Methods of treating COVID-19 using methylbacosolon or analogs thereof

Abstract

The present invention provides methods of treating patients infected with a coronavirus. In particular, methods of treating or preventing COVID-19 or its symptoms or complications in a patient in need thereof, and / or preventing the onset of COVID-19 in a patient infected with SARS-CoV-2 using bardoxolone methyl or an analog thereof are provided.

Description

[0001] Reference to relevant applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 053,056, filed July 17, 2020, and U.S. Provisional Application No. 63 / 022,479, filed May 9, 2020, the full contents of each of which are incorporated herein by reference.

[0003] background

[0004] 1. Field

[0005] This disclosure generally pertains to the fields of medicine and biology. More specifically, in some aspects, it relates to methods of treating or preventing COVID-19 or its symptoms using methylbardosolone and its analogues.

[0006] 2. Description of related technologies

[0007] The World Health Organization (WHO) has declared the coronavirus disease 2019 (COVID-19) outbreak a pandemic. This virus is linked to other coronaviruses that caused the 2002 pandemic known as Severe Acute Respiratory Syndrome (SARS-CoV) and the 2012 pandemic known as Middle East Respiratory Syndrome (MERS-CoV). The virus that causes COVID-19 has been named SARS-CoV-2 because it shares nearly 80% of its genome with SARS-CoV.

[0008] Methylbardoxazolon has been shown to improve estimated glomerular filtration rate (eGFR) and measured glomerular filtration rate (mGFR) in patients with CKD caused by type 2 diabetes. Methylbardoxazolon and several of its analogues have also been shown to inhibit pro-fibrotic signaling pathways and reduce oxidative stress and inflammation in various CKD models. These compounds have also been shown to reduce pro-inflammatory cytokines and chemokines, prevent organ damage (lung, liver, and pancreas), and increase survival in systemic inflammation models.

[0009] Acute kidney injury (AKI) has been reported in up to 28% of all COVID-19 patients and up to 72% of non-survivors. Unfortunately, there are no specific drugs or vaccines for the coronavirus. Therefore, new therapies for COVID-19 are needed. Summary of the Invention

[0010] In one aspect, the present invention provides a method for treating or preventing symptoms or complications of coronavirus infection in patients in need. Such methods are described in the following portions, including, for example, the claims portion, which is incorporated herein by reference.

[0011] In some embodiments, the compound is methylbardosolone (BARD, CDDO-Me, or RTA 402). In some of these embodiments, at least a portion of the CDDO-Me is present as a polymorphic form, wherein the polymorphic form is a crystalline form having an X-ray diffraction pattern (CuKα) containing prominent diffraction peaks at approximately 8.8, 12.9, 13.4, 14.2, and 17.4°2θ. In non-limiting embodiments, the X-ray diffraction pattern (CuKα) is substantially as shown in Figure 1A or Figure 1B.

[0012] In some of these embodiments, at least a portion of CDDO-Me exists as a polymorphic form, wherein the polymorphic form is a crystalline form having an X-ray diffraction pattern (CuKα) containing prominent diffraction peaks at approximately 6.2, 12.4, 15.4, 18.6, and 24.9°2θ. In some aspects, the crystalline form is further characterized by one, two, three, four, or five additional diffraction peaks selected from a set of the following members: 8.6, 13.3, 13.7, 17.1, and 21.7°2θ. In a non-limiting embodiment, the X-ray diffraction pattern (CuKα) is substantially as shown in Figure 1 of WO 2019 / 014412, which is incorporated herein by reference in its entirety.

[0013] In some of these embodiments, at least a portion of CDDO-Me exists as a polymorphic form, wherein the polymorphic form is a crystalline form with an X-ray diffraction pattern (CuKα) containing prominent diffraction peaks at approximately 3.6, 7.1, 10.8, 12.4, and 16.5°2θ. In some aspects, the crystalline form is further characterized by one, two, three, four, or five additional diffraction peaks selected from a set of the following members: 12.9, 13.9, 14.8, 18.6, and 20.6°2θ. In a non-limiting embodiment, the X-ray diffraction pattern (CuKα) is substantially as described in WO 2019 / 014412. Figure 2 As shown, it is incorporated herein by reference in its entirety. In some respects, the crystalline form is further characterized by having crystalline values ​​of 2949, 1671, 1618, and 1464 ± 4 cm⁻¹. -1 The Raman spectrum of the peak at the specified location. In a non-limiting embodiment, the Raman spectrum is substantially as shown in Figures 4 and 5 of WO 2019 / 014412, which is incorporated herein by reference in its entirety.

[0014] In some of these embodiments, at least a portion of the CDDO-Me exists as a polymorphic form, wherein the polymorphic form is a toluene solvate crystalline form having an X-ray diffraction pattern (CuKα) containing diffraction peaks at approximately 9.65, 7.58, 7.18, 6.29, 6.06, 5.47, 5.21, 4.77, and 3.07°2θ. In a non-limiting embodiment, the X-ray diffraction pattern (CuKα) is substantially as shown in Figure 1 of CN102887936, which is incorporated herein by reference in its entirety.

[0015] In some of these embodiments, at least a portion of the CDDO-Me exists as a polymorphic form, wherein the polymorphic form is a crystalline form of a half-dioxane solvate having an X-ray diffraction pattern (CuKα) containing diffraction peaks at approximately 10.01, 7.09, 6.84, 6.23, 5.29, 5.20, 5.10, 4.84, and 4.61°2θ. In a non-limiting embodiment, the X-ray diffraction pattern (CuKα) is substantially as shown in Figure 4 of CN102887936, which is incorporated herein by reference in its entirety.

[0016] In some of these embodiments, at least a portion of the CDDO-Me exists as a polymorphic form, wherein the polymorphic form is a semi-tetrahydrofuran solvate crystalline form having an X-ray diffraction pattern (CuKα) containing diffraction peaks at approximately 10.00, 7.14, 6.80, 6.65, 6.10, 5.62, 5.29, 4.88, and 4.50°2θ. In a non-limiting embodiment, the X-ray diffraction pattern (CuKα) is substantially as shown in Figure 8 of CN102887936, which is incorporated herein by reference in its entirety.

[0017] In some of these embodiments, at least a portion of the CDDO-Me exists as a polymorphic form, wherein the polymorphic form is a methanol solvate crystalline form having an X-ray diffraction pattern (CuKα) containing diffraction peaks at approximately 8.86, 8.45, 8.17, 7.90, 7.26, 4.67, 6.63, 6.46, and 3.64°2θ. In a non-limiting embodiment, the X-ray diffraction pattern (CuKα) is substantially as shown in Figure 1 of CN102875634, which is incorporated herein by reference in its entirety.

[0018] In some of these embodiments, at least a portion of the CDDO-Me exists as a polymorphic form, wherein the polymorphic form is an anhydrous crystalline form having an X-ray diffraction pattern (CuKα) containing diffraction peaks at approximately 12.05, 8.90, 8.49, 8.13, 7.92, 7.29, 6.64, 4.67, and 3.65°2θ. In a non-limiting embodiment, the X-ray diffraction pattern (CuKα) is substantially as described in CN102875634. Figure 2 As shown, it is incorporated herein by reference in its entirety.

[0019] In some of these embodiments, at least a portion of the CDDO-Me exists as a polymorphic form, wherein the polymorphic form is a dihydrate crystalline form having an X-ray diffraction pattern (CuKα) containing diffraction peaks at approximately 8.81, 8.48, 7.91, 7.32, 5.09, 4.24, 3.58, 3.36, and 3.17°2θ. In a non-limiting embodiment, the X-ray diffraction pattern (CuKα) is substantially as shown in Figure 3 of CN102875634, which is incorporated herein by reference in its entirety.

[0020] In some of these embodiments, at least a portion of the CDDO-Me exists as a polymorphic form, wherein the polymorphic form is an amorphous form having an X-ray diffraction pattern (CuKα) containing a halo peak at approximately 13.5°2θ (essentially as shown in Figure 1C) and a T g In some variants, the compound is in an amorphous form. In some variants, the compound is in the form of a glassy solid of CDDO-Me, having an X-ray powder diffraction pattern containing a halo peak at approximately 13.5°2θ (as shown in Figure 1C) and a T... g In some variants, the T g The value falls within the range of approximately 120°C to approximately 135°C. In some variants, the T... g The value ranges from approximately 125°C to approximately 130°C.

[0021] In some embodiments, the compound is administered locally. In some embodiments, the compound is administered systemically. In some embodiments, the compound is administered orally, via adipose tissue, arterial tissue, joint tissue, cranial tissue, dermal tissue, lesion tissue, muscle tissue, nasal tissue, ocular tissue, pericardial tissue, peritoneal tissue, pleural tissue, prostate tissue, rectal tissue, sheath tissue, tracheal tissue, tumor tissue, umbilical cord tissue, vaginal tissue, intravenous tissue, bladder tissue, vitreous tissue, in liposome form, locally, mucosally, orally, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topically, buccally, transdermally, vaginally, in emulsion form, in lipid composition form, via catheter, via irrigation, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, via local perfusion, by direct immersion in target cells, or any combination thereof. For example, in some variants, the compound is administered intravenously, intra-arterially, or orally. For example, in some variants, the compound is administered orally.

[0022] In some embodiments, the compound is formulated into hard or soft capsules, tablets, syrups, suspensions, solid dispersions, rice paper encapsulations, or elixirs. In some variations, the soft capsule is a gelatin capsule. In other variations, the compound is formulated into a solid dispersion. In some variations, the hard capsule, soft capsule, tablet, or rice paper encapsulation further comprises a protective coating. In some variations, the formulated compound contains an agent that delays absorption. In some variations, the formulated compound further contains an agent that enhances solubility or dispersibility. In some variations, the compound is dispersed in liposomes, oil-in-water emulsions, or water-in-oil emulsions.

[0023] In some embodiments, the pharmaceutically effective amount is a daily dose from about 0.1 mg to about 500 mg of the compound. In some variations, the daily dose is from about 1 mg to about 300 mg of the compound. In some variations, the daily dose is from about 10 mg to about 200 mg of the compound. In some variations, the daily dose is about 25 mg of the compound. In other variations, the daily dose is about 75 mg of the compound. In other variations, the daily dose is about 150 mg of the compound. In other variations, the daily dose is from about 0.1 mg to about 30 mg of the compound. In some variations, the daily dose is from about 0.5 mg to about 20 mg of the compound. In some variations, the daily dose is from about 1 mg to about 15 mg of the compound. In some variations, the daily dose is from about 1 mg to about 10 mg of the compound. In some variations, the daily dose is from about 1 mg to about 5 mg of the compound. In some variations, the daily dose is from about 2.5 mg to about 30 mg of the compound. In some variations, the daily dose is about 2.5 mg of the compound. In other variants, the daily dose is about 5 mg of the compound. In other variants, the daily dose is about 10 mg of the compound. In other variants, the daily dose is about 15 mg of the compound. In other variants, the daily dose is about 20 mg of the compound. In still other variants, the daily dose is about 30 mg of the compound.

[0024] In some embodiments, the pharmaceutically effective amount is a daily dose of 0.01-25 mg compound / kg body weight. In some variations, the daily dose is 0.05-20 mg compound / kg body weight. In some variations, the daily dose is 0.1-10 mg compound / kg body weight. In some variations, the daily dose is 0.1-5 mg compound / kg body weight. In some variations, the daily dose is 0.1-2.5 mg compound / kg body weight.

[0025] In some embodiments, the pharmaceutically effective amount is administered as a single daily dose. In some embodiments, the pharmaceutically effective amount is administered as two or more daily doses.

[0026] In some embodiments, the patient is a mammal such as a primate. In some variations, the primate is a human. In other variations, the patient is a cow, horse, dog, cat, pig, mouse, rat, or guinea pig.

[0027] In some variations of the above methods, the compound substantially does not contain its optical isomers. In some variations of the above methods, the compound is in the form of a pharmaceutically acceptable salt. In other variations of the above methods, the compound is not a salt.

[0028] In some embodiments, the compound is formulated into a pharmaceutical composition comprising (i) a therapeutically effective amount of the compound and (ii) an excipient selected from the group consisting of: (A) carbohydrates, carbohydrate derivatives, or carbohydrate polymers; (B) synthetic organic polymers; (C) organic acid salts; (D) proteins, polypeptides, or peptides; and (E) high molecular weight polysaccharides. In some variants, the excipient is a synthetic organic polymer. In some variants, the excipient is selected from the group consisting of: hydroxypropyl methylcellulose, poly[1-(2-oxo-1-pyrrolyl)ethylene] or copolymers thereof, and methacrylic acid-methyl methacrylate copolymers. In some variants, the excipient is hydroxypropyl methylcellulose phthalate. In some variants, the excipient is PVP / VA. In some variants, the excipient is methacrylic acid-ethyl acrylate copolymer. In some variants, the methacrylic acid and ethyl acrylate may be present in a ratio of about 1:1. In some variants, the excipient is copovidone.

[0029] Unless otherwise specified, any embodiments discussed herein with respect to one aspect of the invention are also applicable to other aspects of the invention.

[0030] For example, other aspects and embodiments of the invention are set forth in more detail in the claims section and the embodiments section, which are incorporated herein by reference.

[0031] Other objects, features, and advantages of this disclosure will become apparent from the following detailed description. However, it should be understood that while the detailed description and specific embodiments indicate particular embodiments of the invention, they are given by way of example only, as those skilled in the art will understand from the detailed description various changes and modifications within the spirit and scope of the invention. It should be noted that the fact that a particular compound is classified into one general formula does not mean that it cannot also belong to another general formula. Brief description of the attached diagram

[0033] The following figures form part of this specification and are included to further illustrate certain aspects of the invention. A better understanding of the invention can be achieved by referring to one or more of these figures in conjunction with the detailed description of the specific embodiments presented herein.

[0034] Figure 1A-C X-ray powder diffraction (XRPD) spectra of forms A and B of RTA 402. Figure 1A shows unmicronized form A; Figure 1B shows micronized form A; Figure 1C shows form B.

[0035] Figure 2 - A schematic diagram of the research design for Phase II and Phase III.

[0036] Detailed description

[0037] In one aspect, the present invention provides a novel method for treating or preventing COVID-19 or its symptoms or complications, or for preventing the onset of symptoms caused by SAR-CoV-2 infection in patients, using methylbardosorone and its analogues.

[0038] Methylbardoxolone and its analogues have demonstrated potent anti-inflammatory activity in vitro. Furthermore, bardoxolone and its analogues inhibited inflammation and tissue damage in animal models of acute lung injury and reduced mortality in systemic inflammation models. In addition to their anti-inflammatory and tissue-protective effects, methylbardoxolone and its analogues have been shown to possess potent antiviral activity. AKI is a serious complication of COVID-19 and frequently occurs in patients with severe symptoms. Methylbardoxolone has protected the kidneys in several animal models of CKD and AKI and improved renal function in patients with diabetes, Allport syndrome, ADPKD, IgAN, and FSGS. Therefore, collective data suggest that methylbardoxolone may reduce the excessive production of cytokines and chemokines and prevent ARDS and AKI in COVID-19 patients.

[0039] Some patients with moderate to severe COVID-19 develop symptoms rapidly, leading to serious complications such as ARDS, AKI, and multiple organ failure. The severity of COVID-19 and the occurrence of serious complications are associated with an imbalance in the immune system's response to infection and the excessive production of pro-inflammatory cytokines and chemokines. This article provides compounds that can be used to reduce pro-inflammatory cytokines and / or chemokines in patients infected with coronaviruses (e.g., β-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent acute respiratory distress syndrome in patients infected with coronaviruses (e.g., β-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent acute kidney injury in patients infected with coronaviruses (e.g., β-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent multiple organ failure in patients infected with coronaviruses (e.g., β-coronaviruses; e.g., SARS-CoV-2).

[0040] These and other aspects of the invention are described in more detail below.

[0041] I. SARS-CoV-2 and COVID-19

[0042] Coronavirus infections include infections caused by viruses of the genera α-coronavirus, β-coronavirus (including SARS-CoV, SARS-CoV-2, and MERS-CoV), γ-coronavirus, and δ-coronavirus. This disclosure provides compositions comprising compounds of this disclosure that can be used to treat coronavirus infections, and methods of treating these infections by administering the compounds to a patient infected with the viruses.

[0043] The World Health Organization (WHO) has declared the coronavirus disease 2019 (COVID-19) outbreak a pandemic. This virus is linked to other coronaviruses that caused the 2002 pandemic known as Severe Acute Respiratory Syndrome (SARS-CoV) and the 2012 pandemic known as Middle East Respiratory Syndrome (MERS-CoV). The virus that causes COVID-19 has been named SARS-CoV-2 because it shares nearly 80% of its genome with SARS-CoV.

[0044] Following viral infection, viral RNA is detected by pattern recognition receptors (PRRs). TLR3, TLR7, TLR8, and TLR9 sense viral RNA (and DNA) in the endosome. RIG-I, MDA5, and cGAS sense viral RNA (and DNA) in the cytoplasm. As part of the innate immune response, PRRs recruit adaptors (including TRIF, MAVS, and STING) and activate NF-κB and IRF3, leading to the production of type I interferon (IFNα / β) and a series of pro-inflammatory cytokines and chemokines. Innate and adaptive immune cells are recruited and activated, including CD8+. + Specific cytotoxic T cells, CD4 + Helper T cells and antigen-specific B cells. This adaptive immune response controls viral infection and determines clinical recovery.

[0045] Like SARS-CoV-1, SARS-CoV-2 (COVID-19) virus enters alveolar epithelial cells by binding to angiotensin-converting enzyme-2 (ACE-2), leading to the formation of endosomes and the release of viral RNA (Ahmadppor and Rostaing, 2020). Type I interferon inhibits viral replication and promotes T cell stimulation, differentiation, and proliferation, which leads to the killing of virus-infected cells. Highly pathogenic human coronaviruses typically encode viral proteins with the ability to antagonize the production of type I interferon (Fung et al., 2020; Sun et al., 2012; Chen et al., 2014). The exact mechanisms by which SARS-CoV-2 (COVID-19) may counteract host antiviral defenses remain to be elucidated (Fung et al., 2020). When the body fails to mount an adequate adaptive response to a virus, persistent, innately induced inflammation can subsequently lead to a cytokine storm, acute respiratory distress syndrome (ARDS) (Potey et al., 2019; Kellner et al., 2017), acute kidney injury (AKI), and multiple organ failure (Sarzi-Puttini, 2020; Huang, 2020; Chen, 2020; Guan, 2020). This article provides compounds that can be used to treat or prevent cytokine storms in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent acute respiratory distress syndrome in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent acute kidney injury in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent multiple organ failure in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2).

[0046] Mechanical lung ventilation is a standard treatment for patients with ARDS. However, mechanical ventilation itself can increase lung inflammation and worsen clinical condition due to ventilation-induced lung injury (VILI) (Kellner et al., 2017). The periodic stretching of the bronchial epithelium caused by mechanical ventilation increases the production of reactive oxygen species (ROS) (Chapman et al., 2005). The absence of Nrf2 (a key regulator of inflammation and oxidative stress) increases susceptibility to ventilation-induced lung injury, and Nrf2 activation has a protective effect in many lung injury models (Papaiahgari et al., 2017; Zhao et al., 2017). Therefore, while medically necessary, mechanical lung ventilation may exacerbate the production of cytokines and ROS, key characteristics of ARDS. This article provides compounds that can be used to reduce lung inflammation in patients infected with coronaviruses (e.g., β-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to induce Nrf2 activation in patients infected with coronaviruses (e.g., β-coronaviruses; e.g., SARS-CoV-2).

[0047] Regarding involvement of other organs, the SARS-CoV-2 cell receptor angiotensin-converting enzyme 2 (ACE2) is also present on cells of the heart, blood vessels, kidneys, neurocortex, and brainstem. Patients infected with SARS-CoV-2 have an increased incidence of thrombosis, heart attack, cardiac inflammation, stroke, seizures, encephalitis, and kidney damage (including acute kidney injury). The effects seen in various organs may stem from direct infection with SARS-CoV-2 or systemic complications of SARS-CoV-2 infection, such as inflammation. This article provides compounds that can be used to treat or prevent thrombosis in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent heart attack in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent cardiac inflammation in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent stroke in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent seizures in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent encephalitis in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent kidney injury (e.g., acute kidney injury) in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2).

[0048] Many complications of infectious diseases also involve dysregulation of the inflammatory response (e.g., cytokine storm). While the inflammatory response can kill invading pathogens, an excessive inflammatory response can also be quite destructive and, in some cases, a major source of damage in infected tissues. Furthermore, an excessive inflammatory response can lead to systemic complications due to the overproduction of inflammatory cytokines such as TNF-α and IL-1. Cytokine storms involve the overproduction of pro-inflammatory cytokines and chemokines, are associated with lung injury, and predict disease severity (Yang et al., 2020; Liu et al., 2020). Table 1 summarizes the cytokines found to be elevated in COVID-19. This article provides compounds that can be used to reduce or inhibit the production of inflammatory cytokines and / or chemokines in patients infected with coronaviruses (e.g., β-coronaviruses; e.g., SARS-CoV-2).

[0049] Table 1. Cytokines that are elevated in COVID-19

[0050]

[0051]

[0052] The Keap1-Nrf2 system rapidly responds to cellular stress by initiating a carefully designed genetic program that enhances cellular protective functions, including detoxification, antioxidant, and anti-inflammatory networks (Dinkova-Kostova, 2015). Methylbardoxolone and related analogues activate the Keap1-Nrf2 system, increasing the expression of antioxidant and cytoprotective genes and decreasing the expression of pro-inflammatory NF-κB target genes (Lee, 2009; Dinkova-Kostova, 2005; Rojas-Rivera, 2012; Osburn and Kensler, 2008). Consistent with this activity, methylbardoxolone and its analogues inhibit pro-inflammatory cytokines and chemokines and reduce oxidative stress in response to a variety of inflammatory triggers in many cell types (Chen, 2015; Thimmulappa, 2007; Pei, 2019; Nichols, 2009). Approximately 3,200 individuals have been exposed to methylbardoxolone in clinical trials, including studies in patients with cancer, chronic kidney disease (CKD), and pulmonary hypertension (PH).

[0053] The potent anti-inflammatory effects of methylbardoxolone in cultured cells have been translated into broad protective activity in animal models of acute lung injury and inflammation (Nichols, 2009; Chen, 2015; Pei, 2019; Reddy, 2009; Zhang, 2019; Nagashima, 2019; Kulkarni, 2013). Methylbardoxolone and its analogues significantly reduced neutrophil and macrophage infiltration and inhibited the levels of pro-inflammatory cytokines and chemokines in the lungs of mice treated with inflammatory stimuli (Nichols, 2009; Chen, 2015; Reddy, 2009). In these models, methylbardoxolone and its analogues also reduced pulmonary edema, decreased lung injury scores, prevented fibrosis, and improved lung function (Chen, 2015; Pei, 2019; Kulkarni, 2013). Methylbardoxolone and its analogues also reduce pro-inflammatory cytokines and chemokines, prevent organ damage (lung, liver, and pancreas), and increase survival in systemic inflammation models (Thimmulappa, 2006; Auletta, 2010; Osburn, 2008; Keleku-Lukwete, 2015; Robles, 2016). This article provides compounds that can be used to reduce neutrophil and / or macrophage infiltration in patients infected with coronaviruses (e.g., β-coronaviruses; e.g., SARS-CoV-2).

