Treatment of symptomatic viral diseases

Abstract

The present invention provides compositions for the treatment of viral diseases or disorders. [Solution] Provided is a composition comprising a phenylpyrrole-aminoguanidine derivative represented by formula (I) for use in methods for treating viral disorders and diseases, including symptomatic COVID-19. TIFF2026065136000016.tif79162

Description

Technical Field

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

Background Art

[0002] Background Historically, infectious diseases, particularly those caused by viruses, have been one of the most important contributing factors to human morbidity and mortality. They account for a large proportion of deaths and disabilities worldwide and remain the most important cause of disease in certain regions. The burden of viral diseases and disorders is exemplified by the recent coronavirus disease 2019 (COVID-19) outbreak.

[0003] 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 respiratory infection COVID-19 is also known as 2019-nCoV acute respiratory disease (2019-nCoV ARD) and novel coronavirus pneumonia (NCP).

[0004] Most people infected with the COVID-19 virus are affected by mild to moderate respiratory diseases similar to mild pneumonia and recover without special treatment. The elderly, as well as people with medical problems such as cardiovascular disease, diabetes, chronic respiratory disease and cancer, are more likely to develop severe diseases. Common symptoms include fever, fatigue and dry cough. Other symptoms include shortness of breath, dull pain and aches, and sore throat.

[0005] The clinical spectrum of COVID-19 ranges from asymptomatic or mild forms to clinical conditions characterized by respiratory failure requiring mechanical ventilation and intensive care unit support, and to multi-organ and systemic symptom development related to sepsis, septic shock, and multi-organ dysfunction syndrome.

[0006] Severe illness presents with dyspnea, increased respiratory rate, decreased blood oxygen saturation, and / or pulmonary infiltration. Critical illness presents with respiratory failure, septic shock, and / or multiple organ failure (MOD) or multiple organ failure (MOF).

[0007] Infection of the upper and lower respiratory tracts by the COVID-19 virus can cause mild to severe acute respiratory syndrome, accompanied by the resulting release of pro-inflammatory 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 are found to predict the severity of COVID-19.

[0008] Initially, there was no specific vaccine or treatment for COVID-19. Several treatments to date have shown some effectiveness. In many cases, treatments are symptomatic, and oxygen therapy is the primary treatment intervention for patients with severe infection. Strategies for addressing respiratory failure include protective mechanical ventilation and high-flow nasal oxygen (HFNO) or non-invasive ventilation (NIV).

[0009] Viral induced ARDS (Acute Respiratory Distress Syndrome) is characterized by capillary damage and plasma leakage into the alveolar sacs, disrupting the blood-air barrier and severely impairing blood oxygen supply. This can occur directly as a result of viral injury, and indirectly as a result of hyperactivation of the immune system that triggers the infiltration of immune cells such as neutrophils and macrophages into the lungs, accompanied by a "cytokine storm"—that is, the excessive or uncontrolled production of cytokines such as TNF, interleukin (IL)-1b, IL-6, IL-12, and IFNc, as well as chemokines such as IL-8, MCP-1, and IP-10. While this is essentially a protective response that limits viral transmission, it can end up being more harmful than beneficial. Although some of the details may differ, cytokine storms are a common complication of respiratory infections caused by influenza A, SARS-CoV, MERS-CoV, and SARS-CoV-2 viruses.

[0010] The melanocortin system is a combination of neuropeptide and immunoendocrine signaling pathways that plays an integrated role in regulating homeostasis of diverse physiological functions, including melanin formation, stress response, inflammation, immunomodulation, and adrenocortical steroid production. It consists of five G protein-coupled melanocortin receptors, namely melanocortin receptor 1 (MC1R) to MC5R; peptide ligands; α,β,γ-melanocyte-stimulating hormone (α,β,γ-MSH), which is adrenocorticotropic hormone (ACTH) secreted by the anterior pituitary gland; and several other components, including endogenous antagonists. The biological functions of the melanocortin system are mediated by five melanocortin receptors (MCRs), which have completely different tissue secretion characteristics, carry different signals, and exert various biological activities in different organ systems.

[0011] Phenylpyrrole-aminoguanidine derivatives that are active on melanocortin receptors are disclosed in WO2007 / 141343. An example of such a compound is the anti-inflammatory AP1189 ((E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}-aminoguanidium acetate), which was initially shown to bind to MC1R (WO2007 / 141343) and later identified as a biased dual agonist on the MC1R and MC3R receptors that do not induce canonical cAMP production. The mechanism of action of AP1189 is to promote the resolution of inflammation through direct activation of melanocortin receptors on macrophages, thereby reducing the pro-inflammatory activity of macrophages and stimulating macrophage efferocytosis, a specific ability to cleanse inflammatory cells (Montero-Melendez et al. 2015). This effect has been shown to be effective in disease models of inflammatory and autoimmune diseases, and the clinical potential of this approach is currently being tested in a Phase 2 clinical trial in patients with active rheumatoid arthritis. [Overview of the project] [Problems that the invention aims to solve]

[0012] overview The inventors have found that the phenylpyrrole aminoguanidine derivative AP1189 ((E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}-aminoguanidium acetate) reduces the levels of pro-inflammatory cytokines IL-1 and IL-1β and reduces neutrophil accumulation compared to the vehicle. This suggests that AP1189 and related compounds are candidate substances for the treatment of symptomatic COVID-19.

[0013] Samples from COVID-19 pneumonia patients have shown that macrophages make up up to 80% of all cells in the alveoli and play a crucial role in the hyperinflammation associated with the devastating effects of COVID-19 infection.

[0014] Clinical trial data demonstrated that patients with COVID-19-induced lung failure who received AP1189 did not require more intensive lung support, and therefore, the patients were discharged between day 3 and day 9 of treatment.

[0015] AP1189 and related compounds are therefore promising candidates for the treatment of viral diseases and disorders through their ability to control or suppress inflammation, including inappropriate hyperactivation of the immune system and the resulting hyperinflammation, while simultaneously stimulating the immune system in some cases, allowing it to fully fight the underlying viral infection. This is called resolution therapy. [Means for solving the problem]

[0016] One aspect of this disclosure relates to formula (I), including tautomers and stereoisomers, for use in the treatment of viral diseases and disorders, such as symptomatic viral diseases and disorders with respiratory symptoms including respiratory failure and ARDS: [ka] The objective is to provide a composition comprising a compound represented by (wherein n is 1; 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.

[0017] One aspect of this disclosure relates to formula (I), including tautomers and stereoisomers, for use in the treatment of symptomatic COVID-19, such as symptomatic COVID-19 with respiratory symptoms including respiratory failure and ARDS: [ka] To provide a composition comprising a compound represented by (where n is 1; 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.

[0018] In one embodiment, the compound is (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium and a pharmaceutically acceptable salt thereof.

[0019] In one embodiment, the compound is (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium acetate (AP1189). BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Test substance A = AP1189 (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium acetate [Figure 1] Pretreatment with AP1189 reduces the level of pro-inflammatory cytokine IL-1β by 37% compared to pretreatment with vehicle. [Figure 2] Pretreatment with AP1189 reduces the level of pro-inflammatory cytokine IL-6 by 59% compared to pretreatment with vehicle. [Figure 3] Pretreatment with AP1189 reduces neutrophil accumulation by 70% compared to pretreatment with vehicle. MODE FOR CARRYING OUT THE INVENTION

[0021] Definitions As used in the context of this specification, the term "pharmaceutically acceptable derivative" includes pharmaceutically acceptable salts that are not harmful to patients. Such salts include pharmaceutically acceptable base or acid addition salts, as well as pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. Pharmaceutically acceptable derivatives further include esters, prodrugs or other precursors of the active compound, or compounds that can be biologically metabolized into the crystalline form of the compound. In one embodiment, the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt.

[0022] The term "acid addition salt" is intended to include "pharmaceutically acceptable acid addition salts" that are not harmful to patients. Acid addition salts include salts of inorganic 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, bis(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, p-toluenesulfonic acid, and the like. Further 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.

[0023] As used herein, the term “therapeutic effective dose” of a compound refers to an amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially halt the clinical manifestation of a given disease or disorder and its complications. The amount appropriate to accomplish this is defined as the “therapeutic effective dose.” Each effective dose for a given purpose will depend on the severity of the disease or injury, as well as the subject's weight and overall condition. Determining the appropriate dosage may be achieved through routine experimentation by constructing a matrix of values ​​and testing different points in the row, and it will be understood that this is all within the scope of the routine skills of a trained physician or veterinarian.

