Compositions and methods for the treatment of COVID-19

Abstract

Provided herein is a composition for use in treating fibrosis and treating COVID-19, preferably moderate COVID-19, comprising Compound 1 or a pharma- ceutically acceptable salt thereof. [Formula 1] JPEG2025502175000019.jpg54116Also provided herein is a method for treating COVID-19, preferably moderate COVID-19, comprising administering Compound 1 in an amount of 10 mg / day to 30 mg / day to a patient in need thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS Benefit is claimed to U.S. Provisional Patent Application No. 63 / 302,575, filed January 25, 2022, the contents of which are incorporated by reference in their entirety herein.

[0002] Technical Field The present disclosure relates to the treatment of COVID-19. [Background technology]

[0003] Coronaviruses (CoVs) are members of the Nidovirales order, which includes enveloped viruses with large (~30 kb) positive-sense, single-stranded RNA genomes that generate a characteristic set of nested subgenomic mRNAs during replication in the cytoplasm of infected cells. The genome organization of coronaviruses is highly conserved, with the 5'-two-thirds of the genome encoding the replicase polyprotein, followed by sequences encoding the canonical structural proteins spike, envelope, membrane, and nucleocapsid. Many CoVs contain accessory genes interspersed among the genes for the structural proteins. These accessory genes are not necessarily required for viral replication and are generally not highly conserved within the virus family, but many encode proteins that modulate the host response. Interestingly, the highly conserved coronavirus replicase proteins can also act as antagonists that block or delay the host's innate immune response to infection. A large number of coronavirus-encoded accessory and non-accessory proteins have been shown to shape the host antiviral response, suggesting that virus-mediated subversion of host defenses is a critical component of infection.

[0004] In the case of coronaviruses, there are multiple viruses that affect humans, including SARS, MERS, and SARS-CoV-2.

[0005] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of COVID-19, emerged in China in late 2019. The majority of COVID-19 infections are either asymptomatic or mild. However, a significant proportion of older infected individuals develop respiratory disease requiring hospitalization. COVID-19 can rapidly progress to severe disease with hypoxemic respiratory failure and may require prolonged mechanical ventilatory support. The pathophysiology of severe COVID-19 is dominated by an acute pneumonia process with extensive radiographic opacification. Autopsy reveals diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis. Host immune responses are thought to play a key role in avian influenza, severe acute respiratory syndrome (SARS), and pandemic and seasonal influenza. Inflammatory organ damage can occur in severe COVID-19, and inflammatory markers such as C-reactive protein, ferritin, and interleukin 1 and 6 are significantly elevated in some patients. Several therapeutic interventions have been proposed for the treatment of viral pneumonia to reduce inflammatory organ injury, although the value of corticosteroids has been widely debated.Among COVID-19 patients admitted to UK hospitals, the case fatality rate is over 26%, and among patients requiring invasive mechanical ventilation, the case fatality rate is over 37%.

[0006] Acute hyperglycemia is considered a risk factor for severe disease and has been identified as an independent risk factor for adverse outcomes in such patients, including severe infection, multiple organ failure, and death. Acute hyperglycemia has also been shown to cause long-term damage to insulin-secreting pancreatic islet cells. Patients with type II diabetes or metabolic syndrome are particularly susceptible to severe COVID-19 after infection. Acute hyperglycemia makes it difficult to control glucose in such patients in the intensive care unit setting. [Prior art documents] [Non-patent literature]

[0007]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0008] Glucocorticoids are known to significantly increase blood glucose levels in patients. In the RECOVERY trial, in which dexamethasone was administered to COVID-19 patients, blood glucose levels were significantly increased in diabetic patients (Rayman G, Lumb AN, Kennon B, Cottrell C, Nagi D, Page E, Voigt D, Courtney HC, Atkins H, Higgins K, Platts J, Dhatariya K, Patel M, Newland-Jones P, Narendran P, Kar P, Burr O, Thomas S, Stewart R.Dexamethasone therapy in COVID-19 patients: implications and guidance for the management of blood glucose in people with and without diabetes.Diabet Med.2021 Jan;38(1):e14378.doi:10.1111 / dme.14378.Epub 2020 Sep 21). Dexamethasone may be beneficial in COVID-19, but should be administered with extreme caution to patients in whom acute hyperglycemia is particularly problematic, such as those with diabetes and metabolic syndrome. [Means for solving the problem]

[0009] overview Provided herein is a composition for use in treating COVID-19, preferably moderate COVID-19, comprising Compound 1 or a pharma- ceutically acceptable salt thereof. Also provided is a composition for use in treating fibrosis. [ka]

[0010] Also provided herein is a method for treating COVID-19, preferably moderate COVID-19, comprising administering Compound 1 in an amount of 10 mg / day to 30 mg / day to a patient in need thereof.