[0054] In addition to their anti-inflammatory and tissue-protective activities, methylbardoxolone and its analogues have been shown to inhibit viral replication, viral infection, viral gene transcription, and prevent reactivation of latent viruses in vitro (Vázquez, 2005; Shao, 2016; Chandra, 2018; Patra, 2019; Nio, 2019; Wyler, 2019; Rothan, 2019). Consistent with the mechanisms of action of these compounds, Nrf2 target heme oxygenase-1 (HO-1) has been shown to exhibit significant antiviral activity (Espinoza, 2017). This article provides compounds that can be used to inhibit viral replication in patients infected with coronaviruses (e.g., β-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to inhibit viral gene transcription in patients infected with coronaviruses (e.g., β-coronaviruses; e.g., SARS-CoV-2).

[0055] Finally, preclinical studies have confirmed that methylbardoxolone and its analogues protect kidney tissue, reduce inflammation, prevent fibrosis, and enhance kidney function in many different animal models of kidney disease, including: ischemia-reperfusion induced acute kidney injury (AKI) (Liu, 2014), chemically induced acute kidney injury (AKI) (Tanaka, 2008; Aleksunes, 2010; Wu, 2014), CKD associated with diabetes and / or obesity (Chin, 2013; Tan, 2014; Camer, 2016), CKD caused by nephron loss (Aminzadeh, 2013; Aminzadeh, 2014; Son, 2015), CKD caused by glomerulonephritis (Nagasu, 2019), autoimmune-related kidney disease (Wu, 2014), and hypertension-related kidney disease (Hisamichi, 2018). This article provides compounds that can be used to protect kidney tissue in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to increase kidney function in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent fibrosis in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to treat or prevent chronic kidney disease in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2).

[0056] Approximately 3200 individuals have been exposed to methylbardoxolone in clinical trials, including studies in healthy subjects and patients with cancer, pulmonary hypertension (PH), and various forms of chronic kidney disease (CKD). Methylbardoxolone has been shown to improve renal function in patients with CKD caused by diabetes, Allport syndrome, autosomal dominant polycystic kidney disease (ADPKD), IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), cancer, and pulmonary hypertension (PH), assessed using multiple measures, including measurements of inulin clearance, creatinine clearance, and estimated glomerular filtration rate (GFR) (Pergola, 2011; Pergola, 2019; de Zeeuw, 2013) (Table 2). The clinical activity of methylbardoxolone in various forms of CKD with different etiologies suggests that its anti-inflammatory and anti-fibrotic effects target the common final pathways contributing to GFR loss in multiple forms of CKD. This article provides compounds that can be used to increase measured inulin clearance in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to reduce serum creatinine levels in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2). This article provides compounds that can be used to increase estimated glomerular filtration rate in patients infected with coronaviruses (e.g., beta-coronaviruses; e.g., SARS-CoV-2).

[0057] Methylbardoxazoline was initially considered for development in cancer patients, and in two phase 1 studies, a decrease in serum creatinine levels was observed, corresponding to an increase in eGFR (Hong, 2012). The decrease in serum creatinine concentration and the resulting increase in eGFR were time-dependent and were observed in the majority (82%) of patients studied. In subsequent studies that enrolled over 2600 patients with type 2 diabetes and CKD, methylbardoxazoline has been shown to consistently produce clinically and statistically significant improvements in eGFR, lasting for at least one year in treated patients (Chin, 2018; Pergola, 2011). Changes in serum creatinine were not associated with a reduction in creatinine production (Chertow, 2018); improved renal function was demonstrated in a study of Japanese patients with type 2 diabetes, where GFR was measured using inulin clearance and estimated using the standard GFR estimation equation (Nangaku, 2020).

[0058] Table 2. Crossover study comparison of increased eGFR, inulin clearance, and creatinine clearance with methylbadoxazoline treatment

[0059]

[0060]

[0061] a Unless otherwise stated, data represent the mean change in eGFR relative to baseline in patients with methylbardosorone, and p-values ​​are calculated using a two-sided paired t-test comparing the change in eGFR to 0.

[0062] b The number of patients recruited in groups 1 and 2.

[0063] AKI has been reported in up to 28% of all patients and up to 72% of non-survivors in COVID-19 patients (Fanelli, 2020; Yang, 2020; Zhou, 2020; Naicker, 2020). Methylbardoxolone and its analogues have protected renal tissue, reduced inflammation, prevented fibrosis, and enhanced renal function in animal models of chronic kidney disease and AKI (Chin, 2013; Tanaka, 2008; Wu, 2011; Aminzadeh, 2013).

[0064] The property of increasing eGFR with methylbardoxazoline reflects its multiple protective and anti-inflammatory effects. The significant early improvement in eGFR within the first 4 weeks of methylbardoxazoline treatment may be attributed to the reversal of acute, dynamic inflammatory-mediated processes, such as endothelial dysfunction and glomerular mesangial cell contraction, leading to an increase in glomerular filtration surface area (Aminzadeh, 2013; Chin, 2018; Ding, 2013; Ferguson, 2010). This article provides compounds that can be used to treat or prevent endothelial dysfunction and / or conditions associated with endothelial dysfunction in patients infected with coronaviruses (e.g., β-coronaviruses; e.g., SARS-CoV-2).

[0065] II. Chemicals used to treat COVID-19 or its symptoms or complications, or to prevent the symptoms or complications of COVID-19. thing

[0066] In one aspect of this disclosure, a method of treating or alleviating symptoms of COVID-19 in a patient is provided, comprising administering to the patient a therapeutically effective amount of methylbardosolone, an analogue thereof, or a composition comprising methylbardosolone or an analogue thereof. Analogs of methylbardosolone include compounds of the following formula or pharmaceutically acceptable salts thereof:

[0067]

[0068] in:

[0069] R1 is -CN, halogen, -CF3, or -C(O)R a, where R a It is -OH, alkoxy (C1-4) -NH2, alkylamino (C1-4) or -NH-S(O)2-alkyl (C1-4) ;

[0070] R2 is either hydrogen or methyl;

[0071] R3 and R4 are each independently hydrogen, hydroxyl, methyl, or when any of these groups is combined with group R. c When connected together, it is defined as follows; and

[0072] Y is:

[0073] -H, -OH, -SH, -CN, -F, -CF3, -NH2, or -NCO;

[0074] alkyl (C≤8) cycloalkyl (C≤8) alkenyl (C≤8) , acetylenic (C≤8) aryl (C≤12) Aryl groups (C≤12) , heteroaryl (C≤8) heterocyclic alkyl (C≤12) alkoxy (C≤8) cycloalkoxy (C≤8) , aryloxy group (C≤12) acyloxy (C≤8) alkylamino (C≤8) cycloalkylamino (C≤8) Dialkylamino (C≤8) arylamino (C≤8) Arylamino (C≤8) alkyl thio (C≤8) Acyl thio group (C≤8) alkylsulfonylamino (C≤8) cycloalkylsulfonylamino (C≤8) Or a substituted form of any of these groups;

[0075] -Alkyl (C≤8) -R b ,-olefin dimethyl (C≤8) -R b Or a substituted form of any of these groups, wherein R b yes:

[0076] Hydrogen, hydroxyl, halogen, amino, or thiol; or

[0077] heteroaryl (C≤8) alkoxy (C≤8) cycloalkoxy (C≤8) alkenyloxy (C≤8) , aryloxy group (C≤8) arylalkoxy(C≤8) heteroaryloxy (C≤8) acyloxy (C≤8) alkylamino (C≤8) cycloalkylamino (C≤8) Dialkylamino (C≤8) arylamino (C≤8) Arylamino (C≤8) heteroarylamino (C≤8) alkylsulfonylamino (C≤8) cycloalkylsulfonylamino (C≤8) acylamino (C≤8) -OC(O)NH-alkyl (C≤8) Or a substituted form of any of these groups;

[0078] -(CH2) m C(O)R c Where m is 0-6 and R c yes:

[0079] Hydrogen, hydroxyl, halogen, amino, -NHOH, or thiol group; or

[0080] alkyl (C≤8) cycloalkyl (C≤8) alkenyl (C≤8) , acetylenic (C≤8) aryl (C≤8) Aryl groups (C≤8) , heteroaryl (C≤8) heterocyclic alkyl (C≤8) alkoxy (C≤8) cycloalkoxy (C≤8) alkenyloxy (C≤8) , aryloxy group (C≤8) arylalkoxy (C≤8) heteroaryloxy (C≤8) acyloxy (C≤8) alkylamino (C≤8) cycloalkylamino (C≤8) Dialkylamino (C≤8) arylamino (C≤8) alkylsulfonylamino (C≤8) cycloalkylsulfonylamino (C≤8) acylamino (C≤8) -NH-alkoxy (C≤8) -NH-heterocyclic alkyl (C≤8) -NH-acylamino (C≤8) Or a substituted form of any of these groups;

[0081] R c Together with R3, they form -O- or -NR. d -, where R d It is hydrogen or alkyl (C≤4) ;or

[0082] R c Together with R4, they form -O- or -NR. d -, where R d It is hydrogen or alkyl (C≤4) ;or

[0083] -NHC(O)R e , where R e yes:

[0084] Hydrogen, hydroxyl, amino; or

[0085] alkyl (C≤8) cycloalkyl (C≤8) alkenyl (C≤8) , acetylenic (C≤8) aryl (C≤8) Aryl groups (C≤8) , heteroaryl (C≤8) heterocyclic alkyl (C≤8) alkoxy (C≤8) cycloalkoxy (C≤8) , aryloxy group (C≤8) arylalkoxy (C≤8) heteroaryloxy (C≤8) acyloxy (C≤8) alkylamino (C≤8) cycloalkylamino (C≤8) Dialkylamino (C≤8) arylamino (C≤8) Or a substituted form of any of these groups.

[0086] These compounds are known as antioxidant modulators of inflammation. Their ability to activate Nrf2 has been demonstrated, as measured by increased expression of one or more Nrf2 target genes (e.g., NQO1 or HO-1; Dinkova-Kostova et al., 2005). Furthermore, these compounds are capable of indirectly and directly inhibiting pro-inflammatory transcription factors, including NF-κB and STAT3 (Ahmad et al., 2006; Ahmad et al., 2008). In some aspects, methods are provided for preventing the progression of COVID-19 or its symptoms or complications in subjects or patients in need, comprising administering methylbardoxolone or an analogue thereof to the subject or patient in an amount sufficient to prevent the progression of COVID-19 or its symptoms or complications. Additionally, one or more compounds described herein may be used in methods for preventing the onset of one or more symptoms of COVID-19 or for preventing the progression of COVID-19.

[0087] Triterpenoids, biosynthesized in plants via the cyclization of squalene, are used for medicinal purposes in many Asian countries; and some of them, such as ursolic acid and oleanolic acid, are known to have anti-inflammatory and anticancer properties (Huang et al., 1994; Nishino et al., 1988). However, the biological activity of these naturally occurring molecules is relatively weak, and therefore new analogs have been synthesized to enhance their potency (Honda et al., 1997; Honda et al., 1998). Continued efforts to improve the anti-inflammatory and anti-proliferative activities of oleanolic acid and ursolic acid analogs have led to the discovery of 2-cyano-3,12-dioxooleanolic-1,9(11)-diene-28-acid (CDDO) and related compounds (Honda et al., 1997, 1998, 1999, 2000a, 2000b, 2002; Suh et al., 1998; 1999; 2003; Place et al., 2003; Liby et al., 2005). Several potent oleanolic acid derivatives have been identified, including methyl-2-cyano-3,12-dioxooleanolic-1,9-diene-28-acid (CDDO-Me; RTA 402; methylbardoxolone). RTA402 is an antioxidant inflammatory modulator (AIM) that inhibits the induction of several important inflammatory mediators (such as iNOS, COX-2, TNFα, and IFNγ) in activated macrophages, thereby restoring redox homeostasis in inflamed tissues. RTA 402 has also been reported to activate the Keap1 / Nrf2 / ARE signaling pathway, leading to the production of several anti-inflammatory and antioxidant proteins such as heme oxygenase-1 (HO-1). It induces the cytoprotective transcription factor Nrf2 and inhibits the activity of pro-oxidative and pro-inflammatory transcription factors NF-κB and STAT3. In vivo, RTA 402 has demonstrated significant single-agent anti-inflammatory activity in several animal models of inflammation, such as kidney injury in a cisplatin model and acute kidney injury in an ischemia-reperfusion model. Furthermore, a significant reduction in serum creatinine has been observed in patients treated with RTA 402.

[0088] Therefore, in cases involving oxidative stress alone or oxidative stress exacerbated by inflammation, treatment may comprise administering to the subject or patient a therapeutically effective amount of the compounds of the present invention, such as those described above or throughout this specification. Treatment may be administered prophylactically prior to a predictable state of oxidative stress (e.g., in organ transplant recipients or cancer patients) or therapeutically in the context of established oxidative stress and inflammation.

[0089] Non-limiting examples of triterpenoid compounds that can be used according to the method of the present invention are shown herein.

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114] Table 3 summarizes the in vitro results for several of these compounds, in which RAW264.7 macrophages were pretreated with DMSO or different concentrations (nM) of the drug for 2 hours, followed by treatment with 20 ng / mL IFNγ for 24 hours. NO concentration in the culture medium was determined using the Griess reagent system; cell viability was determined using the WST-1 reagent. NQO1CD represents the concentration required to induce a two-fold increase in NQO1 (an Nrf2-regulated antioxidant enzyme) expression in Hepa1c1c7 mouse hepatocellular carcinoma cells (Dinkova-Kostova et al., 2005). All these results are several orders of magnitude higher than, for example, the activity of the parent oleanolic acid molecule. This is partly because the induction of antioxidant pathways induced by Nrf2 activation provides important protection against oxidative stress and inflammation; therefore, analogues of RTA 402 could also be used to treat COVID-19 or its symptoms or complications and / or prevent the onset of COVID-19 symptoms.

[0115] Table 3. Inhibition of IFNγ-induced NO production

[0116]

[0117] Unbound by theory, the potency of the compounds of this invention (e.g., RTA 402) derives primarily from the addition of α,β-unsaturated carbonyl groups. In in vitro assays, the introduction of dithiothreitol (DTT), N-acetylcysteine ​​(NAC), or glutathione (GSH) eliminates much of the compound's activity; the thiol-containing moiety interacts with the α,β-unsaturated carbonyl group (Wang et al., 2000; Ikeda et al., 2003; 2004; Shishodia et al., 2006). Biochemical assays have determined that RTA 402 directly interacts with and inhibits the activity of a key cysteine ​​residue (C179) on IKKβ (see below) (Shishodia et al., 2006; Ahmad et al., 2006). IKKβ controls NF-κB activation via a "classical" pathway involving phosphorylation-induced IκB degradation, leading to the release of NF-κB dimers into the nucleus. In macrophages, this pathway is responsible for producing a number of pro-inflammatory molecules in response to TNFα and other pro-inflammatory stimuli.

[0118] RTA 402 also inhibits the JAK / STAT signaling pathway at multiple levels. JAK proteins are recruited to transmembrane receptors (e.g., IL-6R) upon activation by ligands such as interferons and interleukins. JAK then phosphorylates the intracellular portion of the receptor, leading to the recruitment of STAT transcription factors. STAT is then phosphorylated by JAK, forming dimers, and translocates to the nucleus, where they activate the transcription of several genes involved in inflammation. RTA 402 inhibits constitutive and IL-6-induced STAT3 phosphorylation and dimer formation, and binds directly to cysteine ​​residues in the kinase domains of STAT3 (C259) and JAK1 (C1077). Biochemical assays have also determined that triterpenoids interact directly with key cysteine ​​residues on Keap1 (Dinkova-Kostova et al., 2005). Keap1 is an actin tethering protein that, under normal conditions, isolates the transcription factor Nrf2 in the cytoplasm (Kobayashi and Yamamoto, 2005). Oxidative stress leads to the oxidation of regulatory cysteine ​​residues on Keap1 and the release of Nrf2. Nrf2 then translocates to the nucleus and binds to antioxidant response elements (AREs), resulting in the transcriptional activation of numerous antioxidant and anti-inflammatory genes. Another target of the Keap1 / Nrf2 / ARE pathway is heme oxygenase 1 (HO-1). HO-1 breaks down heme into bilirubin and carbon monoxide and exerts many antioxidant and anti-inflammatory effects (Maines and Gibbs, 2005). HO-1 has recently been shown to be effectively induced by triterpenoids, including RTA 402 (Liby et al., 2005). RTA 402 and many structural analogs have also been shown to be effective inducers of expression of other stage 2 proteins (Yates et al., 2007). RTA 402 is a potent inhibitor of NF-κB activation. Furthermore, RTA 402 activates the Keap1 / Nrf2 / ARE pathway and induces HO-1 expression.

[0119] The compounds used can be prepared using the methods described in the following literature: Honda et al. (2000a); Honda et al. (2000b); Honda et al. (2002); and U.S. Patent Application Publications 2009 / 0326063, 2010 / 0056777, 2010 / 0048892, 2010 / 0048911, 2010 / 0041904, 2003 / 0232786, 2008 / 0261985, and 2010 / 0048887, all of which are incorporated herein by reference. These methods can be further modified and optimized using principles and techniques of organic chemistry applied by those skilled in the art. Such principles and techniques are taught, for example, in Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2013), which is incorporated herein by reference. Furthermore, using the principles and techniques of process chemistry applied by those skilled in the art, the synthetic methods can be further modified and optimized for preparation, pilot-scale, or large-scale production (batch or continuous). Such principles and techniques are taught, for example, in Anderson, Practical Process Research & Development - A Guide for Organic Chemists (2012), which is incorporated herein by reference.

[0120] The compounds of the present invention may contain one or more asymmetrically substituted carbon or nitrogen atoms and may be separable in optically active or racemic forms. Therefore, unless a specific stereochemical or isomer is specifically indicated, all chiral, diastereomeric, racemic, epimeric, and geometrical isomers of the chemical formula are intended. The compounds may exist as racemates and racemic mixtures, as single enantiomers, mixtures of diastereomers, and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral center of the compounds of the present invention may have an S or R configuration.

[0121] The chemical formula used to represent the compounds of this invention typically shows only one of several possible tautomers. For example, many types of ketone groups are known to exist in equilibrium with the corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is described for a given compound, and whichever is the most general, it means all tautomers of the given chemical formula.

[0122] Furthermore, the atoms constituting the compounds of this invention are intended to include all isotopic forms of such atoms. Isotopes as used herein include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include… 13 C and 14 C.

[0123] Polymorphic forms of the compounds of the present invention, such as forms A, B, C, D, and I-VI of CDDO-Me, can be used according to the method of the present invention. Form B exhibits unexpectedly better bioavailability than form A. Specifically, when monkeys were orally administered equivalent doses of the two forms in gelatin capsules, form B of CDDO-Me showed higher bioavailability than form A. See U.S. Patent Application Publication 2009 / 0048204, PCT Publication WO 2019014412, Chinese Patent Publication CN102887936, and Chinese Patent Publication CN 102875634, each of which is incorporated herein by reference in its entirety.

[0124] The "form A" of CDDO-Me (RTA 402) is unsolvable (non-hydrated) and can be characterized by a unique crystal structure with space group P43 212 (number 96). and The cell size of form A can be characterized by a filled structure in which three molecules are helically packed along the b-axis of the crystal. In some embodiments, form A can also be characterized by an X-ray powder diffraction (XRPD) pattern (CuKα) containing prominent diffraction peaks at approximately 8.8, 12.9, 13.4, 14.2, and 17.4°θ. In some variants, the X-ray powder diffraction of form A is essentially as shown in Figure 1A or Figure 1B.

[0125] Unlike Form A, "Form B" of CDDO-Me is a single phase, but lacks such a well-defined crystal structure. The Form B sample does not exhibit long-range molecular correlations, i.e., higher than approximately... Furthermore, thermal analysis of the form B sample revealed a glass transition temperature (Tg) in the range of approximately 120 °C to approximately 130 °C. g In contrast, disordered nanocrystalline materials did not exhibit T. g Only the melting temperature (T) is displayed. mAbove this temperature, the crystalline structure becomes liquid. Form B is represented by an XRPD pattern (Figure 1C) different from that of Form A (Figure 1A or Figure 1B). Because it lacks a defined crystalline structure, Form B also lacks distinctive XRPD peaks, such as those characteristic of Form A, and is instead characterized by a general "halo" XRPD pattern. Specifically, amorphous Form B belongs to the "X-ray amorphous" solid category because its XRPD pattern exhibits three or fewer primary diffraction halos. In this category, Form B is a "glassy" material.

[0126] Forms A and B of CDDO-Me can be readily prepared from various solutions of the compound. For example, form B can be prepared by rapid or slow evaporation in MTBE, THF, toluene, or ethyl acetate. Form A can be prepared in several ways, including by rapid evaporation, slow evaporation, or slow cooling of a solution of CDDO-Me in ethanol or methanol. The preparation of CDDO-Me in acetone can use rapid evaporation to produce form A or slow evaporation to produce form B.

[0127] Various characterization techniques can be used together to distinguish forms A and B of CDDO-Me from each other and from other forms of CDDO-Me. Examples of techniques suitable for this purpose are solid-state nuclear magnetic resonance (NMR), X-ray powder diffraction (compare Figures 1A and B with Figure 1C), X-ray crystallography, differential scanning calorimetry (DSC), dynamic vapor adsorption / desorption (DVS), Karl Fischer analysis (KF), hot-stage microscopy, modulated differential screening calorimetry, FT-IR, and Raman spectroscopy. Specifically, analysis of XRPD and DSC data can distinguish forms A, B, and the hemiphthalic ester forms of CDDO-Me. See U.S. Patent Application Publication 2009 / 0048204, which is incorporated herein by reference in its entirety.

[0128] Further details regarding the polymorphic forms of CDDO-Me are described in U.S. Patent Application Publication 2009 / 0048204, PCT Publication WO 2009 / 023232, PCT Publication WO 2010 / 093944, PCT Publication WO 2019014412, Chinese Patent Publication CN 102887936, and Chinese Patent Publication CN 102875634, all of which are incorporated herein by reference in their entirety.

[0129] Non-limiting specific formulations of the compounds disclosed herein include CDDO-Me polymer dispersions. See, for example, PCT Publication WO 2010 / 093944, which is incorporated herein by reference in its entirety. Some of the formulations reported therein exhibit higher bioavailability than micronized or nanocrystalline formulations of A. Furthermore, polymer dispersion-based formulations have shown a further remarkable improvement in oral bioavailability compared to micronized formulations of B. For example, the methacrylic acid copolymer, type C, and HPMC-P formulations showed the greatest bioavailability in monkey subjects.

[0130] The compounds used in the methods of this invention can also be in prodrug form. Because prodrugs enhance many desirable properties of drugs, such as solubility, bioavailability, and manufacturing processes, the compounds used in certain methods of this invention can be delivered in prodrug form if desired. Therefore, this invention covers prodrugs of the compounds of this invention and methods for delivering prodrugs. Prodrugs of the compounds used in this invention can be prepared by modifying functional groups present in the compounds in such a way that the modification is cleaved in conventional operation or in vivo to form the parent compound. Thus, prodrugs include, for example, compounds described herein in which a hydroxyl, amino, or carboxyl group is bonded to any group that, when administered to a subject or patient, cleaves to form a hydroxyl, amino, or carboxylic acid, respectively.