[0024] As used herein, the terms “treatment” and “to treat” refer to the management and care of a patient for the purpose of overcoming a disease, illness, or disorder. This term encompasses the entire scope of treatment for a given disease in which the patient is suffering. The patient being treated is preferably a mammal, more specifically a human. However, treatment of animals such as mice, rats, dogs, cats, horses, cows, sheep, and pigs is also within the scope of the present invention. The patient being treated may be of various ages.

[0025] Detailed description Melanocortin (MC) receptors (MC1R-MC5R), a family of class AG protein-coupled receptors (GPCRs), are attractive therapeutic targets for numerous diseases due to their broad distribution and the diversity of physiological processes they regulate. MC1R, due to its expression in leukocytes, regulates UV-induced sunburn and other immune responses. MC2R regulates cortisol production in the adrenal glands, while MC5R plays a role in secretion in endocrine glands. MC3R and MC4R exert non-overlapping functions in energy homeostasis, in addition to specific anti-inflammatory roles; however, activation of MC3R is particularly protective against joint inflammation such as arthritis, and MC4R provides neuroprotection in encephalitis. Therefore, numerous pathological conditions, including skin diseases, cardiovascular diseases, joint inflammation, obesity, and cachexia, can be targeted with MCR drugs.

[0026] Peripheral MC1R and MC3R can be pharmacologically activated to induce anti-inflammatory activity. Like other protective mediators, the endogenous agonist α-melanocyte-stimulating hormone (αMSH) is released by immune cells to counteract pro-inflammatory signals, thus preventing excessive tissue damage. Consistent with the convergence of the concept of inflammation, therapeutic agents targeting MC1R and MC3R may act by mimicking the body's own protective substances and may feature less burdensome side effects.

[0027] The use of corticotropin or adrenocorticotropic hormone (ACTH) has been shown to be effective for rheumatic diseases since the 1950s, but its use declined with the availability of synthetic glucocorticoids. However, the discovery of alternative anti-inflammatory mechanisms for ACTH involving the activation of peripheral MC receptors on immune cells has revived interest in developing novel ACTH-like molecules that do not have steroid effects for the treatment of joint diseases such as gout or RA (rheumatoid arthritis). However, the bridging delivery of novel MC drugs other than commercially available ACTH formulations is limited by the lack of receptor selectivity achieved so far.

[0028] Innovative approaches to drug discovery for G protein-coupled receptors may help overcome this limitation. Allosteric regulation lies in the ability of molecules to enhance (positively regulate) or reduce (negatively regulate) the effect of endogenous ligands by binding to a completely different receptor protein site called the allosteric site. The fewer allosteric regions there are among the five MCRs, the higher the selectivity is expected, and in fact, allosteric regulators of MC4R are currently under development for the treatment of obesity.

[0029] Another emerging concept attracting significant therapeutic interest is biased agonism. The old notion that receptors can exist in two specific conformations—an active conformation and an inactive conformation—has been replaced by the idea that multiple active conformations can exist, each generating entirely different signals and producing multiple functional outcomes. Rather than being linear and static, receptor activation emerges as a highly dynamic and multidimensional process, in which the diversity of active conformations can be induced by different molecules, leading to entirely different effects.

[0030] The small molecule AP1189 ((E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}-aminoguanidium acetate) is characterized as a biased agonist at receptors MC1R and MC3R. It does not induce canonical cAMP production but triggers ERK1 / 2 phosphorylation, a signaling pathway responsible for the proefferocytic effect induced in primary mouse macrophages. AP1189 has been shown to reduce cytokine release within macrophages, but melanin formation was not induced by AP1189 in melanocytes. In vivo, oral AP1189 induced anti-inflammatory effects and accelerated the convergence phase in peritonitis and gave a significant reduction in macroscopic and histological parameters of joint destruction in experimental inflammatory arthritis. Therefore, AP1189 is a biased dual agonist at MC1R and MC3R that possesses anti-inflammatory properties along with no effect on melanin formation.

[0031] Unregulated cytokine release has been identified as a significant underlying factor contributing to poor outcomes in respiratory viral infections. This "cytokine storm" leads to excessive inflammation and immune responses, particularly in the lungs, resulting in acute respiratory distress (ARDS), pulmonary edema, and multiple organ failure. Alleviating this inflammatory state is essential for improving prognosis.

[0032] Patients with respiratory conditions requiring mechanical ventilation, such as pneumonia and ARDS, often present with local inflammation, which can develop into life-threatening systemic inflammation. A key challenge in these patients is to control inflammation without inhibiting or blocking it (e.g., hyperactivated inflammatory cascades), while simultaneously ensuring the immune system remains effective in overcoming the disease. In such situations, AP1189 can make a difference, at least in such patients, by inhibiting inflammation and simultaneously stimulating the immune system's ability to clear it more rapidly. This is known as convergent therapy.

[0033] Viral diseases and disorders One aspect of this disclosure is a formula (I) including tautomers and stereoisomers for use in the treatment of a viral disease or disorder, such as for use in the treatment of a symptomatic viral disease or disorder: [ka] The objective is to provide a composition comprising a compound represented by (wherein n is 1; 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.

[0034] Similarly, one embodiment is for the manufacture of a pharmaceutical [ka] The objective is to provide the use of a composition containing the compound shown or a pharmaceutically acceptable derivative thereof.

[0035] Also disclosed is equation (I): [ka] A method for treating a viral disease or disorder, such as a symptomatic viral disease or disorder, comprising one or more steps of administering a composition containing the compound shown or a pharmaceutically acceptable derivative thereof to an individual in need.

[0036] In certain embodiments, compositions for use according to the present disclosure include formula (II) with tautomer and stereoisomer forms: [ka] This includes compounds represented by [the specified symbol], or pharmaceutically acceptable salts thereof, and other pharmaceutically acceptable derivatives thereof.

[0037] In one embodiment, the composition for use according to the present disclosure is i) An agonist of one or more MC receptors, ii) An agonist of MC1R and MC3R, and / or iii) A biased agonist of MC1R and MC3R, Contains compounds.

[0038] Also disclosed are compositions for use according to the present disclosure, for use in the treatment of viral diseases or disorders, such as symptomatic viral diseases or disorders, comprising compounds selected from the group consisting of {3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}aminoguanidine and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}aminoguanidine or pharmaceutically acceptable salts thereof.

[0039] In one embodiment, the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt of an inorganic acid or an organic acid.

[0040] In such embodiments, the organic acids referenced herein are 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, bismethylenesalicylic 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.

[0041] In a specific embodiment, the organic acid is acetic acid, succinic acid, tartaric acid, or propionic acid, such as acetic acid.

[0042] In such embodiments, the organic acid referenced herein is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and nitric acid.

[0043] Also disclosed are compositions for use in the treatment of viral diseases or disorders, such as symptomatic viral diseases or disorders, comprising compounds selected from the group consisting of {3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}aminoguanidinium acetate and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}aminoguanidinium acetate.

[0044] In one embodiment, the Disclosure provides a composition comprising (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}-aminoguanidinium or a pharmaceutically acceptable salt thereof for use in the treatment of viral diseases or disorders, such as symptomatic viral diseases or disorders.

[0045] In a specific embodiment, the Disclosure provides a composition comprising (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}-aminoguanidinium acetate (AP1189) for use in the treatment of viral diseases or disorders, such as symptomatic viral diseases or disorders.

[0046] The viral illness or disorder described herein refers to any illness or disorder caused by such viral infection, including any symptoms or downstream effects of the viral infection.

[0047] One embodiment provides a composition for use in the treatment of a viral disease or disorder, comprising a compound represented by formula (I) or (II) as defined herein, such treatment of a viral disease or disorder includes treatment, improvement, and / or mitigation of such a viral disease or disorder. It is understood that treatment, improvement, and / or mitigation of a viral disease or disorder encompasses treatment, improvement, and / or mitigation of one or more symptoms of the viral disease or disorder.

[0048] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of one or more symptoms of a viral disease or disorder.

[0049] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a symptomatic viral disease or disorder.

[0050] In one embodiment, the viral disease or disorder, or one or more symptoms of the symptomatic viral disease or disorder, is inflammation such as excessive inflammation.

[0051] In one embodiment, a viral disease or disorder, or one or more symptoms of the symptomatic viral disease or disorder, is inflammation such as excessive inflammation in one or more organs. Inflammation in one or more organs may be referred to as local inflammation.

[0052] In one embodiment, the viral disease or disorder, or the symptomatic viral disease or disorder, presents with inflammation such as excessive inflammation.