[0011] The above and other objects, features and advantages will become more apparent from the following detailed description which proceeds with reference to the accompanying drawings. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 is a graph of survival of various groups of mice in a bleomycin pulmonary fibrosis model receiving either early (E) or late (L) administration of compound 1 according to an embodiment of the present invention, and dexamethasone (DEX), vehicle or naive groups. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description I. Terminology Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise. "Comprise" means "include." The abbreviation "eg" comes from the Latin "exempli gratia" and is used herein to indicate non-limiting examples. Thus, the abbreviation "eg" is synonymous with the term "for example." In case of conflict, the present specification, including explanations of terms, will control. Furthermore, all materials, methods, and examples are illustrative and not intended to be limiting.

[0014] Administration: The introduction of a composition into a subject by a selected route. Administration of an active compound or composition can be by any route known to those of skill in the art. Administration can be local or systemic. Examples of local administration include, but are not limited to, topical, intratumoral, subcutaneous, intramuscular, intrathecal, intraocular, topical ophthalmic, or inhalation administration to the nasal mucosa or lungs. Additionally, local administration includes routes of administration that are typically used for systemic administration, for example, by targeting intravascular administration for the arterial supply of a particular organ. Thus, in certain embodiments, local administration includes intraarterial and intravenous administration, where administration targets the vascular system supplying a particular organ. Local administration also includes incorporating active compounds and agents into implantable devices or constructs, such as the drug delivery devices described herein, which release active agents and compounds over time for sustained therapeutic effect. The implantable devices are "implanted" by any means known in the art for insertion into the tissue or tissue environment that is the desired treatment area.

[0015] Systemic administration includes any route of administration designed to distribute an active compound or composition generally throughout the body via the circulatory system. Thus, systemic administration includes, but is not limited to, intra-arterial and intravenous administration. Systemic administration also includes, but is not limited to, topical, subcutaneous, intramuscular, or inhalation administration, where such administration is intended for absorption and distribution throughout the body via the circulatory system.

[0016] Fibrosis: A condition in which fibrous tissue is formed, which can occur as a result of inflammation or injury to tissues in various organs, not just the lungs. In the lungs, fibrosis is called "pulmonary fibrosis". COVID-19 can induce pulmonary fibrosis. In addition, other conditions such as cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced lung injury, and fibrothorax can also cause pulmonary fibrosis. Fibrosis can also occur in the liver, heart, or kidneys.

[0017] Moderate COVID-19: Patients with moderate COVID-19 have a positive RT-PCR test for SARS-CoV-2 in a nasopharyngeal or oropharyngeal swab; fever, cough, with or without sore throat / throat irritation, body aches / headache, fatigue / weakness, diarrhea or gastrointestinal problems, with or without loss of appetite / nausea / vomiting, loss of smell and / or taste, shortness of breath / shortness of breath and difficulty breathing; respiratory rate greater than 24 but less than 30 breaths per minute, and SpO2 on room air between 90-93%.

[0018] Hyperglycemia: A condition in which serum glucose levels exceed 200 mg / dL.

[0019] Pharmaceutically acceptable salts: The term "pharmaceutical acceptable salts" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and the like.

[0020] Standard of Care: An approved treatment that is based on scientific evidence and prescribed in guidelines as appropriate treatment for a given indication.

[0021] Subject: Living multicellular organisms, including vertebrates, a category that includes both human and non-human mammals.

[0022] Subject susceptible to a disease or condition: A subject capable of, susceptible to, or predisposed to developing a disease or condition. It is understood that a subject who already has or exhibits symptoms of a disease or condition is considered to be "susceptible" because they have already developed it.

[0023] Therapeutically effective amount: A sufficient amount of a compound to obtain a desired effect in a treated subject. An effective amount of a compound can be administered in a single dose or in several divided doses over the course of treatment, for example, daily. However, the effective amount will depend on the compound applied, the subject being treated, the severity and type of affliction, and the mode of administration of the compound.

