without blocking it while ensuring that the immune system remains effective in fighting the condition is an important task. In this case, AP1189 can at least have an impact on such patients because it suppresses inflammation while stimulating the immune system, including the ability to clear inflammation faster. This is called resolution therapy.

[0047] Viral diseases and conditions

[0048] One aspect of the present disclosure provides a composition comprising a compound of formula (I):

[0049]

[0050] including tautomeric and stereoisomeric forms thereof; wherein n is 1; and R1 is CF3, CCl3, F, Cl, NO2 or CN, and R2, R3, R4, R5, R6 and R7 are hydrogen; or a pharmaceutically acceptable derivative thereof,

[0051] It is used to treat viral diseases or conditions,

[0052] For example, for the treatment of symptomatic viral diseases or disorders.

[0053] Another aspect provides the use of a composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the preparation of a medicament for treating a viral disease or condition, for example, for the preparation of a medicament for treating a symptomatic viral disease or condition:

[0054]

[0055] Also disclosed is a method for treating a viral disease or condition, such as a symptomatic viral disease or condition, comprising one or more steps of administering to an individual in need thereof a composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof:

[0056]

[0057] In certain embodiments, the compositions according to the present disclosure comprise a compound of formula (II):

[0058]

[0059] including tautomeric and stereoisomeric forms thereof; or pharmaceutically acceptable derivatives thereof, including pharmaceutically acceptable salts thereof.

[0060] In one embodiment, the composition according to the present disclosure comprises a compound which is:

[0061] i) is an agonist of one or more MC receptors,

[0062] ii) is an agonist of MC1R and MC3R, and / or

[0063] iii) It is a partial agonist of MC1R and MC3R.

[0064] Also disclosed is a composition according to the present disclosure, comprising a compound selected from {3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine or a pharmaceutically acceptable salt thereof, for use in treating a viral disease or disorder, such as a symptomatic viral disease or disorder.

[0065] In one embodiment, the pharmaceutically acceptable derivatives thereof are pharmaceutically acceptable salts of inorganic or organic acids.

[0066] In such an embodiment, the organic acid referred to herein is selected from the group consisting of formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, di-methylene salicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid and p-toluenesulfonic acid.

[0067] In a specific embodiment, the organic acid is acetic acid, succinic acid, tartaric acid or propionic acid; for example acetic acid.

[0068] In such an embodiment, the organic acid referred to herein is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid and nitric acid.

[0069] Also disclosed is a composition comprising a compound selected from {3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate for use in treating a viral disease or condition, such as a symptomatic viral disease or condition.

[0070] In one embodiment, the present disclosure provides a composition comprising (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine or a pharmaceutically acceptable salt thereof for use in treating a viral disease or disorder, such as a symptomatic viral disease or disorder.

[0071] In a specific embodiment, the present disclosure provides a composition comprising (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate (AP1189) for use in treating a viral disease or disorder, such as a symptomatic viral disease or disorder.

[0072] A viral disease or disorder according to the present disclosure is a disease or disorder caused by a viral infection, such as any symptoms or downstream effects of such a viral infection.

[0073] In one aspect, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or condition, wherein the treatment of a viral disease or condition includes treating, improving and / or alleviating such a viral disease or condition. It should be understood that treating, improving and / or alleviating a viral disease or condition includes treating, improving and / or alleviating one or more symptoms of a viral disease or condition.

[0074] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating one or more symptoms of a viral disease or disorder.

[0075] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a symptomatic viral disease or disorder.

[0076] In one embodiment, one or more symptoms of the viral disease or disorder or the symptomatic viral disease or disorder is inflammation, such as excessive inflammation.

[0077] In one embodiment, the one or more symptoms of the viral disease or disorder, or the symptomatic viral disease or disorder is inflammation, such as excessive inflammation, in one or more organs. Inflammation in one or more organs may also be referred to as local inflammation.

[0078] In one embodiment, the viral disease or disorder or the symptomatic viral disease or disorder exhibits inflammation, such as excessive inflammation.

[0079] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral-induced excessive inflammation.

[0080] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral-induced inflammatory condition.

[0081] In one embodiment, excessive inflammation is characterized by C-reactive protein (CRP) > 100 mg / l or ferritin 900 ng / ml.

[0082] In one embodiment, the viral disease or disorder or the symptomatic viral disease or disorder exhibits inflammation, such as excessive inflammation, in one or more organs.

[0083] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or disorder associated with inflammation (eg excessive inflammation) in one or more organs.

[0084] In one embodiment, the one or more organs are selected from the group consisting of lung, respiratory tract, kidney, liver, pancreas, spleen, exocrine glands, endocrine glands, lymph nodes, brain, heart, muscle, bone marrow, skin, bone, bladder, reproductive organs including fallopian tubes, eyes, ears, vascular system, gastrointestinal tract including small intestine, colon, rectum, anal canal and prostate.

[0085] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating end-organ damage in a viral disease or disorder.

[0086] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of an inflammatory viral disease or disorder.

[0087] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder associated with local or systemic inflammation.

[0088] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder associated with a local inflammatory condition.

[0089] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder (e.g. a symptomatic viral disease or disorder) associated with a local inflammatory condition in one or more organs selected from the group consisting of the lungs, respiratory tract, kidneys, liver, pancreas, spleen, exocrine glands, endocrine glands, lymph nodes, brain, heart, muscle, bone marrow, skin, bone, bladder, reproductive organs including fallopian tubes, eyes, ears, vascular system, gastrointestinal tract including small intestine, colon, rectum, anal canal and prostate.

[0090] It should be noted that reference to a viral disease or disorder and reference to a symptomatic viral disease or disorder are used interchangeably herein.

[0091] Respiratory system

[0092] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or condition, which is a viral respiratory tract infection, such as a viral lower respiratory tract infection.

[0093] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral respiratory tract infection, such as a viral lower respiratory tract infection.

[0094] In one embodiment, the viral disease or disorder is a viral respiratory tract infection with impaired oxygenation, such as a viral lower respiratory tract infection with impaired oxygenation.

[0095] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or disorder of the lung.

[0096] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral respiratory disease or disorder.

[0097] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder associated with inflammation in the respiratory system, for example in the lungs and / or respiratory tract.

[0098] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder associated with one or more respiratory symptoms.

[0099] In one embodiment, the viral disease or disorder with one or more respiratory symptoms demonstrates impaired oxygenation.

[0100] In one embodiment, the one or more respiratory symptoms are selected from cough, dry cough, dyspnea, impaired oxygenation, respiratory illness, respiratory dysfunction, respiratory failure, respiratory syndrome and acute respiratory disease (ARD).

[0101] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or condition, wherein the viral disease or condition is a severe disease. Severe disease is manifested as dyspnea, increased respiratory rate, decreased blood oxygen saturation and / or pulmonary infiltrates.

[0102] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or condition, wherein the viral disease or condition is a critical illness. Critical illness manifests as respiratory failure, septic shock and / or multiple organ dysfunction (MOD) or multiple organ failure (MOF).

[0103] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral disease or condition, wherein the viral disease or condition comprises viral pneumonia, including mild pneumonia, pneumonia and pneumonia with abnormal findings.

[0104] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral pneumonia.

[0105] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or disorder, wherein the viral disease or disorder comprises viral bronchiolitis.

[0106] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder with respiratory failure.

[0107] Respiratory failure is caused by inadequate gas exchange in the respiratory system, which means that arterial oxygen, carbon dioxide, or both are not maintained at normal levels. A decrease in the oxygen carried in the blood is called hypoxemia; an increase in arterial carbon dioxide levels is called hypercapnia. Respiratory failure is classified as type 1 or type 2, depending on whether high carbon dioxide levels are present, and can be acute or chronic. The definition of respiratory failure in clinical trials usually includes an increased respiratory rate, abnormal blood gases (hypoxemia, hypercapnia, or both), and evidence of increased work of breathing. Respiratory failure leads to altered mental status due to cerebral ischemia.