[0053] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of virus-induced hyperinflammation.

[0054] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a virus-induced inflammatory condition.

[0055] In one embodiment, excessive inflammation is characterized by C-reactive protein (CRP) levels greater than 100 mg / l or ferritin levels of 900 ng / ml.

[0056] In one embodiment, the viral disease or disorder, or the symptomatic viral disease or disorder, presents with inflammation, such as excessive inflammation, in one or more organs.

[0057] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of inflammation-related viral diseases or disorders, such as excessive inflammation in one or more organs.

[0058] In one embodiment, the one or more organs are selected from the group consisting of the lungs, airways, kidneys, liver, pancreas, spleen, exocrine glands, endocrine glands, lymph nodes, brain, heart, muscles, bone marrow, skin, skeleton, reproductive organs including the bladder and fallopian tubes, eyes, ears, vascular system, digestive tract including the small intestine, colon, rectum, and anal canal, and the prostate gland.

[0059] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of extremity organ injury in viral diseases or disorders.

[0060] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of an inflammatory viral disease or disorder.

[0061] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder having local or systemic inflammation.

[0062] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder having a local inflammatory state.

[0063] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder (such as a symptomatic viral disease or disorder) having a local inflammatory state in one or more organs selected from the group consisting of the lungs, airways, kidneys, liver, pancreas, spleen, exocrine glands, endocrine glands, lymph nodes, brain, heart, muscle, bone marrow, skin, skeleton, reproductive organs including the bladder and fallopian tubes, eyes, ears, vascular system, digestive tract including the small intestine, colon, rectum, and anal canal, and prostate gland.

[0064] Please note that references to viral diseases or disorders and to symptomatic viral diseases or disorders may be used interchangeably in this specification.

[0065] respiratory system In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder which is a viral respiratory infection such as a viral lower respiratory infection.

[0066] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral respiratory infections, such as viral lower respiratory infections.

[0067] In one embodiment, the viral disease or disorder is a viral respiratory infection with impaired oxygen supply, such as a viral lower respiratory infection with impaired oxygen supply.

[0068] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder of the lung.

[0069] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral respiratory diseases or disorders.

[0070] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral diseases or disorders, including inflammation in the respiratory system such as the lungs and / or airways.

[0071] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of one or more viral diseases or disorders having respiratory symptoms.

[0072] In one embodiment, a viral disease or disorder having one or more respiratory symptoms presents with impaired oxygen supply.

[0073] In one embodiment, the one or more respiratory symptoms are selected from the group consisting of cough, dry cough, dyspnea, impaired oxygen supply, respiratory disease, respiratory dysfunction, respiratory failure, respiratory syndrome, and acute respiratory illness (ARD).

[0074] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder, wherein the viral disease or disorder is a severe disease. The severe disease presents with dyspnea, increased respiratory rate, decreased blood oxygen saturation and / or pulmonary infiltration.

[0075] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder, wherein the viral disease or disorder is a serious disease. The serious disease presents with respiratory failure, septic shock, and / or multiple organ failure (MOD) or multiple organ failure (MOF).

[0076] In one embodiment, a composition is provided for use in the treatment of a viral disease or disorder, comprising a compound represented by formula (I) or (II) as defined herein, wherein the viral disease or disorder includes viral pneumonia, including mild pneumonia, pneumonia, and pneumonia with abnormal findings.

[0077] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral pneumonia.

[0078] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder, wherein the viral disease or disorder includes viral bronchitis.

[0079] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder having respiratory failure.

[0080] Respiratory failure results from insufficient gas exchange by the respiratory system, meaning that arterial oxygen, carbon dioxide, or both cannot be maintained at normal levels. A decrease in oxygen carried in the blood is known as hypoxia, and an increase in arterial carbon dioxide is called hypercapnia. Respiratory failure is classified as either type 1 or type 2 based on the presence of high carbon dioxide levels, and can be either acute or chronic. In clinical trials, the definition of respiratory failure usually includes evidence of increased respiratory rate, abnormal blood gases (hypoxia, hypercapnia, or both), and increased work of breathing. Respiratory failure can lead to changes in mental state due to cerebral ischemia.

[0081] In one embodiment, the respiratory failure is type 1 respiratory failure. In one embodiment, the respiratory failure is type 2 respiratory failure. In one embodiment, the respiratory failure is acute. In one embodiment, the respiratory failure is chronic.

[0082] In one embodiment, the viral disease or disorder is acute respiratory distress syndrome (ARDS).

[0083] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder having acute respiratory distress syndrome (ARDS).

[0084] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral acute respiratory distress syndrome (ARDS).

[0085] Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by the rapid onset of widespread inflammation of the lungs. Symptoms include shortness of breath, rapid breathing, and bluish skin. A decline in quality of life is common among survivors. Underlying mechanisms include diffuse damage to cells that form the microscopic air sac barrier, surfactant dysfunction, activation of the immune system, and dysfunction of the body's thrombosis regulation. In essence, ARDS impairs the lungs' ability to exchange oxygen and carbon dioxide. Primary treatment includes mechanical ventilation along with treatment of the underlying cause.

[0086] Localized inflammatory conditions, such as acute respiratory distress syndrome, can develop into life-threatening illnesses including systemic inflammatory distress syndrome (SIDS) and sepsis. The development of SIDS is associated with high circulating levels of pro-inflammatory cytokines such as IL-1β and IL-6.

[0087] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral diseases and disorders having acute respiratory distress syndrome (ARDS) and systemic inflammatory distress syndrome (SIDS).

[0088] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral diseases and disorders having systemic inflammatory distress syndrome (SIDS) and / or sepsis.

[0089] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral systemic inflammatory distress syndrome (SIDS) and / or viral sepsis.

[0090] In one embodiment, a composition comprising a compound represented by formula (I) or (II) as defined herein is provided for use in the treatment of viral diseases and disorders requiring mechanical ventilation. In one embodiment, the mechanical ventilation includes protective mechanical ventilation, high-flow nasal oxygen (HFNO), and non-invasive ventilation (NIV).

[0091] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral diseases and disorders having pulmonary failure.

[0092] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of virus-induced lung failure, such as viral lung failure.

[0093] In one embodiment, lung failure is defined as requiring an oxygen supply to maintain a normal saturation level.

[0094] In one embodiment, lung failure is defined as SaPO2 less than 93% of spontaneous respiration.

[0095] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder, wherein the compound for said use reduces the time to recovery.

[0096] In one embodiment, the compound for use reduces the recovery time by 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, at least 1 day, or 1 day or more. In one embodiment, the compound for use reduces the recovery time by 1-2 days, 2-3 days, 3-4 days, 4-5 days, 5-6 days, 6-7 days, etc.

[0097] Reducing the recovery time in one embodiment means reducing the median recovery time. Reducing the recovery time in one embodiment means reducing the time to full recovery.

[0098] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder, wherein the compound for said use promotes the resolution of inflammation.

[0099] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder, wherein the compound for said use reduces the risk of developing severe inflammation.

[0100] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder, wherein the compound for said use reduces the risk of developing severe acute respiratory distress syndrome (ARDS).

[0101] In one embodiment, a composition is provided for use in the treatment of a viral disease or disorder, comprising a compound represented by formula (I) or (II) as defined herein, wherein the compound for said use reduces the requirement for supplying oxygen to maintain a normal saturation.

[0102] In one embodiment, a composition is provided for use in the treatment of a viral disease or disorder, comprising a compound represented by formula (I) or (II) as defined herein, wherein the compound for said use reduces the risk of requiring more intensive lung support.

[0103] overview In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral diseases or disorders having high levels of one or more cytokines, such as one or more pro-inflammatory cytokines, including IL-6 and / or IL-1β.

[0104] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder having a cytokine storm (also known as hypercytokinemia).

[0105] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of infectious cytokine storms (hypercytokinemia), such as virus-induced cytokine storms (hypercytokinemia).

[0106] A cytokine storm is a physiological response in which the innate immune system triggers an uncontrolled and excessive release of pro-inflammatory cytokines. While cytokines are normally part of the body's immune response to infection, their sudden and massive release can lead to multi-system organ failure and death. Cytokine storms can be triggered by multiple infectious and non-infectious etiologies, particularly viral respiratory infections.

[0107] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of multisystem organ failure caused by viral hypercytokinemia.

[0108] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder having cytokine release syndrome (CRS). CRS is a form of systemic inflammatory response syndrome (SIRS) that can be induced by various factors such as infection and certain drugs.