[0131] It should be understood that the specific anion or cation forming part of any salt of the present invention is not essential, as long as the salt as a whole is pharmacologically acceptable. Examples of pharmaceutically acceptable salts, along with their preparation and use, are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

[0132] In some embodiments, the compounds used in the methods described in the invention have the advantages of being more effective, less toxic, having a longer duration of action, being more potent, producing fewer side effects, being more easily absorbed, and / or having better pharmacokinetic properties (e.g., higher oral bioavailability and / or lower clearance) compared to compounds known in the prior art (whether for the indications described herein or otherwise), and / or having other useful pharmacological, physical, or chemical properties.

[0133] III. Drug Formulation and Administration

[0134] Given the potential toxicity of the drugs (if any), the administration of the compounds of the present invention to patients will follow general drug administration protocols. It is anticipated that treatment cycles will be repeated as necessary.

[0135] The compounds of the present invention can be administered by a variety of methods, such as oral administration or by injection (e.g., subcutaneous, intravenous, intraperitoneal, etc.). Depending on the route of administration, the active compounds may be coated with a material to protect them from acids and other natural conditions that may inactivate them. They can also be administered by continuous perfusion / infusion to the site of disease or injury. Specific examples of formulations, including polymer-based dispersions of CDDO-Me exhibiting improved oral bioavailability, are provided in U.S. Patent Application Publication No. 2009 / 0048204 (which is incorporated herein by reference in its entirety). Those skilled in the art will recognize that other manufacturing methods can be used to produce dispersions of the present invention having equivalent properties and utilities (see, Repka et al., 2002 and references cited therein). Such alternative methods include, but are not limited to, solvent evaporation, extrusion (such as hot melt extrusion), and other techniques.

[0136] To administer an active compound via a route other than parenteral administration, it may be necessary to coat the compound with a substance to prevent its inactivation, or to administer the compound co-administered with such a substance. For example, the active compound may be administered to the patient in a suitable carrier (e.g., liposomes or diluents). Pharmaceutically acceptable diluents include saline and buffered aqueous solutions. Liposomes include water-in-oil-in-water CGF emulsions and conventional liposomes.

[0137] Therapeutic compounds can also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. Dispersions can be prepared in, for example, glycerol, liquid polyethylene glycol, mixtures thereof, and in oils. Under normal storage and use conditions, these formulations may contain preservatives to prevent microbial growth.

[0138] Suitable pharmaceutical compositions for injection include sterile aqueous solutions (in the case of water solubility) or dispersions, as well as sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In all cases, the composition must be sterile and must be fluid to achieve ease of injection. It must be stable under preparation and storage conditions and must be preserved from contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Suitable fluidity can be maintained, for example, by using coatings such as lecithin, by maintaining the desired particle size (in the case of dispersions), and by using surfactants. Inhibition of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include isotonic agents in the composition, such as sugars, sodium chloride, or polyols such as mannitol and sorbitol. Extended absorption of injectable compositions can be achieved by including a delayed-absorption agent (e.g., aluminum monostearate or gelatin) in the composition.

[0139] Sterile injectable solutions can be prepared by incorporating a therapeutic compound in a desired amount into a suitable solvent, which, if desired, contains one or a combination of the components listed above, followed by sterile filtration. Dispersions are typically prepared by incorporating a therapeutic compound into a sterile carrier containing a base dispersion medium and any other desired components from those listed above. For sterile powders used to prepare sterile injectable solutions, preferred methods of preparation include vacuum drying and freeze-drying, which produce a powder containing the active ingredient (i.e., the therapeutic compound) plus any additional desired components from its previously sterile filtered solution.

[0140] Therapeutic compounds can be administered orally, for example, with an inert diluent or an absorbable, edible carrier. Therapeutic compounds and other ingredients can also be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or directly incorporated into the diet of the subject or patient. For oral therapeutic administration, the therapeutic compound can be incorporated with excipients and used in the form of ingestible tablets, sublingual tablets, lozenges, capsules, elixirs, suspensions, syrups, rice paper capsules, etc. The percentage of the therapeutic compound in the composition and formulation can, of course, vary. The amount of the therapeutic compound in the composition in which it is useful for such treatment results in a suitable dosage.

[0141] For ease of administration and dosage consistency, it is particularly advantageous to formulate parenteral compositions in unit dosage form. As used herein, “unit dosage form” refers to physically discrete units suitable as a unit dose to a subject or patient to be treated; each unit contains a predetermined amount of therapeutic compound, calculated to produce the desired therapeutic effect, in combination with the desired pharmaceutical carrier. The specifications of the unit dosage form of the present invention are determined by and directly depend on: (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations within the field of formulating such therapeutic compounds for the treatment of selected conditions in patients.

[0142] Therapeutic compounds can also be applied topically to the skin, eyes, or mucous membranes. Alternatively, if local delivery to the lungs is desired, the therapeutic compound can be administered by inhalation in the form of a dry powder or aerosol formulation.

[0143] Therapeutic compounds can be formulated in biocompatible matrices for use in drug-eluting stents.

[0144] In some implementations, the effective dose range of a therapeutic compound can be extrapolated from effective doses determined in animal studies on a variety of different animals. Typically, the human equivalent dose (HED) in mg / kg can be calculated using the following formula (see, for example, Reagan-Shaw et al., FASEB J., 22(3):659-661, 2008, which is incorporated herein by reference):

[0145] HED (mg / kg) = Animal dose (mg / kg) × (Animal K) m / personK m )

[0146] K m The use of factors in the transformation produces more accurate HED values, namely K. m The factor is based on body surface area (BSA) rather than just weight. K in humans and various animals... m The value is well-known. For example, an average person weighing 60kg has a BSA of 1.6m. 2 K m The value is 37, while for a 20kg child (BSA is 0.8m). 2 ) has 25 K m K in some relevant animal models m Also well known, including: mouse K m 3 (given a weight of 0.02 kg and a BSA of 0.007); Hamster K m 5 (given a weight of 0.08 kg and a BSA of 0.02); rat K m For 6 (given a weight of 0.15 kg and a BSA of 0.025) and monkey Km The value is 12 (given a weight of 3 kg and a BSA of 0.24).

[0147] The precise amount of a therapeutic composition depends on the judgment of the practitioner and is specific to each individual. Nevertheless, the calculated HED dosage can still provide general guidance. Other factors affecting dosage include the patient's physical and clinical condition, route of administration, intended treatment goals, and the potency, stability, and toxicity of the specific therapeutic agent.

[0148] The actual dose of the compound of the present invention or a composition containing the compound of the present invention administered to a subject or patient may depend on physical and physiological factors such as age, sex, weight, severity of the condition, type of disease being treated, prior or concurrent treatment interventions, idiopathic conditions of the subject or patient, and route of administration. These factors may be determined by a skilled technician. The practitioner responsible for administration will typically determine the concentration of the active ingredient in the composition and the appropriate dose for the individual subject or patient. In the event of any complications, a single physician may adjust the dose.

[0149] In some embodiments, the pharmaceutically effective amount is a daily dose from about 0.1 mg to about 500 mg of the compound. In some variations, the daily dose is from about 1 mg to about 300 mg of the compound. In some variations, the daily dose is from about 10 mg to about 200 mg of the compound. In some variations, the daily dose is about 25 mg of the compound. In other variations, the daily dose is about 75 mg of the compound. In still other variations, the daily dose is about 150 mg of the compound. In other variations, the daily dose is from about 0.1 mg to about 30 mg of the compound. In some variations, the daily dose is from about 0.5 mg to about 20 mg of the compound. In some variations, the daily dose is from about 1 mg to about 15 mg of the compound. In some variations, the daily dose is from about 1 mg to about 10 mg of the compound. In some variations, the daily dose is from about 1 mg to about 5 mg of the compound.

[0150] In some embodiments, the pharmaceutically effective amount is a daily dose of 0.01-25 mg compound / kg body weight. In some variations, the daily dose is 0.05-20 mg compound / kg body weight. In some variations, the daily dose is 0.1-10 mg compound / kg body weight. In some variations, the daily dose is 0.1-5 mg compound / kg body weight. In some variations, the daily dose is 0.1-2.5 mg compound / kg body weight.

[0151] In some embodiments, the pharmaceutically effective amount is a daily dose of 0.1-1000 mg compound / kg body weight. In some variations, the daily dose is 0.15-20 mg compound / kg body weight. In some variations, the daily dose is 0.20-10 mg compound / kg body weight. In some variations, the daily dose is 0.40-3 mg compound / kg body weight. In some variations, the daily dose is 0.50-9 mg compound / kg body weight. In some variations, the daily dose is 0.60-8 mg compound / kg body weight. In some variations, the daily dose is 0.70-7 mg compound / kg body weight. In some variations, the daily dose is 0.80-6 mg compound / kg body weight. In some variations, the daily dose is 0.90-5 mg compound / kg body weight. In some variations, the daily dose ranges from about 1 mg to about 5 mg compound / kg body weight.

[0152] Effective doses typically range from about 0.001 mg / kg to about 1,000 mg / kg, from about 0.01 mg / kg to about 750 mg / kg, from about 0.1 mg / kg to about 500 mg / kg, from about 0.2 mg / kg to about 250 mg / kg, from about 0.3 mg / kg to about 150 mg / kg, from about 0.3 mg / kg to about 100 mg / kg, from about 0.4 mg / kg to about 75 mg / kg, from about 0.5 mg / kg to about 50 mg / kg, and from about 0.6 mg / kg to about The dosage ranges from 30 mg / kg, from about 0.7 mg / kg to about 25 mg / kg, from about 0.8 mg / kg to about 15 mg / kg, from about 0.9 mg / kg to about 10 mg / kg, from about 1 mg / kg to about 5 mg / kg, from about 100 mg / kg to about 500 mg / kg, from about 1.0 mg / kg to about 250 mg / kg, or from about 10.0 mg / kg to about 150 mg / kg, with one or more doses administered daily for one or several days (depending on the administration pattern and the factors discussed above). Other suitable dosage ranges include mg to 10,000 mg per day, 100 mg to 10,000 mg per day, 500 mg to 10,000 mg per day, and 500 mg to 1,000 mg per day. In certain specific embodiments, the amount is less than 10,000 mg per day, having a range of, for example, 750 mg to 9,000 mg per day.

[0153] The effective dose can be less than 1 mg / kg / day, less than 500 mg / kg / day, less than 250 mg / kg / day, less than 100 mg / kg / day, less than 50 mg / kg / day, less than 25 mg / kg / day, less than 10 mg / kg / day, or less than 5 mg / kg / day. Alternatively, it can be in the range of 1 mg / kg / day to 200 mg / kg / day. For example, regarding the treatment of COVID-19 patients, the unit dose can be an amount that reduces urinary protein concentration by at least 40% compared to untreated subjects or patients. In another embodiment, the unit dose is an amount that reduces urinary protein concentration to within ±10% of the urinary protein level of healthy subjects or patients.

[0154] In other non-limiting examples, the dosage may also include, per administration, a range from about 1 microgram / kg / body weight, about 5 micrograms / kg / body weight, about 10 micrograms / kg / body weight, about 50 micrograms / kg / body weight, about 100 micrograms / kg / body weight, about 200 micrograms / kg / body weight, about 350 micrograms / kg / body weight, about 500 micrograms / kg / body weight, about 1 mg / kg / body weight, about 5 mg / kg / body weight, about 10 mg / kg / body weight, about 50 mg / kg / body weight, about 100 mg / kg / body weight, about 200 mg / kg / body weight, about 350 mg / kg / body weight, about 500 mg / kg / body weight to about 1000 mg / kg / body weight or more, and any range derived therefrom. In non-limiting examples of the ranges that can be derived from the figures listed herein, based on the figures above, a range of about 1 mg / kg / body weight to about 5 mg / kg / body weight, a range of about 5 mg / kg / body weight to about 100 mg / kg / body weight, a range of about 5 micrograms / kg / body weight to about 500 mg / kg / body weight, etc., can be administered.

[0155] In some embodiments, the pharmaceutical composition of the present invention may comprise, for example, at least about 0.1% of the compound of the present invention. In other embodiments, the compound of the present invention may comprise, for example, between about 2% and about 75% by weight, or between about 25% and about 60% by weight, and any range thereof.

[0156] Consider whether the reagent is administered in a single or multiple dose. Those skilled in the art can determine the desired time intervals for multiple dose deliveries using no more than routine experiments. As an example, two doses may be administered to a subject or patient daily at approximately 12-hour intervals. In some embodiments, the reagent is administered once daily.

[0157] The agent can be administered according to a regular schedule. A regular schedule, as used herein, refers to a predetermined, specified period of time. A regular schedule may cover the same period of time or periods of different lengths, as long as the schedule is predetermined. For example, a regular schedule may include administration twice daily, once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once weekly, once monthly, or any set number of days or weeks between. Alternatively, a predetermined regular schedule may include administration twice daily for the first week, followed by administration once daily for several months, etc. In other embodiments, the invention specifies that the agent can be administered orally, and the timing of administration may or may not depend on food intake. Thus, for example, the agent may be administered every morning and / or every evening, whether the subject or patient has eaten or is about to eat.

[0158] Non-limiting specific formulations include CDDO-Me polymer dispersions (see U.S. Patent Application Publication No. 2009 / 0048204, filed August 13, 2008, which is incorporated herein by reference). Some of the reported formulations exhibit higher bioavailability than micronized or nanocrystalline formulations of form A. Furthermore, polymer dispersion-based formulations have shown a further remarkable improvement in oral bioavailability compared to micronized formulation B. For example, the methacrylic acid copolymer, type C, and HPMC-P formulations showed the greatest bioavailability in tested monkeys.

[0159] IV. Combination Therapy

[0160] In addition to being used as a monotherapy, the compounds of the present invention can also be used in combination therapies. Effective combination therapies can be achieved with a single composition or pharmacological formulation comprising two agents, or with two different compositions or formulations administered simultaneously, wherein one composition comprises a compound of the present invention and the other composition comprises a second agent. Alternatively, the therapy can be administered before or after other agent treatments, at intervals ranging from minutes to months.

[0161] Various combinations can be used, such as when the compound of the present invention is "A" and "B" represents a second agent, and non-limiting examples are described below:

[0162] A / B / AB / A / BB / B / AA / A / BA / B / BB / A / AA / B / B / BB / A / B / B

[0163] B / B / B / AB / B / A / BA / A / B / BA / B / A / BA / B / B / AB / B / A / A

[0164] B / A / B / AB / A / A / BA / A / A / BB / A / A / AA / B / A / AA / A / B / A

[0165] Considering that other therapeutic agents can be used in combination with the treatment of the present invention, in some embodiments, the present invention contemplates the use of one or more other therapies for treating COVID-19, including the use of antiviral agents, antiplatelet drugs, anticoagulants, or steroids. In some embodiments, the present invention contemplates the use of one or more other therapies for treating COVID-19, including the use of SARS-CoV-2 protease inhibitors, antiplatelet drugs, anticoagulants, human type I interferon, corticosteroids, or remdesivir.

[0166] In some embodiments, the antiviral drug is baloxavir, chloroquine phosphate, favipiravir, viral protease inhibitors (e.g., lopinavir, atazanavir, darunavir, nelfinavir, ritonavir, saquinavir, telanavir), hydroxychloroquine, neuraminidase inhibitors (e.g., oseltamivir), remdesivir, GS-441524, GS-443902, SARS-CoV-2 specific monoclonal antibodies (e.g., casirivimab (REGN10933), imdevimab (REGN10987), bamlanivimab (LY-CoV555), etesevimab (LY-CoV016), VIR-7831 (GSK4182136), AZD7442, COVID-GUARD (STI-1499), COVI-AMG (STI-2020)) or umifenovir.

[0167] In some embodiments, the antiplatelet drug is aspirin, an ADP receptor antagonist (e.g., ticlopidine, clopidogrel, cangreloxol, prasugrel, ticagrelor, thienopyridine) or a glycoprotein IIb / IIIa receptor inhibitor (e.g., abciximab, epitubatide, ticofiban).

[0168] In some embodiments, the anticoagulant is rivaroxaban, apixaban, dipyridamole, cilostazol, atromentin, edoxaban, fondaparinux, betroxaban, letaxaban, eribaxaban, hirudin, thrombin inhibitors (e.g., lepirudine, disiludin, dabigatran, bivalirudin, cimetidine), argatroban, batroxobin, hementin, low molecular weight heparin, unlysaturated heparin, vitamin E or vitamin K antagonists (e.g., warfarin (cormidin), acenitroprusside, phenylpropanoidin, phenylindanedione).

[0169] Human type I interferons (IFNs) are a large class of interferon proteins that help regulate the activity of the immune system. Mammalian types are designated as IFN-α (alpha), IFN-β (beta), IFN-κ (kappa), IFN-δ (delta), IFN-ε (epsilon), IFN-τ (tau), IFN-ω (omega), and IFN-ζ (zeta, also known as limitin). Type I interferons have been shown to be effective against various viral replications, including Zika virus, chikungunya virus, flaviviruses, and hepatitis C virus. "Interferon compounds" include interferon-α, interferon-α analogs, interferon-α derivatives, interferon-α conjugates, interferon-β, interferon-β analogs, interferon-β derivatives, interferon-β conjugates, and mixtures thereof. The whole protein or fragments thereof can be fused with other peptides and proteins such as immunoglobulins and other cytokines. Interferon-α and interferon-β conjugates can represent, for example, compositions comprising interferon-β coupled to a non-naturally occurring polymer comprising a polyalkylene glycol moiety. Preferred interferon compounds include Alfacon-1, interferon-α, interferon-α analogs, pegylated interferon-α, polymerized interferon-α, dimerized interferon-α, carrier-conjugated interferon-α, interferon-α as an oral inhaler, interferon-α as an injectable composition, interferon-α as a topical composition analog, analog, analogues and analog, Analogs, Alfacon-1 analogs, interferon β, Avonex™, Betaseron™, Betaferon™, Rebif™, interferon-β analogs, pegylated interferon-β, polymerized interferon-β, dimerized interferon-β, carrier-conjugated interferon-β, interferon-β as an oral inhaler, interferon-β as an injectable composition, interferon-β as a topical composition, Avonex™ analogs, Betaseron™, Betaferon™ analogs, and Rebif™ analogs. Alternatively, agents that induce the production of interferon-α or interferon-β or mimic the effects of interferon-α or interferon-β may also be used. Interferon inducers include telotron, poly(I)-poly(C), imiquimod, cridanimod, and brompirimidine.

[0170] Other agents can be considered for use in combination with certain aspects of the present invention to improve therapeutic efficacy. These additional agents include antiviral agents, corticosteroids (e.g., dexamethasone, hydrocortisone, methylprednisolone, prednisone, budesonide), antirheumatic drugs (e.g., anaprost, baricitinib, sarilumab, tocilizumab), chloroquine, decitabine, hydroxychloroquine, remdesivir, favipiravir, lopinavir, ritonavir, ascorbic acid, macrolide antibiotics (e.g., azithromycin), colchicine, prostacyclin (e.g., eprostol, iloprost), interferon (e.g., IFNβ-1a, IFNβ-1b, pegylated interferon β-1a, IFNα, early...). IFNα-2b), nitric oxide, antitumor agents (e.g., sutuximab, ruxolitinib), sirolimus, vitamin D, zinc, ACE inhibitors, angiotensin II receptor blockers, anticoagulants, famotidine, fluvoxamine, HMG-CoA reductase inhibitors (e.g., statins), immunoglobulins (e.g., mixed plasma from adult blood, mixed plasma from individuals who have recovered from COVID-19), anthelmintics (e.g., ivermectin, niclosamide), nitrozole, nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, indomethacin), and thrombolytic agents (e.g., t-PA).

[0171] V. Characteristics of patients who may be excluded from methylbardoxolone treatment

[0172] Several clinical studies have confirmed that treatment with methylbardoxolone improves renal function (including estimated glomerular filtration rate or eGFR), insulin resistance, and markers of endothelial dysfunction (Pergola et al., 2011). Based on these observations, a large phase 3 trial of methylbardoxolone (BEACON) was initiated in patients with stage 4 CKD and type 2 diabetes. The primary endpoint of the BEACON trial was a composite measure of progression to end-stage renal disease (ESRD) and all-cause mortality. The trial was terminated due to excessive serious adverse events and mortality in the group of patients treated with methylbardoxolone.

[0173] As discussed below, subsequent analysis of the BEACON trial data revealed that most serious adverse events and deaths involved heart failure and were highly associated with the presence of one or more risk factors, including: (a) elevated baseline levels of B-type natriuretic peptide (BNP; e.g., >200 pg / mL); (b) baseline eGFR <20; (c) a history of left-sided heart disease; (d) a high baseline albumin-to-creatinine ratio (ACR; e.g., >300 mg / g, defined by 3+ macerated proteinuria); and (e) advanced age (e.g., >75 years). This analysis suggests that heart failure events may be associated with the occurrence of acute fluid overload during the first three to four weeks of methylbardoxolone treatment, and this may be due to inhibition of endothelial angiotensin-1 signaling in the kidneys. Previous trials of endothelial angiotensin receptor antagonists in stage 4 CKD patients were terminated due to a pattern of adverse events and deaths very similar to those observed in the BEACON trial. Subsequent nonclinical studies confirmed that methylbardoxolone, at physiologically relevant concentrations, inhibits the expression of endothelial angiotensin-1 in proximal renal tubular epithelial cells and suppresses the expression of endothelial angiotensin receptors in human glomerular mesangial cells and endothelial cells. Therefore, patients at risk of adverse events related to inhibition of endothelial angiotensin signaling may be excluded from future clinical use of methylbardoxolone.

[0174] This invention relates to novel methods for treating symptoms and complications of COVID-19, comprising altering the glomerular basement membrane as a key contributing factor. It also relates to the preparation of pharmaceutical compositions for treating such disorders. In certain embodiments of the invention, patients are selected for treatment based on several criteria: (1) a diagnosis of a disorder involving endothelial dysfunction as a key contributing factor; (2) the absence of elevated levels of B-type natriuretic peptide (BNP; e.g., BNP titer must be <200 pg / mL); (3) the absence of chronic kidney disease (e.g., eGFR >60) or advanced chronic kidney disease (e.g., eGFR >45); (4) the absence of a history of left-sided cardiomyopathy; and (5) the absence of high ACR (e.g., ACR <300 mg / g). In certain embodiments of the invention, patients diagnosed with type 2 diabetes are excluded. In certain embodiments of the invention, patients diagnosed with cancer are excluded. In certain embodiments, elderly patients (e.g., >75 years old) are excluded. In certain embodiments, patients are closely monitored for rapid weight gain (which suggests fluid overload). For example, patients can be instructed to weigh themselves daily for the first four weeks of treatment and to contact their prescribing physician if they observe an increase of more than five pounds.

[0175] This article provides compounds that can be used to treat coronavirus (e.g., β-coronavirus; e.g., SARS-CoV-2) infection in patients with no elevated baseline BNP levels (e.g., less than or equal to 200 pg / mL), and to treat or prevent its symptoms or complications. This article also provides compounds that can be used to treat patients with BNP levels greater than 20, greater than 25, greater than 30, greater than 35, greater than 40, greater than 45, greater than 50, greater than 55, or greater than 60 mL / min / 1.73 m 2 This article provides compounds that can be used to treat coronavirus (e.g., β-coronavirus; e.g., SARS-CoV-2) infection and to treat or prevent its symptoms or complications in patients with a baseline eGFR. This article also provides compounds that can be used to treat coronavirus (e.g., β-coronavirus; e.g., SARS-CoV-2) infection and to treat or prevent its symptoms or complications in patients with a low baseline albumin-to-creatinine ratio (e.g., less than or equal to 300 mg / g). This article further provides compounds that can be used to treat coronavirus (e.g., β-coronavirus; e.g., SARS-CoV-2) infection and to treat or prevent its symptoms or complications in patients without a history of left-sided cardiomyopathy.