[0108] In one embodiment, the respiratory failure is type 1 respiratory failure.

[0109] In one embodiment, the respiratory failure is type 2 respiratory failure.

[0110] In one embodiment, the respiratory failure is acute.

[0111] In one embodiment, the respiratory failure is chronic.

[0112] In one embodiment, the viral disease or disorder is acute respiratory distress syndrome (ARDS).

[0113] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder associated with acute respiratory distress syndrome (ARDS).

[0114] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral acute respiratory distress syndrome (ARDS).

[0115] Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid and widespread inflammation of the lungs. Symptoms include shortness of breath, rapid breathing, and bluish skin coloration. For those who survive, a decreased quality of life is common. The underlying mechanisms include diffuse damage to the cells that form the barrier of the microscopic air sacs in the lungs, surfactant dysfunction, activation of the immune system, and dysfunction of the body's regulation of blood clotting. In essence, ARDS impairs the lungs' ability to exchange oxygen and carbon dioxide. The main treatment involves mechanical ventilation and treatment of the underlying cause.

[0116] Local inflammatory conditions, such as acute respiratory distress syndrome, can progress to life-threatening conditions with the development of systemic inflammatory distress syndrome (SIDS) and sepsis. The development of SIDS is associated with high circulating levels of proinflammatory cytokines such as IL-1β and IL-6.

[0117] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral diseases and disorders associated with acute respiratory distress syndrome (ARDS) and systemic inflammatory distress syndrome (SIDS).

[0118] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral diseases and disorders associated with systemic inflammatory distress syndrome (SIDS) and / or sepsis.

[0119] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral systemic inflammatory distress syndrome (SIDS) and / or viral sepsis.

[0120] In one embodiment, a composition comprising a compound of formula (I) or (II) as defined herein is provided for use in the treatment of viral diseases and conditions requiring mechanical ventilation. In one embodiment, the mechanical ventilation comprises protective mechanical ventilation, high flow nasal oxygen therapy (HFNO) and non-invasive ventilation (NIV).

[0121] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral diseases and disorders associated with pulmonary insufficiency.

[0122] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral-induced pulmonary insufficiency, such as viral pulmonary insufficiency.

[0123] In one embodiment, the lung insufficiency is defined as requiring supplemental oxygen to maintain normal saturations.

[0124] In one embodiment, the lung insufficiency is defined as a SaPO2 of less than 93% during spontaneous breathing.

[0125] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or disorder, wherein the compound reduces the time to recovery.

[0126] In one embodiment, the compound reduces the recovery time, for example, reduces the recovery time by one or more days, for example, by 7 days, for example, by 6 days, for example, by 5 days, for example, by 4 days, for example, by 3 days, for example, by 2 days, for example, by 1 day, for example, by at least 1 day. In one embodiment, the compound reduces the recovery time by 1-2 days, for example, by 2-3 days, for example, by 3-4 days, for example, by 4-5 days, for example, by 5-6 days, for example, by 6-7 days.

[0127] In one embodiment, reducing the recovery time is reducing the median recovery time. In one embodiment, reducing the recovery time is reducing the full recovery time.

[0128] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or disorder, wherein the compound promotes resolution of inflammation.

[0129] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or disorder, wherein the compound reduces the risk of developing severe inflammation.

[0130] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or disorder, wherein the compound reduces the risk of developing severe acute respiratory distress syndrome (ARDS).

[0131] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or disorder, wherein the compound reduces the need for supplemental oxygen to maintain normal saturations.

[0132] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or disorder, wherein the compound reduces the risk of developing the need for more intense lung support.

[0133] General

[0134] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or disorder having elevated levels of one or more cytokines (e.g. one or more proinflammatory cytokines, such as IL-6 and / or IL-1β).

[0135] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder associated with a cytokine storm (also known as hypercytokinemia).

[0136] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of an infectious cytokine storm (hypercytokinemia), such as a virus-induced cytokine storm (hypercytokinemia).

[0137] A cytokine storm is a physiological response in which the innate immune system causes an uncontrolled and excessive release of proinflammatory cytokines. Normally, cytokines are part of the body's immune response to infection, but their sudden and massive release can lead to multisystem organ failure and death. Cytokine storms can be caused by a variety of infectious and non-infectious etiologies, especially viral respiratory infections.

[0138] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of multi-system organ failure caused by viral hypercytokinemia.

[0139] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or condition associated with cytokine release syndrome (CRS). CRS is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors, such as infection and certain drugs.

[0140] Other organs

[0141] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder associated with renal inflammation and / or renal dysfunction.

[0142] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder associated with acute or chronic renal failure.

[0143] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder associated with end stage renal disease.

[0144] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral kidney infection (pyelonephritis), viral urinary tract infection (UTI) and / or viral kidney inflammation (nephritis).

[0145] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral bladder infection and / or viral bladder inflammation (cystitis).

[0146] In one embodiment, the viral disease or disorder is cystitis. In one embodiment, the viral disease or disorder is severe haemorrhagic cystitis. In one embodiment, the viral disease or disorder is urinary tract obstruction.

[0147] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral liver infection and / or viral liver inflammation (hepatitis), such as acute hepatitis and chronic hepatitis.

[0148] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral cirrhosis.

[0149] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral pancreatic infection and / or viral pancreatic inflammation (pancreatitis).

[0150] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral enteric infection and / or viral enteric inflammation, such as viral enteric infection and / or viral enteric inflammation of the small intestine and / or large intestine.

[0151] In one embodiment, the viral disease or disorder is colitis. In one embodiment, the viral disease or disorder is enteritis.

[0152] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral brain infection and / or viral brain inflammation.

[0153] In one embodiment, the viral disease or disorder is encephalitis.

[0154] In one embodiment, the viral disease or disorder is progressive multifocal leukoencephalopathy (PML).

[0155] In one embodiment, the viral brain infection and / or viral brain inflammation is progressive multifocal leukoencephalopathy, a rare and often fatal viral disease characterized by progressive damage or inflammation of the white matter at multiple locations in the brain.

[0156] In one embodiment, the viral brain infection and / or viral brain inflammation is inflammation of the white matter at one or more locations in the brain.

[0157] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral ocular infection and / or viral ocular inflammation.

[0158] In one embodiment, the viral disease or disorder is retinitis.

[0159] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of splenomegaly / atrophy, especially viral-induced splenomegaly / atrophy.

[0160] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of diffuse lymphoid organ atrophy, especially viral-induced diffuse lymphoid organ atrophy.

[0161] Viral infection

[0162] In one aspect, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder caused by a viral infection.

[0163] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or condition caused by a viral infection selected from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), commonly referred to as the COVID-19 virus; SARS-CoV, MERS-CoV, dengue virus and influenza virus (including types A, B and C).

[0164] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of acute respiratory distress syndrome (ARDS) or pneumonia caused by a viral infection selected from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), commonly known as the COVID-19 virus; SARS-CoV, MERS-CoV, dengue virus and influenza virus (including type A, type B and type C).

[0165] In one aspect, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of dengue fever.

[0166] Dengue fever is a mosquito-borne tropical disease caused by the dengue virus. Symptoms typically include high fever, headache, vomiting, muscle and joint pain, and a characteristic rash. In a few cases, the disease can develop into severe dengue fever, also known as dengue hemorrhagic fever, which causes bleeding, low platelet levels and plasma leakage, or develop into dengue shock syndrome, in which blood pressure becomes dangerously low.

[0167] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of dengue hemorrhagic fever or dengue shock syndrome.

[0168] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of acute respiratory distress syndrome (ARDS) caused by dengue virus.

[0169] In one aspect, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral pneumonia caused by dengue virus.

[0170] In one aspect there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating influenza.