[0109] Other organs In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder having inflammation of the kidneys and / or renal failure.

[0110] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder having acute or chronic renal failure.

[0111] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder with end-stage renal failure.

[0112] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral kidney infections (pyelonephritis), viral urinary tract infections (UTIs), and / or viral kidney inflammation (nephritis).

[0113] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral bladder infection and / or viral cystitis (cystitis).

[0114] In one embodiment, the viral disease or disorder is cystitis. In one embodiment, the viral disease or disorder is severe hemorrhagic cystitis. In one embodiment, the viral disease or disorder is urinary tract obstruction.

[0115] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral liver infections and / or viral hepatitis (hepatitis), such as acute hepatitis and chronic hepatitis.

[0116] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral cirrhosis of the liver.

[0117] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral pancreatic infection and / or viral pancreatic inflammation (pancreatitis).

[0118] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral enteric infections and / or viral enteritis, such as in the small intestine and / or large intestine.

[0119] In one embodiment, the viral disease or disorder is colitis.

[0120] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral brain infection and / or viral encephalitis.

[0121] In one embodiment, the viral disease or disorder is encephalitis. In one embodiment, the viral disease or disorder is progressive multifocal leukoencephalopathy (PML).

[0122] In one embodiment, the viral brain infection and / or viral encephalitis is progressive multifocal leukoencephalopathy, a rare and often fatal viral disease characterized by progressive damage or inflammation of the brain's white matter in multiple locations.

[0123] In one embodiment, the viral brain infection and / or viral encephalitis is inflammation of the brain white matter at one or more locations.

[0124] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of the viral eye infection and / or viral eye inflammation.

[0125] In one embodiment, the viral disease or disorder is retinitis.

[0126] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of splenomegaly / splenic atrophy, particularly virus-induced splenomegaly / splenic atrophy.

[0127] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of diffuse lymphoid atrophy, particularly virus-induced diffuse lymphoid atrophy.

[0128] Virus infection One embodiment provides a composition comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral diseases or disorders caused by viral infections.

[0129] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein, for use in the treatment of a viral disease or disorder caused by a viral infection selected from the group consisting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), often referred to as COVID-19 virus; SARS-CoV, MERS-CoV, dengue virus, and influenza virus (types A, B, and C, etc.).

[0130] In one embodiment, a composition is provided for use in the treatment of acute respiratory distress syndrome (ARDS) or pneumonia caused by viral infection selected from the group consisting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), often referred to as COVID-19 virus; SARS-CoV, MERS-CoV, dengue virus, and influenza virus (types A, B, and C, etc.). The composition comprises a compound represented by formula (I) or (II) as defined herein.

[0131] One embodiment provides a composition for use in the treatment of dengue fever, comprising a compound represented by formula (I) or (II) as defined herein.

[0132] Dengue fever is a mosquito-borne tropical disease caused by the dengue virus. Typical symptoms include high fever, headache, vomiting, muscle and joint pain, and a characteristic skin rash. In a small percentage of cases, the disease develops into severe dengue, also known as dengue hemorrhagic fever, which involves bleeding, low levels of platelets and plasma leakage, or into dengue shock syndrome, which involves critical hypotension.

[0133] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of dengue hemorrhagic fever or dengue shock syndrome.

[0134] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of acute respiratory distress syndrome (ARDS) caused by dengue virus.

[0135] One embodiment provides a composition comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral pneumonia caused by dengue virus.

[0136] One embodiment provides a composition for use in the treatment of influenza, comprising a compound represented by formula (I) or (II) as defined herein.

[0137] One embodiment provides a composition comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral illness or disorder caused by influenza.

[0138] Influenza, commonly known as "flu," is an infectious disease caused by the influenza virus. Symptoms range from mild to severe and commonly include high fever, runny nose, sore throat, muscle and joint pain, headache, cough, and fatigue.

[0139] One embodiment provides a composition comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of viral pneumonia caused by influenza.

[0140] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of acute respiratory distress syndrome (ARDS) caused by the influenza virus.

[0141] Symptomatic COVID-19 One aspect of this disclosure relates to formula (I), including tautomer and stereoisomer forms, for use in the treatment of symptomatic COVID-19: [ka] The objective is to provide a composition comprising a compound represented by (wherein n is 1; 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.

[0142] Similarly, one embodiment relates to the manufacture of a pharmaceutical for the treatment of symptomatic COVID-19, formula (I): [ka] The objective is to provide the use of a composition containing the compound shown or a pharmaceutically acceptable derivative thereof.

[0143] Also disclosed is equation (I): [ka] A method for treating symptomatic COVID-19 comprising one or more steps of administering a composition containing the compound shown or a pharmaceutically acceptable derivative thereof to an individual in need.

[0144] In a particular embodiment, the composition for use according to this disclosure includes formula (II), which comprises tautomer and stereoisomer forms, for use in the treatment of symptomatic COVID-19: [ka] This includes the compounds shown, or their pharmaceutically acceptable derivatives.

[0145] In a preferred embodiment, the composition for use according to the present disclosure comprises (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-arylidene}-aminoguanidinium acetate (AP1189).

[0146] In one embodiment, the composition for use according to the present disclosure is i) An agonist of one or more MC receptors, ii) An agonist of MC1R and MC3R, and / or iii) A biased agonist of MC1R and MC3R, Contains compounds.

[0147] Also disclosed are compositions for use according to this disclosure, for use in the treatment of symptomatic COVID-19, comprising compounds selected from the group consisting of {3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}aminoguanidine and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}aminoguanidine or pharmaceutically acceptable salts thereof.

[0148] In one embodiment, the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt of an inorganic acid or an organic acid.

[0149] In such embodiments, the organic acids referenced herein are 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, bismethylenesalicylic 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.

[0150] In a specific embodiment, the organic acid is acetic acid, succinic acid, tartaric acid, or propionic acid, such as acetic acid.

[0151] In such embodiments, the organic acid referenced herein is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and nitric acid.

[0152] Also disclosed is a composition for use in the treatment of symptomatic COVID-19, comprising a compound selected from the group consisting of {3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}aminoguanidinium acetate and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}aminoguanidinium acetate.

[0153] In one embodiment, the Disclosure provides a composition comprising (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}-aminoguanidinium or a pharmaceutically acceptable salt thereof for use in the treatment of symptomatic COVID-19.

[0154] In a specific embodiment, the Disclosure provides a composition comprising (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-arylidene}-aminoguanidinium acetate for use in the treatment of symptomatic COVID-19.

[0155] In one embodiment, the composition comprising a compound represented by formula (I) or (II) as defined herein is intended for use in methods of improving and / or alleviating symptomatic COVID-19, such as improving and / or alleviating one or more symptoms of COVID-19.

[0156] In one embodiment, a composition is provided for use in the treatment of symptomatic COVID-19, comprising a compound represented by formula (I) or (II) as defined herein, wherein symptomatic COVID-19 comprises one or more respiratory symptoms.

[0157] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of symptomatic COVID-19 in patients with impaired oxygen supply.

[0158] In one embodiment, the one or more respiratory symptoms are selected from the group consisting of cough, dry cough, dyspnea, impaired oxygen supply, respiratory disease, respiratory dysfunction, respiratory failure, respiratory syndrome, and 2019-nCoV acute respiratory disease (2019-nCoV ARD).

[0159] In one embodiment, a composition is provided for use in the treatment of symptomatic COVID-19, wherein the symptomatic COVID-19 is a severe disease. The severe disease presents with dyspnea, increased respiratory rate, decreased blood oxygen saturation and / or pulmonary infiltration.

[0160] In one embodiment, a composition is provided for use in the treatment of symptomatic COVID-19, comprising a compound represented by formula (I) or (II) as defined herein, wherein symptomatic COVID-19 is a serious illness. The serious illness presents with respiratory failure, septic shock, and / or multiple organ failure (MOD) or multiple organ failure (MOF).

[0161] In one embodiment, a composition is provided for use in the treatment of symptomatic COVID-19, comprising a compound represented by formula (I) or (II) as defined herein, wherein symptomatic COVID-19 includes mild pneumonia, pneumonia, pneumonia with abnormal findings, and viral pneumonia including novel coronavirus pneumonia (NCP).

[0162] In one embodiment, a composition is provided for use in the treatment of symptomatic COVID-19, comprising a compound represented by formula (I) or (II) as defined herein, wherein the symptomatic COVID-19 exhibits high levels of one or more cytokines, such as one or more pro-inflammatory cytokines, including IL-6 and / or IL-1β.