[0176] A.BEACON Research

[0177] 1. Research Design

[0178] The study BEACON (402-C-0903), titled "Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: The Occurrence of Renal Events," was a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multinational, multicenter study designed to compare the potency and safety of bardoxolone (BARD) versus placebo (PBO) in patients with stage 4 chronic kidney disease and type 2 diabetes. A total of 2,185 patients were randomized 1:1 to either bardoxolone (20 mg) or placebo once daily. The primary efficacy endpoint was time to the first event in the composite endpoint, defined as end-stage renal disease (ESRD; requiring long-term dialysis, kidney transplantation, or kidney death) or cardiovascular (CV) death. The study had three secondary power endpoints: (1) estimated changes in glomerular filtration rate (eGFR); (2) time to first hospitalization due to heart failure or death due to heart failure; and (3) time to the first event of the composite endpoint, which consisted of nonfatal myocardial infarction, nonfatal stroke, hospitalization due to heart failure, or cardiovascular death.

[0179] A subset of BEACON patients consented to additional 24-hour assessments, including ambulatory blood pressure monitoring (ABPM) and 24-hour urine collection. An independent event adjudication committee (EAC), unaware of the study treatment allocation, evaluated whether renal, cardiovascular, and neurological events met the pre-defined definitions of the primary and secondary endpoints. An IDMC (comprised of external clinical experts supported by an independent statistical panel) reviewed the unblinded safety data throughout the study and provided recommendations as appropriate.

[0180] 2. Population demographics and baseline characteristics of the population

[0181] Table 4 presents summary statistics of selected demographic and baseline characteristics of patients recruited to BEACON. The demographic characteristics of the two treatment groups were comparable. In all pooled treatment groups, the mean age was 68.5 years, and 57% of patients were male. The methylbardosolone group had a slightly higher proportion of patients in the ≥75-year age subgroup compared to the placebo group (27% in the methylbardosolone group vs. 24% in the placebo group). The mean weight and BMI for the two treatment groups were 95.2 kg and 33.8 kg / m², respectively. 2Baseline renal function was roughly similar in both treatment groups; the mean baseline eGFR, measured by the 4-variable modified diet for kidney disease (MDRD) equation, was 22.5 mL / min / 1.73 mcg. 2 Furthermore, the geometric mean albumin / creatinine ratio (ACR) in the combined treatment group was 215.5 mg / g.

[0182] Table 4. Selected demographic and baseline characteristics of patients receiving methylbardoxazoline (BARD) versus placebo (PBO) in the BEACON (ITT population).

[0183]

[0184] Administer a placebo or 20 mg of methylbardoxolone to the patient once daily.

[0185] B.BEACON Results

[0186] 1. Effect of methylbardoxorubicin on eGFR

[0187] On average, patients treated with methylbardoxolone were expected to show an increase in eGFR at week 4 of treatment and maintain it above baseline until week 48. In contrast, patients treated with placebo, on average, showed no change or a slight decrease from baseline. The proportion of patients with a decrease in eGFR was significantly lower in methylbardoxolone compared to placebo. The eGFR trajectory and the proportion of patients with a decrease observed in BEAMON after one year of treatment were consistent with the simulated expectations and results from the BEAM study (RTA402-C-0804). As shown in Table 5, the number of patients experiencing serious adverse events (SAEs) of renal and urinary disorders was lower in the methylbardoxolone group than in the placebo group (52 vs. 71, respectively). Additionally, and as discussed below, slightly fewer ESRD events were observed in the methylbardoxolone group than in the placebo group. Overall, these data suggest that methylbardoxolone treatment does not cause a rapid or prolonged deterioration of renal status.

[0188] Table 5. Incidence of treatment-emergency serious adverse events in BEACON within each major system organ classification (safe population)

[0189]

[0190] The table only includes serious adverse events that occurred more than 30 days after the patient's last dose of the study drug. The column headers are the counts and the denominator is the number of patients in the safety population. Each patient is counted at most once in each system organ classification and preferred clause.

[0191] 2. Main synthesis results in BEACON

[0192] Table 6 provides a summary of the adjudicated primary endpoints that occurred on or before the study termination date (October 18, 2012). Although the number of ESRD events was slightly lower in the methylbardoxolone group compared to the placebo group, the number of composite primary endpoints was equal in both treatment groups (HR = 0.98) due to a slight increase in cardiovascular death events, as depicted in the graph of time to the first composite primary event analysis.

[0193] Table 6. Primary endpoints of methylbardoxolone (BARD) versus placebo (PBO) in the BEACON (ITT population)

[0194]

[0195] a Using a Cox proportional hazards model, with the treatment group, continuous baseline eGFR, and continuous baseline log ACR as covariates, the hazard ratio (methylbadoxolone / placebo) and 95% confidence interval (CI) were estimated. Breslow's method for handling event-time relationships was used.

[0196] b The treatment group comparison was performed using the type 3 chi-square test of SAS and two-tailed p-values ​​related to the treatment group variables in the Cox proportional hazards model.

[0197] C. Effects of methylbardoxazoline on heart failure and blood pressure

[0198] 1. Heart failure in the BEACON ruling

[0199] The data in Table 7 present a post-hoc analysis of the demographics and selected laboratory parameters of BEACON patients categorized by treatment group, as well as the occurrence of adjudicated heart failure events. The number of heart failure patients includes all events up to the last day of exposure (ITT group).

[0200] A comparison of baseline characteristics in patients with definitive heart failure events revealed that patients with heart failure treated with methylbardoxolone and those treated with placebo were more likely to have a history of cardiovascular disease and heart failure, and had higher baseline B-type natriuretic peptide (BNP) levels and Fredericia-corrected QTc intervals (QTcF). Despite the higher risk of heart failure in patients treated with methylbardoxolone, these data suggest that the development of heart failure in both groups appears to be associated with conventional risk factors for heart failure. Baseline ACR was significantly higher in patients with heart failure events treated with methylbardoxolone than in those without such events. Also noteworthy is the significant increase in mean baseline BNP levels in patients experiencing heart failure in both treatment groups, suggesting that these patients may have had fluid retention and subclinical heart failure prior to randomization.

[0201] Table 7. Selected demographic and baseline characteristics of patients receiving methylbardoxazoline as a result of heart failure status classification versus placebo.

[0202]

[0203] ap < 0.05, BARD patients with HF compared to BARD patients without HF

[0204] bp < 0.05, PBO patients with HF compared to PBO patients without HF

[0205] cp < 0.05, BARD relative to PBO patients with HF

[0206] 2. Assessment of clinical parameters associated with increased BNP

[0207] As a substitute for fluid retention, a post-hoc analysis was performed on a subset of patients for whom BNP data were available at baseline and week 24. Patients in the methylbardoxolone group experienced significantly greater increases in BNP compared to those in the placebo group (mean ± SD: 225 ± 598 vs. 34 ± 209 pg / mL, p < 0.01). It was also noted that at week 24, a higher proportion of patients treated with methylbardoxolone had increased BNP compared to those treated with placebo (Table 8).

[0208] The increase in BNP at week 24 appeared to be independent of baseline BNP, baseline eGFR, changes in eGFR, or changes in ACR. However, in patients treated with methylbardoxolone alone, baseline ACR was significantly correlated with changes in BNP at week 24 relative to baseline, suggesting that the tendency for fluid retention may be associated with the baseline severity of renal dysfunction as defined by albuminuria status, rather than with general changes in renal function as assessed by eGFR (Table 9).

[0209] Furthermore, these data suggest that the increase in eGFR originating from the glomerulus is anatomically different because sodium and water regulation occurs in the renal tubules.

[0210] Table 8. Analysis of BNP and eGFR values ​​of methylbardoxazoline patients relative to placebo patients, graded by changes in BNP from baseline at week 24.

[0211]

[0212] Post-hoc analysis of BNP changes in BEACON during week 24.

[0213] Table 9. Correlation between change in BNP relative to baseline and baseline ACR at week 24 in patients receiving methylbardoxolone versus placebo in BEACON.

[0214] treat N Correlation coefficient P-value PBO 216 0.05 0.5 BARD 211 0.20 <0.01

[0215] Post-hoc analysis of BNP changes at week 24 in BEACON. Only patients with baseline and week 24 BNP values ​​were included in the analysis.

[0216] 3. Serum electrolytes

[0217] For a subset of patients who underwent 24-hour urine collection, no clinically significant changes were found in serum potassium or sodium (Table 10). Changes in serum magnesium levels in patients treated with methylbardoxolone were consistent with changes observed in previous studies.

[0218] Table 10. Changes in serum electrolytes relative to baseline at week 4 in patients in the 24-hour ABPM sub-study of methylbardoxazoline versus placebo

[0219]

[0220]

[0221] Data only include BEACON patients recruited into the 24-hour ABPM sub-study. Changes in serum electrolyte values ​​were calculated only for patients with baseline and week 4 data. *p<0.05, week 4 relative to baseline within each treatment group; Changes in BARD patients relative to PBO patients at week 4

[0222] 4.24-hour urine collection

[0223] A subset of patients consented to additional 24-hour ambulatory blood pressure monitoring (ABPM) and 24-hour urine collection at selected visits (sub-study). Data on urinary sodium excretion from patients in the BEACON sub-study revealed clinically significant reductions in urine volume and sodium excretion at week 4 compared to baseline (Table 11). These reductions were significantly different from the week 4 changes in urine volume and urinary sodium observed in placebo-treated patients. It is also noteworthy that the decrease in serum magnesium was not associated with renal magnesium loss.

[0224] Furthermore, in a pharmacokinetic study (402-C-1102) of patients with type 2 diabetes and stage 3b / 4 CKD who received methylbardoxolone for 8 weeks, the reduction in urinary sodium and water excretion was significantly greater in stage 4 CKD patients than in stage 3b CKD patients (Table 12).

[0225] Table 11. Changes in 24-hour urine volume, urinary sodium, and urinary potassium relative to baseline in patients in the sub-study of methylbardoxolone versus placebo at week 4.

[0226]

[0227] Data include only BEACON patients recruited into the 24-hour ABPM sub-study. Changes at week 4 were calculated only for patients with baseline and week 4 data. *p<0.05, week 4 relative to baseline within each treatment group; Changes in BARD patients relative to PBO patients at week 4

[0228] Table 12. Changes in 24-hour urine volume and 24-hour urinary sodium relative to baseline at week 8 in patients treated with methylbardoxolone, grouped by CKD severity (from patient pharmacokinetic studies).

[0229]

[0230] Patients were treated with 20 mg of methylbardoxolone once daily for 56 consecutive days; follow-up was conducted on day 84 of the study. Data are mean values. Data include patients with baseline and week 8 data.

[0231] 5. Hospital records from the EAC adjudication package

[0232] The first predetermined post-baseline assessment in BEACON was at week 4. Because many heart failure events occur before week 4, the clinical database provides limited information to characterize these patients. EAC case packages of heart failure cases occurring before week 4 were reviewed post-hoc to evaluate the clinical, vital signs, laboratory, and imaging data collected at the time of the first heart failure event (Tables 13 and 14).

[0233] Examination of these records revealed a co-report of rapid weight gain immediately after randomization, dyspnea and orthopnea, peripheral edema, imaging evidence of central / pulmonary edema, elevated blood pressure and heart rate, and preserved ejection fraction. The data suggest that heart failure is caused by rapid fluid retention occurring simultaneously with preserved ejection fraction and elevated blood pressure. Preserved ejection fraction is consistent with the clinical features of heart failure arising from diastolic dysfunction stemming from ventricular sclerosis and impaired diastolic relaxation. This set of signs and symptoms clinically differs from heart failure with reduced ejection fraction, which occurs due to weakened cardiac pumping function or systolic impairment (Vasan et al., 1999). Therefore, rapid fluid accumulation in patients with stiff ventricles and minimal renal reserve may lead to increased fluid retention in the lungs and the aforementioned clinical manifestations.

[0234] Baseline central laboratory values ​​from clinical databases were compared with local laboratory values ​​obtained at admission for heart failure included in the EAC package. Invariant serum creatinine, sodium, and potassium concentrations in patients treated with methylbardoxazoline who experienced heart failure events within the first four weeks after randomization (Table 14) suggest that heart failure was not associated with acute renal deterioration or acute kidney injury. Overall, the clinical data suggest that the etiology of heart failure is not due to direct renal or cardiotoxic effects, but more likely due to sodium and fluid retention.

[0235] Table 13. Post-hoc analysis of cardiovascular parameters in patients receiving methylbardoxazoline versus placebo who experienced heart failure events within the first four weeks of treatment.

[0236]

[0237]

[0238] Post-hospital analysis of heart failure cases at BEACON. Vital signs at baseline were calculated from the mean of three standard cuff measurements. Vital signs from HF hospitalization were obtained from admission records included in the EAC adjudication package and represent a single assessment performed using different BP monitoring devices. LVEF was assessed only during HF hospitalization. HF admission timing was calculated from the event onset date and treatment onset date and varied between 0 and 4 weeks for each patient.

[0239] Table 14. Post-hoc analysis of serum electrolytes in patients receiving methylbardoxazoline versus placebo who experienced heart failure events within the four weeks prior to treatment.

[0240]

[0241] Post-hospital analysis of heart failure cases at BEACON. Baseline clinical chemistry was assessed at the central laboratory. Clinical chemistry from HF inpatients was obtained from hospital records included in the EAC adjudication package and represented assessments performed at different local laboratories.

[0242] 6. Blood pressure in BEACON

[0243] The mean changes in systolic and diastolic blood pressure relative to baseline were determined based on the average of three standardized blood pressure cuff measurements collected at each visit. Compared to the placebo group, the methylbardosolone group showed an increase in blood pressure, with a mean increase of 1.9 mmHg in systolic blood pressure and a mean increase of 1.4 mmHg in diastolic blood pressure observed prior to week 4 (the first assessment after randomization). By week 32, the increase in systolic blood pressure (SBP) appeared to have decreased, while the increase in diastolic blood pressure (DBP) persisted.

[0244] In ABPM measurements, patients treated with methylbardoxolone showed a more significant increase in SBP and DBP at week 4 compared to those treated with placebo. This difference in magnitude may be due to the different techniques used or differences in baseline characteristics among patients in the ABPM substudy. Patients in the ABPM substudy had higher baseline ACR than the general population. Regardless, the data suggest that methylbardoxolone increased blood pressure in the BEACON patient population.

[0245] 7. Blood pressure changes in previous CKD studies

[0246] In the label-disclosure, dose-range study (402-C-0902) of patients with type 2 diabetes and stage 3b-4 CKD, no dose-related trend or change in blood pressure was observed after 85 consecutive days of treatment with methylbardoxolone (an amorphous dispersion, as used in BEACON) ranging from 2.5 to 30 mg. Post-hoc analysis of blood pressure data by CKD stage classification suggested that blood pressure tended to increase relative to baseline in stage 4 CKD patients treated with methylbardoxolone, with the most significant effect observed in the three highest dose groups, while no significant change was observed in stage 3b CKD patients treated with methylbardoxolone (Table 15). Although the sample sizes of the dose groups by CKD stage classification were small, these data suggest that the effect of methylbardoxolone treatment on blood pressure may be related to CKD stage.

[0247] Blood pressure values ​​from the phase 2b study (BEAM, 402-C-0804) using methylbardoxolone (which used an early crystallized formulation of the drug and employed a titration design) varied considerably. Although increases were noted in some methylbardoxolone treatment groups, no significant dose-related trend in blood pressure was observed.

[0248] Table 15. Changes in systolic and diastolic blood pressure relative to baseline in patients with type 2 diabetes and stage 3b-4 CKD classified by baseline CKD stage who received methylbardoxazoline.

[0249]

[0250] Administer methylbardoxolone once daily at doses of 2.5, 5, 10, 15, or 30 mg for 85 days.

[0251] 8. Blood pressure and QTcF in healthy volunteers

[0252] Intensive blood pressure monitoring was employed in a separate, comprehensive QT study conducted in healthy volunteers. In two methylbardoxolone treatment groups, one receiving a therapeutic dose of 20 mg (also studied in BEACON) and the other a super-therapeutic dose of 80 mg, after 6 days of once-daily administration, the changes in blood pressure were not different from those observed in placebo-treated patients. Methylbardoxol did not increase QTcF as assessed by placebo-corrected QTcF change (ΔΔQTcF) after 6 days of treatment with 20 or 80 mg.

[0253] Methylbardoxolone has also been tested in non-CKD settings. In early clinical studies of methylbardoxolone in cancer patients (RTA402-C-0501, RTA402-C-0702), no mean change in blood pressure was observed in any treatment group after 21 consecutive days of treatment at doses ranging from 5 to 1300 mg / day (crystalline formulation). Similarly, in a randomized, placebo-controlled study in patients with hepatic impairment (RTA402-C-0701), 14 consecutive days of treatment with methylbardoxolone at doses of 5 and 25 mg / day (crystalline formulation) resulted in a mean decrease in systolic and diastolic blood pressure (Table 16).

[0254] Overall, these data suggest that methylbardoxolone does not prolong the QT interval or cause an increase in blood pressure in patients without baseline cardiovascular disease or stage 4 CKD.

[0255] Table 16. Changes in blood pressure relative to baseline in patients with hepatic dysfunction treated with methylbardoxazoline

[0256]

[0257] 9. Summary and analysis of heart failure

[0258] A comparison of baseline characteristics in patients with heart failure events showed that, although patients treated with methylbardoxolone had a higher risk of heart failure, both methylbardoxolone-treated and placebo-treated patients with heart failure were more likely to have a history of cardiovascular disease and heart failure, and on average, had higher baseline ACR, BNP, and QTcF. Therefore, the development of heart failure in these patients may be associated with traditional risk factors for heart failure. Furthermore, many patients with heart failure were in subclinical heart failure prior to randomization, as indicated by their high baseline BNP levels.

[0259] As an alternative to fluid retention after randomization, a post-hoc analysis was performed on a subset of patients with available BNP data. At week 24, the increase was significantly greater in patients treated with methylbardoxolone compared to those treated with placebo, and the increase in BNP in methylbardoxolone-treated patients was directly correlated with baseline ACR. Urinary sodium excretion data from the BEACON ABPM sub-study revealed that only in patients treated with methylbardoxolone did there be a clinically meaningful reduction in urine volume and sodium excretion relative to baseline at week 4. In another study, urinary sodium levels and water excretion were reduced in stage 4 CKD patients, but not in stage 3b CKD patients. In summary, these data suggest that methylbardoxolone has different effects on sodium and water management, with more pronounced retention in stage 4 CKD patients.

[0260] Consistent with this phenotype of fluid retention, a post-hoc review of narrative descriptions of heart failure events provided in admission records and anecdotal reports from researchers indicated that heart failure events in patients treated with methylbardoxolone often preceded a rapid increase in fluid weight and were not associated with acute renal or cardiac decompensation.

[0261] As measured by standardized blood pressure cuff monitoring in BEACON, the change in blood pressure (indicating total volume status) was also increased in the methylbardoxolone group relative to the placebo group. Pre-specified blood pressure analyses in studies of healthy volunteers showed no change in systolic or diastolic blood pressure. Although intention-to-treat (ITT) analyses of phase 2 CKD studies with methylbardoxolone showed no significant change in blood pressure, post-hoc analyses of these studies suggest that increases in both systolic and diastolic blood pressure depend on the stage of CKD. In conclusion, these data suggest that the effect of methylbardoxolone treatment on blood pressure may be related to the severity of CKD.

[0262] Therefore, urinary electrolytes, BNP, and blood pressure data collectively support the idea that methylbardoxolone treatment can affect volume status differently, with no clinically detectable effects in healthy volunteers or early-stage CKD patients, but potentially promoting fluid retention in patients with more advanced renal impairment and conventional risk factors associated with heart failure at baseline. The increase in eGFR is likely due to glomerular effects, while the effects on sodium and water regulation originate from the glomerulus. Since changes in eGFR are not associated with heart failure, these data suggest that the effects on eGFR, as well as sodium and water regulation, are anatomically and pharmacologically distinct.

[0263] No increased risk of heart failure or related adverse events was observed with methylbardoxolone in previous studies (Table 17). However, because previous studies of methylbardoxolone recruited 10-fold fewer patients, any increased risk, if present, might have gone undetected. Furthermore, BEACON limited recruitment to stage 4 CKD patients, a population known to have a higher risk of cardiovascular events compared to stage 3b CKD patients. Therefore, the advanced nature of kidney disease and the significant cardiovascular risk burden in the BEACON cohort (manifested as low baseline eGFR, high baseline ACR, and high baseline BNP levels, among other biomarkers) may be important factors contributing to the observed pattern of cardiovascular events.

[0264] To further examine the relationship between key endpoints in BEACON and clinically meaningful thresholds for traditional risk factors for fluid overload, an additional post-hoc analysis was performed. Various eligibility criteria associated with these risk factors were applied to exclude patients at the highest risk and to explore the final outcomes of BEACON. A combination of selected criteria was used, including exclusion of patients with an eGFR of 20 mL / min / 1.73 mcg. 2 Patients with lower or lower proteinuria levels, significantly elevated proteinuria levels, and those over 75 years of age or with BNP greater than 200 pg / mL eliminated the observed imbalance (Table 18). Applying these same criteria to SAE also significantly improved or eliminated the noted imbalance (Table 19). In summary, these findings suggest the utility of these and other renal and cardiovascular risk markers in the selection criteria for future clinical studies using methylbardoxolone.

[0265] Table 17. Treatment-emergency adverse events related to heart failure in major system organ categories (SOCs) observed in previous chronic kidney disease studies using methylbardoxazoline. 1 frequency

[0266]

[0267] In 402-C-0804, patients were given 25, 75, or 150 mg of methylbardoxolone (crystalline formulation) or placebo once daily for 52 weeks. In RTA402-C-0903, patients were given 2.5, 5, 10, 15, or 30 mg of methylbardoxolone (SDD formulation) once daily for 85 days.

[0268] 1 Adverse events with preferred terms that match the standardized MedDRA query for heart failure as outlined in the BEACON EAC charter (submission sequence number 133, dated February 2, 2012).

[0269] Table 18. Effects of excluding patients with selected baseline characteristics on primary endpoints, heart failure, and all-cause mortality in BEACON.

[0270]

[0271]

[0272] Post-hoc analysis of results in BEACON. Total number of patients with heart failure, all-cause, and cardiovascular death observed, and ESRD includes all events up to the last day of exposure (ITT population).

[0273] Table 19. Effect of excluding patients with selected baseline characteristics on treatment-emergency serious adverse events in major SOCs in the BEACON (ITT population)

[0274]

[0275] Post-hoc analysis of treatment-emergent serious adverse events in BEACON. Total events include only SAEs that began no more than 30 days after the patient's last dose of the study drug.

[0276] D. Potential mechanisms of fluid overload in BEACON

[0277] Data presented in the previous section suggest that methylbardoxazoline promotes fluid retention in the subset of patients at highest risk of heart failure, independent of drug administration. The data also suggest that these effects are not associated with acute or chronic kidney or cardiotoxicity. Therefore, a comprehensive list of well-defined renal mechanisms affecting volume status (Table 20) was explored to determine if any etiologies matched the clinical phenotypes observed with methylbardoxazoline.

[0278] Preliminary investigations focused on the potential activation of the renin-angiotensin-aldosterone system. Activation of this pathway, due to increased renal excretion, would decrease serum potassium. However, in the BEACON sub-study, methylbardoxazoline did not affect serum potassium and slightly decreased urinary potassium (Table 10).