[0024] II. Overview of Some Embodiments Provided herein are methods for the treatment of COVID-19 using Compound 1, and compositions for use in the treatment of COVID-19 that include Compound 1. Also provided herein are methods for the treatment of COVID-19, particularly moderate COVID-19, that include administering a therapeutically effective amount of a compound of the following structure: [ka] wherein R1 is a direct bond; or a C1-C12 linear or branched alkyl group; R2 is hydrogen or fluorine; R3 is hydrogen or a methyl group, and R4 is a hydroxyl or ketone group, and at least one pharma- ceutically acceptable carrier. Preferably, the compound or a pharma- ceutically acceptable salt thereof is administered in an amount of 10-30 mg / day. A further aspect of the invention relates to the aforementioned compound for the treatment of a disease associated with fibrosis, preferably a disease associated with pulmonary, hepatic, renal or cardiac fibrosis. Optionally, pulmonary fibrosis is treated. Optionally, compound 1 is a drug used in the method for the treatment of the disease. Macrophages are white blood cells involved in the functioning of the immune system. Macrophages are involved in the defense of the body against pathogens, wound healing, and immune regulation. Macrophages are broadly divided into two phenotypes: M1 macrophages, also called "classically activated" macrophages. M1 macrophages are generally pro-inflammatory, whereas M2 macrophages are generally anti-inflammatory. A variety of agents can trigger macrophage activation, including cytokines such as interferon-γ and bacterial endotoxins such as lipopolysaccharide. Impaired macrophage function can lead to abnormal repair, with uncontrolled production of inflammatory mediators and growth factors, failure to generate anti-inflammatory macrophages, or impaired communication between macrophages and epithelial, endothelial, fibroblast, stem, and tissue progenitor cells, all of which may contribute to a persistent state of injury and lead to the development of pathological fibrosis (Immunity. 2016 March 15; 44(3): 450-462).

[0025] Macrophages can be infected by SARS-CoV-2, and the infection is associated with the induction of a macrophage-specific transcriptional program characterized by the secretion of immunomodulatory cytokines and the upregulation of M2-type molecules (J Infect Dis 2021 Aug 2;224(3):395-406). Macrophages, particularly M2 macrophages, play a key role in the development of fibrosis (Semin Liver Dis.2010 August;30(3):245-257). Inhibiting profibrotic macrophages may provide a rational approach for the treatment or prevention of fibrosis. In contrast to other approaches to treat COVID-19, the compounds described herein are suggested to be antifibrotic in that they can specifically target M2 macrophages. In the clinical setting of fibrotic diseases and COVID-19, this is suggested to ameliorate the profibrotic effects of M2 macrophages.

[0026] According to one embodiment, described herein is a compound having the following structure: [ka] wherein R1 is a direct bond; or a C1-C12 straight chain or branched alkyl group optionally substituted with at least one halogen atom selected from fluorine, chlorine, and bromine, a hydroxyl group, a carboxyl group, an amine group, or a benzyl group; R2 is hydrogen or fluorine; R3 is hydrogen or a methyl group, and R4 is a hydroxyl group or a ketone group; and the dotted line represents a single or double bond, and at least one pharma- ceutical composition comprising a therapeutically effective amount of a compound having the formula: and at least one pharma- ceutical acceptable carrier. Optionally, R1 is an unsubstituted C1-C10 alkyl group. Optionally, R1 is an unsubstituted (CH2)3 group. Optionally, R2 and R3 are H, R4 is a ketone group, and the dotted line is a double bond. Optionally, R2 is fluorine, R3 is methyl, and R4 is a hydroxyl group, and the dotted line is a double bond. Optionally, R2 is H, R3 is H, and R4 is a hydroxyl group, and the dotted line is a single bond. Optionally, R2 is H, R3 is H, and R4 is a ketone group, and the dotted line is a single bond. Optionally, the compound has the structure: [ka]

[0027] Optionally, the composition is for the treatment of fibrosis, optionally of the lung, liver, kidney, heart, muscle, skin, ovary or testis, preferably of the lung. Optionally, the composition is for the treatment of pulmonary fibrosis associated with COVID-19. Optionally, the compound is administered in an amount of 10 mg / day to 30 mg / day.

[0028] Further described herein is a method for the treatment of COVID-19, comprising administering to a patient in need thereof 10 mg / day to 30 mg / day of Compound 1, having the following structure: [ka]

[0029] Optionally, the patient is administered 20 mg / day of Compound 1. Optionally, the patient is suffering from moderate COVID-19. Optionally, Compound 1 is administered for at least 3 consecutive days. Optionally, the patient's recovery is improved compared to treatment with dexamethasone. Optionally, the patient is further treated with at least one of oxygen enrichment, hydration, antipyretics, antitussives, multivitamins, antibiotics for co-infections, ivermectin, remdesivir, baricitinib, tofacitinib, tocilizumab, and sarilumab. Optionally, Compound 1 is administered intravenously. Optionally, the patient does not experience hyperglycemia after administration. Optionally, the patient is suffering from long-term COVID-19. Optionally, the patient is further treated with standard of care.