[0163] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of symptomatic COVID-19 with respiratory failure.

[0164] Respiratory failure results from insufficient gas exchange by the respiratory system, meaning that arterial oxygen, carbon dioxide, or both cannot be maintained at normal levels. A decrease in oxygen carried in the blood is known as hypoxia, and an increase in arterial carbon dioxide is called hypercapnia. Respiratory failure is classified as either type 1 or type 2 based on the presence of high carbon dioxide levels, and can be either acute or chronic. In clinical trials, the definition of respiratory failure usually includes evidence of increased respiratory rate, abnormal blood gases (hypoxia, hypercapnia, or both), and increased work of breathing. Respiratory failure can lead to changes in mental state due to cerebral ischemia.

[0165] In one embodiment, the respiratory failure is type 1 respiratory failure. In one embodiment, the respiratory failure is type 2 respiratory failure. In one embodiment, the respiratory failure is acute. In one embodiment, the respiratory failure is chronic.

[0166] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of symptomatic COVID-19 with acute respiratory distress syndrome (ARDS).

[0167] Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by the rapid onset of widespread inflammation of the lungs. Symptoms include shortness of breath, rapid breathing, and bluish skin. A decline in quality of life is common among survivors. Underlying mechanisms include diffuse damage to cells that form the microscopic air sac barrier, surfactant dysfunction, activation of the immune system, and dysfunction of the body's thrombosis regulation. In essence, ARDS impairs the lungs' ability to exchange oxygen and carbon dioxide. Primary treatment includes mechanical ventilation along with treatment of the underlying cause.

[0168] Localized inflammatory conditions, such as acute respiratory distress syndrome, can lead to life-threatening illnesses including systemic inflammatory distress syndrome (SIDS) and sepsis. The development of SIDS is associated with high circulating levels of pro-inflammatory cytokines such as IL-1β and IL-6.

[0169] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of symptomatic COVID-19 having acute respiratory distress syndrome (ARDS) and systemic inflammatory distress syndrome (SIDS).

[0170] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of symptomatic COVID-19 with systemic inflammatory distress syndrome (SIDS) and / or sepsis.

[0171] In one embodiment, a composition comprising a compound represented by formula (I) or (II) as defined herein is provided for use in the treatment of symptomatic COVID-19 requiring mechanical ventilation. In one embodiment, the mechanical ventilation includes protective mechanical ventilation, high-flow nasal oxygen (HFNO), and non-invasive ventilation (NIV).

[0172] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of pulmonary failure induced by COVID-19.

[0173] In one embodiment, COVID-19-induced lung failure is defined as requiring an oxygen supply to maintain normal saturation.

[0174] In one embodiment, COVID-19-induced lung failure is defined as a SaPO2 of less than 93% of spontaneous respiration.

[0175] In one embodiment, a composition is provided for use in the treatment of symptomatic COVID-19, comprising a compound represented by formula (I) or (II) as defined herein, wherein the compound for said use reduces the time to recovery.

[0176] In one embodiment, the compound for use reduces the recovery time by 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, at least 1 day, or 1 day or more. In one embodiment, the compound for use reduces the recovery time by 1-2 days, 2-3 days, 3-4 days, 4-5 days, 5-6 days, 6-7 days, etc.

[0177] Reducing the recovery time in one embodiment means reducing the median recovery time. Reducing the recovery time in one embodiment means reducing the time to full recovery.

[0178] In one embodiment, a composition is provided for use in the treatment of symptomatic COVID-19, comprising a compound represented by formula (I) or (II) as defined herein, wherein the compound for said use promotes the resolution of inflammation.

[0179] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of symptomatic COVID-19, wherein the compound for said use reduces the risk of developing severe inflammation.

[0180] In one embodiment, a composition is provided for use in the treatment of symptomatic COVID-19, comprising a compound represented by formula (I) or (II) as defined herein, wherein the compound for said use reduces the risk of developing severe acute respiratory distress syndrome (ARDS).

[0181] In one embodiment, a composition is provided for use in the treatment of symptomatic COVID-19, comprising a compound represented by formula (I) or (II) as defined herein, wherein the compound for said use reduces the requirement for supplying oxygen to maintain normal saturation.

[0182] In one embodiment, a composition is provided for use in the treatment of symptomatic COVID-19, comprising a compound represented by formula (I) or (II) as defined herein, wherein the compound for said use reduces the risk of requiring more intensive lung support.

[0183] subject The compositions of the present invention, comprising compounds represented by formula (I) or (II) as defined herein, are intended for use in the treatment of viral diseases or disorders described herein, in the subjects where such treatment is required.

[0184] In some embodiments, the subject is infected with a virus.

[0185] In one embodiment, the subject is a mammal. In particular, the subject may be a human. In another embodiment, the subject is a pet such as a cat, dog, rabbit, or horse, or livestock such as cattle or poultry, such as cows, bulls, sheep, goats, pigs, chickens, or turkeys.

[0186] In individuals with weakened immune systems, such as those who are HIV-positive, viral infections and symptomatic viral disorders or diseases can potentially lead to life-threatening multi-organ diseases.

[0187] Immune deficiencies may be a result of immunosuppressants routinely administered to graft recipients, or they may be a consequence of a genetic disorder or a disease such as HIV infection.

[0188] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of a viral disease or disorder in a subject with an immunodeficiency.

[0189] In one embodiment, the immune deficiency is a T cell deficiency.

[0190] In one embodiment, the immune deficiency is a primary (or hereditary) immune deficiency of T cells. These include severe combined immunodeficiency (SCID), Omen syndrome, and chondrohair dysplasia, which result in complete T cell deficiency.

[0191] In one embodiment, the immune deficiency is a secondary (or acquired) immune deficiency of T cells. These include immune deficiencies caused by HIV / AIDS, cancer immunotherapy, lymphocytes, and glucocorticoid therapy.

[0192] In one embodiment, the immune deficiency is complete or partial.

[0193] In some embodiments, the subjects are HIV-positive.

[0194] In some embodiments, compositions comprising compounds represented by formula (I) or (II) as defined herein are provided for use in the treatment of viral diseases or disorders in high-risk populations. These include HSCT patients (hematopoietic stem cell transplants), SOT patients (solid organ grafts), elderly subjects, and very young subjects.

[0195] In one embodiment, the elderly target is 65 years of age or older. In another embodiment, the elderly target is 70 years of age or older.

[0196] In one embodiment, a very young subject is 1 year old or younger. In one embodiment, a very young subject is 6 months old or younger. In one embodiment, a very young subject is 3 months old or younger.

[0197] In one embodiment, a composition is provided comprising a compound represented by formula (I) or (II) as defined herein for use in the treatment of symptomatic COVID-19 in subjects selected from a group consisting of high-risk populations including immunodeficiency subjects, HSCT patients (hematopoietic stem cell transplantation), SOT patients (solid organ grafts), elderly subjects, and very young subjects.

[0198] Combination therapy In one embodiment, a composition comprising a compound represented by formula (I) or (II) disclosed herein, or a pharmaceutically acceptable derivative thereof, comprises one or more additional active pharmaceutical ingredients separately or together.

[0199] In one embodiment, the one or more additional active pharmaceutical ingredients are used to treat a viral disease or disorder.

[0200] In one embodiment, the one or more additional active pharmaceutical ingredients are used to treat symptomatic COVID-19.

[0201] In one embodiment, a composition comprising a compound represented by formula (I) or (II) disclosed herein, or a pharmaceutically acceptable derivative thereof, is an add-on therapy to an existing treatment.

[0202] In one embodiment, a composition comprising a compound represented by formula (I) or (II) for use disclosed herein, or a pharmaceutically acceptable derivative thereof, is an add-on therapy to one or more additional treatments used for the treatment of a viral disease or disorder.

[0203] In one embodiment, the add-on therapy includes one or more of a nasal oxygen catheter and mechanical ventilation.

[0204] In one embodiment, the symptomatic COVID-19 is also treated with nasal oxygen catheterization and / or mechanical ventilation, such as a nasal oxygen catheter at a flow rate of 2–5 LO2 / min.

[0205] Route of administration It will be noted that the preferred route of administration depends on the general condition and age of the person being treated, the nature of the disease being treated, the location of the tissue being treated in the body, and the selected active ingredient.

[0206] In one embodiment, a composition comprising a compound represented by formula (I) or (II) as defined herein is administered systemically, topically, enterally, or parenterally. Suitable dosage forms for such administration may be prepared by prior art.