[0171] In one aspect, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or condition caused by influenza. In one aspect, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating an influenza virus disease or condition.

[0172] Influenza, commonly known as "flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and usually include: high fever, runny nose, sore throat, muscle and joint pain, headache, cough and feeling tired.

[0173] In one aspect, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of viral pneumonia caused by influenza.

[0174] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of acute respiratory distress syndrome (ARDS) caused by influenza virus.

[0175] Symptomatic COVID-19

[0176] In one aspect of the present disclosure, there is provided a composition comprising a compound of formula (I):

[0177]

[0178] including tautomeric and stereoisomeric forms thereof; wherein n is 1; and R1 is CF3, CCl3, F, Cl, NO2 or CN, and R2, R3, R4, R5, R6 and R7 are hydrogen; or a pharmaceutically acceptable derivative thereof,

[0179] It is used to treat symptomatic COVID-19.

[0180] In another aspect, there is provided a use of a composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the preparation of a medicament for treating symptomatic COVID-19:

[0181]

[0182] Also disclosed is a method of treating symptomatic COVID-19, comprising one or more steps of administering to an individual in need thereof a composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof:

[0183]

[0184] In certain embodiments, the compositions according to the present disclosure comprise a compound of formula (II):

[0185]

[0186] Including its tautomeric and stereoisomeric forms; or its pharmaceutically acceptable derivatives, for treating symptomatic COVID-19.

[0187] In a preferred embodiment, the composition according to the present disclosure comprises (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate (AP1189).

[0188] In one embodiment, the composition according to the present disclosure comprises a compound which is:

[0189] i) is an agonist of one or more MC receptors,

[0190] ii) is an agonist of MC1R and MC3R, and / or

[0191] iii) It is a partial agonist of MC1R and MC3R.

[0192] Also disclosed is a composition according to the present disclosure, comprising a compound selected from {3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine or a pharmaceutically acceptable salt thereof, for treating symptomatic COVID-19.

[0193] In one embodiment, the pharmaceutically acceptable derivatives thereof are pharmaceutically acceptable salts of inorganic or organic acids.

[0194] In such an embodiment, the organic acid referred to herein is selected from the group consisting of formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylene salicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid and p-toluenesulfonic acid.

[0195] In a specific embodiment, the organic acid is acetic acid, succinic acid, tartaric acid or propionic acid; for example acetic acid.

[0196] In such an embodiment, the organic acid referred to herein is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and nitric acid.

[0197] Also disclosed is a composition comprising a compound selected from {3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate for treating symptomatic COVID-19.

[0198] In one embodiment, the present disclosure provides a composition comprising (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine or a pharmaceutically acceptable salt thereof for treating symptomatic COVID-19.

[0199] In a specific embodiment, the present disclosure provides a composition comprising (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate for treating symptomatic COVID-19.

[0200] In one embodiment, the composition comprising a compound of formula (I) or (II) as defined herein is used in a method for improving and / or alleviating symptomatic COVID-19, for example, improving and / or alleviating one or more symptoms of COVID-19.

[0201] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating symptomatic COVID-19, wherein the symptomatic COVID-19 comprises one or more respiratory symptoms.

[0202] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating symptomatic COVID-19 with impaired oxygenation.

[0203] In one embodiment, the one or more respiratory symptoms are selected from cough, dry cough, dyspnea, impaired oxygenation, respiratory disease, respiratory dysfunction, respiratory failure, respiratory syndrome, and 2019-nCoV acute respiratory disease (2019-nCoV ARD).

[0204] In one embodiment, a composition comprising a compound of formula (I) or (II) as defined herein is provided for use in treating symptomatic COVID-19, wherein the symptomatic COVID-19 is severe disease. Severe disease is manifested by dyspnea, increased respiratory rate, decreased blood oxygen saturation and / or lung infiltrates.

[0205] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating symptomatic COVID-19, wherein the symptomatic COVID-19 is a critical illness. Critical illness is manifested as respiratory failure, septic shock and / or multiple organ dysfunction (MOD) or failure (MOF).

[0206] In one embodiment, a composition comprising a compound of formula (I) or (II) as defined herein is provided for use in treating symptomatic COVID-19, wherein the symptomatic COVID-19 includes viral pneumonia, including mild pneumonia, pneumonia, pneumonia with abnormal findings, and novel coronavirus pneumonia (NCP).

[0207] In one embodiment, a composition comprising a compound of formula (I) or (II) as defined herein is provided for use in treating symptomatic COVID-19, wherein the symptomatic COVID-19 exhibits elevated levels of one or more cytokines, such as one or more proinflammatory cytokines, such as IL-6 and / or IL-1β.

[0208] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating symptomatic COVID-19 associated with respiratory failure.

[0209] Respiratory failure is caused by inadequate gas exchange in the respiratory system, which means that arterial oxygen, carbon dioxide, or both are not maintained at normal levels. A decrease in the oxygen carried in the blood is called hypoxemia; an increase in arterial carbon dioxide levels is called hypercapnia. Respiratory failure is classified as type 1 or type 2, depending on whether high carbon dioxide levels are present, and can be acute or chronic. The definition of respiratory failure in clinical trials usually includes an increased respiratory rate, abnormal blood gases (hypoxemia, hypercapnia, or both), and evidence of increased work of breathing. Respiratory failure leads to altered mental status due to cerebral ischemia.

[0210] In one embodiment, the respiratory failure is type 1 respiratory failure.

[0211] In one embodiment, the respiratory failure is type 2 respiratory failure.

[0212] In one embodiment, the respiratory failure is acute.

[0213] In one embodiment, the respiratory failure is chronic.

[0214] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of symptomatic COVID-19 associated with acute respiratory distress syndrome (ARDS).

[0215] Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid and widespread inflammation of the lungs. Symptoms include shortness of breath, rapid breathing, and bluish discoloration of the skin. For those who survive, a decreased quality of life is common. The underlying mechanisms include diffuse damage to the cells that form the barrier of the microscopic alveoli in the lungs, surfactant dysfunction, activation of the immune system, and dysfunction of the body's regulation of blood clotting. In essence, ARDS impairs the lungs' ability to exchange oxygen and carbon dioxide. The main treatment involves mechanical ventilation and treatment of the underlying cause.

[0216] Local inflammatory conditions, such as acute respiratory distress syndrome, can progress to life-threatening conditions with the development of systemic inflammatory distress syndrome (SIDS) and sepsis. The development of SIDS is associated with high circulating levels of proinflammatory cytokines such as IL-1β and IL-6.

[0217] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of symptomatic COVID-19 associated with acute respiratory distress syndrome (ARDS) and systemic inflammatory distress syndrome (SIDS).

[0218] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in the treatment of symptomatic COVID-19 associated with systemic inflammatory distress syndrome (SIDS) and / or sepsis.

[0219] In one embodiment, a composition comprising a compound of formula (I) or (II) as defined herein is provided for use in treating symptomatic COVID-19 requiring mechanical ventilation. In one embodiment, the mechanical ventilation includes protective mechanical ventilation, high-flow nasal oxygen therapy (HFNO) and non-invasive ventilation (NIV).

[0220] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating COVID-19 induced pulmonary insufficiency.

[0221] In one embodiment, the COVID-19-induced lung insufficiency is defined as the requirement for supplemental oxygen to maintain normal saturations.

[0222] In one embodiment, the COVID-19-induced pulmonary insufficiency is defined as a SaPO2 of less than 93% during spontaneous breathing.

[0223] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating symptomatic COVID-19, wherein the compound reduces recovery time.

[0224] In one embodiment, the compound reduces the recovery time, for example, reduces the recovery time by one or more days, for example, by 7 days, for example, by 6 days, for example, by 5 days, for example, by 4 days, for example, by 3 days, for example, by 2 days, for example, by 1 day, for example, by at least 1 day. In one embodiment, the compound reduces the recovery time by 1-2 days, for example, by 2-3 days, for example, by 3-4 days, for example, by 4-5 days, for example, by 5-6 days, for example, by 6-7 days.