[0279] Another potential mechanism for this study is whether changes in the transtubular ion gradient could lead to sodium and subsequent water reabsorption, since methylbardoxazoline affects serum magnesium and other electrolytes. However, this mechanism also involves potassium regulation, and baseline serum magnesium does not appear to be associated with fluid retention or hospitalization for heart failure.

[0280] After ruling out other causes listed in Table 19, inhibition of endothelial angiotensin signaling is the main remaining potential mechanism for volume regulation, consistent with the effects of methylbadoxazoline in BEACON. Therefore, extensive investigations into the regulation of the endothelial angiotensin pathway have been conducted as a potential explanation for the fluid retention observed in the BEACON study.

[0281] Table 20. Identified renal mechanisms affecting volumetric status

[0282]

[0283]

[0284] The mechanisms and characteristics of fluid retention.

[0285] 1. Regulation of the endothelial vasoconstrictor system

[0286] The most directly comparable clinical data for comparing the effects of known endothelial angiotensin pathway modulators on the BEACON study are those for the endothelial angiotensin receptor antagonist (ERA), avosentan. Avosentan was studied in stage 3–4 CKD patients with diabetic nephropathy in the ASCEND study, a large outcomes study used to assess the time to first doubling of serum creatinine, ESRD, or death (Mann et al., 2010). Although the baseline eGFR in this study was slightly higher than the mean baseline eGFR in BEACON, the mean ACR in patients in the ASCEND study was approximately seven times that in BEACON (Table 21). Therefore, the overall cardiovascular risk profile is likely similar between the two studies.

[0287] Similar to the BEACON study, the ASCEND study was terminated early due to hospitalization for heart failure and early imbalances in fluid overload events. Importantly, avosentan-induced fluid overload-related adverse events (both serious and non-serious) increased only during the first month of treatment.

[0288] Examination of key endpoints in the ASCEND study revealed an approximately three-fold increased risk of congestive heart failure (CHF), with a modest and non-significant increase in mortality. Furthermore, a small numerical reduction in ESRD events was observed. The BEACON study confirmed similar findings, although the incidence of heart failure events was lower. Nevertheless, the two studies showed striking similarities in clinical presentation and timing of heart failure, as well as in their effects on other key endpoints (Table 22).

[0289] Table 21. Selected demographic and baseline characteristics of patients in the Aschend* and Beacon (ITT population)

[0290]

[0291]

[0292] *Results from a randomized, double-blind, placebo-controlled trial of 1,392 patients with type 2 diabetes and significant kidney disease who received avosentan (25 or 50 mg) or placebo, along with sustained angiotensin-converting enzyme inhibition and / or angiotensin receptor blockade (ASCEND).

[0293] Table 22. Occurrence of death, end-stage renal disease, or heart failure in the Aschend and Beacon (ITT populations)

[0294]

[0295] The occurrence of CHF, death, and ESRD events adjudicated in ASCEND and BEACON. In ASCEND, for an event meeting the CHF criteria, the patient must have typical signs and / or symptoms of heart failure, have received new treatment for CHF, and have been hospitalized for at least 24 hours; ESRD is defined as requiring dialysis or kidney transplantation or eGFR <15 mL / min / 1.73 mcg. 2 The percentages for BEACON include all CHF and ESRD events up to the last contact date, as well as the total number of deaths at the time the database was locked (March 21, 2013). ESRD in BEACON is defined as requiring long-term dialysis, kidney transplantation, or kidney death; additional details and definitions of heart failure are outlined in the BEACON EAC bylaws. *p<0.05, relative to placebo.

[0296] 2. Mechanisms of endothelial angiotensin receptor antagonist-induced fluid overload

[0297] The role of endothelial angiotensin-constricting peptides (ET-1) in fluid overload has been extensively studied. Using knockout models in mice, researchers have demonstrated that salt attacks following acute disruption of the ET-1 pathway promote fluid overload. Specific knockouts of ET-1, ET-1 receptor type A (ETA), ET-1 receptor type B (ETB), or combinations of ETA and ETB have been shown to promote fluid overload in animals with clinical phenotypes consistent with ERA-mediated fluid overload in patients. These effects are induced by acute activation of epithelial sodium channels (ENaC), expressed in the collecting ducts of the kidneys, where they reabsorb sodium and promote fluid retention (Vachiery and Davenport, 2009).

[0298] 3. The relationship between plasma and urinary endothelial angiotensin-1 in humans.

[0299] The assessment of plasma and urinary levels of endothelial angiotensin-1 (ET-1) in humans has been previously reported, with eGFR values ​​ranging from stage 5 CKD to above-normal (8-131 mL / min / 1.73 mcg). 2 (Dhaun et al., 2009). Plasma levels were significantly negatively correlated with eGFR, but due to the moderate slope of the curve, significant differences in ET-1 were not apparent across the large eGFR range assessed. As an alternative to ET-1 production by the kidneys (which is the organ that produces the most ET-1), the fractional excretion of ET-1 was calculated by assessing plasma and urinary ET-1 levels. The range was from eGFR >100 to approximately 30 mL / min / 1.73 m 2 Urine levels remained relatively constant. However, in patients with stage 4 and 5 CKD, ET-1 levels appeared to increase exponentially with decreasing eGFR. These data suggest that renal ET-1 is primarily dysregulated in patients with advanced (stage 4 and 5) CKD. Based on these published data, the inventors hypothesize that the different effects of methylbardoxazoline on fluid management (if regulated by endothelial vasoconstrictor peptides) may be attributable to different endogenous production of ET-1 in the kidneys, which is significantly increased in patients with stage 4 and 5 CKD.

[0300] 4. Methylbardoxazoline regulates endothelial angiotensin signaling.

[0301] As mentioned above, methylbardoxazoline reduces ET-1 expression in human cell lines, including glomerular mesangial cells and endothelial cells found in the kidney. Furthermore, in vitro and in vivo data suggest that methylbardoxazoline and its analogues reduce ET-1 expression by inhibiting vasomotor ET-1. A Receptors and restoration of vasodilatory ET BNormal levels of receptors regulate the endothelial angiotensin pathway to promote a vasodilatory phenotype. Therefore, effective activation of Nrf2-related genes with methylbardoxolone is associated with inhibition of pathological endothelial angiotensin signaling and promotes vasodilation by modulating ET receptor expression.

[0302] The principle of E.BEACON termination

[0303] 1. Heart failure as determined by the ruling

[0304] Hospitalization due to heart failure or death due to heart failure was defined as a cardiovascular event adjudicated by EAC. The imbalance between adjudicated heart failure and related events was a major finding contributing to the early termination of BEACON. Furthermore, heart failure-related adverse events such as edema led to a higher-than-expected discontinuation rate. The overall imbalance in time to the first adjudicated heart failure appeared to stem primarily from events occurring within the first three to four weeks after treatment initiation. Kaplan-Meyer analysis indicated that after this initial phase, event rates appeared to maintain parallel trajectories between treatment groups. The pattern reflects that acute physiological effects, compared to cumulative toxic effects, prompted hospitalization for heart failure.

[0305] 2. Mortality rate

[0306] At the end of the study, more deaths occurred in the methylbardoxolone group than in the placebo group, and the relationship between mortality and heart failure was unclear. Most fatal outcomes (49 of 75 deaths) occurring before the clinical database closed (March 4, 2013) were confirmed to be cardiovascular in nature (29 methylbardoxolone patients vs. 20 placebo patients). Based on the pre-defined definitions outlined in the BEACON EAC charter, most cardiovascular deaths were classified as “cardiac death – no further specification.” At the time of the final analysis, Kaplan-Meier analysis of overall survival showed no significant dissociation before approximately week 24. Three fatal heart failure events occurred, all in patients treated with methylbardoxolone. Furthermore, as reflected in Table 16, a higher percentage of deaths occurred in patients over 75 years of age compared to those treated with placebo. Notably, if patients over 75 years of age were excluded, the number of fatal events in the methylbardoxolone group was 20 compared to 23 in the placebo group.

[0307] 3. Overview of other security data from BEACON

[0308] In addition to the effects of methylbardoxolone treatment on eGFR and renal SAEs, the number of hepatobiliary SAEs was reduced in the methylbardoxolone group compared to the placebo group (4 vs. 8, Table 5), and no cases of Hy's Law were observed. The number of vegetation-related SAEs was also balanced between the two groups. Finally, as assessed by ECG at week 24, methylbardoxolone treatment was not associated with QTc prolongation (Table 23).

[0309] Table 23. Changes in QTcF relative to baseline at week 24 in patients receiving methylbardoxazoline versus placebo in the BEACON (safe population)

[0310]

[0311] Data includes only ECG assessments collected at or before the patient's last dose of the study drug. The presentation was relative to the patient's first dose of the study drug.

[0312] F.BEACON's conclusion

[0313] In summary, inquiry into research data using methylbardoxolone revealed that the drug differentially modulates fluid retention, with no clinically detectable effects in healthy volunteers or early-stage CKD patients, while potentially pharmacologically promoting fluid retention in patients with advanced renal impairment. Since the occurrence of heart failure in patients treated with methylbardoxolone and those treated with placebo is associated with traditional risk factors for heart failure, this pharmacological effect in patients with baseline cardiac impairment may explain the increased risk of heart failure induced by methylbardoxolone treatment in BEACON. These data suggest that in future clinical studies, reducing the overall risk of heart failure by selecting patient populations with lower baseline risk of heart failure will avoid an increase in heart failure associated with methylbardoxolone treatment. Importantly, the available data indicate that fluid overload in BEACON is not caused by direct renal or cardiotoxicity. The clinical phenotype of fluid overload is similar to that observed with ERA in patients with advanced CKD, and preclinical data confirm that methylbardoxolone modulates the endothelial angiotensin pathway. Since acute disruption of the endothelial angiotensin pathway in advanced CKD patients is known to activate specific sodium channels (ENaC) that can promote acute sodium and volume retention (Schneider, 2007), these mechanistic data, along with clinical profiles of heart failure patients treated with methylbardoxolone, provide a reasonable hypothesis regarding the mechanism of fluid retention in BEACON. Because impaired renal function may be a significant factor contributing to a patient's inability to compensate for short-term fluid overload, and because the number of early CKD patients treated to date is relatively limited, excluding CKD patients from BARD and other AIM treatments (e.g., patients with GFR < 60) can be prudent and may be included as an element of this invention.

[0314] VI. Diagnostic tests

[0315] Measurement of AB-type natriuretic peptide (BNP) levels

[0316] B-type natriuretic peptide (BNP) is a 32-amino acid neurohormone synthesized in the ventricular myocardium and released into circulation in response to ventricular dilation and pressure overload. Functions of BNP include urinary sodium excretion, vasodilation, inhibition of the renin-angiotensin-aldosterone axis, and inhibition of sympathetic nerve activity. Plasma concentrations of BNP are elevated in patients with congestive heart failure (CHF) and increase proportionally to the degree of left ventricular dysfunction and the severity of CHF symptoms.

[0317] Skilled technicians are familiar with numerous methods and devices for measuring BNP levels in patient samples, including serum and plasma. For peptides such as BNP, immunoassay devices and methods are frequently used. See, for example, U.S. Patents 6,143,576, 6,113,855, 6,019,944, 5,985,579, 5,947,124, 5,939,272, 5,922,615, 5,885,527, 5,851,776, 5,824,799, 5,679,526, 5,525,524, and 5,480,792. These devices and methods can utilize labeled molecules in various sandwich, competitive, or non-competitive assay formats to generate a signal related to the presence or amount of the analyte of interest. Alternatively, certain methods and devices, such as biosensors and optical immunoassays, can be used to determine the presence or amount of an analyte without the need for labeled molecules. See, for example, U.S. Patents 5,631,170 and 5,955,377. In one particular embodiment, B-type natriuretic peptide (BNP) levels can be determined by a protein immunoassay as described in U.S. Patent Publication 2011 / 0201130, which is incorporated herein by reference in its entirety. Furthermore, numerous commercially available methods exist (e.g., Rawlins et al., 2005, which is incorporated herein by reference in its entirety).

[0318] B. Measurement of albumin / creatinine ratio (ACR)

[0319] Proteinuria is conventionally diagnosed through a simple immersion tablet test. Traditionally, the immersion tablet protein test is quantified by measuring the total amount of protein in a 24-hour urine collection test.

[0320] Alternatively, the concentration of protein in urine can be compared to the creatinine level in a spot urine sample. This is known as the protein / creatinine ratio (PCR). The UK Chronic Kidney Disease Guidelines (2005; incorporated herein by reference in its entirety) state that PCR is a better test than 24-hour urine protein measurement. Proteinuria is defined as a protein / creatinine ratio greater than 45 mg / mmol (which is equivalent to an albumin / creatinine ratio greater than 30 mg / mmol or approximately 300 mg / g, defined by 3+ macerated plate proteinuria), with very high levels of proteinuria defined by a PCR greater than 100 mg / mmol.

[0321] The results of a urine protein smear test should not be confused with the amount of protein detected on a microalbuminuria test, where microalbuminuria refers to the amount of protein in urine in mg / day, compared to the value of protein in a urine protein smear test in mg / dL. That is, a baseline level of proteinuria can be below 30 mg / day, which is considered non-pathological. Values ​​between 30 and 300 mg / day are called microalbuminuria and are considered pathological. A urine protein laboratory value of >30 mg / day corresponds to a detection level in the “trace” to “1+” range of a urine protein smear test. Therefore, any positive indication of protein detected on a urine protein smear test does not require a urine microalbuminuria test, as this exceeds the upper limit of microalbuminuria.

[0322] C. Measurement to estimate glomerular filtration rate (eGFR)

[0323] Numerous formulas have been designed to estimate GFR values ​​based on serum creatinine levels. These formulas are used to estimate creatinine clearance rate (eC). Cr A commonly used alternative biomarker for creatinine clearance is the Cockcroft-Gault (CG) formula, which estimates GFR in mL / min. It uses serum creatinine measurements and patient weight to predict creatinine clearance. The originally published formula was:

[0324]

[0325] The formula requires weight to be measured in kilograms and creatinine in mg / dL, consistent with US standards. If the patient is female, the resulting value is multiplied by a constant of 0.85. This formula is usable because it is simple to calculate and can often be performed without a calculator.

[0326] When serum creatinine is measured in μmol / L, then:

[0327]

[0328] The constant is 1.23 for males and 1.04 for females.

[0329] An interesting feature of the Cockcroft and Gault equations is that they show C Cr The estimation depends on age. The age term is (140 - age). This means that, for the same serum creatinine level, a 20-year-old (140 - 20 = 120) has twice the creatinine clearance of an 80-year-old (140 - 80 = 60). The CG equation assumes that, at the same serum creatinine level, women have a 15% lower creatinine clearance than men.

[0330] Alternatively, the eGFR value can be calculated using the Diet Improvement for Kidney Disease (MDRD) formula. The four-variable formula is as follows:

[0331] eGFR = 175 × standardized serum creatinine -1.154 ×age -0.203 ×C

[0332] For Black males, C was 1.212; for Black females, C was 0.899; and for non-Black females, C was 0.742. Serum creatinine values ​​were based on IDMS-traceable creatinine measurements (see below).

[0333] Chronic kidney disease is defined as a blood flow rate of less than 60 mL / min / 1.73 m³ / min. 2 The GFR exists for three months or longer.

[0334] D. Measurement of serum creatinine levels

[0335] The serum creatinine test measures the level of creatinine in the blood and provides an estimate of glomerular filtration rate. Serum creatinine values ​​in the BEACON and BEAM tests are based on isotope dilution mass spectrometry (IDMS) traceable creatinine determinations. Other commonly used methods for creatinine determination include (1) alkaline picrate methods (e.g., the Jaffe method [classical] and compensated [modified] Jaffe methods), (2) enzymatic methods, (3) high-performance liquid chromatography (HPLC), (4) gas chromatography (GC), and (5) liquid chromatography (LC). The IDMS method is widely considered the most accurate determination (Peake and Whiting, 2006, which are incorporated herein by reference in their entirety).

[0336] VII. Definition

[0337] When used in the context of chemical groups: "hydrogen" refers to -H; "hydroxyl" refers to -OH; "oxo" refers to =O; "carbonyl" refers to -C(=O)-; "carboxyl" refers to -C(=O)OH (also written as -COOH or -CO2H); "halogen" independently refers to -F, -Cl, -Br, or -I; "amino" refers to -NH2; "hydroxyamino" refers to -NHOH; "nitro" refers to -NO2; "imino" refers to =NH; "cyano" refers to -NH2; "hydroxyamino" refers to -NH2; "nitro" refers to -NO2; "imino" refers to =NH2; "cyano" refers to -NH2; "hydroxyamino" refers to -NH2; "oxoamino ...oxoamino" refers to -NH2; "oxoamino" refers to -NH2; "oxoamino" refers to -NH2; "oxoamino" refers to -NH2; "oxoamino" refers to -NH2; "oxoamino" refers to -NH2; "oxoamino" refers to - "-CN" refers to -CN; "isocyanate" refers to -N=C=O; "azide" refers to -N3; ​​in the context of monovalent, "phosphate ester" refers to -OP(O)(OH)2 or its deprotonated form; in the context of divalent, "phosphate ester" refers to -OP(O)(OH)O- or its deprotonated form; "thiol" refers to -SH; and "thio" refers to =S; "sulfonyl" refers to -S(O)2-; and "sulfinyl" refers to -S(O)-.

[0338] In the context of chemical formulas, the symbol "-" indicates a single bond, "=" indicates a double bond, and "≡" indicates a triple bond. Represents an optional key, which, if present, is either a single or double key. Symbol This represents a single or double bond. Therefore, the formula... Coverage, for example, Furthermore, it should be understood that no single ring atom forms part of more than one double bond. Additionally, it should be noted that when connecting one or two stereo atoms, the covalent bond symbol "-" does not indicate any preferred stereochemistry. Instead, it encompasses all stereoisomers and their mixtures. When drawn perpendicularly through the bond (e.g., for methyl groups), ),symbol This indicates the connection point of the group. It should be noted that this method is typically used only for larger groups to identify the connection point, to help the reader clearly identify it. (Symbol) This refers to a single bond, where the group attached to the thicker end of the wedge "comes out of the paper." (Symbol) This refers to a single bond, where the group attached to the thicker end of the wedge "enters the paper." (Symbol) This refers to a single bond, where the geometry (e.g., E or Z) around the double bond is undetermined. Therefore, both options and their combinations are contemplated. Any undefined valence on an atom in the structure shown in this application implicitly represents a hydrogen atom bonded to that atom. Bold dots on carbon atoms indicate that the hydrogen atom bonded to that carbon is facing outwards from the plane of the paper.

[0339] When a variable is described as a “floating group” in a ring system, for example, group “R” in the following formula:

[0340]

[0341] This variable can then substitute for any hydrogen atom attached to any ring atom, including depicted, implied, or explicitly defined hydrogens, as long as a stable structure is formed. When a variable is described as a "floating group" on a fused ring system, for example, group "R" in the following formula:

[0342]

[0343] This variable can substitute for any hydrogen atom bonded to any ring atom in the fused ring, unless otherwise specified. Substituted hydrogens include the depicted hydrogen (e.g., the hydrogen bonded to nitrogen in the above formula), implicit hydrogens (e.g., hydrogens not shown but understood to exist in the above formula), explicitly defined hydrogens, and optional hydrogens whose presence depends on the identity of the ring atom (e.g., the hydrogen bonded to group X when X equals -CH-), as long as a stable structure is formed. In the example shown, R can be located on a 5- or 6-membered ring in the fused ring system. In the above formula, the subscript letter "y" immediately following R in parentheses indicates a numerical variable. Unless otherwise specified, this variable can be any integer of 0, 1, 2, or greater than 2, limited only by the maximum number of substituted hydrogen atoms in the ring or ring system.

[0344] For chemical groups and compound categories, the number of carbon atoms in that group or category is indicated as follows: "Cn" defines the exact number (n) of carbon atoms in that group / category. "C≤n" defines the maximum number (n) of carbon atoms that can be in that group / category, while the minimum number is as small as possible for the group / category in question. For example, it should be understood that in the group "alkyl"... (C≤8) “Cycloalkyldiyl” (C≤8) "Miscellaneous aromatic compounds" (C≤8) "and "acyl" (C≤8) The minimum number of carbon atoms in the group "" is 1, and the number of carbon atoms in the group "alkenyl" is 1. (C≤8) "Alkyne" (C≤8) "and heterocyclic alkyl" (C≤8) The minimum number of carbon atoms in the group "" is 2, and the minimum number of carbon atoms in the group "cycloalkyl" is 2. (C≤8) The minimum number of carbon atoms in the group "" is 3, and the group "aryl" is... (C≤8) "and "aromatic dimethyl (C≤8) The minimum number of carbon atoms in the group is 6. "Cn-n′" defines the minimum number (n) and maximum number (n′) of carbon atoms in the group. Therefore, "alkyl" (C2-10) The term "C5 olefin" indicates alkyl groups having 2-10 carbon atoms. These carbon number indicators may precede or follow the chemical group or class they modify, and they may or may not be enclosed in parentheses without indicating any change in meaning. Thus, the terms "C5 olefin," "C5-olefin," and "olefin" are used interchangeably. (C5) "and "olefins" C5 "Substituted" is synonymous with "substituted". When any chemical group or class of compounds defined herein is modified by the term "substituted", any carbon atoms in the portion replacing a hydrogen atom are not counted. Therefore, a methoxyhexyl group having a total of seven carbon atoms is a substituted alkyl group. (C1-6) One example. Unless otherwise stated, any chemical group or class of compounds listed in the claims that does not have a carbon atom limit has a carbon atom limit of 12 or less.

[0345] When used to modify compounds or chemical groups, the term "saturated" means that the compound or chemical group does not have carbon-carbon double or triple bonds, unless otherwise specified below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted forms of saturated groups, one or more carbon-oxygen or carbon-nitrogen double bonds may be present. And when such bonds are present, the possibility of carbon-carbon double bonds appearing as part of keto-enol tautomerism or imine / enamine tautomerism is not excluded. When the term "saturated" is used to modify a solution of a substance, it means that no more of the substance can dissolve in the solution.

[0346] The term "aliphatic," used without the modifier "substituted," refers to a compound or chemical group that is acyclic or cyclic, but non-aromatic, hydrocarbon compound or group. In aliphatic compounds / groups, carbon atoms can be linked together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds / groups can be saturated, i.e., linked by a single carbon-carbon bond (alkane / alkyl), or unsaturated, having one or more carbon-carbon double bonds (alkene / alkenyl) or one or more carbon-carbon triple bonds (alkynyl / alkynyl).

[0347] The term "aromatic" when used to modify compounds or chemical groups refers to a planar unsaturated ring with atoms containing 4n+2 electrons in a fully conjugated cyclic π system.