[0207] Systemic administration Systemic administration allows for the introduction of compounds into the bloodstream, ultimately targeting the desired site of action.

[0208] Such routes of administration are any appropriate route, including enteral, oral, rectal, nasal, pulmonary, oral, sublingual, percutaneous, intracisional, intraperitoneal, and parenteral (subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) routes.

[0209] In one embodiment, a composition comprising a compound represented by formula (I) or (II) as defined herein is administered by systemic administration.

[0210] Oral administration Oral administration is typically for enteral drug delivery, where the compound is delivered through the intestinal mucosa. Commonly used are solid oral dosage forms such as syrups, tablets, capsules, and similar structures.

[0211] In one embodiment, a composition comprising a compound represented by formula (I) or (II) as defined herein is administered orally.

[0212] Parenteral administration Parenteral administration refers to any route of administration other than the oral / enteral route that avoids first-pass metabolism in the liver. Therefore, parenteral administration includes any injection and infusion, such as bolus injections or continuous infusions including intravenous, intramuscular, and subcutaneous administration. Furthermore, parenteral administration also includes inhalation and topical administration.

[0213] Therefore, the compound may be administered as a topical agent across any mucous membrane of the animal to which the bioactive substance is to be administered, preferably the mucous membrane of the nose or mouth, for example, in the nose, vagina, eyes, mouth, reproductive tract, lungs, gastrointestinal tract, or rectum. Therefore, parenteral administration may include oral, sublingual, nasal, transrectal, transvaginal, and intraperitoneal administration, as well as transpulmonary and intrabronchial administration by inhalation or induction. The compound may also be administered as a topical agent across the skin.

[0214] Subcutaneous and intramuscular forms of parenteral administration are generally preferred.

[0215] Local treatment The compounds disclosed herein are used in one embodiment as a topical treatment, i.e., directly introduced to the site(s) of action. Thus, the compounds may be applied directly to the skin or mucous membranes, or they may be injected into the site of action, for example, into the affected tissue or into a terminal artery directly connected to the affected tissue.

[0216] Dosage According to this disclosure, compositions comprising the compound represented by formula (I) or (II) are administered in pharmaceutically effective doses to individuals in need of treatment. The therapeutically effective dose of the compound is sufficient to cure, prevent, reduce, alleviate, or partially halt the clinical manifestation of a given disease and its complications. The dose effective for a specific therapeutic purpose will depend on the severity and type of the disorder, as well as the subject's weight and overall condition. The compound may be administered one or more times per day, such as 1 to 8 times / day, 1 to 6 times / day, 1 to 5 times / day, 1 to 4 times / day, 1 to 3 times / day, 1 to 2 times / day, 2 to 4 times / day, 2 to 3 times / day, etc. Alternatively, the compound may be administered less than once a day, for example, once a day, once every two days, for example, once every three days, once every four days, for example, once every five days, once every six days, for example, once a week.

[0217] In one embodiment, a composition comprising a compound represented by formula (I) or (II) as defined herein is administered in a therapeutically effective dose, such as 1 mg to 1000 mg of the compound represented by formula (I) or (II) per day.

[0218] In one embodiment, the compound is administered in doses of 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20 mg, 20-30 mg, 30-60 mg, 60-80 mg, 80-100 mg, 100-130 mg, 130-160 mg, 160-200 mg, 200-240 mg, 240-280 mg, 280-320 mg, 320-360 mg per day. It is administered in amounts ranging from 1 mg to 1000 mg, such as 360-400 mg, 400-440 mg, 440-500 mg, 500-560 mg, 560-620 mg, 620-680 mg, 680-740 mg, 740-800 mg, 800-860 mg, 860-920 mg, 920-980 mg, 980-1000 mg, etc.

[0219] The daily dose may be a single dose, including once daily (QD), twice daily (BID), and / or three times daily (TID), or it may be divided into multiple doses per day.

[0220] In one embodiment, the compound is administered once daily in amounts of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 100 mg.

[0221] In one embodiment, the compound is administered once daily in a dose of 100 mg.

[0222] In one embodiment, the compound is administered in doses of 100 mg twice daily (BID) or 100 mg three times daily (TID).

[0223] In one embodiment, the compound is administered in doses of 200 mg twice daily (BID) or 200 mg three times daily (TID).

[0224] In one embodiment, the compound is administered orally once daily as 100 mg of AP1189.

[0225] In another embodiment, the compound is administered in amounts ranging from 0.01 mg / kg body weight 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 mg 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, etc., for example, 0.01 mg / kg body weight to 40 mg / kg body weight.

[0226] compound In one embodiment, a composition comprising a compound represented by formula (I) or (II) as defined herein is a pharmaceutical composition such as a pharmaceutically safe composition. A composition comprising a compound represented by formula (I) or (II) as defined herein may be administered by any suitable method, for example, orally, sublingually, or parenterally, and may be supplied in any suitable form for such administration, for example, in the form of a solution, suspension, aerosol, tablet, capsule, powder, syrup, implant, or dispersion for injection.

[0227] In one embodiment, a composition comprising a compound represented by formula (I) or (II) as defined herein is formulated as a suspension.

[0228] In one embodiment, a composition comprising a compound represented by formula (I) or (II) as defined herein is formulated as an oral dosage form, such as a solid oral dosage form like a tablet or capsule, or a pharmaceutical substance, or a liquid oral dosage form. Methods for preparing solid pharmaceutical preparations are well known in the art.

[0229] In another embodiment, a composition comprising a compound represented by formula (I) or (II) as defined herein is formulated as an injectable dosage form.

[0230] In one embodiment, a composition comprising a compound represented by formula (I) or (II) as defined herein is formulated in the form of a solid pharmaceutical substance, optionally as a tablet or capsule.

[0231] Compound (I) or (II) as a free base or a salt thereof may be administered alone or in combination with a pharmaceutically acceptable carrier or excipient, in either a single dose or multiple doses. The pharmaceutical composition may be formulated with a pharmaceutically acceptable carrier or diluent, as well as any other known adjuvants and excipients, in accordance with prior art, such as that disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