[0225] In one embodiment, reducing the recovery time is reducing the median recovery time. In one embodiment, reducing the recovery time is reducing the full recovery time.

[0226] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating symptomatic COVID-19, wherein the compound promotes resolution of inflammation.

[0227] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating symptomatic COVID-19, wherein the compound reduces the risk of developing severe inflammation.

[0228] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating symptomatic COVID-19, wherein the compound reduces the risk of developing severe acute respiratory distress syndrome (ARDS).

[0229] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating symptomatic COVID-19, wherein the compound reduces the need for supplemental oxygen to maintain normal saturations.

[0230] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating symptomatic COVID-19, wherein the compound reduces the risk of developing the need for more intensive lung support.

[0231] Subjects

[0232] Compositions of the invention comprising a compound of formula (I) or (II) as defined herein are useful for treating a viral disease or disorder as described herein in a subject in need thereof.

[0233] In some embodiments, the subject is infected with a virus.

[0234] In one embodiment, the subject is a mammal. In particular, the subject can be a human. In other embodiments, the subject is an animal, such as a pet, including, for example, a cat, dog, rabbit, horse, or a farm animal, such as a cattle or poultry, such as a cow, bull, sheep, goat, pig, chicken, or turkey.

[0235] In subjects with weakened immune systems, such as HIV-positive subjects, viral infections and symptomatic viral conditions or diseases may result in potentially life-threatening multi-organ disease.

[0236] The immunodeficiency may be the result of immunosuppressive agents routinely administered to transplanted subjects, or it may be the result of a condition such as a genetic condition or HIV infection.

[0237] In one embodiment there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or disorder in an immunodeficient subject.

[0238] In one embodiment, the immunodeficiency is a T cell deficiency.

[0239] In one embodiment, the immunodeficiency is a primary (or inherited) immunodeficiency of T cells. These include some conditions that result in a complete deficiency of T cells, such as severe combined immunodeficiency (SCID), Omenn syndrome, and cartilage-hair hypoplasia.

[0240] In one embodiment, the immunodeficiency is a secondary (or acquired) immunodeficiency of T cells. These include immunodeficiencies caused by HIV / AIDS, cancer chemotherapy, lymphoma, and glucocorticoid therapy.

[0241] In one embodiment, the immunodeficiency is complete or partial.

[0242] In some embodiments, the subject is HIV positive.

[0243] In one embodiment, there is provided a composition comprising a compound of formula (I) or (II) as defined herein for use in treating a viral disease or illness in a subject from a high-risk population. These include HSCT patients (hematopoietic stem cell transplantation), SOT patients (solid organ transplantation), elderly subjects, and very young subjects.

[0244] In one embodiment, the elderly subject is 65 years of age or older. In one embodiment, the elderly subject is 70 years of age or older.

[0245] In one embodiment, very young subjects are 1 year old or younger. In one embodiment, very young subjects are 6 months old or younger. In one embodiment, very young subjects are 3 months old or younger.

[0246] In one embodiment, a composition comprising a compound of formula (I) or (II) as defined herein is provided for use in treating symptomatic COVID-19 in a subject selected from subjects from high-risk groups, such as subjects with immunodeficiency, HSCT patients (hematopoietic stem cell transplantation), SOT patients (solid organ transplantation), elderly subjects and very young subjects.

[0247] Combination therapy

[0248] In one embodiment, the composition comprising a compound of formula (I) or (II) as disclosed herein, or a pharmaceutically acceptable derivative thereof, alone or together comprises one or more additional active pharmaceutical ingredients.

[0249] In one embodiment, the one or more additional active pharmaceutical ingredients are used to treat a viral disease or condition.

[0250] In one embodiment, the one or more additional active pharmaceutical ingredients are used to treat symptomatic COVID-19.

[0251] In one embodiment, a composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable derivative thereof as disclosed herein is an add-on therapy to an existing therapy.

[0252] In one embodiment, a composition comprising a compound of formula (I) or (II), or a pharmaceutically acceptable derivative thereof, as disclosed herein is an add-on therapy to one or more additional therapies for treating a viral disease or disorder.

[0253] In one embodiment, the additional therapy comprises one or more of oxygen on nasal catheter and mechanical ventilation.

[0254] In one embodiment, the symptomatic COVID-19 is also treated with: nasal cannula oxygen, such as nasal cannula oxygen at a flow rate between 2-5 LO2 / min, and / or mechanical ventilation.

[0255] Route of administration

[0256] It will be appreciated that the preferred route of administration will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated, the location in the body of the tissue to be treated and the active ingredient chosen.

[0257] In one embodiment, the composition comprising a compound of formula (I) or (II) as defined herein is administered by systemic, topical, enteral or parenteral administration. Appropriate dosage forms for such administration may be prepared by conventional techniques.

[0258] Systemic administration

[0259] Systemic administration enables the introduction of the compound into the bloodstream to ultimately target the site of desired action.

[0260] Such administration route is any suitable route, such as enteral, oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal, intraperitoneal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) routes.

[0261] In one embodiment, the composition comprising a compound of formula (I) or (II) as defined herein is administered by systemic administration.

[0262] Oral administration

[0263] Oral administration is commonly used for enteral drug delivery, where the compound is delivered through the intestinal mucosa. Syrups and solid oral dosage forms such as tablets, capsules, etc. are commonly used.

[0264] In one embodiment, the composition comprising a compound of formula (I) or (II) as defined herein is administered by oral administration.

[0265] Parenteral administration

[0266] Parenteral administration is any route of administration other than oral / enteral routes whereby the drug avoids first-pass degradation in the liver. Thus, parenteral administration includes any injection and infusion, such as bolus injection or continuous infusion, such as intravenous administration, intramuscular administration, subcutaneous administration. In addition, parenteral administration includes inhalation and topical administration.

[0267] Thus, the compound can be applied externally to cross any mucous membrane of an animal to which the biologically active substance is to be administered, for example, in the nose, vagina, eye, mouth, reproductive tract, lungs, gastrointestinal tract or rectum, preferably in the nose or mouth, and thus, parenteral administration can also include buccal, sublingual, nasal, rectal, vaginal and intraperitoneal administration, as well as pulmonary and bronchial administration by inhalation or instillation (installation). In addition, the compound can be applied externally to cross the skin.

[0268] The subcutaneous and intramuscular forms of parenteral administration are generally preferred.

[0269] Topical treatments

[0270] In one embodiment, the compounds disclosed herein are used as topical treatments, i.e., introduced directly to the site of action. Thus, the compounds can be applied directly to the skin or mucous membranes, or the compounds can be injected into the site of action, e.g., into the diseased tissue or into an end artery that leads directly to the diseased tissue.

[0271] dose

[0272] According to the present disclosure, the composition comprising the compound of formula (I) or (II) is applied to the individual in need of treatment with a pharmaceutically effective dose. The therapeutically effective amount of the compound is enough to cure, prevent a given disease and its complications, reduce the risk of a given disease and its complications, alleviate or partially prevent the clinical manifestations of a given disease and its complications. The amount effective for a specific treatment purpose will depend on the severity and type of the disease and the weight and overall state of the subject. The compound can be applied once or multiple times a day, for example, 1 to 8 times a day, for example, 1 to 6 times a day, for example, 1 to 5 times a day, for example, 1 to 4 times a day, for example, 1 to 3 times a day, for example, 1 to 2 times a day, for example, 2 to 4 times a day, for example, 2 to 3 times a day. Alternatively, the compound can be applied less than once a day, for example, once a day, for example, once every two days, for example, once every three days, for example, once every four days, for example, once every five days, for example, once every six days, for example, once a week.

[0273] In one embodiment, the composition comprising a compound of formula (I) or (II) as defined herein is administered in a therapeutically effective amount, for example in an amount of 1 mg to 1000 mg of the compound of formula (I) or (II) per day.