[0030] Further described herein is a method for treating fibrosis in a patient, comprising administering to the patient a therapeutically effective amount of Compound 1, optionally in an amount of 10 mg / day to 30 mg / day, optionally 20 mg / day. Optionally, Compound 1 is administered intravenously. Optionally, the fibrosis is pulmonary, liver, kidney, heart, muscle, skin, testis, or ovarian fibrosis. Optionally, the fibrosis is pulmonary fibrosis. Optionally, Compound 1 is administered for only 3 days. Optionally, administration of Compound 1 is continued at a constant rate without tapering.

[0031] The following examples are provided to illustrate particular features and / or embodiments and should not be construed as limiting the disclosure to the particular features or embodiments described. EXAMPLES

[0032] Example 1: Preparation of Compound 1 Compound 1 was prepared as follows.

[0033] Step 1: (2R,3R,4S,5S,6S)-2-(acetoxymethyl)-6-(3-bromopropoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound R1) [ka] 1,2,3,4,6-Penta-O-acetyl-D-mannopyranoside (8 gr, 20.5 mmol) was dissolved in CHCl (80 mL) and 3-bromopropan-1-ol (3.13 gr, 22.5 mmol) was added followed by boron trifluoride etherate (10.1 mL, 82.0 mmol). The reaction was stirred for 24 h in the dark under nitrogen atmosphere. TLC analysis (Hexane: EtOAc = 1:1) was performed. A new spot was detected. DCM was added and the reaction mixture was neutralized by adding saturated NaHCO3 solution. The phases were separated and the aqueous phase was washed with DCM. The combined organic phases were dried over NaSO4, filtered and evaporated. The crude product was purified by column chromatography (3:1 to 1:1 gradient - Hexane: EtOAc) and the product was isolated as a colorless oil in 64% yield.

[0034] Step 2: (2R,3R,4S,5S,6S)-2-(acetoxymethyl)-6-(3-((1,3-dioxoisoindolin-2-yl)oxy)propoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound R2) [ka] To a solution of compound R1 (3.5 gr, 7.5 mmol) and N-hydroxylphthalimide (1.35 gr, 8.25 mmol) in DMF (15 mL), DBU (1.1 mL, 8.25 mmol) was added and the red solution was stirred at room temperature under nitrogen for 18 h. The reaction was monitored by TLC (hexane / EtOAc = 1 / 1) and LCMS (SB1090) and no starting material remained. The yellow-orange solution was added dropwise to a solution of 1N HCl (50 mL). A white solid separated and was dissolved in EtOAC. The aqueous phase was extracted with EtOAc, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography (gradient 0-50% EtOAc in hexane). 3 gr (73% yield) of white solid was obtained.

[0035] Step 3: (2R,3R,4S,5S,6S)-2-(acetoxymethyl)-6-(3-(aminooxy)propoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound R3) [ka] Compound R2 (3.04 gr, 5.51 mmol) was dissolved in methanol (100 mL) over 30 min due to difficulty in dissolving, and 1.5 eq. hydrazine hydrate (0.401 mL, 8.27 mmol) was added. Stirring was continued for 4 h and the reaction was monitored by TLC (EtOAc) and LCMS (SB1090). The solvent was removed by evaporation, leaving a white solid (by-product). The crude product was washed with EtOAc, the suspension was filtered and the mother liquor was evaporated. This EtOAc wash was repeated 4 times, followed by a further wash with CHCl3. The mother liquor was evaporated to dryness. 1.85 gr (80% yield) of a colorless oil was obtained. NMR and LCMS (SB1090) analysis confirmed the structure.

[0036] Step 4: (2R,3R,4S,5S,6S)-2-(acetoxymethyl)-6-(3-(((8S,9R,10S,11S,13S,14S,16R,17R,E)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-ylidene)amino)propoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (compound R4) [ka]

[0037] The previously prepared oxime R3 (1.8 gr, 4.27 mmol) was added to a solution of dexamethasone (1.11 gr, 2.85 mmol) in EtOH (25 mL), followed by PTSA (0.27 gr, 1.42 mmol). The reaction mixture was refluxed for 4 h while being monitored by LCMS (SB1090). After 1 h, 95% conversion was detected. Also, mono / di-deprotected products of acetate groups were observed by LCMS. The reaction mixture was cooled to room temperature, NaHCO3 (1 g) was added, the suspension was stirred for 5 min and filtered. EtOH was evaporated to dryness. Purification by column chromatography (gradient 50% to 100% EtOAc in hexane) gave a mixture of product and partially deprotected by-products. Yield: 1.66 gr. This mixture was used in the next step.