[0348] The term "alkyl" used without the modifier "substituted" indicates a monovalent saturated aliphatic group with a carbon atom as a linker, having a straight-chain or branched acyclic structure, and containing no atoms other than carbon and hydrogen. Examples of alkyl groups include -CH3(Me), -CH2CH3(Et), -CH2CH2CH3(n-Pr or propyl), and -CH(CH3)2(i-Pr). i Pr or isopropyl), -CH2CH2CH2CH3(n-Bu), -CH(CH3)CH2CH3(sec-butyl), -CH2CH(CH3)2(isobutyl), -C(CH3)3(tert-butyl, tert-butyl, t-Bu or tBu) and -CH2C(CH3)3 (neopentyl) are non-limiting examples of alkyl groups. The term "alkyl dieryl" as used without the modifier "substituted" indicates a divalent saturated aliphatic group having one or two saturated carbon atoms as connecting points, having a straight-chain or branched acyclic structure, without carbon-carbon double or triple bonds, and without atoms other than carbon and hydrogen. The groups -CH2- (methylene), -CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2CH2- are non-limiting examples of alkyl dieryl groups. The term "alkylene" as used without the modifier "substituted" indicates a divalent group =CRR′, where R and R′ are independently hydrogen or alkyl. Non-limiting examples of alkylene groups include: =CH2, =CH(CH2CH3), and =C(CH3)2. "Alkane" indicates a class of compounds having the formula HR, where R is an alkyl group, as defined above. When any of these terms is used with the modifier “substituted”, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. The following groups are non-limiting examples of substituted alkyl groups: -CH2OH, -CH2Cl, -CF3, -CH2CN, -CH2C(O)OH, -CH2C(O)OCH3, -CH2C(O)NH2, -CH2C(O)CH3, -CH2OCH3, -CH2OC(O)CH3, -CH2NH2, -CH2N(CH3)2, and -CH2CH2Cl. The term "haloalkyl" is a subset of substituted alkyl groups in which hydrogen substitution is limited to halogens (i.e., -F, -Cl, -Br, or -I), such that no atoms other than carbon, hydrogen, and halogens exist. The group -CH2Cl is a non-limiting example of a haloalkyl group. The term "fluoroalkyl" is a subset of substituted alkyl groups in which hydrogen substitution is limited to fluorination, such that no atoms other than carbon, hydrogen, and fluorine exist. The groups -CH2F, -CF3, and -CH2CF3 are non-limiting examples of fluoroalkyl groups.

[0349] The term "cycloalkyl" as used without the modifier "substituted" refers to a monovalent saturated aliphatic group having a carbon atom as a connecting point, said carbon atom forming part of one or more non-aromatic ring structures, without carbon-carbon double or triple bonds, and without atoms other than carbon and hydrogen. Non-limiting examples include: -CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). The term as used herein does not exclude the presence of one or more alkyl groups (permitted by carbon number restrictions) connected to a carbon atom in a non-aromatic ring structure. The term "cycloalkyldiyl" as used without the modifier "substituted" refers to a divalent saturated aliphatic group having two carbon atoms as connecting points, without carbon-carbon double or triple bonds, and without atoms other than carbon and hydrogen. This is a non-limiting example of a cycloalkane dimethyl group. "Cycloalkane" signifies a class of compounds having the formula HR, where R is a cycloalkyl group, as defined above. When any of these terms is used with the modifier "substituted," one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[0350] The term "alkenyl," used without the modifier "substituted," refers to a monovalent unsaturated aliphatic group having carbon atoms as connecting points, a straight-chain or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH=CH2 (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH2CH=CH2 (allyl), -CH2CH=CHCH3, and -CH=CHCH=CH2. The term "alkene diel," used without the modifier "substituted," refers to a divalent unsaturated aliphatic group having two carbon atoms as connecting points, a straight-chain or branched, straight-chain or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond, and no atoms other than carbon and hydrogen. The groups -CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2-, and -CH2CH=CHCH2- are non-limiting examples of olefinic dimethyl groups. It should be noted that although olefinic dimethyl groups are aliphatic, once connected at both ends, it does not preclude the group from forming part of an aromatic structure. The terms "olefin" and "chain olefin" are synonymous and refer to a class of compounds having the formula HR, where R is an alkenyl group, as defined above. Similarly, the terms "terminal olefin" and "α-olefin" are synonymous and refer to an olefin having exactly one carbon-carbon double bond, where the bond is the vinyl portion at the end of the molecule. When any of these terms is used with the modifier "substituted," one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. The groups -CH=CHF, -CH=CHCl, and -CH=CHBr are non-limiting examples of substituted alkenyl groups.

[0351] The term "alkynyl" as used herein, without the modifier "substituted," refers to a monovalent unsaturated aliphatic group having a carbon atom as a connecting point, possessing a straight-chain or branched acyclic structure, at least one carbon-carbon triple bond, and having no atoms other than carbon and hydrogen. The term alkynyl as used herein does not exclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups -C≡CH, -C≡CCH3, and -CH2C≡CCH3 are non-limiting examples of alkynyl groups. "Alkyne" refers to a class of compounds having the formula HR, where R is an alkynyl group. When any of these terms is used with the modifier “substituted”, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[0352] The term "aryl," used without the modifier "substituted," refers to a monovalent unsaturated aromatic group having an aromatic carbon atom as a linker, said carbon atom forming part of one or more aromatic ring structures, each aromatic ring structure having six ring atoms, all of which are carbon, and said group not consisting of atoms other than carbon and hydrogen. If more than one ring is present, said ring can be fused or unfused. Unfused rings are connected by covalent bonds. The term aryl as used herein does not exclude the presence of one or more alkyl groups (carbon number restrictions allow) connected to the first aromatic ring or any other aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C6H4CH2CH3 (ethylphenyl), naphthyl, and monovalent groups derived from biphenyl (e.g., 4-phenylphenyl). The term "aromatic diel" as used without the modifier "substituted" refers to a divalent aromatic group having two aromatic carbon atoms as connecting points, said carbon atoms forming part of one or more six-membered aromatic ring structures, each aromatic ring structure having six ring atoms, all of which are carbon, and said divalent group not consisting of atoms other than carbon and hydrogen. The term aromatic diel as used herein does not exclude the presence of one or more alkyl groups (permitted by carbon number restrictions) connected to the first aromatic ring or any other present aromatic ring. If more than one ring is present, said ring can be fused or unfused. Unfused rings are connected by covalent bonds. Non-limiting examples of aromatic diel groups include:

[0353]

[0354] "Aromatic hydrocarbon" refers to a class of compounds having the formula HR, where R is an aryl group, as defined above. Benzene and toluene are non-limiting examples of aromatic hydrocarbons. When any of these terms is used with the modifier "substituted," one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[0355] The term "aralkyl" used without the "substituted" modifier indicates a monovalent group -alkanediyl-aryl, where the terms alkanediyl and aryl are used in a manner consistent with the definitions provided above. Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl. When the term aralkyl is used with the "substituted" modifier, one or more hydrogen atoms from the alkanediyl and / or aryl groups have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. Non-limiting examples of substituted aralkyl groups are: (3-chlorophenyl)-methyl and 2-chloro-2-phenyl-ethyl-1-yl.

[0356] The term "heteroaryl," used without the modifier "substituted," refers to a monovalent aromatic group having an aromatic carbon or nitrogen atom as a linker, said carbon or nitrogen atom forming part of one or more aromatic ring structures, each aromatic ring structure having 3-8 ring atoms, wherein at least one ring atom is nitrogen, oxygen, or sulfur, and said heteroaryl is not composed of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. If more than one ring is present, said ring can be fused or unfused. Unfused rings are connected by covalent bonds. The term heteroaryl as used herein does not exclude the presence of one or more alkyl or aryl groups (as permitted by carbon number restrictions) connected to an aromatic ring or aromatic ring system. Non-limiting examples of heteroaryl groups include furanyl, imidazolyl, indolyl, indazolyl (Im), isoxazolyl, methylpyridyl, oxazolyl, phenylpyridyl, pyridyl (pyridyl), pyrroleyl, pyrimidinyl, pyrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thiopheneyl, and triazolyl. The term "N-heteroaryl" refers to a heteroaryl group having a nitrogen atom as a connecting point. "Heteroaryl hydrocarbon" refers to a class of compounds having the formula HR, where R is a heteroaryl group. Pyridine and quinoline are non-limiting examples of heteroaryl hydrocarbons. When these terms are used with the modifier “substituted”, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[0357] The term "heterocyclic alkyl" as used without the modifier "substituted" refers to a monovalent non-aromatic group having a carbon or nitrogen atom as a linker, said carbon or nitrogen atom forming part of one or more non-aromatic ring structures, each non-aromatic ring structure having 3-8 ring atoms, wherein at least one ring atom is nitrogen, oxygen, or sulfur, and said heterocyclic alkyl is not composed of atoms other than carbon, hydrogen, nitrogen, oxygen, and sulfur. If more than one ring is present, said rings may be fused or unfused. The term as used herein does not exclude the presence of one or more alkyl groups (as permitted by carbon number restrictions) linked to a ring or ring system. Furthermore, the term does not exclude the presence of one or more double bonds in a ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocyclic alkyl groups include azirropropyl, azirrobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, pyranyl, oxacyclopropyl, and oxacyclobutyl. The term "N-heterocyclic alkyl" indicates a heterocyclic alkyl group having a nitrogen atom as a connecting point. N-pyrrolidinyl is an example of such a group. When these terms are used with the modifier "substituted", one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[0358] The term "acyl" used without the modifier "substituted" indicates the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, or aryl, as defined above. The groups -CHO, -C(O)CH3 (acetyl, Ac), -C(O)CH2CH3, -C(O)CH(CH3)2, -C(O)CH(CH2)2, -C(O)C6H5, and -C(O)C6H4CH3 are non-limiting examples of acyl groups. "Thioacyl" is defined similarly, but the oxygen atom in the group -C(O)R has been replaced with a sulfur atom, -C(S)R. The term "aldehyde" corresponds to an alkyl group as defined above attached to the -CHO group. When any of these terms is used with the modifier “substituted”, one or more hydrogen atoms (including hydrogen atoms directly attached to carbon atoms of the carbonyl or thiocarbonyl groups, if any) have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. The groups -C(O)CH2CF3, -CO2H (carboxyl), -CO2CH3 (methylcarboxyl), -CO2CH2CH3, -C(O)NH2 (carbamoyl), and -CON(CH3)2 are non-limiting examples of substituted acyl groups.

[0359] The term "alkoxy" used without the modifier "substituted" indicates a group -OR, where R is an alkyl group, as defined above. Non-limiting examples include: -OCH3 (methoxy), -OCH2CH3 (ethoxy), -OCH2CH2CH3, -OCH(CH3)2 (isopropoxy), or -OC(CH3)3 (tert-butoxy). The terms "cycloalkoxy," "alkenyloxy," "alkynyloxy," "aryloxy," "arylalkoxy," "heteroaryloxy," "heterocycloalkoxy," and "acyloxy" used without the modifier "substituted" indicate a group defined as -OR, where R is cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The terms "alkylthio" and "acylthio" used without the modifier "substituted" indicate a group -SR, where R is alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane as defined above, where at least one hydrogen atom has been replaced by a hydroxyl group. The term "ether" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been replaced with an alkoxy group. When any of these terms is used with the modifier "substituted," one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[0360] The term "alkylamino" used without the modifier "substituted" indicates the group -NHR, where R is an alkyl group, as defined above. Non-limiting examples include -NHCH3 and -NHCH2CH3. The term "dialkylamino" used without the modifier "substituted" indicates the group -NRR′, where R and R′ can be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include -N(CH3)2 and -N(CH3)(CH2CH3). The terms "cycloalkylamino," "alkenylamino," "alkynylamino," "arylamino," "aralkylamino," "heteroarylamino," "heterocyclic alkylamino," "alkoxyamino," "alkylsulfonylamino," or "cycloalkylsulfonylamino" used without the modifier "substituted" indicate a group defined as -NHR, where R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclic alkyl, alkoxy, alkylsulfonyl, and cycloalkylsulfonyl, respectively. A non-limiting example of an arylamino group is -NHC6H5. The term "acylamino" (acylamino) used without the "substituted" modifier indicates the group -NHR, where R is an acyl group, as defined above. A non-limiting example of an acylamino group is -NHC(O)CH3. When any of these terms is used with the "substituted" modifier, one or more hydrogen atoms attached to the carbon atom have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. The groups -NHC(O)OCH3 and -NHC(O)NHCH3 are non-limiting examples of substituted amide groups.

[0361] The terms "alkylsulfonyl" and "alkylsulfinyl" used without the modifier "substituted" represent the groups -S(O)₂R and -S(O)R, respectively, where R is an alkyl group, as defined above. The terms "cycloalkylsulfonyl," "alkenylsulfonyl," "alkynylsulfonyl," "arylsulfonyl," "aralkylsulfonyl," "heteroarylsulfonyl," and "heterocyclic alkylsulfonyl" are defined in a similar manner. When any of these terms is used with the modifier “substituted”, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[0362] When used in conjunction with the term "comprising" in the claims and / or description, the use of the words "a" or "a kind" can mean "a / kind", but it is also consistent with the meaning of "a / kind or more / kinds", "at least one / kind" and "a / kind or more than one / kind".

[0363] Throughout this application, the term "about" is used to indicate that a value includes inherent variations in apparatus error, variations in the method used to determine the value, or variations present in study subjects or patients. When used in the context of X-ray powder diffraction, the term "about" indicates a value that differs from the reported value by ±0.2°2θ, preferably ±0.1°2θ. When used in the context of differential scanning calorimetry or glass transition temperature, the term "about" indicates a value relative to the maximum value of the peak by ±10°C, preferably ±2°C. When used in other contexts, the term "about" indicates a value that is ±10% of the reported value, preferably ±5%. It should be understood that whenever the term "about" is used, it also includes a specific reference to the exact numerical value shown.

[0364] "Active ingredient" (AI) (also known as active compound, active substance, active agent, pharmaceutical reagent, pharmaceutical preparation, bioactive molecule, or therapeutic compound) is a biologically active ingredient in a pharmaceutical or pesticide formulation. Similar terms such as active pharmaceutical ingredient (API) and bulk active substance are also used in pharmaceuticals, and the term active substance can be used in pesticide formulations.

[0365] The average molecular weight used in this article refers to the weight-average molecular weight (Mw) determined by static light scattering.

[0366] The terms “comprises,” “has,” and “includes” are open-ended copulas. Any form or tense of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes,” and “including,” is also open-ended. For example, any method that “comprises,” “has,” or “includes” one or more steps is not limited to having only those steps, but also covers other steps not listed.

[0367] When used in this specification and / or claims, the term "effective" means sufficient to achieve the desired, anticipated, or desired result. When used in the context of treating a patient or subject with a compound, "effective amount," "therapeutic effective amount," or "pharmaceutical effective amount" means an amount of compound that, when administered to a patient or subject for the treatment or prevention of a disease, is sufficient to achieve the treatment or prevention of said disease. In one particular embodiment, the measure of effective treatment is a reduction in urinary protein concentration to less than 300 mg / dL. In a preferred embodiment, the treatment is sufficient to reduce urinary protein concentration to less than 100 mg / dL, or in a more preferred embodiment, less than 30 mg / dL. When the presence of blood is used as a marker of treatment effectiveness, effective treatment results in the absence of visible blood in the urine, although microscopic blood may still be present. In a preferred embodiment, effective treatment results in the absence of any blood, including microscopic blood visible only by a microscope or urinalysis. Finally, effective treatment will produce an improvement in glomerular filtration rate. Several different methods can be used to estimate glomerular filtration rate using creatinine, including the Cockcroft-Gault formula, the Diet Improvement for Kidney Disease (MDRD) formula, the Collaborative Epidemiological Study of Chronic Kidney Disease (CKD-EPI) formula, the Mayo quadratic formula, or the Schwartz formula. Generally, the Schwartz formula can be used for children under 12 years of age. These methods are further described in detail in the foregoing sections and in the following examples. For example, effective treatment can produce a glomerular filtration rate greater than 60 mL / min / 1.73 mcg. 2 The glomerular filtration rate (or estimated glomerular filtration rate). More preferably, effective treatment can produce a glomerular filtration rate greater than 90 mL / min / 1.73 m 2 Glomerular filtration rate.

[0368] "Excipients" are pharmaceutically acceptable substances formulated with the active ingredient of a drug, pharmaceutical composition, formulation, or drug delivery system. Excipients can be used to stabilize a composition, increase its size (and are therefore often referred to as "increasers," "fillers," or "diluents" when used for this purpose), or impart therapeutic enhancements to the active ingredient in the final dosage form, such as promoting drug absorption, reducing viscosity, or increasing solubility. Excipients include pharmaceutically acceptable forms of anti-sticking agents, binders, coating agents, pigments, disintegrants, flavoring agents, flow aids, lubricants, preservatives, adsorbents, sweeteners, and mediators. The primary excipient that acts as a medium for transporting the active ingredient is often referred to as the mediator. Excipients can also be used in the manufacturing process, for example, to assist in the handling of the active substance, such as by promoting powder flowability or non-stick properties, and to assist in in vitro stability, such as preventing denaturation or aggregation during the expected shelf life. The suitability of excipients often varies depending on the route of administration, dosage form, active ingredient, and other factors.

[0369] When used as a modifier for a compound, the term "hydrate" means that the compound has fewer than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water molecules bound to each compound molecule (such as the solid form of the compound).

[0370] The term "IC" as used in this article 50 "Indicates the amount of inhibitor required to achieve 50% of the maximum response. This quantitative measure indicates the amount of a specific drug or other substance (inhibitor) required to inhibit a given biological, biochemical, or chemical process (or a component of the process, i.e., enzyme, cell, cell receptor, or microorganism) by half."

[0371] An "isomer" of the first compound is a separate compound in which each molecule contains the same component atoms as the first compound, but the three-dimensional configuration of those atoms is different.

[0372] As used herein, the terms "patient" or "subject" refer to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or a transgenic species thereof. In some embodiments, the patient or subject is a primate. Non-limiting examples of human patients include adults, adolescents, infants, and fetuses.

[0373] The term “pharmaceutically acceptable” as used in this article generally means a compound, material, composition, and / or dosage form that is suitable, within reasonable medical judgment, for contact with human and animal tissues, organs, and / or body fluids without excessive toxicity, irritation, allergic response, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0374] "Pharmaceutically acceptable salt" means a salt of the compounds of the present invention that are pharmaceutically acceptable as defined above and have the desired pharmacological activity. Non-limiting examples of such salts include acid addition salts formed with: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4′-methylenebis(3-hydroxy-2-en-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-en-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, etc. Acids, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfate, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, and trimethylacetic acid. Pharmaceutically acceptable salts also include base addition salts that can be formed when the acidic protons are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Non-limiting examples of acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylreduced glucosamine. It should be understood that the specific anion or cation forming part of any salt of the present invention is not essential, as long as the salt as a whole is pharmacologically acceptable. Other examples of pharmaceutically acceptable salts and their preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (edited by P.H.Stahl and C.G.Wermuth, Verlag Helvetica Chimica Acta, 2002).

[0375] A pharmaceutically acceptable carrier, a drug carrier, or simply a carrier, is a pharmaceutically acceptable substance formulated with an active pharmaceutical ingredient (API) that participates in the transport, delivery, and / or transport of chemical reagents. Drug carriers can be used to improve drug delivery and efficacy, including, for example, controlled-release technologies to modulate drug bioavailability, reduce drug metabolism, and / or reduce drug toxicity. Some drug carriers may improve the effectiveness of drug delivery to specific target sites. Examples of carriers include: liposomes, microspheres (e.g., made of poly(lactic-co-glycolic acid)), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, erythrocytes, virions, and dendritic polymers.

[0376] "Pharmaceutical drugs" (also known as medicines, pharmaceutical reagents, pharmaceutical products, pharmaceutical compositions, pharmaceutical preparations, pharmaceutical products, medical products, pharmaceuticals, medicaments, drugs, or simply medicines) are medicines used to diagnose, cure, treat, or prevent disease. An active ingredient (AI) (defined above) is a biologically active component in a pharmaceutical drug or pesticide. Similar terms such as active pharmaceutical ingredient (API) and bulk active substance are also used in pharmaceuticals, and the term active substance can be used in pesticide formulations. Some pharmaceutical preparations and pesticide products may contain more than one active ingredient. Unlike active ingredients, inactive ingredients are often referred to as excipients (defined above) in the context of pharmaceuticals.

[0377] "Prevention" or "avoidance" includes: (1) suppressing the onset of a disease in a subject or patient who may be at risk of and / or susceptible to the disease but has not yet experienced or exhibited any or all symptoms of the disease; and / or (2) slowing the onset of symptoms of a disease in a subject or patient who may be at risk of and / or susceptible to the disease but has not yet experienced or exhibited any or all symptoms of the disease.

[0378] "Prodrug" refers to a compound that can be metabolized in vivo to become an inhibitor according to the invention. The prodrug itself may or may not be active against a given target protein. For example, compounds containing a hydroxyl group can be administered as esters that are converted into hydroxyl compounds by hydrolysis in vivo. Non-limiting examples of suitable esters that can be converted into hydroxyl compounds in vivo include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-di-β-hydroxynaphthyl carboxylate, gentianates, hydroxyethyl sulfonates, di-p-toluyl tartrate, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylaminosulfonates, quinates, and esters of amino acids. Similarly, compounds containing an amino group can be administered as amides that are converted into amine compounds by hydrolysis in vivo.

[0379] "Stereoisomers" or "optical isomers" are isomers of a given compound in which identical atoms are bonded to the same other atoms, but those atoms have different three-dimensional configurations. "Enantiomers" are stereoisomers of a given compound that are mirror images of each other, like the left and right hands. "Diabeta-isomers" are stereoisomers of a given compound that are not diastereomers. Chiral molecules contain a chiral center (also called a stereocenter or stereo-center), which is any point (though not necessarily an atom) in a molecule carrying multiple groups, such that the interchange of any two groups produces stereoisomers. In organic compounds, the chiral center is typically a carbon, phosphorus, or sulfur atom, although other atoms can also be stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, resulting in many stereoisomers. In compounds whose stereoisomerism can be attributed to a tetrahedral stereocenter (e.g., tetrahedral carbon), it is assumed that the total number of possible stereoisomers will not exceed 2^n, where n is the number of tetrahedral stereocenters. Molecules with symmetry often have a smaller number than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is called a racemic mixture. Additionally, mixtures of enantiomers can be enantiomer-enriched, such that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. It is anticipated that for any stereocenter or chiral axis whose stereochemistry is not yet defined, it may exist in its R form, S form, or as a mixture of said R and S forms (including racemic and non-racemic mixtures). The phrase "substantially free of other stereoisomers" as used herein means that the composition contains ≤15%, more preferably ≤10%, even more preferably ≤5%, or most preferably ≤1% of one or more other stereoisomers.

[0380] "Treatment or treating" includes (1) suppressing the disease of a subject or patient who is experiencing or exhibiting symptoms of the disease (e.g., preventing further development of the symptoms and / or signs), (2) improving the disease of a subject or patient who is experiencing or exhibiting symptoms of the disease (e.g., reversing the symptoms and / or signs), and / or (3) causing any measurable reduction in the disease of a subject or patient who is experiencing or exhibiting symptoms of the disease.

[0381] The above definitions supersede any conflicting definitions found in any references incorporated herein by reference. However, the fact that some terms are defined should not be construed as implying that any undefined term is indeterminate. Rather, all terms used are intended to describe the invention in a manner that will enable those skilled in the art to understand the scope of the invention and to practice it.

[0382] VIII. Examples

[0383] The following embodiments are included to demonstrate preferred embodiments of the invention. Those skilled in the art should understand that the techniques disclosed in the following embodiments represent techniques discovered by the inventors that work well in the practice of the invention and can therefore be considered as preferred modes of practice. However, those skilled in the art, upon considering this disclosure, should understand that many changes can be made to the specific embodiments disclosed and similar or identical results can still be obtained without departing from the spirit and scope of the invention.

[0384] Example 1 – A Phase II / III, randomized, double-blind, placebo-controlled trial of the effect of methylbardoxazoline in patients infected with SARS-CoV-2 (COVID-19).