[0274] Thus, in one embodiment, the compound is administered in an amount of 1 mg to 1000 mg per day, for example, 1 to 5 mg per day, 5 to 10 mg per day, 10 to 15 mg per day, 15 to 20 mg per day, 20 to 30 mg per day, 30 to 60 mg per day, 60 to 80 mg per day, 80 to 100 mg per day, 100 to 130 mg per day, 130 to 160 mg per day, 160 to 200 mg per day, 200 to 240 mg per day, 240 to 280 mg per day, 280 to 300 mg per day. In some embodiments, the present invention relates to an amount of at least one iodine-containing compound, such as 1-20 mg per day, 320-360 mg per day, 360-400 mg per day, 400-440 mg per day, 440-500 mg per day, 500-560 mg per day, 560-620 mg per day, 620-680 mg per day, 680-740 mg per day, 740-800 mg per day, 800-860 mg per day, 860-920 mg per day, 920-980 mg per day, 980-1000 mg per day, for example, 500 to 1000 mg per day.

[0275] Daily means that the dosage can be given in one dose per day or divided into multiple doses per day, including once a day (QD), twice a day (BID) and / or three times a day (TID).

[0276] In one embodiment, the compound is administered in an amount of 100 mg once a day, 200 mg once a day, 300 mg once a day, 400 mg once a day, 500 mg once a day, 600 mg once a day, 700 mg once a day, 800 mg once a day, 900 mg once a day, or 100 mg once a day.

[0277] In one embodiment, the compound is administered in an amount of 100 mg once daily.

[0278] In one embodiment, the compound is administered in an amount of 100 mg twice daily (BID) or 100 mg three times daily (TID).

[0279] In one embodiment, the compound is administered in an amount of 200 mg twice daily (BID) or 200 mg three times daily (TID).

[0280] In one embodiment, the compound is administered as a once daily oral dose of 100 mg AP1189.

[0281] In another embodiment, the compound is administered in an amount of 0.01 mg / kg to 40 mg / kg body weight, e.g., 0.01 mg / kg to 0.05 mg / kg body weight, 0.05 to 0.1 mg / kg body weight, 0.1 to 0.5 mg / kg body weight, 0.5 to 1 mg / kg body weight, 1 to 2 mg / kg body weight, 2 to 3 mg / kg body weight, 3 to 5 mg / kg body weight, 5 to 10 mg / kg body weight, 10 to 15 mg / kg body weight, 15 to 20 mg / kg body weight, 20 to 30 mg / kg body weight, e.g., 30 to 40 mg / kg body weight.

[0282] preparation

[0283] In one embodiment, the composition comprising a compound of formula (I) or (II) as defined herein is a pharmaceutical composition, e.g., a pharmaceutically safe composition. The composition comprising a compound of formula (I) or (II) as defined herein may be administered in any suitable manner, e.g., orally, sublingually or parenterally, and may be presented in any form suitable for such administration, e.g., in the form of a solution, suspension, aerosol, tablet, capsule, powder, syrup, implant, or dispersion for injection.

[0284] In one embodiment, the composition comprising a compound of formula (I) or (II) as defined herein is formulated as a suspension.

[0285] In one embodiment, the composition comprising a compound of formula (I) or (II) as defined herein is formulated into an oral dosage form, such as a solid oral dosage form or pharmaceutical entity, such as a tablet or capsule, or a liquid oral dosage form. Methods for preparing solid pharmaceutical formulations are well known in the art.

[0286] In another embodiment, the composition comprising a compound of formula (I) or (II) as defined herein is formulated as an injectable dosage form.

[0287] In one embodiment, the composition comprising a compound of formula (I) or (II) as defined herein is formulated in the form of a solid pharmaceutical entity, suitably in the form of a tablet or capsule.

[0288] Compound (I) or (II) in the form of a free base or a salt thereof can be administered alone or in combination with a pharmaceutically acceptable carrier or excipient in a single dose or multiple doses. Pharmaceutical compositions can be formulated according to conventional techniques (e.g., those disclosed in Remington: The Science and Practice of Pharmacy, 19th edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995) with a pharmaceutically acceptable carrier or diluent and any other known adjuvant and excipient.

[0289] item

[0290] 1. A composition comprising a compound of formula (I):

[0291]

[0292] including tautomeric and stereoisomeric forms thereof; wherein n is 1; and R1 is CF3, CCl3, F, Cl, NO2 or CN, and R2, R3, R4, R5, R6 and R7 are hydrogen; or a pharmaceutically acceptable derivative thereof,

[0293] For the treatment of symptomatic COVID-19.

[0294] 2. The composition according to item 1, wherein the compound has formula (II):

[0295]

[0296] including tautomeric and stereoisomeric forms thereof; or pharmaceutically acceptable derivatives thereof.

[0297] 3. A composition according to any one of the preceding items, wherein the compound is selected from {3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine or a pharmaceutically acceptable salt thereof.

[0298] 4. The composition according to any one of the preceding items, wherein the pharmaceutically acceptable derivative thereof is a pharmaceutically acceptable salt of an inorganic acid or an organic acid.

[0299] 5. The composition according to item 4, wherein the organic acid is selected from the group consisting of formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, di-methylene salicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0300] 6. The composition according to any one of items 4 to 5, wherein the organic acid is acetic acid, succinic acid, tartaric acid or propionic acid.

[0301] 7. The composition according to item 4, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid and nitric acid.

[0302] 8. The composition according to item 6, wherein the organic acid is acetic acid.

[0303] 9. A composition according to any of the preceding items, wherein the compound is selected from {3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate.

[0304] 10. The composition according to any of the preceding items, wherein the compound is (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate (AP1189).

[0305] 11. A composition according to any one of the preceding items, wherein the compound:

[0306] i) is an agonist of one or more MC receptors,

[0307] ii) is an agonist of MC1R and MC3R, and / or

[0308] iii) It is a partial agonist of MC1R and MC3R.

[0309] 12. A composition according to any of the preceding items, wherein the symptomatic COVID-19 comprises one or more respiratory symptoms.

[0310] 13. A composition according to any of the preceding items, wherein the symptomatic COVID-19 comprises one or more respiratory symptoms selected from cough, dry cough, dyspnea, respiratory disease, respiratory dysfunction, respiratory failure, respiratory syndrome and 2019-nCoV acute respiratory disease (2019-nCoV ARD).

[0311] 14. A composition according to any of the preceding items, wherein the symptomatic COVID-19 includes viral pneumonia, including mild pneumonia, pneumonia, pneumonia with abnormal findings, and novel coronavirus pneumonia (NCP).

[0312] 15. A composition according to any of the preceding items, wherein the symptomatic COVID-19 is a severe disease.

[0313] 16. A composition according to any of the preceding items, wherein the symptomatic COVID-19 is a critical illness.

[0314] 17. A composition according to any of the preceding items, wherein the symptomatic COVID-19 exhibits elevated levels of one or more proinflammatory cytokines, such as IL-6 and / or IL-1β.

[0315] 18. A composition according to any of the preceding items, wherein the symptomatic COVID-19 is COVID-19 with respiratory failure.

[0316] 19. A composition according to any of the preceding items, wherein the symptomatic COVID-19 is COVID-19 with acute respiratory distress syndrome (ARDS).

[0317] 20. A composition according to any of the preceding items, wherein the symptomatic COVID-19 is COVID-19 with systemic inflammatory distress syndrome (SIDS).

[0318] 21. A composition according to any of the preceding items, wherein the symptomatic COVID-19 requires mechanical ventilation.

[0319] 22. A composition according to any of the preceding items, wherein the symptomatic COVID-19 is COVID-19-induced pulmonary insufficiency.

[0320] 23. A composition according to any of the preceding items, wherein the COVID-19-induced lung insufficiency is defined as the need for supplemental oxygen to maintain normal saturation.