[0038] Step 5: 1-((8S,9R,10S,11S,13S,14S,16R,17R,E)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-((3-(((2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)propoxy)imino)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-hydroxyethan-1-one (compound 1) [ka] Compound R4 (1.66 gr) was dissolved in 60 mL of MeOH / Et3N / H2O (8:1:1). The reaction mixture was stirred at room temperature and monitored by LCMS (SB1090). After stirring for 4 hours, only the desired product (m / z 628) was observed. The solvent was evaporated and the product (1.33 g crude) was purified by silica gel chromatography, eluted with DCM / MeOH=85 / 15 and monitored by TLC (DCM / MeOH=80 / 20). 0.7 gr of a white solid was isolated and characterized by NMR and LCMS (SB1090) which confirmed the structure.

[0039] Example 2: In vivo model of pulmonary fibrosis Pulmonary fibrosis (PF) after COVID-19 infection is defined as having persistent and distinct fibrotic cross-sectional changes, often accompanied by impairments in pulmonary function tests. The pathogenesis of PF after COVID-19 infection is partially known but is likely multifactorial. Excessive production of reactive oxygen species and non-protective mechanical ventilation may be triggers of PF after COVID-19 infection. To investigate the beneficial effects of compound 1 in pulmonary fibrosis, we utilized a bleomycin-induced PF mouse model. Bleomycin is known for its ability to induce lung injury resulting in an acute inflammatory response, with fibrotic changes occurring after the inflammatory phase. In this model, administration of bleomycin directly to the lungs reduces survival of treated mice due to extensive lung injury. The study was performed in five treatment groups (n=10-12 per group) of C57BL / 6 mice, including early or late treatment with compound 1 (1 mg / mouse), early treatment with 0.45 mg / mouse dexamethasone (DEX), vehicle and naive control groups. Early treatment was initiated on day 1, the same day as bleomycin administration. Late treatment was initiated on day 14. Vehicle, dexamethasone and early compound 1 groups were infused with the test article on days 1, 2, 3, 7, 14, 21 and 28. Late treatment groups were infused with compound 1 on days 14, 15, 16, 21, 28 and 31. Test articles were infused intravenously via the tail vein after pulmonary fibrosis model induction (bleomycin induced by intratracheal administration of bleomycin (3.5 U / kg)). Animals were monitored for morbidity, mortality, weight and clinical signs. Selected clinical signs (i.e. physical appearance, activity, ability to respond to external stimuli, ocular and respiratory quality) were scored to provide a clinical score. Cytokine levels were measured in BALF (bronchoalveolar lavage fluid) (day 33) and serum (days 17 and 32).

[0040] As shown in Figure 1, similar mortality rates were observed in the vehicle (dashed line), DEX (thin line with hollow mark) and compound 1 early (designated "E", double line) treatment groups, which were higher than the naive (dotted line, hollow mark) control group. The compound 1 late treatment group (designated "L", solid line) showed lower mortality rates than the DEX and compound 1 early treatment groups and similar mortality rates to the naive group.

[0041] Extensive damage to lung tissue is a precursor to the development of pulmonary fibrosis. Chronic exposure to drugs, industrial pollutants, radiation, or acute pneumonia can cause lung tissue damage, which can result in scarring and fibrosis. Histopathological evaluation remains an accurate method to assess the severity of pulmonary fibrosis. Analysis of serum and BALF cytokines showed no statistically significant changes between groups in most of the serum cytokine values ​​measured on days 17 and 32 (data not shown). Histopathological evaluation (from the end of the study on day 33) revealed that pulmonary fibrosis was reduced after late treatment with Compound 1 and DEX compared to the vehicle control group. Pathological and fibrosis scores after late treatment with Compound 1, as well as the percentage of pulmonary fibrosis by digital morphometry, were slightly lower compared to DEX treatment, as shown in Table 1 below. Values ​​are reported as mean ± standard deviation.

[0042] [Table 1]

[0043] Histopathological evaluation of H&E and MT stained lung sections after bleomycin showed typical pathological features of subacute inflammation and fibrosis throughout the lung tissue. Overall, late treatment with compound 1 appears to have a more profound effect in terms of mortality and disease progression as indicated by histopathological evaluation in the bleomycin pulmonary fibrosis model compared to early treatment with DEX or compound 1. This indicates the potential of compound 1 as a treatment for moderate to severe COVID-19 cases. As pulmonary fibrosis has recently emerged as an important complication in the long-term follow-up management of COVID-19, compound 1, which has been shown to have improved efficacy in suppressing fibrosis over dexamethasone, may be an effective therapy when administered after lung injury has begun.

[0044] In addition to reducing pulmonary fibrosis, it is suggested that the treatment of other types of fibrosis, such as cardiac, hepatic or renal fibrosis, may be improved or prevented using Compound 1.