[0385] This multicenter, double-blind, placebo-controlled, randomized phase 2 / 3 trial will investigate the safety, tolerability, and efficacy of methylbardosulon in approximately 400–440 hospitalized patients diagnosed with COVID-19. Methylbardosulon or placebo will be administered during hospitalization (until recovery) for up to 29 days. The final follow-up will be 60 days after randomization. The total duration of participation in the study is estimated to be approximately 2 months.

[0386] Patients will be randomly assigned in a 1:1 ratio to receive once-daily methylbardoxolone (20 mg) or a matched placebo using a replacement block randomization. In some cases, dose titration may be used to treat patients. Dose titration may be, for example, from 5 to 10 to 20 to 30 mg or from 10 to 20 to 30 mg. In any case, dose titration may be limited to 20 mg. Patients may be graded by age (≤50, 50–70, or ≥70 years). Randomization will be graded by research center and by whether or not invasive mechanical ventilation (i.e., mechanical ventilation with endotracheal intubation) was used at baseline. Randomization will be performed using an interactive network response system (IWRS). Following randomization on day 1, patients will be assessed on days 3, 5, 8, 11, 15, 22, and 29 of hospitalization. Assessments will include clinical status assessment, vital sign measurements, clinical chemistry collection, and adverse event collection. Patients who recover by day 29 will complete a treatment end visit. Regardless of treatment adherence and recovery status prior to day 29, patients will be followed up in person on day 29 and for safety at 60 days post-randomization for clinical status assessment, vital sign measurement, clinical chemistry collection, and adverse event collection. Subsequent in-person visits are preferred, but it is recognized that isolation and other factors may limit a subject's ability to return to the field for consultation. In such cases, consultations may be conducted by telephone.

[0387] Recruitment of patients ≥70 years of age may be limited during the safety review by the DSMB and the Executive Committee (e.g., no more than 10% of all randomized patients). Treatment will be administered during hospitalization (until recovery), with an expected duration of 10 days. For patients requiring hospitalization for more than 10 days, treatment may continue for a maximum of 29 days. Dose reductions (as low as 10 mg) are permitted during the study if clinically indicated. Once a patient's dose has been reduced, escalation back to a higher dose is permitted.

[0388] The Phase 2 portion of the trial will include approximately 40 patients and is primarily designed to provide a preliminary assessment of the safety of methylbardoxolone in COVID-19 patients compared to matched placebo (e.g., frequency, intensity, and relationship to the study drug of serious adverse events [including unexpected death], changes in vital signs relative to baseline, and laboratory assessments). The Phase 2 primary endpoint will be assessed during the treatment phase, defined as during hospitalization and up to day 15.

[0389] Following confirmation of safety and proof of concept in the Phase 2 cohort, recruitment for the Phase 3 cohort will commence. The Phase 3 portion of the trial will include approximately 360–400 additional patients and will primarily aim to (1) determine whether methylbardoxolone, compared to matched placebo, increases the likelihood of recovery within 29 days in COVID-19 patients (defined as alive, without respiratory failure [e.g., requiring non-invasive or invasive mechanical ventilation, high-flow oxygen, or ECMO], and without renal replacement therapy [RRT]) (WHO Ordinal Scale score ≤5 and no RRT) and (2) assess the safety of methylbardoxolone compared to matched placebo in COVID-19 patients. The Phase 3 primary endpoint will be assessed during the treatment phase, defined as hospitalization up to day 29. Secondary objectives are to assess the effects of methylbardoxolone compared to matched placebo on other endpoints, including renal function (e.g., change in eGFR from baseline up to day 29 (or at the end of treatment)) and the number of days without mechanical ventilation during hospitalization up to day 29.

[0390] Other exploratory efficacy endpoints include:

[0391] • Number of days without renal replacement therapy (RRT) during hospitalization and up to day 29

[0392] Recovery time up to day 29

[0393] Recovery on day 29

[0394] Recovery on day 60

[0395] • Using an 11-class ordinal scale, the proportion of subjects who experienced a deterioration in their clinical status from baseline (defined by a 1-point deterioration) to the end of treatment or day 29 (whichever comes first):

[0396] ο0 - Not infected; no viral RNA detected.

[0397] ο1 - Asymptomatic; viral RNA detected

[0398] ο2-Symptoms present; independent

[0399] ο3 - Symptoms present; support needed

[0400] ο4-Hospitalization; without oxygen therapy

[0401] ο5-Hospitalization; oxygen supply via mask or nasal cannula

[0402] ο6-Hospitalization; NIV or high-flow oxygen therapy

[0403] ο7-Intubation and mechanical ventilation; pO2 / FIO2> / =150 or SpO2 / FIO2> / =200

[0404] ο8- Mechanical ventilation pO2 / FIO2 < 150 (SpO2 / FIO2 < 200) or vasopressors

[0405] ο9- Mechanical ventilation pO2 / FIO2 <150 and vasopressors, dialysis or ECMO

[0406] ο10-Death

[0407] All-cause mortality rate

[0408] • Changes in PaO2 / FiO2 relative to baseline (during hospitalization on days 5, 8, 15 and at the end of treatment)

[0409] • Changes in D-dimer, C-reactive protein (CRP), LDH, troponin, and cytokine levels relative to baseline (during hospitalization on days 5, 8, 15, and at the end of treatment).

[0410] Dosage: Several dose-range studies with methylbardoxolone have shown that changes in eGFR are dose-dependent. The 20 mg dose of methylbardoxolone used in this study provided near-optimal pharmacological activity and potency while minimizing potential tolerability issues. Furthermore, most available clinical safety and potency data for methylbardoxolone have been collected using a 20 mg dose.

[0411] The study drug will be administered orally to the patient once daily, starting from day 1, while the patient remains hospitalized. Each dose of the study drug should be administered at approximately the same time each day, preferably in the morning. The time points for administration of the study drug will be listed in Table 24. Patients who cannot receive oral medication (e.g., due to intubation and / or mechanical ventilation) may receive the contents of the capsule via a water-flushed nasogastric tube or orogastric tube. Vomited doses must not be substituted. Double doses must not be administered (e.g., a dose missed the previous day and the dose given on the current day).

[0412] Regarding the patient inclusion criteria for the study, individuals must meet all of the following criteria:

[0413] 1. Laboratory-confirmed COVID-19 infection as determined by polymerase chain reaction (PCR)

[0414] 2. Inpatients who meet one of the following conditions:

[0415] (i) Radiographically confirmed infiltrations (chest X-ray, CT scan, etc.); or

[0416] (ii) At rest, blood oxygen saturation ≤94%; or

[0417] (iii) Needs supplemental oxygen; or

[0418] (iv) Requires non-invasive ventilation; or

[0419] (v) Mechanical ventilation is required for up to 2 days.

[0420] 3. Age ≥18 years. Recruitment of patients ≥70 years of age may be limited (e.g., no more than 10% of all randomized patients).

[0421] 4. The participant or their legally authorized representative is willing to sign an informed consent form.

[0422] Regarding the patient exclusion criteria for the study, all patients meeting any of the following conditions or characteristics will be excluded from the study:

[0423] 1. Intubation and mechanical ventilation (invasive) for three days or longer during randomized allocation.

[0424] 2. Known left ventricular ejection fraction (LVEF) <40% or hospitalized due to heart failure

[0425] 3. Cardiac arrest

[0426] 4. Shock

[0427] 5. Uncontrolled bacterial, fungal, or non-COVID virus infections

[0428] 6. eGFR < 15 ml / min / 1.73 m 2 or a history of needing dialysis

[0429] 7. ALT or AST > 5 times ULN

[0430] 8. History of cirrhosis, chronic active hepatitis, or severe liver disease

[0431] 9. Pregnant or breastfeeding women

[0432] 10. Enrollment in other trials of unapproved therapies is permitted unless approved by the trial's principal investigator. Generally, co-enrollment is allowed unless there are safety concerns, mechanical incompatibility, or the inability to determine serious adverse events. Concomitant use with potent CYP3A4 inhibitors is prohibited. If a potent CYP3A4 inhibitor is medically necessary, the investigational drug should be temporarily discontinued. Concomitant use with moderate CYP3A4 inhibitors should be avoided whenever possible, and alternative agents should be considered.

[0433] 11. If the clinical team believes that death is imminent and inevitable within the next 24 hours, regardless of whether treatment is provided.

[0434] Regarding safety endpoints, the following safety endpoints will be assessed during the study: (1) all serious, unexpected, and reasonably likely adverse events related to the study drug; and (2) all unexpected deaths.

[0435] An adverse event (AE) is any symptom, sign, illness, or experience that occurs or worsens in severity during the study. Concurrent illnesses or injuries should be considered adverse events. An abnormal outcome of a diagnostic procedure is considered an adverse event if the abnormality: leads to study withdrawal; is associated with a serious adverse event; is associated with a clinical sign or symptom; leads to additional treatment or other diagnostic testing; or is deemed clinically significant by the investigator.

[0436] Adverse events are classified as serious or non-serious. Serious adverse events are any AEs that are: fatal; life-threatening; require or prolong hospitalization; result in lasting or severe disability or incapacity; have a congenital abnormality or birth defect; or are significant medical events. Significant medical events are those that may not be immediately life-threatening but are clearly of great clinical significance. They may harm the subject and may require intervention to prevent one of the other serious consequences described above. For example, drug overdose or abuse, seizures that do not result in hospitalization, or intensive treatment of bronchospasm in the emergency department are generally considered serious. All adverse events that do not meet any of the serious criteria should be considered non-serious adverse events.

[0437] The severity of each adverse event will be graded using the NCI Common Terminology Standard for Adverse Events (CTCAE) system. All adverse events will be logged.

[0438] • Level 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observation only; no intervention indicated.

[0439] Level 2: Moderate; indicates minimal, localized or non-invasive interventions; limits age-appropriate daily living activities using instruments.

[0440] • Level 3: Severe or medically significant but not immediately life-threatening; instruction to hospitalization or prolongation of hospitalization; disability; limited ability to perform daily activities.

[0441] Level 4: Life-threatening consequences; requires emergency intervention.

[0442] Level 5: Deaths related to AE (Adverse Events).

[0443] For all collected adverse events (AEs), the clinician examining and evaluating the participants will determine the causal relationship of the AEs based on the time relationship and his / her clinical judgment. The degree of certainty of causation will be rated using the following classification.

[0444] • Clearly relevant events include: (a) the reasonable chronological order of the study drug or study procedure; (b) events that cannot be explained by known characteristics of the participant’s clinical condition or other therapies; and (c) assessments of the participant’s clinical condition that indicate to the researchers that the experience is definitely relevant to the study procedure.

[0445] • Probably relevant - Events should be evaluated using the same criteria as "clearly relevant". If researchers believe that at least one or more criteria are not met, an event can be assessed as "probably" relevant.

[0446] • Potentially relevant - Events should be evaluated using the same criteria as those that are "clearly relevant". If researchers believe that at least one or more criteria are not met, an event can be evaluated as "potentially" relevant.

[0447] • Probably irrelevant - This event occurs when a participant receives a study drug / intervention or undergoes a study procedure, but this can be reasonably explained by known characteristics of the participant's clinical condition or other therapies.

[0448] • Clearly irrelevant - The event was clearly caused by the participant's clinical condition or by other therapies administered to the participant.

[0449] • Uncertain relationships - events that do not meet any of the criteria listed above.

[0450] The researcher responsible for each local site will be responsible for determining whether an adverse event (AE) is anticipated or unexpected. An AE will be considered unexpected if its nature, severity, or frequency is inconsistent with the risk information previously described for the study drug.

[0451] An excessive number of adverse events, including death, are expected to be related to COVID-19 infection rather than drug use. Some examples of anticipated COVID-19-related AEs include (but are not limited to) death, intubation, need for compression, mechanical circulatory support, cardiac arrest resuscitation, acute kidney injury, infection (non-COVID-19), LFT > 5 times ULN, disseminated intravascular coagulation, and symptomatic venous thromboembolism.

[0452] Using a permutation block randomization, a total sample size of approximately 400 participants (approximately 200 methylbardosuloron; approximately 200 placebo) were randomly assigned 1:1 (phase 2 and phase 3 combined, or phase 3 alone) to provide approximately 80% capability at a two-sided significance level of 0.05 to detect a hazard ratio of 1.28, which corresponds to a 28% increase in the probability of recovery, as hypothesized as follows:

[0453] • Follow-up events were conducted 28 days (up to day 29) after randomization.

[0454] • 2% of patients in each group withdrew before recovery.

[0455] • The 28% increase in the recovery probability corresponds to 50% of patients randomly assigned to the placebo group recovering, compared to 64% of patients randomly assigned to the methylbardoxolone group recovering.

[0456] Because of the uncertainty surrounding the recovery rate of COVID-19 patients, this protocol allows for a recalculation of the sample size during the trial. Interim analyses of efficacy, safety, invalidity, and possible sample size recalculations will be conducted at designated times during the trial (approximately 70% of the cumulative projected sample size). A simulation study will be used to estimate capacity based on the primary analytical method, which accounts for competing mortality events. If necessary, the sample size will be adjusted to maintain the expected capacity. Details of the sample size recalculation will be specified in the statistical analysis plan. Because these analyses will be based on aggregated blinded data, the recalculation will not affect the Type I error rate or the data integrity of the study.

[0457] This analysis will be based on intention to treatment, using a generalized linear model to compare the probability of recovery within 29 days. The phase 2 safety analysis will not assess the primary endpoint and will not affect the overall type I error rate of the trial. If the DSMB deems the trial should proceed to the phase 3 portion, then patients in phase 2 will be included in the phase 3 portion of the study (unless phase 2 is unblinded).

[0458] eGFR measurement. eGFR values ​​will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation:

[0459] eGFR (mL / min / 1.73m) 2 )=141×min(S cr / κ,1) α ×max(S cr / κ,1) -1.209 ×0.993 年龄 ×1.018 [If female] ×1.159 [If black]

[0460] The patient's age at the date of consent was used, S cr This refers to serum creatinine (mg / dL), κ is 0.7 (for women) or 0.9 (for men), and α is -0.329 (for women) or -0.411 (for men). min indicates S cr / κ or 1 minimum value, max indicates S cr The maximum value of / κ or 1.

[0461] The PaO2 / FiO2 ratio is calculated as follows: PaO2 from arterial blood gas is used and then divided by the estimated FiO2 of the oxygen delivery method (0.21 for room air, 0.21 + (oxygen flow rate * 0.03) for nasal cannula, 0.80 for non-circulating respirator masks, or the recorded FiO2 for non-invasive or invasive ventilation) (Brown et al., 2016).

[0462] Fluid overload. Similar to endothelial angiotensin receptor blockers (ERAs) in certain patient populations (including bosentan in advanced congestive heart failure and avosentan in advanced CKD), methylbardoxolone treatment was found to be associated with an increased risk of fluid overload and hospitalization for heart failure in the BEACON trial, which recruited patients with stage 4 CKD (eGFR 15-29 mL / min / 1.73 mcg). 2Patients with type 2 diabetes and type 2 diabetes (Chin, 2014). The overall increased risk of fluid overload and heart failure events caused by methylbardoxolone appears to be limited to the first 3 to 4 weeks after treatment initiation. Patients with fluid overload events treated with intravenous diuretics generally experience relief of their symptoms. Elevated BNP and previous hospitalization for heart failure were identified as risk factors contributing to an increased risk of these events. For patients without these baseline characteristics, the risk of heart failure events was similar between patients treated with methylbardoxolone and those treated with placebo (2%) (Chin, 2014). No increased risk of these events was observed with methylbardoxolone treatment in six previous CKD studies, which primarily focused on patients with stage 3b CKD (eGFR 30–44 mL / min / 1.73 mcg). 2 The study was conducted on patients with liver dysfunction, cancer patients, or healthy volunteers.

[0463] Subsequent studies enrolling over 1500 patients employed risk mitigation procedures to reduce the likelihood of methylbardoxolone-induced fluid overload. These procedures excluded patients with identified risk factors and ensured close monitoring of fluid retention during the first month of treatment. Because these exclusions were applied, no increased risk of acute fluid overload adverse events (AEs) induced by methylbardoxol was observed.

[0464] In managing fluid status, specific risk mitigation procedures will be employed to reduce the likelihood of methylbardoxolone-induced fluid overload. These include exclusion of patients with any severe renal disease (defined as eGFR <15 mL / min / 1.73 mcg). 2 Patients with a known left ventricular ejection fraction (LVEF) or requiring dialysis will be excluded from the study. To exclude patients with significant cardiac dysfunction, patients with a known left ventricular ejection fraction (LVEF) of <40% or who have been previously hospitalized for heart failure will be excluded.

[0465] Elevated transaminases and gamma-glutamyl transferase (GGT). In clinical studies of methylbardoxazoline, almost all patients experienced elevated transaminases above baseline upon initiation of treatment, following a consistent pattern. These increases were not associated with elevated bilirubin or other signs of hepatotoxicity. In BEACON, fewer hepatobiliary SAEs were observed in the methylbardoxazoline group than in the placebo group. Elevations begin immediately upon initiation of treatment or dose escalation; they peak after approximately 2–4 weeks. In most patients, the transaminase elevation is mild, but approximately 4% to 11% of patients experienced an elevation exceeding 3 times the ULN. While patients continued administration of the study drug, the elevation decreased to below the ULN level in most of all patients with elevations within two weeks of peaking. Patients experiencing elevations exceeding 3 times the ULN sometimes required additional time to resolve. Although some patients already had elevations exceeding 3 times the ULN, sustained elevations exceeding 3 times the ULN have not been observed, and such elevations do not recur once resolved unless caused by other factors.

[0466] Methylbardoxazolon regulates GGT, a known Nrf2 target gene. In clinical studies, low-level GGT elevations during treatment are common, mild, and typically persist longer than ALT / AST elevations. Bilirubin levels in patients who develop transaminase or GGT elevations due to methylbardoxazolon treatment remain at baseline or decrease. In patients continuing treatment with the investigational drug, ALT, AST, and GGT elevations are usually self-limiting.

[0467] Regarding the management of elevated transaminase levels (ALT and / or AST) in this trial, it is anticipated that almost all cases of elevated transaminase levels due to methylbadoxazoline treatment will be asymptomatic. If ALT or AST levels are found to be more than 5 times the upper limit of normal (ULN), transaminase levels (as well as total bilirubin (TBL), GGT, alkaline phosphatase (ALP), and international normalized ratio (INR)) will be checked within 48–72 hours. The trial will be repeated every 72–96 hours until transaminase levels are below 5 times the upper limit of normal (ULN) and remain below this level for at least one week or until the patient withdraws consent.

[0468] Muscle cramps. Muscle cramps were the most frequently reported adverse event in CKD patients with concurrent type 2 diabetes mellitus. Muscle cramps most commonly occurred during the first two months of treatment and resolved spontaneously or empirically. They primarily occurred at night, in the lower extremities, and were generally mild to moderate in severity. Muscle cramps may be caused by improved insulin sensitivity and glucose uptake in skeletal muscle cells. Increased glucose uptake in response to methylbardosole was observed in a specific subset of patients recruited into the phase 2a study, as assessed by the hyperinsulin-euglycemic clamp procedure. Clinical signs and laboratory findings associated with reported muscle cramps were inconsistent with muscle toxicity. No subjects receiving methylbardosole showed significant increases in laboratory findings associated with muscle toxicity, such as increased serum marker levels, including creatinine, creatine kinase, lactate dehydrogenase (LDH), BUN, uric acid, phosphorus, and potassium.

[0469] Regarding the management of muscle cramps in this trial, basic symptom relief is the first step, including walking, adequate hydration, wearing socks, and stretching before bedtime. Assessment of electrolyte levels such as magnesium, calcium, and potassium may indicate the need for supplementation. If vitamin D levels are low, supplementation may be necessary. Muscle relaxants may also help relieve symptoms.

[0470] Table 24. Evaluation Timeline

[0471]

[0472]

[0473] a Day 1 is the day the first dose is administered.

[0474] b Patients who discontinue the study drug before resumption of treatment or before day 29 will undergo a safety assessment 60 days after randomization. This will be done through in-person visits or telephone follow-ups, where possible.

[0475] c Screening assessments conducted on the same randomly assigned day (Day 1) do not need to be repeated.

[0476] d Perform before administering the medication on day 1.

[0477] e A serum pregnancy test will be performed during a screening for WOCBP or at any point when pregnancy is suspected. Additional pregnancy assessments will be performed more frequently if required by local law, local regulatory agency, or IRB / EC.

[0478] fThe assessment of adverse events (AEs) on day 1 should be performed after administration of the study drug. Only serious AEs with a reasonable likelihood of being related to the study drug should be collected.

[0479] g It should be performed on day 15 or at the end of treatment, whichever is earlier.

[0480] h The suitability of results obtained from tests conducted according to nursing standards can be reviewed. If unavailable or incomplete, the test does not need to be performed.

[0481] i This test is not required during screening. A confirmatory positive test is sufficient to meet the inclusion criteria for the study.

[0482] j The end-of-treatment visit can occur on day 29 or earlier. If the end-of-treatment visit is on day 29, follow the end-of-treatment assessment schedule.

[0483] k All patients, regardless of their treatment adherence and recovery status prior to day 29, will be followed up on day 29. This will be done through an in-person visit or by telephone, if possible.

[0484] Example 2 - Results of Phase II Test

[0485] The Phase 2 portion of this trial included 40 patients and primarily aimed to provide a preliminary assessment of the safety of methylbardoxolone in patients with COVID-19 compared to matched placebo. All patients were hospitalized for laboratory-confirmed COVID-19 and met at least one of the following criteria: (a) radiographically confirmed infiltration; (b) oxygen saturation ≤94% at rest; (c) requirement for supplemental oxygen; (d) requirement for non-invasive ventilation; and (e) requirement for invasive mechanical ventilation for no more than 2 days. Patients requiring intubation and invasive mechanical ventilation for three days or longer were excluded. Demographic and baseline characteristics were similar between the placebo and methylbardoxolone treatment groups (Table 25). There were no significant differences in COVID-19-related therapies or current standard of care between the treatment groups (Table 26).

[0486] Table 25. Patient Demographics

[0487]

[0488] Table 26. Drugs of Concern Related to COVID-19

[0489]

[0490] If a patient is recorded as having taken a medication at any time in the baseline medication form or concomitant medication log, the patient is counted in each unit.

[0491] Forty patients were recruited for the study and randomly assigned 1:1 to either the placebo or methylbardoxolone treatment group. Two patients randomly assigned to the placebo group did not receive the study drug and were excluded from the mITT and safety populations. Patient management is shown in Table 27.

[0492] Table 27. Disposal

[0493]

[0494]

[0495] Efficacy endpoint: Fewer patients died in the methylbardoxolone treatment group, with an odds ratio of 0.19 for all-cause mortality (Table 28). Similarly, more patients treated with methylbardoxolone recovered by day 29, with an odds ratio of 0.17 (Table 29). The median time from randomization to discharge decreased from 8 days in placebo patients to 5 days in methylbardoxolone-treated patients (Table 30). On day 29, the mean and median WHO score were lower in the methylbardoxolone treatment group (Table 31). Compared with placebo, methylbardoxolone treatment increased eGFR (Table 32).

[0496] Table 28. All-cause mortality rate and deterioration

[0497]

[0498] Table 29. Recovery and Correction of Recovery (ITT Analysis 1)

[0499]

[0500] 1 This includes all patients on day 29, regardless of their condition at baseline or prior to day 29.