[0321] 24. A composition according to any of the preceding items, wherein the COVID-19-induced pulmonary insufficiency is defined as a SaPO2 of less than 93% during spontaneous breathing.

[0322] 25. The composition according to any of the preceding clauses, wherein the compound reduces recovery time.

[0323] 26. A composition according to any of the preceding clauses, wherein the compound promotes resolution of inflammation.

[0324] 27. The composition according to any of the preceding items, wherein the compound reduces the risk of developing severe inflammation.

[0325] 28. A composition according to any of the preceding items, wherein the compound reduces the risk of developing severe acute respiratory distress syndrome (ARDS).

[0326] 29. A composition according to any of the preceding clauses, wherein the compound reduces the need for supplemental oxygen to maintain normal saturation.

[0327] 30. A composition according to any of the preceding clauses, wherein the compound reduces the risk of developing the need for greater lung support.

[0328] 31. A composition according to any of the preceding items, wherein the composition comprises one or more additional active pharmaceutical ingredients, either separately or in combination, such as one or more additional active pharmaceutical ingredients for the treatment of symptomatic COVID-19.

[0329] 32. A composition according to any of the preceding items, wherein the composition is an additional therapy to an existing therapy.

[0330] 33. A composition according to any of the preceding items, wherein the symptomatic COVID-19 is treated with nasal cannula oxygen administration, such as nasal cannula oxygen administration at a flow rate between 2-5LO2 / min.

[0331] 34. A composition according to any of the preceding items, wherein the compound is administered in an amount of 1 mg to 1000 mg per day, for example, 1 to 5 mg per day, 5 to 10 mg per day, 10 to 15 mg per day, 15 to 20 mg per day, 20 to 30 mg per day, 30 to 60 mg per day, 60 to 80 mg per day, 80 to 100 mg per day, 100 to 130 mg per day, 130 to 160 mg per day, 160 to 200 mg per day, 200 to 240 mg per day, 240 to 280 mg per day, 200 to 290 mg per day, 200 to 210 mg per day, 200 to 220 mg per day, 200 to 230 mg per day, 200 to 240 mg per day, 200 to 250 mg per day, 200 to 260 mg per day, 200 to 270 mg per day, 200 to 280 mg per day, 200 to 290 mg per day, 200 to 30 ... The dosage may be 280 to 320 mg per day, 320 to 360 mg per day, 360 to 400 mg per day, 400 to 440 mg per day, 440 to 500 mg per day, 500 to 560 mg per day, 560 to 620 mg per day, 620 to 680 mg per day, 680 to 740 mg per day, 740 to 800 mg per day, 800 to 860 mg per day, 860 to 920 mg per day, 920 to 980 mg per day, 980 to 1000 mg per day, for example, 500 to 1000 mg per day.

[0332] 35. A composition according to any of the preceding items, wherein the compound is administered in an amount of 100 mg once a day, 200 mg once a day, 300 mg once a day, 400 mg once a day, 500 mg once a day, 600 mg once a day, 700 mg once a day, 800 mg once a day, 900 mg once a day or 100 mg once a day.

[0333] 36. A composition according to any of the preceding items, wherein the compound is administered in an amount of 100 mg once a day.

[0334] 37. The composition according to any of the preceding items, wherein the compound is administered in an amount of 100 mg twice a day (BID) or 100 mg three times a day (TID).

[0335] 38. The composition according to any of the preceding items, wherein the compound is administered in an amount of 200 mg twice a day (BID) or 200 mg three times a day (TID).

[0336] 39. The composition according to any of the preceding items, wherein the compound is administered in a once daily oral dose of 100 mg AP1189.

[0337] 40. A composition according to any of the preceding items, wherein the composition is pharmaceutically safe. Example

[0338] Example 1

[0339] As with other local inflammatory conditions such as acute respiratory distress syndrome (ARDS), acute peritonitis can develop into a life-threatening condition with the development of systemic inflammatory distress syndrome (SIDS) and sepsis. The development of SIDS is associated with high circulating levels of proinflammatory cytokines including IL-1β and IL-6.

[0340] Acute peritonitis was induced in mice by ip injection of 1mg zymosan A (Sigma-Aldrich) in 0.5ml sterile PBS. Twelve hours later, mice were killed by CO2 exposure, and the peritoneal cavity was washed with 4ml ice-cold PBS containing 3mM EDTA. Cells were stained with Turk solution (3% acetic acid solution of 0.01% crystal violet) and counted using a Neubauer hemocytometer, or stained with FITC-coupled mAb and corresponding isotype controls for Ly-6G / Gr1, F4 / 80 (eBioscience, Hatfield, UK), and flow cytometry analysis was performed using BD FACSCalibur platform (BD Biosciences, Oxford, UK).

[0341] ELISA Ready-SET-Go! (eBioscience) was used to quantify IL-1β and IL-6 levels in snap-frozen samples according to the manufacturer's instructions. All animal studies were approved by the Ethical Committee for the Use of Animals, Barts and The London School of Medicine and conducted in accordance with their guidelines and the Guidance on the Operation of Animals, Scientific Procedures Act, 1986. Male (7-8 weeks old) C57BL / 6J wild-type (WT) mice were purchased from Charles River Laboratories.

[0342] Test item A = AP1189(E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate.

[0343] Test item A 1 mg / kg or vehicle treatment was intraperitoneally administered 30 minutes before induction of acute peritonitis. N=6 in both groups.

[0344] result:

[0345] Pretreatment with Test Item A reduced the levels of proinflammatory cytokines IL-1β and IL-6 by 37% and 59%, respectively, compared to pretreatment with vehicle (p<0.05 vs. vehicle).

[0346] Neutrophil accumulation was reduced by 70% after pretreatment with Test Item A compared to vehicle treatment.

[0347] Example 2

[0348] SynAct has initiated dosing in Part 2 of a Phase II clinical study with AP1189 in patients infected with Covid-19.

[0349] SynAct Pharma AB ("SynAct") announced today that dosing has begun in the second part of an exploratory Phase 2 study of AP1189 in patients with Covid-19, conducted under the RESOVIR collaboration, following completion of the initial open-label portion of the study. Part 2 is a randomized, double-blind, placebo-controlled study in 54 [corrected from 56] patients with Covid-19 at the Clinical Center of the Universidade Federal de Minas, Belo Horizonte, Brazil.

[0350] The initial open-label portion of the study was conducted in six patients referred to the hospital with Covid-19-induced pulmonary insufficiency (defined as the need for supplemental oxygen to maintain normal saturations). The patients were four women and two men, aged between 38 and 59 years, all with SaPO2 less than 93% while breathing spontaneously, and all six patients were treated with nasal cannula oxygen at a flow rate between 2-5LO2 / min. Patients were treated with 100 mg of AP1189 orally once daily as an add-on to standard therapy.

[0351] The compound was found to be safe and well tolerated, and patients were discharged from the hospital between days 3 and 9 of treatment, as none of them required more intensive lung support.

[0352] As no safety issues were identified, recruitment for Part 2 of the study has begun. As of March 16, 2021, 16 patients have been enrolled in Part 2 of the study.

[0353] The second part of the study is set up to evaluate the safety and efficacy of a two-week dosing regimen of AP1189 relative to placebo as an add-on therapy for patients with Covid-19-induced pulmonary insufficiency (defined as the need for supplemental oxygen to maintain normal saturations). Up to 54 patients will be randomized in a 2:1 ratio to receive AP1189 100 mg or placebo once daily in addition to standard of care. The primary clinical objective of the study is to show a reduction in respiratory recovery time (i.e., the time to normalization of oxygen saturation on ambient air). Top line results from the study are expected in the second quarter of 2021.

[0354] "There is a growing need for effective treatments to stop the severe inflammation we see in patients infected with Covid-19. We have already started Phase 2 of our study to investigate whether AP1189 can promote resolution of inflammation, thereby reducing recovery time and the risk of developing severe ARDS."