[0045] Example 3: Safety of Compound 1 in Humans We have initiated a Phase I, single-center, open-label, dose-escalation study to evaluate the safety of Compound 1 in healthy volunteers. This Phase I study included 15 healthy volunteers who received a single ascending dose in Study Part 1, followed by a 3-day repeat dose in Study Part 2 to evaluate the safety of Compound 1 in COVID-19 patients prior to the study and to identify dose-limiting toxicity (DLT).

[0046] The Phase I study, involving 15 subjects, was designed to include a single ascending dose Part 1 study followed by a 3-day repeat dose Part 2 study to evaluate the safety of Compound 1 in healthy subjects and to identify dose-limiting toxicities (DLTs) prior to testing in patients with COVID-19.

[0047] Initially, a cohort of three participants was enrolled and received a single intravenous dose of 10 mg of Compound 1. A second cohort of three participants received a single intravenous dose of 20 mg of Compound 1, and a third cohort of six participants received a single intravenous dose of 30 mg of Compound 1. The 10, 20, and 30 mg doses corresponded to the equivalent of 6.3, 12.5, and 18.8 mg of free dexamethasone, based on molecular weight calculations of Compound 1, which has a molecular weight of 627.31 g / mol, and dexamethasone, which has a molecular weight of 392.464 g / mol.

[0048] In the next phase, three participants received Compound 1 at 30 mg once daily for three consecutive days. A total of 33 adverse events (AEs) were reported during the study. Four of the 33 AEs were reported before and 29 after IP exposure, and of the 29 after exposure, six AEs were assessed as not related to IP, 13 AEs as related, and 10 AEs as probably related. Of the 23 possible or definite AEs related, six (26.1%) were hematological, eight (34.8%) were chemical, two (8.7%) were insomnia, two (8.7%) were fatigue reports, two (8.7%) were skin rash, one (4.34%) was anxiety, one (4.34%) was hypertension, and one (4.34%) was noncardiac chest pain. All these events were mild to moderate in severity. All volunteers were discharged at the time points planned by the protocol. The results of this Phase 1 study showed no correlation between dose escalation of Compound 1 and the frequency or severity of AEs. No acquired Serious Adverse Events (SAEs) or severe AEs were detected. No DLTs were reported during the study.

[0049] According to the literature, the most frequently reported side effect with DEX is the presence of insomnia. Two cases of insomnia, one case of anxiety, and one case of non-cardiac chest pain were reported during administration of Compound 1. These events could be explained by the discomfort of hospitalization or participation in a clinical trial, however, further investigation is required to determine the probability and frequency of these events. One case of hyperglycemia was detected, but this event was mild and transient (blood glucose level increased from 97 to 105 (mg / dL) in one individual) and was unchanged 4 hours after administration of any of the 24 doses of Compound 1.

[0050] Example 4: Efficacy of Compound 1 in treating COVID-19 in human subjects A prospective, randomized, multicenter, parallel-group, double-blind, adaptive Phase II / III study will be conducted to evaluate the safety and efficacy of Compound 1 versus dexamethasone in patients with moderate COVID-19 disease in line with standard of care. The total duration of treatment administration for all patients will be 3 days. The endpoint of this study will be to evaluate the efficacy of Compound 1 compared to dexamethasone in patients with moderate COVID-19.

[0051] Compound 1 is packaged in vials, each containing 20 mg of Compound 1, to be reconstituted in saline (0.9% NaCl) for bolus intravenous (IV) injection of 5 ml of solution.

[0052] The study was designed to measure rates of treatment-emergent adverse events (AEs) and serious adverse events (SAEs), including changes in clinical symptoms, vital signs, and laboratory values, and to determine the time to clinical recovery (TTCR) [Days 1-10], with Day of recovery defined as the first day that a patient showed a 2-point improvement (relative to the patient's best score) on the 11-point ordinal scale described in Table 2:

[0053] [Table 2]

[0054] Other endpoints in the study include: reduction in mortality at 28 or 60 days after dosing; reduction in intensive care unit (ICU) admission rate; reduction in mechanical ventilation or vasopressor therapy (28-day follow-up); improvement in clinical recovery rate [time frame: day 10] - the proportion of patients who recovered within 10 days, with recovery defined as a 2-point improvement on an 11-point ordinal scale; improvement in temperature, heart rate, and oxygen saturation on days 1, 2, 4, and 7; reduction in viral load relative to admission levels by RT-PCR from nasopharyngeal swabs on days 3, 5, and 10; changes in CRP, ferritin, and CBC (with differential) levels; changes in cytokine profile and lymphocyte subpopulations; and measurements of ACTH and morning cortisol levels.