[0232] item 1. Formula (I), including tautomer and stereoisomer forms, for use in the treatment of symptomatic COVID-19: [ka] A composition comprising a compound represented by (wherein n is 1; 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. 2. Formula (II) of the compound includes tautomers and stereoisomers: [ka] A composition for use in accordance with item 1, which is the same as or a pharmaceutically acceptable derivative thereof. 3. A composition for use according to any of the above items, wherein the compound is selected from the group consisting of {3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}aminoguanidine and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}aminoguanidine or pharmaceutically acceptable salts thereof. 4. A composition for use according to any of the above items, wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt of an inorganic acid or an organic acid. 5. A composition for use 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, bismethylenesalicylic 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. 6. A composition for use according to any of items 4-5, wherein the organic acid is acetic acid, succinic acid, tartaric acid, or propionic acid. 7. A composition for use 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. 8. A composition for use according to item 6, wherein the organic acid is acetic acid. 9. A composition for use according to any of the above items, wherein the compound is selected from the group consisting of {3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}aminoguanidinium acetate and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}aminoguanidinium acetate. 10. A composition for use according to any of the above items, wherein the compound is (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}-aminoguanidinium acetate (AP1189). 11. The compound is i) An agonist of one or more MC receptors, ii) An agonist of MC1R and MC3R, and / or iii) A biased agonist of MC1R and MC3R, A composition for use in any of the above items. 12. A composition for use by any of the above items, wherein the symptomatic COVID-19 comprises one or more respiratory symptoms. 13. A composition for use in any of the above items, wherein the symptomatic COVID-19 comprises one or more respiratory symptoms selected from the group consisting of cough, dry cough, dyspnea, respiratory disease, respiratory dysfunction, respiratory failure, respiratory syndrome, and 2019-nCoV acute respiratory disease (2019-nCoV ARD). 14. A composition for use in any of the above items, wherein the symptomatic COVID-19 includes mild pneumonia, pneumonia, pneumonia with abnormal findings, and viral pneumonia including novel coronavirus pneumonia (NCP). 15. A composition for use in any of the above items, wherein the symptomatic COVID-19 is a severe illness. 16. A composition for use in any of the above items, wherein the symptomatic COVID-19 is a serious illness. 17. A composition for use in any of the above items, wherein the symptomatic COVID-19 exhibits high levels of one or more pro-inflammatory cytokines such as IL-6 and / or IL-1β. 18. A composition for use by any of the above items, wherein the symptomatic COVID-19 is COVID-19 having respiratory failure. 19. A composition for use in any of the above items, wherein the symptomatic COVID-19 is COVID-19 having acute respiratory distress syndrome (ARDS). 20. A composition for use in any of the above items, wherein the symptomatic COVID-19 is COVID-19 having systemic inflammatory distress syndrome (SIDS). 21. A composition for use in any of the above items, in which symptomatic COVID-19 requires mechanical ventilation. 22. A composition for use in any of the above items, wherein the symptomatic COVID-19 is pulmonary failure induced by COVID-19. 23. A composition for use in any of the above items, defined as lung failure induced by COVID-19 requiring supplied oxygen to maintain normal saturation. 24. A composition for use in any of the above items, wherein lung failure induced by COVID-19 is defined as having a SaPO2 of less than 93% of spontaneous respiration. 25. A composition for use according to any of the above items, wherein the compound for use reduces the time to recovery. 26. A composition for use according to any of the above items, wherein the compound for use promotes the resolution of inflammation. 27. A composition for use according to any of the above items, wherein the compound for use reduces the risk of developing severe inflammation. 28. A composition for use according to any of the above items, wherein the compound for use reduces the risk of developing severe acute respiratory distress syndrome (ARDS). 29. A composition for use according to any of the above items, wherein the compound for use reduces the requirement for supplying oxygen to maintain a normal saturation. 30. A composition for use in any of the above items, wherein the compound for use reduces the risk of creating a need for more intensive lung support. 31. A composition for use in any of the foregoing items, comprising, separately or together, one or more additional active pharmaceutical ingredients, such as one or more additional active pharmaceutical ingredients used in the treatment of symptomatic COVID-19. 32. Compositions for use in any of the above items, which are add-on therapies to existing treatments. 33. A composition for use in any of the above items, wherein the symptomatic COVID-19 is treated with a nasal oxygen catheter, such as a nasal oxygen catheter, at a flow rate of 2 to 5 LO2 / min. 34. The above compound is consumed in doses of 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-30 mg, 30-60 mg, 60-80 mg, 80-100 mg, 100-130 mg, 130-160 mg, 160-200 mg, 200-240 mg, 240-280 mg, 280-320 mg, 320-360 mg, 360-400 mg, and 400-440 mg per day. A composition for use according to any of the above items, administered in amounts of 1 mg to 1000 mg per day, such as 440-500 mg, 500-560 mg, 560-620 mg, 620-680 mg, 680-740 mg, 740-800 mg, 800-860 mg, 860-920 mg, 920-980 mg, 980-1000 mg, for example, 500-1000 mg. 35. A composition for use according to any of the above items, wherein the compound is administered once daily in amounts of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 100 mg. 36. A composition for use according to any of the above items, wherein the compound is administered once daily in an amount of 100 mg. 37. A composition for use according to either of the above items, wherein the compound is administered in an amount of 100 mg twice daily (BID) or 100 mg three times daily (TID). 38. A composition for use according to either of the above items, wherein the compound is administered in an amount of 200 mg twice daily (BID) or 200 mg three times daily (TID). 39. A composition for use according to any of the above items, wherein the compound is administered as an oral dose of AP1189 100 mg once daily. 40. A composition that is pharmaceutically safe for use in any of the above-mentioned items.

[0233] Examples Example 1 Acute peritonitis, like other localized inflammatory conditions such as acute respiratory distress syndrome (ARDS), can develop into life-threatening illnesses, including systemic inflammatory distress syndrome (SIDS) and sepsis. The development of SIDS is associated with high circulating levels of pro-inflammatory cytokines, including IL-1β and IL-6.

[0234] Acute peritonitis was induced in mice by injection of 1 mg of zymosan A (Sigma-Aldrich) ip in 0.5 ml of sterile PBS. After 12 hours, the mice were euthanized by CO2 exposure, and the peritoneal cavity was lavaged with 4 ml of ice-cold PBS containing 3 mM EDTA. Cells were stained with Turck's solution (0.01% crystal violet in 3% acetic acid) and counted using a Neubauer hemocytometer, or stained with FITC-conjugated mAbs for Ly-6G / Gr1, F4 / 80, and corresponding isotype controls (eBioscience, Hatfield, UK) and subjected to flow cytometry analysis using the BD FACSCalibur platform (BD Biosciences, Oxford, UK).

[0235] Levels of IL-1β and IL-6 in rapidly frozen samples were quantified using ELISA Ready-SET-Go! (eBioscience) according to the manufacturer's instructions. All animal studies were authorized and conducted in accordance with the guidelines of the Ethical Committee for the Use of Animals, Barts, and The London School of Medicine, as well as the regulations of the UK Home Office (Guidance on the Operation of Animals, Scientific Procedures Act, 1986). Male (7-8 week old) C57BL / 6J wild-type (WT) mice were purchased from Charles River Laboratories.

[0236] Test substance A = AP1189 (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}-aminoguanidium acetate

[0237] Test substance A (1 mg / kg) or vehicle treatment was administered intraperitoneally 30 minutes before the induction of acute peritonitis. N=6 in both groups.

[0238] result: Pretreatment with test substance A reduced the levels of pro-inflammatory cytokines IL-1β and IL-6 by 37% and 59%, respectively (p<0.05 compared to vehicle pretreatment).

[0239] Neutrophil accumulation was reduced by 70% after pretreatment with test substance A compared to vehicle treatment.

[0240] Example 2 SynAct was initiated in Part 2 of the Phase 2 clinical trial of AP1189 in patients infected with COVID-19.

[0241] SynAct PharmaAB (“SynAct”) today announced that administration in Part 2 of the exploratory Phase 2 clinical trial of AP1189 in COVID-19 patients, conducted under the RESOVIR collaboration, has commenced following completion of the initial open-label part of the trial. Part 2 is a randomized, double-blind, placebo-controlled trial involving 54 (corrected from 56) COVID-19 patients in clinical settings at the Universidade Federal de Minas in Belo Horizonte, Brazil.

[0242] The initial open-label part of the study was conducted in six hospital-referred patients with COVID-19-induced pulmonary failure defined as requiring supplied oxygen to maintain normal saturation. The patients consisted of four women and two men, aged between 38 and 59 years, all with spontaneous respiration and less than 93% SaPO2. All six patients were treated with nasal oxygen catheters at flow rates between 2–5 LO2 / min. Patients were treated with once-daily oral administration of AP1189 100 mg as an add-on to standard care.

[0243] The compound was found to be safe and well-tolerated, and none of the patients required more intensive lung support, so they were discharged between days 3 and 9 of treatment.

[0244] Since no safety concerns were identified, mobilization for Part 2 of the trial began. As of March 16, 2021, 16 patients had been enrolled in Part 2 of the trial.

[0245] Part 2 of the trial is set to evaluate the safety and efficacy of a two-week dosing regimen of AP1189 compared to placebo as an add-on therapy in patients with COVID-19-induced pulmonary failure defined as requiring supplemental oxygen to maintain normal saturation. Up to 54 patients will be randomized in a 2:1 ratio to receive either AP1189 100 mg once daily or placebo in addition to standard care. The primary clinical objective of the trial is to demonstrate a reduction in time to respiratory recovery (i.e., time to normalization of oxygen saturation in air). Top-line results for this trial are projected in Q2 2021.

[0246] The inventors recognize the growing need for effective treatments to quell severe inflammation observed in patients with Covid-19 infection. To investigate whether AP1189 can accelerate inflammation resolution, thereby reducing recovery time and lowering the risk of developing severe ARDS, the inventors initiated Phase 2 of this trial.

[0247] Samples from patients with Covid-19 pneumonia have shown that macrophages constitute up to 80% of all cells in the alveoli and play a significant role in the excessive inflammation associated with the devastating effects of Covid-19 infection. Since AP1189 specifically targets macrophages, the inventors are very much looking forward to further testing the potential benefits provided by the treatment of Covid-19 patients with AP1189.

[0248] Importantly, the trial aims not only to test the potential impact on the clinical readout as time to recovery, but also to examine the effect of the compound on the activated inflammatory pathways in patients with Covid-19 infection. This work starts with the serial collection of samples from patients and is carried out in the Vero Horizonte laboratory and the London laboratory as an integrated part of the RESOVIR consortium.

[0249] Example 3 The effect of treatment with AP1189 was tested in patients with Covid-19 infection.

[0250] The test population consisted of patients admitted with Covid-19 infection with impaired oxygen supply. The trial was conducted at the site of Vero Horizonte, Brazil.