[0355] "Samples from patients with Covid-19 pneumonia have shown that macrophages make up 80% of the total cells in the alveoli and play a key role in the excessive inflammation associated with the damaging effects of Covid-19 infection. As AP189 specifically targets macrophages, we are very much looking forward to further investigating the potential benefits of using AP1189 to treat Covid-19 patients."

[0356] Importantly, the study aims not only to test potential effects on clinical readouts such as recovery time, but also to investigate the effects of the compounds on activated inflammatory pathways in patients infected with Covid-19. This work has already begun, continues with the collection of samples from patients, and will be carried out in laboratories in Belo Horizonte and London (as part of the RESOVIR collaboration).

[0357] Example 3

[0358] The effects of treatment with AP1189 were tested in patients infected with Covid-19.

[0359] The study population consisted of patients hospitalized with COVID-19 infection with impaired oxygenation. The study was conducted at a site in Belo Horizonte, Brazil.

[0360] The study consists of two parts:

[0361] Part 1: An open-label study testing the safety and tolerability of once-daily oral administration of AP1189 in six (6) hospitalized patients with Covid-19 infection.

[0362] Part 2: A randomized, double-blind, placebo-controlled clinical trial testing once-daily oral administration of AP1189 or placebo in a total of 54 hospitalized Covid-19 infected patients randomized 2:1. After the safety evaluation of Part 1, Part 2 was initiated when the study safety monitoring committee found the compound to be safe and well tolerated.

[0363] Dosing has begun in the second part of an exploratory Phase 2 study with AP1189 in patients with Covid-19 following completion of the initial open-label portion of the study.

[0364] The study was designed to determine a statistically significant treatment effect, defined as a reduction in time to recovery relative to a placebo-treated control group, at a significance level of 0.05 with a power of 80%, assuming that the median time to full recovery in patients treated with placebo was 11 days and that treatment with AP1189 would reduce the median time to recovery by 3 days.

[0365] After successful screening, consenting subjects who meet the inclusion criteria are and have been treated with AP1189 100 mg once daily as an add-on to any ongoing therapy in Part A. In Part B, patients will be randomized in a 2:1 ratio to either the active or placebo group:

[0366] Active group (36 subjects): AP1189, 100 mg, once daily for 2 weeks (14 days), as an add-on therapy to any ongoing treatment;

[0367] Placebo group (18 subjects): Placebo, once daily for 2 weeks (14 days), as an add-on therapy to any ongoing treatment.

[0368] Stopping rules

[0369] The investigator may decide to stop the study if a serious medical event (e.g., stroke, convulsion, etc.) or any SAE (serious adverse event) occurs that is considered to be related to the study drug.

[0370] Study Group

[0371] The study population consisted of hospitalized subjects with COVID-19 infection and impaired oxygenation.

[0372] 1.1. Subject selection criteria

[0373] The study can achieve its objectives only if suitable subjects are recruited. The following eligibility criteria are designed to select subjects for whom the regimen treatment is considered appropriate. All relevant medical and non-medical circumstances should be considered in deciding whether the regimen is appropriate for a subject.

[0374] 1.2 Inclusion criteria

[0375] Prior to inclusion of a subject in a study, the subject's eligibility should be reviewed and documented by an appropriately qualified member of the investigator's research team. The following are the requirements for entry into a study:

[0376] a. Written informed consent was obtained before commencing any study-specific procedures.

[0377] b. Male and female subjects aged 18-85 years hospitalized due to COVID-19 infection

[0378] C. COVID-19 infection is confirmed by the presence of SARS-CoV-2 nucleic acid detected by polymerase chain reaction (PCR)

[0379] d. Evidence of impaired oxygenation defined as SpO2 ≤ 93% in ambient air.

[0380] e. Illness duration < 10 days from the first symptom before admission

[0381] f. Females of childbearing potential who use reliable contraceptive methods or are postmenopausal (have stopped menstruating for at least 12 months prior to trial inclusion) or have undergone surgical sterilization (the procedure must have been performed at least 6 months prior to screening)

[0382] g. Women of childbearing potential with negative pregnancy

[0383] h. Tests are performed at screening and baseline.

[0384] 1.3. Exclusion criteria

[0385] Subjects who meet any of the following criteria are not eligible to participate in the study:

[0386] a. The researchers believe that death is imminent and inevitable regardless of the treatment provided

[0387] b. Participating in other drug clinical trials (participating in COVID-19 antiviral trials, in which the compounds being studied are intended to reduce viral infection. However, doses not exceeding 10 mg / day of remdesivir or dexamethasone are allowed.

[0388] c. Any condition that, in the opinion of the screening physician, would make the patient unable to comply with the study protocol and procedures (e.g., psychiatric illness, dementia, patients receiving palliative care only)

[0389] d. Subjects treated with immunosuppressive drugs (including microphenolate and cyclophosphamide)

[0390] e. HIV infection

[0391] f. Pregnant or breastfeeding mothers

[0392] g. Estimated glomerular filtration rate (eGFR) < 30 ml / min

[0393] h. Severe liver dysfunction (Child-Pugh score C)

[0394] i. History of oral glucocorticoid therapy (except for dexamethasone therapy not exceeding 10 mg / day associated with Covid-19 treatment)

[0395] j. Recruitment of subjects

[0396] Potential subjects for this study will be identified among the patients at the hospital. Potentially suitable subjects will be approached by the site's research staff to determine if they are interested in participating in the study. Interested subjects will receive verbal and written information about the study prior to consenting. No other study procedures will be performed prior to consenting.

[0397] Results - Initial Open-label Part of the Study

[0398] Six patients referred to hospital for Covid-19-induced pulmonary insufficiency received 100 mg of AP1189 orally once daily as an add-on to standard therapy (nasal cannula oxygen flow rate between 2-5 LO2 / min).

[0399] In these patients, the compound was found to be safe and well tolerated, and patients were discharged from the hospital between days 3 and 9 of treatment, with none requiring more intensive lung support. This suggests that the compound has the ability to reduce respiratory recovery time (i.e., the time it takes for oxygen saturation to normalize in ambient air).

Claims

1. Use of a composition for the preparation of a medicament for treating a viral disease or condition caused by SARS-CoV-2 accompanied by pulmonary insufficiency, the composition comprising a compound of formula (II): or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein the compound is selected from {3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine, or a pharmaceutically acceptable salt thereof.

3. The use according to claim 1, wherein the pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of an inorganic acid or an organic acid.

4. The method of claim 3, wherein the organic acid is selected from the group consisting of formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, di-methylene salicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

5. The use according to claim 4, wherein the organic acid is acetic acid, succinic acid, tartaric acid or propionic acid.

6. The use according to claim 3, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid and nitric acid.

7. The use according to claim 5, wherein the organic acid is acetic acid.

8. The use according to claim 5, wherein the organic acid is succinic acid.

9. The use according to claim 1, wherein the compound is selected from {3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate.

10. The use according to claim 9, wherein the compound is (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate.

11. The use according to claim 1, wherein the compound: i) is an agonist of one or more MC receptors, ii) is an agonist of MC1R and MC3R, and / or iii) It is a partial agonist of MC1R and MC3R.

12. The use according to claim 1, wherein the viral disease or condition caused by SARS-CoV-2 is symptomatic COVID-19.

13. The use according to claim 12, wherein the symptomatic COVID-19 comprises one or more respiratory symptoms.

14. The use according to claim 12, wherein the symptomatic COVID-19 comprises one or more respiratory symptoms selected from cough, dry cough, dyspnea, respiratory disease, respiratory dysfunction, respiratory failure and respiratory syndrome.