[0055] Patients will be screened for demographics, physical exam including vital signs, signs and symptoms of COVID-19, medical and surgical history, medication history, RT-PCR, assessment of WHO ordinal score and cycle threshold (CT) values, urine pregnancy test (women of childbearing potential only), hematology, biochemistry, and urinalysis.Patients with well-controlled medical conditions such as diabetes, cardiovascular disease including hypertension, CAD, chronic pulmonary / liver or renal disease will be included in the study based on the investigator's discretion.

[0056] Approximately 318 eligible patients will be randomized 1:1 to one of two treatment arms: Arm 1: Compound 1 at 20 mg per day plus standard of care; Arm 2: Dexamethasone 6 mg per day plus standard of care.

[0057] Standard treatment may include oxygen enrichment, hydration, antipyretics, cough suppressants, multivitamins, antibiotics for co-infections, ivermectin, optionally 12 mg daily; remdesivir, baricitinib, tofacitinib, tocilizumab, or sarilumab. Optionally, remdesivir is administered for 5 days, 200 mg intravenously on the first day, followed by 100 mg intravenously daily for the remaining 4 days.

[0058] The expected total study duration is approximately 60 days consisting of: 7 days prior to randomization (Day -7 to Day 1). Treatment Period: Days 1 to 3. End of Treatment Assessment: Day 3 (for subjects receiving Compound 1) and Day X (for the dexamethasone group, at the investigator's discretion). Post-Treatment Follow-Up: Days 4, 5, 10, 14, and 28. End of Study Assessment: Day 60. The total study participation period for each subject may vary depending on the number of days required to perform all screening procedures. Screening will involve: Patients will be required to sign an informed consent form; inclusion and exclusion criteria will be identified; medical, surgical and medication history will be recorded; SARS-COV-2 testing, including both qualitative and quantitative (RT-PCR); demographics (age, sex) and patient characteristics; urine pregnancy test if applicable (for women of childbearing potential); and physical examination.

[0059] COVID-19: Signs and symptoms will be determined using the following: laboratory values ​​(hematology, biochemistry including C-reactive protein, ferritin and D-dimer, cytokines by multiplex method, sequential multiplex analysis (SMA), fasting plasma glucose (FPG), morning cortisol, T-cell subsets), urinalysis (routine / microscopy); vital signs (blood pressure, heart rate, respiratory rate and temperature), and pulse oximetry (oxygen saturation [SpO2]), 12-lead ECG, chest x-ray / HRCT (based on investigator's clinical judgment), WHO 11-point ordinal scale of clinical assessment.

[0060] Patients will be enrolled, randomized, and treatment will begin on Day 1. On Days 1 through 3, the following assessments will be performed: COVID-19: signs and symptoms assessment; vital signs (blood pressure, heart rate, respiratory rate, and temperature) and pulse oximetry (oxygen saturation [SpO2]); chest x-ray / HRCT (at the investigator's discretion based on clinical judgment); laboratory values ​​(hematology, biochemistry (including cytokines by multiplex method), sequential multiplex analysis (SMA), fasting plasma glucose (FPG)); urinalysis (routine / microscopic); WHO clinical assessment 11-point ordinal scale.

[0061] Similar assessments are performed on days 5 and 10. Adverse events and serious adverse events are recorded. Vital signs and the WHO 11-point ordinal scale of clinical assessment are performed on days 14, 28, and 60.

[0062] It is expected that recovery from moderate COVID-19 can be accelerated in the group administered compound 1 compared to the dexamethasone group. Also, hyperglycemia is expected to be lower in the compound 1 group compared to the dexamethasone group. It is expected that the parameter of reduced mortality will be enhanced in the compound 1 group.

[0063] In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are merely preferred examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

1. 1. A pharmaceutical composition for use in the treatment of fibrosis, said composition comprising the following structure: 【Chemistry 1】 (In the formula, R １ is a direct bond; or a C1-C12 straight chain or branched alkyl group optionally substituted with at least one halogen atom selected from fluorine, chlorine and bromine, a hydroxyl group, a carboxyl group, an amine group or a benzyl group; R ２ is hydrogen or fluorine; R ３ is hydrogen or a methyl group; and R ４ is a hydroxyl or ketone group; and the dotted line represents a single or double bond. and at least one pharma- ceutically acceptable carrier.

2. R １ The composition of claim 1, wherein is an unsubstituted C1-C10 alkyl group.

3. R １ is unsubstituted (CH ２ ) ３ The composition of claim 2 , wherein the R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -

4. R ２ and R ３ is H, and R ４ The composition of claim 1 , 2 or 3 , wherein is a ketone group and the dotted line is a double bond.

5. R ２ is fluorine, R ３ is a methyl group, and R ４ The composition of claim 1 , 2 or 3, wherein is a hydroxyl group and the dotted line is a double bond.