[0251] The trial consists of two parts: Part 1: An open-label trial to test the safety and tolerability of once-daily oral administration of AP1189 in six (6) hospitalized patients with Covid-19 infection Part 2: A randomized, double-blind, placebo-controlled clinical trial to test once-daily oral administration of AP1189 or placebo in a 2:1 randomization in a total of 54 hospitalized patients with Covid-19 infection. Part 2 was initiated following the safety assessment of Part 1 as the compound was found to be safe and well tolerated by the trial safety monitoring committee.

[0252] Administration in the second part of the exploratory Phase 2 clinical trial with AP1189 in patients with Covid-19 infection was initiated following the completion of the first open-label part of the trial.

[0253] The trial will be sized to identify a statistically significant treatment effect, defined as a reduction in time to recovery compared to a placebo-treated control at a significance level of 0.05 and power of 80%, assuming that the median time to full recovery is 11 days in placebo-treated patients and that the AP1189 treatment reduces the median time to recovery by 3 days.

[0254] Following successful screening, informed subjects meeting the enrollment criteria were treated in Part A with AP1189 100 mg once daily orally as an add-on to any ongoing treatment. In Part B, patients were randomized in a 2:1 ratio to receive either the active drug or placebo. Active drug group (36 patients): AP1189 100 mg once daily for 2 weeks (14 days) as an add-on to any ongoing treatment. Placebo group (18 participants): Placebo was administered once daily for two weeks (14 days) as an add-on to any ongoing treatment.

[0255] Cancellation rules In the event of a serious medical event (e.g., stroke, seizure, etc.) or any SAE (Serious Adverse Event) that is deemed to be related to the investigational drug, researchers may decide to discontinue the study.

[0256] Test group The study population consists of hospitalized patients with COVID-19 infection and impaired oxygen supply.

[0257] 1.1. Selection Criteria for Targeting This trial may only be effective if appropriate subjects are enrolled. The following eligibility criteria are designed to select subjects for whom the protocol treatment is deemed appropriate. All relevant medical and non-medical conditions must be considered when determining whether this protocol is appropriate for a subject.

[0258] 1.2 Inclusion Criteria The eligibility of a subject must be reviewed by a properly qualified member of the researcher's study team and documented before the subject is enrolled in the study. The following are the requirements for enrollment in the study. a. A completed informed consent form is obtained before initiating any procedure specific to the test. b. Men and women aged 18-85 who were hospitalized with COVID-19. c. COVID-19 infection confirmed by the presence of SARS-CoV-2 nucleic acid via polymerase chain reaction (PCR). d. Evidence of oxygen supply damage defined by SpO2 ≤ 93% in the atmosphere e. The duration of the illness from the first symptom onset is less than 10 days prior to hospital admission. f. Women who are capable of bearing children using reliable contraception, or postmenopausal women (whose menstrual period has ceased for at least 12 months prior to enrollment in the study), or women who have become infertile through surgery (the procedure must have been performed at least 6 months prior to screening). g. A woman of childbearing capacity who has a negative pregnancy test. h. Screening and baseline testing

[0259] 1.3. Exclusion criteria Individuals who meet any of the following criteria are not eligible to participate in this examination. a. In the researcher's judgment, death is imminent and unavoidable, regardless of the provision of treatment. b. Participation in other drug clinical trials (Participation in COVID-19 antiviral trials examining the compound is intended to reduce the risk of infection with the virus. However, remdesivir or dexamethasone at doses not exceeding 10 mg / day is acceptable.) c. Any condition in which the screening physician suggests that the patient would be unable to participate in the test protocol and procedures (e.g., psychiatric disorder, dementia, or being in specialized palliative care). d. Subjects treated with immunosuppressants (such as microphenolate and cyclophosphamide) e. HIV infection f. Pregnant women or mothers during lactation (breastfeeding) g. Estimated glomerular filtration rate (eGFR) < 30 ml / min h. Severe liver dysfunction (Child-Pugh score C) i. Medical history of oral glucocorticoid treatment (exception: dexamethasone treatment not exceeding 10 mg / day related to Covid-19 treatment) j. Recruitment of subjects

[0260] Potential subjects for this trial are identified among inpatients. Potentially eligible subjects are approached by on-site researchers to confirm whether the subject is interested in participating in the trial. Interested subjects receive oral and written information about the trial before consent. No other test procedures are performed before consent.

[0261] Results - The first open-label part of the trial Six patients who were referred to the hospital for Covid-19-induced lung failure received once-daily oral administration of 100 mg of AP1189 as an add-on to standard treatment (nasal oxygen catheter at a flow rate between 2 and 5 L O2 / min).

[0262] In these patients, the compound was found to be safe and well tolerated, and the patients all left the hospital between days 3 and 9 of treatment because none of them developed a need for more intensive lung support. This demonstrated the potential of the compound to reduce the time to respiratory recovery (i.e., the time to normalization of oxygen saturation in air).

Claims

1. Formula (II), comprising tautomer and stereoisomer forms, for use in the treatment of viral diseases or disorders with pulmonary failure: 【Chemistry 1】 A composition comprising the compound indicated by or a pharmaceutically acceptable salt thereof.

2. The composition according to claim 1, wherein the compound is (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}-aminoguanidine or a pharmaceutically acceptable salt thereof.

3. The composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt is selected from 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, bismethylenesalicylic 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, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and nitric acid.

4. The composition according to claim 3, wherein the compound is (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}-aminoguanidinium acetate (AP1189).

5. The composition according to claim 3, wherein the compound is (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrole-2-yl]-alilidene}-aminoguanidinium succinate.

6. The composition according to any one of claims 1 to 5, wherein the lung failure is defined as requiring an oxygen supply to maintain a normal saturation level.

7. The aforementioned lung failure is SaPO of less than 93% during spontaneous respiration. ２ The composition according to any one of claims 1 to 6, as defined.

8. The composition according to any one of claims 1 to 7, wherein the treatment reduces the time to recovery.

9. The composition according to any one of claims 1 to 8, wherein the treatment reduces the requirement for supplying oxygen to maintain a normal saturation level.

10. The composition according to any one of claims 1 to 9, wherein the viral disease or disorder having lung failure is a symptomatic viral disease and disorder having lung failure.

11. The composition according to claim 10, wherein the symptomatic viral disease or disorder having lung failure is symptomatic COVID-19.

12. The aforementioned symptomatic COVID-19, a. Including mild pneumonia, pneumonia, pneumonia with abnormal findings, and viral pneumonia including COVID-19 pneumonia (NCP), b. Having a severe or serious illness, c. A respiratory symptom comprising 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), d. COVID-19 with respiratory failure, COVID-19 with acute respiratory distress syndrome (ARDS), or COVID-19 with systemic inflammatory distress syndrome (SIDS), e. The composition according to claim 11, wherein lung failure is induced by COVID-19.

13. The composition according to claim 11 or 12, wherein the composition comprises one or more additional active pharmaceutical ingredients used separately or in combination for the treatment of a viral disease or disorder, and the one or more additional active pharmaceutical ingredients comprises an active pharmaceutical ingredient used for the treatment of symptomatic COVID-19.

14. A composition for the treatment of viral diseases or disorders having one or more respiratory symptoms and pulmonary failure, The composition according to any one of claims 1 to 9, wherein the respiratory symptoms are selected from cough, dry cough, shortness of breath, impaired oxygen supply, respiratory disease, respiratory dysfunction, respiratory failure, respiratory syndrome including respiratory failure, and acute respiratory disease (ARD).

15. The composition according to any one of claims 1 to 9, wherein the viral disease or disorder having lung failure is acute respiratory distress syndrome (ARDS), severe illness, serious illness, viral bronchitis, or viral pneumonia.

16. The composition according to any one of claims 1 to 9, wherein the viral disease or disorder having pulmonary failure is selected from acute respiratory distress syndrome (ARDS) and systemic inflammatory distress syndrome (SIDS).

17. The composition according to any one of claims 1 to 9, wherein the viral disease or disorder having pulmonary failure is caused by a viral infection selected from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, MERS-CoV, dengue virus, and influenza viruses (including types A, B, and C).

18. The composition according to any one of claims 1 to 17, wherein the compound is administered in an amount of 1 mg to 1000 mg per day.

19. The composition according to claim 18, wherein the compound is administered in the following amounts: 100 mg once daily, 200 mg once daily, 300 mg once daily, 400 mg once daily, 500 mg once daily, 600 mg once daily, 700 mg once daily, 800 mg once daily, 900 mg once daily, 100 mg twice daily (BID), 100 mg three times daily (TID), 200 mg twice daily (BID), or 200 mg three times daily (TID).

Images