15. The use according to claim 14, wherein the respiratory disease is 2019-nCoV acute respiratory disease.

16. The use according to claim 12, wherein the symptomatic COVID-19 is viral pneumonia.

17. The use according to claim 16, wherein the viral pneumonia is mild pneumonia and pneumonia with abnormal findings.

18. The use of claim 12, wherein the symptomatic COVID-19 is severe disease.

19. The use according to claim 12, wherein the symptomatic COVID-19 is a critical illness.

20. The use according to claim 12, wherein the symptomatic COVID-19 exhibits elevated levels of one or more pro-inflammatory cytokines.

21. The use according to claim 20, wherein the symptomatic COVID-19 exhibits elevated levels of IL-6 and / or IL-1β.

22. The use according to claim 12, wherein the symptomatic COVID-19 is COVID-19 with respiratory failure.

23. The use according to claim 12, wherein the symptomatic COVID-19 is COVID-19 with acute respiratory distress syndrome.

24. The use according to claim 12, wherein the symptomatic COVID-19 is COVID-19 with systemic inflammatory distress syndrome.

25. The use according to claim 12, wherein the symptomatic COVID-19 requires mechanical ventilation.

26. The use according to claim 12, wherein the symptomatic COVID-19 is COVID-19-induced pulmonary insufficiency.

27. The use according to claim 26, wherein the COVID-19 induced lung insufficiency is defined as the need for supplemental oxygen to maintain normal saturation.

28. The use according to claim 26, wherein the COVID-19 induced lung insufficiency is defined as SaPO2 less than 93% during spontaneous breathing.

29. The use according to claim 1, wherein the viral disease or disorder caused by SARS-CoV-2 is a viral disease or disorder accompanied by inflammation in the respiratory system.

30. The use according to claim 29, wherein the viral disease or disorder caused by SARS-CoV-2 is a viral disease or disorder accompanied by inflammation in the lungs and / or respiratory tract.

31. The use according to claim 1, wherein the viral disease or disorder caused by SARS-CoV-2 is a viral disease or disorder accompanied by one or more respiratory symptoms.

32. The use according to claim 31, wherein the one or more respiratory symptoms are respiratory diseases.

33. The use according to claim 31, wherein the one or more respiratory symptoms are selected from cough, dry cough, dyspnea, impaired oxygenation, respiratory dysfunction, respiratory failure, respiratory syndrome and acute respiratory disease.

34. The use according to claim 31, wherein the respiratory symptom is respiratory failure.

35. The use according to claim 31, wherein the respiratory symptoms are selected from type 1 respiratory failure, type 2 respiratory failure, acute respiratory failure and chronic respiratory failure.

36. The use according to claim 1, wherein the viral disease or disorder is acute respiratory distress syndrome.

37. The use according to claim 1, wherein the viral disease or disorder caused by SARS-CoV-2 is a severe disease.

38. The use according to claim 37, wherein the severe disease manifests itself in one or more of dyspnea, increased respiratory rate, decreased blood oxygen saturation and / or pulmonary infiltrates.

39. The use according to claim 1, wherein the viral disease or condition caused by SARS-CoV-2 is a critical illness.

40. The use according to claim 39, wherein the critical illness manifests one or more of respiratory failure, septic shock, multiple organ dysfunction or multiple organ failure.

41. The use according to claim 1, wherein the viral disease or condition caused by SARS-CoV-2 is viral bronchiolitis.

42. The use according to claim 1, wherein the viral disease or condition caused by SARS-CoV-2 is viral pneumonia.

43. The use according to claim 42, wherein the viral pneumonia is selected from mild pneumonia and pneumonia with abnormal findings.

44. The use according to claim 1, wherein the lung insufficiency is defined as the need for supplemental oxygen to maintain normal saturation.

45. The use according to claim 1, wherein the lung insufficiency is defined as a SaPO2 of less than 93% during spontaneous breathing.

46. ​​The use according to claim 1, wherein the viral disease or condition caused by SARS-CoV-2 requires mechanical ventilation.

47. The use according to claim 46, wherein the mechanical ventilation comprises protective mechanical ventilation, high-flow nasal oxygen therapy and non-invasive ventilation.

48. The use according to claim 1, wherein the viral disease or disorder caused by SARS-CoV-2 is a viral disease or disorder accompanied by systemic inflammation.

49. The use according to claim 1, wherein the viral disease or condition caused by SARS-CoV-2 is systemic inflammatory distress syndrome.

50. The use according to claim 1, wherein the viral disease or condition caused by SARS-CoV-2 is acute respiratory distress syndrome and systemic inflammatory distress syndrome.

51. The use of claim 1, wherein the treatment reduces recovery time.

52. The use of claim 1, wherein the treatment promotes resolution of inflammation.

53. The use according to claim 1, wherein the treatment reduces the risk of developing severe inflammation.

54. The use of claim 1, wherein the treatment reduces the risk of developing severe acute respiratory distress syndrome.

55. The use of claim 1, wherein the treatment reduces the need for supplemental oxygen to maintain normal saturations.

56. The use according to claim 1, wherein the treatment reduces the risk of developing the need for more intense lung support.

57. The method of claim 1, wherein the treatment of a viral disease or condition caused by SARS-CoV-2 is performed in a subject from a high-risk group, wherein the subject from the high-risk group is selected from hematopoietic stem cell transplant patients, solid organ transplant patients, elderly subjects, and very young subjects.

58. The use according to claim 1, wherein the composition comprises, alone or together, one or more additional active pharmaceutical ingredients.

59. The use according to claim 58, wherein the one or more additional active pharmaceutical ingredients are one or more additional active pharmaceutical ingredients for the treatment of a viral disease or condition.

60. The use according to claim 58, wherein the one or more additional active pharmaceutical ingredients are active pharmaceutical ingredients for treating symptomatic COVID-19.

61. The use of claim 1, wherein the composition is an add-on therapy to one or more additional therapies for treating a viral disease or disorder.

62. The use according to claim 1, wherein the viral disease or condition caused by SARS-CoV-2 is treated with: nasal cannula oxygen administration, and / or mechanical ventilation.

63. The use according to claim 62, wherein the nasal cannula oxygen administration is nasal cannula oxygen administration with a flow rate between 2-5 LO2 / min.

64. The use according to claim 1, wherein the compound is administered in an amount of 1 mg to 1000 mg per day.

65. The use of claim 64, wherein the compound is administered in an amount of 1 to 5 mg per day, 10 to 15 mg per day, 20 to 30 mg per day, 60 to 80 mg per day, 100 to 130 mg per day, 160 to 200 mg per day, 240 to 280 mg per day, 320 to 360 mg per day, 400 to 440 mg per day, 500 to 560 mg per day, 620 to 680 mg per day, 740 to 800 mg per day, 860 to 920 mg per day, or 980 to 1000 mg per day.

66. The use of claim 64, wherein the compound is administered in an amount of 5 to 10 mg per day, 15 to 20 mg per day, 30 to 60 mg per day, 80 to 100 mg per day, 130 to 160 mg per day, 200 to 240 mg per day, 280 to 320 mg per day, 360 to 400 mg per day, 440 to 500 mg per day, 560 to 620 mg per day, 680 to 740 mg per day, 800 to 860 mg per day, or 920 to 980 mg per day.

67. The use according to claim 64, wherein the compound is administered in an amount of 100 mg once a day, 200 mg once a day, 300 mg once a day, 400 mg once a day, 500 mg once a day, 600 mg once a day, 700 mg once a day, 800 mg once a day, 900 mg once a day or 1000 mg once a day.

68. The use according to claim 64, wherein the compound is administered in an amount of 100 mg once a day.

69. The use according to claim 64, wherein the compound is administered in an amount of 100 mg twice a day or 100 mg three times a day.

70. The use according to claim 64, wherein the compound is administered in an amount of 200 mg twice a day or 200 mg three times a day.

71. The use according to claim 64, wherein the compound is administered orally once a day at 100 mg of (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine acetate.

72. The use according to claim 1, wherein the composition is pharmaceutically safe.

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