6. R ２ is H, and R ３ is H, and R ４ The composition of claim 1 , 2 or 3, wherein is a hydroxyl group and the dotted line is a single bond.

7. R ２ is H, and R ３ is H, and R ４ The composition of claim 1 , 2 or 3 , wherein is a ketone group and the dotted line is a single bond.

8. The compound has the following structure: 【Chemistry 2】 The composition of claim 1 having the formula:

9. The composition according to any one of claims 1 to 8, wherein the fibrosis is pulmonary, hepatic, renal, cardiac, muscular, cutaneous, ovarian or testicular fibrosis.

10. The composition of claim 9, wherein the fibrosis is pulmonary fibrosis.

11. The composition of any one of claims 1 to 10 for the treatment of pulmonary fibrosis associated with COVID-19.

12. The composition of any one of claims 1 to 11, wherein the compound is administered in an amount of 10 mg / day to 30 mg / day.

13. The structure: 【Chemistry 3】 A composition for use in treating COVID-19, comprising administering to a patient in need thereof 10 mg / day to 30 mg / day of compound 1 having the formula:

14. The composition of claim 13, wherein the patient is administered 20 mg / day of Compound 1.

15. The composition of claim 13 or 14, wherein the patient is suffering from moderate COVID-19.

16. The composition of any one of claims 13 to 15, wherein compound 1 is administered for at least three consecutive days.

17. The composition according to any one of claims 13 to 16, wherein the recovery of the patient is improved compared to treatment with dexamethasone.

18. 18. The composition of any one of claims 13 to 17, wherein the patient is further receiving at least one of the following treatments: oxygen enrichment, hydration, antipyretics, antitussives, multivitamins, antibiotics for co-infections, ivermectin, remdesivir, baricitinib, tofacitinib, tocilizumab, sarilumab.

19. The composition of any one of claims 13 to 18, wherein compound 1 is administered intravenously.

20. The composition of any one of claims 13 to 19, wherein the patient does not experience hyperglycemia after administration.

21. The composition according to any one of claims 13 to 20, wherein the patient is suffering from long-term COVID-19.

22. The composition of any one of claims 13 to 21, wherein the patient is further treated with a standard of care.

23. The composition of any one of claims 13 to 22, wherein compound 1 is administered for only 3 days.

24. The composition according to any one of claims 13 to 23, wherein the administration of compound 1 is continued at a constant rate without tapering.

25. A method for treating fibrosis in a patient, comprising administering a therapeutically effective amount of Compound 1 to the patient.

26. 26. The method of claim 25, wherein the amount is between 10 mg / day and 30 mg / day.

27. 27. The method of claim 26, wherein the amount is 20 mg / day.

28. The method of any one of claims 25 to 27, wherein compound 1 is administered intravenously.

29. The method according to any one of claims 25 to 28, wherein the fibrosis is pulmonary, hepatic, renal, cardiac, muscular, cutaneous, testicular or ovarian fibrosis.

30. 30. The method of claim 29, wherein the fibrosis is pulmonary fibrosis.

31. The method of any one of claims 25 to 30, wherein compound 1 is administered for only 3 days.

32. The method of any one of claims 25 to 31, wherein the administration of Compound 1 is continued at a constant rate without tapering.

33. The method of any one of claims 25 to 32, wherein the fibrosis is associated with COVID-19.

34. A compound having the structure: 【Chemistry 4】 (In the formula, R １ is a direct bond; or a C1-C12 straight chain or branched alkyl group optionally substituted with at least one halogen atom selected from fluorine, chlorine and bromine, a hydroxyl group, a carboxyl group, an amine group or a benzyl group; R ２ is hydrogen or fluorine; R ３ is hydrogen or a methyl group; and R ４ is a hydroxyl group or a ketone group; and the dotted line represents a single or double bond.) and at least one pharma- ceutically acceptable carrier.

35. R １ is an unsubstituted C1-C10 alkyl group.

36. R １ is unsubstituted (CH ２ ) ３ 36. The compound of claim 35, wherein:

37. R ２ and R ３ is H, and R ４ 37. The compound of claim 34, 35 or 36, wherein is a ketone group and the dotted line is a double bond.

38. R ２ is fluorine, R ３ is a methyl group, and R ４ 37. The compound of claim 34, 35 or 36, wherein is a hydroxyl group and the dotted line is a double bond.

39. R ２ is H, and R ３ is H, and R ４ 37. The compound of claim 34, 35 or 36, wherein is a hydroxyl group and the dotted line is a single bond.

40. R ２ is H, and R ３ is H, and R ４ 37. The compound of claim 34, 35 or 36, wherein is a ketone group and the dotted line is a single bond.

41. The compound has the following structure: 【Chemistry 5】 35. The compound of claim 34, having the formula:

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