[0501] 2 Recovery = Survival on day 29 without respiratory failure [e.g., requiring non-invasive or invasive mechanical ventilation, high-flow oxygen, or ECMO], and without renal replacement therapy [RRT] (WHO Ordinal Scale score ≤5 and no RRT).

[0502] 3 Modified recovery = survival on day 29 without any supplemental oxygen therapy and without renal replacement therapy [RRT] (WHO Ordinal Scale score ≤4 and no RRT)

[0503] Table 30. Number of days after discharge

[0504]

[0505] Table 31. WHO score on day 29

[0506]

[0507] Table 32. Changes in eGFR relative to baseline

[0508]

[0509] Safety endpoints: A lower percentage of patients treated with methylbardoxolone (24%) experienced adverse events (AEs) compared to placebo (35%) (Table 33). Similarly, a lower percentage of patients treated with methylbardoxolone (19%) experienced severe adverse events (SAEs) compared to placebo (35%) (Table 33). No cardiovascular SAEs occurred in patients treated with methylbardoxolone (Table 34). No SAEs were related to the study drug. No other safety findings or adverse laboratory trends were observed.

[0510] Table 33. Overview of Adverse Events (Safe Group)

[0511]

[0512] Table 34. Serious Adverse Events (Safe Group)

[0513]

[0514] ***

[0515] Based on this disclosure, all methods disclosed and claimed herein can be implemented and performed without extensive experimentation. While the compositions and methods of the invention have been described in the manner of preferred embodiments, it will be apparent to those skilled in the art that changes may be made to the methods described herein, as well as the steps or sequence of steps thereof, without departing from the concept, spirit, and scope of the invention. More specifically, it will be apparent that certain chemically and physiologically relevant agents can be used to replace the agents described herein, achieving the same or similar results. All such similar substitutions and modifications that are apparent to those skilled in the art are considered to fall within the spirit, scope, and concept of the invention as defined by the appended claims.

[0516] References

[0517] The following references are incorporated herein by reference in any way that provides exemplary operational details or other details that supplement the content described herein.

[0518] US Patent No. 5,480,792

[0519] US Patent No. 5,525,524

[0520] US Patent No. 5,631,170

[0521] US Patent No. 5,679,526

[0522] US Patent No. 5,824,799

[0523] US Patent No. 5,851,776

[0524] US Patent No. 5,885,527

[0525] US Patent No. 5,922,615

[0526] US Patent No. 5,939,272

[0527] US Patent No. 5,947,124

[0528] US Patent No. 5,955,377

[0529] US Patent No. 5,985,579

[0530] US Patent No. 6,019,944

[0531] US Patent No. 6,025,395

[0532] US Patent No. 6,113,855

[0533] US Patent No. 6,143,576

[0534] US Patent Publication 2003 / 0232786

[0535] US Patent Publication 2008 / 0261985

[0536] US Patent Publication 2009 / 0048204

[0537] US Patent Publication 2009 / 0326063

[0538] US Patent Publication 2010 / 0041904

[0539] US Patent Publication 2010 / 0048887

[0540] US Patent Publication 2010 / 0048892

[0541] US Patent Publication 2010 / 0048911

[0542] US Patent Publication 2010 / 0056777

[0543] US Patent Publication 2011 / 0201130

[0544] PCT Public WO 2009 / 023232

[0545] PCT Public WO 2009 / 048204

[0546] PCT Public WO 2010 / 093944

[0547] PCT Publication WO 2019 / 014412

[0548] CN 102875634

[0549] CN 102887936

[0550] Ahmad et al., "Triterpenoid CDDO-Me blocks the NF-κB pathway by directinhibition of IKKβ on Cys-179," J. Biol. Chem., 281:35764-35769, 2006.

[0551] Ahmad et al., "Triterpenoid CDDO-Methyl Ester Inhibits the Janus-Activated Kinase-1(JAK1)→Signal Transducer and Activator of Transciption-3(STAT3)Pathway by Direct Inhibition of JAK1 and STAT3," Cancer Res., 68(8):2920-2926, 2008.

[0552] Ahmadppor and Rostaing, “Why the immune system fails to mount an adaptiveimmune response to a COVID-19 infection.” Transpl. Int., April 1, 2020, doi:10.111 / tri.13611.

[0553] Aleksunes et al., “Transcriptional regulation of renal cytoprotective genes by Nrf2 and its potential use as a therapeutic target to mitigate cisplatin-induced nephrotoxicity,” J. Pharmacol. Exp. Ther., 335(1):2-12, 2010.

[0554] Aminzadeh et al., “The synthetic triterpenoid RTA dh404 (CDDO-dhTFEA) restores endothelial function impaired by reduced Nrf2 activity in chronic kidney disease,” Redox Biol., 1:527-531, 2013.

[0555] Aminzadeh et al., “The synthetic triterpenoid RTA dh404 (CDDO-dhTFEA) restores Nrf2 activity and attenuates oxidative stress, inflammation, and fibrosis in rats with chronic kidney disease,” Xenobiotica, 44(6):570-578, 2014.

[0556] Anderson, Practical Process Research & Development - A Guide for Organic Chemists, 2nd ed., Academic Press, New York, 2012.

[0557] Auletta et al., “The synthetic triterpenoid, CDDO-Me, modulates the proinflammatory response to in vivo lipopolysaccharide challenge,” J. Interferon Cytokine Res., 30:497-508, 2010.

[0558] Brown et al., “Nonlinear imputation of Pao2 / Fio2 from Spo2 / Fio2 among patients with acute respiratory distress syndrome,” Chest, 150(2):307-313, 2016.

[0559] Camer et al., “Bardoxolone methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high-fat diet,” Chem. Biol. Interact., 243:10-18, 2016.

[0560] Chandra et al., “Mesenchymal stem cells are attracted to latent HIV-1-infected cells and enable virus reactivation via a non-canonical PI3K-NFκB signaling pathway,” Sci. Rep., 8:14702, 2018.

[0561] Chapman et al., “Cyclic mechanical strain increases reactive oxygen species production in pulmonary epithelial cells,” Am. J. Physiol. Lung Cell. Mol. Physiol., 289:L834-841, 2005.

[0562] Chen et al., “The protective effect of CDDO-Me on lipopolysaccharide-induced acute lung injury in mice,” Int. Immunopharmacol., 25:55-64, 2015.

[0563] Chen et al., "Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study," The Lancet, 395: 507 - 513, 2020.

[0564] Chen et al., "Clinical and immunological features of severe and moderate coronavirus disease 2019," J. Clin. Invest., Mar. 27, 2020, doi: 10.1172 / JCI137244.

[0565] Chen et al., "SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex," Protein Cell, 5: 369 - 381, 2014.

[0566] Chertow et al., "Effects of Bardoxolone Methyl on Body Weight, Waist Circumference and Glycemic Control in Obese Patients with Type 2 Diabetes Mellitus and Stage 4 Chronic Kidney Disease," J. Diabetes Complications, 32(12): 1113 - 1117, 2018.

[0567] Chin et al., “Bardoxolone Methyl Improves Kidney Function in Patients with Chronic Kidney Disease Stage 4 and Type 2 Diabetes: Post-Hoc Analyses from Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Study,” Am. J. Nephrol., 47:40-47, 2018.

[0568] Chin et al., “Bardoxolone methyl analogs RTA 405 and dh404 are well tolerated and exhibit efficacy in rodent models of Type 2 diabetes and obesity,” Am. J. Physiol. Renal Physiol., 304:F1438-F46, 2013.

[0569] Chin et al., “Mechanisms contributing to adverse cardiovascular events in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl,” Am. J. Nephrol., 39:499-508, 2014.

[0570] de Zeeuw et al., “Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl. J. Med., 369:2492-2503, 2013.

[0571] Dhaun et al., “Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis,” American Journal of Physiology-Renal Physiology, 296: F1477-F1483, 2009.

[0572] Diao et al., “Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19),” Feb. 20, 2020, medRxiv, doi: 10.1101 / 2020.02.18.20024364.

[0573] Ding et al., “The synthetic triterpenoid, RTA 405, increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells,” Kidney Int., 83: 845-854, 2013.

[0574] Dinkova-Kostova et al., “The spatiotemporal regulation of the Keap1-Nrf2 pathway and its importance in cellular bioenergetics,” Biochem. Soc. Trans., 43: 602-610, 2015.

[0575] Dinkova-Kostova et al., “Extremely Potent Triterpenoid Inducers of the Phase 2 Response: Correlations of Protection Against Oxidant and Inflammatory Stress,” Proc. Natl. Acad. Sci., 102: 4584-4589, 2005.

[0576] Espinoza et al., “Modulation of Antiviral Immunity by Heme Oxygenase-1,” Am. J. Pathol., 187:487-493, 2017.

[0577] Fanelli et al., “Acute kidney injury in SARS-CoV-2 infected patients,” Crit. Care, 24:155, 2020.

[0578] Ferguson et al., “Bardoxolone Methyl (BARD) Improves Markers of Endothelial Function in Cultured Cells,” Poster American Society of Nephrology (ASN) 2010.

[0579] Fung et al., “A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses,” Emerg. Microbes Infect., 9:558-570, 2020.

[0580] Guan et al., “Clinical Characteristics of Coronavirus Disease 2019 in China,” N. Engl. J. Med., 382:1708-1720, 2020.

[0581] Handbook of Pharmaceutical Salts: Properties, and Use, Stahl and Wermuth (eds), Verlag Helvetica Chimica Acta, 2002.

[0582] Hisamichi et al., “Role of bardoxolone methyl, a nuclear factor erythroid2-related factor 2 activator, in aldosterone-and salt-induced renal injury,” Hypertens. Res., 41(1):8-17, 2018.

[0583] Honda et al., “New Enone Derivativas of Oleanolic Acid and Ursolic Acidas Inhibitors of Nitric Oxide Production in Mouse Macrophages,” 1997.

[0584] Honda et al., “Design and Synthesis of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, a Novel and Highly Active Inhibitor of Nitric Oxide Production inMouse Macrophages,” Bioorg. Med. Chem. Lett., 8(19):2711-2714, 1998.

[0585] Honda et al., “Novel Synthetic Oleanane Triterpenoids: A Series ofHighlyActive Inhibitors of Nitric Oxide Production in Mouse Macrophages,” Bioorg. Med. Chem. Lett., 9(2):3429-3434, 1999.

[0586] Honda et al., “Novel Synthetic Oleanane and Ursane Triterpenoids withVarious Enone Functionalities in Ring A as Inhibitors ofNitric OxideProduction in Mouse Macropahges,” J. Med. Chem., 43:1866-1877, 2000a.

[0587] Honda et al., “Synthetic Oleanane and Ursane Triterpenoids with Modified Rings A and C: A Series of Highly Active Inhibitors of Nitric Oxide Production in Mouse Macrophages,” J. Med. Chem., 43:4233 - 4246, 2000b.

[0588] Honda et al., “A novel dicyanotriterpenoid, 2 - cyano - 3,12 - dioxooleana - 1,9(11) - dien - 28 - onitrile, active at picomolar concentrations for Inhibition of Nitric Oxide Production,” Bioorg. Med. Chem. Lett., 12:1027 - 1030, 2002.

[0589] Hong et al., “A phase I first - in - human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas,” Clin. Cancer Res., 18:3396 - 3406, 2012.

[0590] Huang et al., “Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China,” Lancet, 395:497 - 506, 2020.

[0591] Huang et al., “Inhibition of Skin Tumorigenesis by Rosemary and its Constituents Carnosol and Ursolic Acid,” Cancer Res., 54:701 - 708, 1994.

[0592] Ikeda et al., “The Novel Triterpenoid CDDO and its Derivatives Induce Apoptosis by Disruption of Intracellular Redox Balance,” Cancer Res., 63:5551 - 5558, 2003.

[0593] Ikeda et al., “Induction of Redox Imbalance and Apoptosis in Multiple Myeloma Cells by the Novel Triterpenoid 2 - cyano - 3,12 - dioxoolean - 1,9 - dien - 28 - oic acid,” Mol. Cancer Ther., 3:39 - 45, 2004.

[0594] Joint Specialty Committee on Renal Medicine of the Royal College of Physicians and the Renal Association, and the Royal College of General Practitioners. Chronic kidney disease in adults: UK guidelines for identification, management and referral. London: Royal College of Physicians, 2006.

[0595] Keleku - Lukwete et al., “Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation,” Proc. Natl. Acad. Sci. USA, 112:12169 - 12174, 2015.

[0596] Kellner et al., "ROS Signaling in the Pathogenesis of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS)," Adv. Exp. Med. Biol., 967:105 - 137, 2017.

[0597] Kellner et al., see: Wang Y - X, ed. Pulmonary Vasculature Redox Signaling in Health and Disease. Cham: Springer International Publishing; pp. 105 - 137, 2017.

[0598] Kobayashi and Yamamoto, "Molecular Mechanism Activating the Nrf2 - Keap1 Pathway of Antioxidant Gene Regulation," Antioxid. Redox. Signal., 7:385 - 394, 2005.

[0599] Kulkarni et al., "The triterpenoid CDDO - Me inhibits bleomycin - induced lung inflammation and fibrosis," PLoS One, 8:e63798, 2013.

[0600] Lee et al., "KEAP1 E3 ligase - mediated downregulation of NF - kB signaling by targeting IKKβ," Molecular Cell, 36:131 - 140, 2009.

[0601] Liby et al., "The Synthetic Triterpenoids, CDDO and CDDO - imidazolide, are Potent Inducers of Heme Oxygenase - 1 and Nrf2 / ARE signaling," Cancer Res., 65:4789 - 4798, 2005.

[0602] Liu et al., “The Nrf2 triterpenoid activator, CDDO-imidazolide, protects kidneys from ischemia-reperfusion injury in mice,” Kidney Int., 85(1):134-141, 2014.

[0603] Liu et al., “2019-novel coronavirus (2019-nCoV) infections trigger an exaggerated cytokine response aggravating lung injury,” Feb. 12, 2020, chinaXiv, doi:10 / 12074 / 202002.00018 /

[0604] Maines and Gibbs, “30 Some Years of Heme Oxygenase: From a ‘molecular wrecking ball’ to a ‘mesmerizing’ Trigger of Cellular Events,” Biochem. Biophys. Res. Commun., 338:568-577, 2005.

[0605] March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 2007.

[0606] Nagashima et al., “Nrf2 Suppresses Allergic Lung Inflammation by Attenuating the Type 2 Innate Lymphoid Cell Response,” J. Immunol., 202:1331-1339, 2019.

[0607] Nagasu et al., “Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function,” FASEB J., 33(11):12253-12263, 2019.

[0608] Naicker et al., “The Novel Coronavirus 2019 epidemic and kidneys,” Kidney Int., 97:824 - 828, 2020.

[0609] Nangaku et al., “Effect of bardoxolone methyl on glomerular filtration rate in diabetic kidney disease patients (TSUBAKI study): a randomized clinical trial. Kidney International Reports. 2020; in press.

[0610] Nichols et al., “The triterpenoid CDDO limits inflammation in preclinical models of cystic fibrosis lung disease,” Am. J. Physiol. Lung Cell. Mol. Physiol., 297: L828 - 836, 2009.

[0611] Nio et al., “Bardoxolone methyl as a novel potent antiviral agent against hepatitis B and C viruses in human hepatocyte cell culture systems,” Antiviral Res., 169:104537, 2019.

[0612] Nishino et al., “Inhibition of the Tumor - Promoting Action of 12 - O - tetradecanoylphorbol - 13 - acetate by some Oleanane - type Triterpenoid Compounds,” Cancer Res., 48:5210 - 5215, 1988

[0613] Osburn and Kensler, “Nrf2 signaling: An adaptive response pathway for protection against environmental toxic insults,” Mutat. Res., 669:319, 2008.

[0614] Osburn et al., “Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice,” Toxicol. Sci., 104:218 - 227, 2008.

[0615] Papaiahgari et al., “Genetic and Pharmacologic Evidence Links Oxidative Stress to Ventilator-induced Lung Injury in Mice,” Am. J. Respir. Crit. Care Med., 176:1222 - 1235, 2007.

[0616] Patra et al., “RA-839, a selective agonist of Nrf2 / ARE pathway, exerts potent anti-rotaviral efficacy in vitro,” Antiviral Res., 161:53 - 62, 2019.

[0617] Peake and Whiting, “Measurement of Serum Creatinine - Current Status and Future Goals,” Clin. Biochem. Rev., 27:173 - 184, 2006.

[0618] Pei et al., “Bardoxolone treatment alleviates lipopolysaccharide (LPS)-induced acute lung injury through suppressing inflammation and oxidative stress regulated by Nrf2 signaling,” Biochem. Biophys. Res. Commun., 516:270-277, 2019.

[0619] Pergola et al., “Bardoxolone methyl and kidney function in CKD with type 2 diabetes,” New Engl. J. Med., 365, 327-336, 2011.

[0620] Pergola et al., “Safety and efficacy of bardoxolone methyl in patients with rare chronic kidney dsieases,” Poster European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), 2019.

[0621] Place et al., “The Novel Synthetic Triterpenoid, CDDO-Imidazolide, Inhibits Inflammatory Response and Tumor Growth In Vivo,” Clin. Cancer Res., 9:2798-2806, 2003.

[0622] Potey et al., “Neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential,” J. Pathol., 247:672-685, 2019.

[0623] Qin et al., “Dysregulation of immune response in patients with COVID-19 in Wuhan, China,” Clin. Infect. Dis., Mar. 12, 2020, doi:10.1093 / cid / ciaa248.

[0624] Rawlins et al., “Performance Characteristics of Four Automated Natriuretic Peptide Assays,” Am. J. Clin. Pathol., 123:439 - 445, 2005.

[0625] Reagan - Shaw et al., “Dose Translation From Animal to Human Studies Revisited,” FASEB J., 22(3):659 - 661, 2008.

[0626] Reddy et al., “The triterpenoid CDDO - imidazolide confers potent protection against hyperoxic acute lung injury in mice,” Am. J. Respir. Crit. Care Med., 180:867 - 874, 2009.

[0627] Repka et al., “Encyclopedia of Pharmaceutical Technology,” New York: Marcel Dekker, 2002.

[0628] Robles et al., “Synthetic Triterpenoid RTA dh404(CDDO - dhTFEA) Ameliorates Acute Pancreatitis,” Pancreas, 45:720 - 729, 2016.

[0629] Rojas - Rivera et al., “Antioxidants in kidney diseases: The impact of bardoxolone methyl. Int J Nephrol 2012;2012:1 - 11.

[0630] Rothan HA, Zhong Y, Sanborn MA, Teoh TC, Ruan J, Yusof R, et al. Small molecule grp94 inhibitors block dengue and Zika virus replication. Antiviral Res. 2019;171:104590.

[0631] Sarzi-Puttini P, Giorgi V, Sirotti S, Marotto D, Ardizzone S, Rizzardini G, et al. COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? Clin Exp Rheumatol. 2020;38(2):337-42.

[0632] Schneider et al., “Contrasting actions of endothelin ETA and ETB receptors in cardiovascular disease,” Annual Review of Pharmacology and Toxicology, 47:731-759, 2007.

[0633] Shao J, Huang J, Guo Y, Li L, Liu X, Chen X, et al. Up-regulation of nuclear factor E2-related factor 2 (Nrf2) represses the replication of SVCV. Fish & Shellfish Immunology. 2016;58:474-82.

[0634] Shishodia et al., “A Synthetic Triterpenoid, CDDO-Me, Inhibits IκBα Kinase and Enhances Apoptosis Induced by TNF and Chemotherapeutic Agents Through Down-Regulation of Expression of Nuclear Factor κB-Regulated Gene Products in Human Leukemic Cells,” Clin. Cancer Res., 12(6):1828-1838, 2006.

[0635] Son et al., “Activation of Nrf2 Restores Klotho Expression and Attenuates Oxidative Stress and Inflammation in CKD,” J. Appl. Health Sci. Int., 2:22-34, 2015.

[0636] Suh et al., “Novel Triterpenoids Suppress Inducible Nitric Oxide Synthase (iNOS) and Inducible Cyclooxygenase (COX-2) in Mouse Macrophages,” Cancer Res., 58:717-723, 1998.

[0637] Suh et al., “A Novel Synthetic Oleanane Triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity,” Cancer Res., 59(2):336-341, 1999.

[0638] Suh et al., “Synthetic Triterpenoids Enhance Transforming Growth Factor β / Smad Signaling,” Cancer Res., 63:1371-1376, 2003.

[0639] Sun et al., “Coronavirus Papain-like Proteases Negatively Regulate Antiviral Innate Immune Response through Disruption of STING-Mediated Signaling,” PLoS One, 7: e30802, 2012.

[0640] Tan et al., “Derivative of bardoxolone methyl, dh404, in an inverse dose-dependent manner lessens diabetes-associated atherosclerosis and improves diabetic kidney disease,” Diabetes, 63(9): 3091 - 3103, 2014.

[0641] Tanaka et al., “Coordinated induction of Nrf2 target genes protects against iron nitrilotriacetate (FeNTA)-induced nephrotoxicity,” Toxicol. Appl. Pharmacol., 231: 364 - 373, 2008.

[0642] Thimmulappa et al., “Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils,” Antioxid. Redox Signal., 9: 1963 - 1970, 2007.

[0643] Thimmulappa et al., “Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide,” Biochem. Biophys. Res. Commun., 351:883-889, 2006.

[0644] Vachiéry and Davenport, “The endothelin system in pulmonary and renal vasculopathy: les liaisons dangereuses,” European Respiratory Review, 18:260-271, 2009.

[0645] Vasan et al., “Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: Prevalence and mortality in a population-based cohort,” Journal of the American College of Cardiology, 33:1948-1955, 1,999.

[0646] Vázquez et al., “Human immunodeficiency virus type 1-induced macrophage gene expression includes the p21 gene, a target for viral regulation,” J. Virol., 79:4479-4491, 2005.

[0647] Wang et al., “A Synthetic Triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a Ligand for the Peroxisome Proliferator-Activated Receptorγ,” Mol. Endocrin., 14(10):1550-1556, 2000.

[0648] Wu et al., “Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARgamma, and HO-1,” Am. J. Physiol. Renal Physiol., 300: F1180 - F1192, 2011.

[0649] Wu et al., “Bardoxolone methyl (BARD) ameliorates aristolochic acid (AA)-induced acute kidney injury through Nrf2 pathway,” Toxicology, 318: 22 - 31, 2014.

[0650] Wu et al., “Prevention of murine lupus nephritis by targeting multiple signaling axes and oxidative stress using a synthetic triterpenoid,” Arthritis Rheumatol., 66(11): 3129 - 3139, 2014.

[0651] Wyler et al., “Single - cell RNA - sequencing of herpes simplex virus 1 - infected cells connects NRF2 activation to an antiviral program,” Nat. Commun., 10: 4878, 2019.

[0652] Yang et al., “Clinical course and outcomes of critically ill patients with SARS - CoV - 2 pneumonia in Wuhan, China: a single - centered, retrospective, observational study,” Lancet Respir. Med., 8: 475 - 481, 2020.

[0653] Yang et al., “Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome,” March 6, 2020, medRxiv, doi:10.1101 / 2020.03.02.20029975.

[0654] Yates et al., “Pharmacodynamic Characterization of Chemopreventive Triterpenoids as Exceptionally Potent Inducers of Nrf2-regulated Genes,” Mol. Cancer Ther., 6:154-162, 2007.

[0655] Zhang et al., “Nrf2 Activator RTA-408 Protects Against Ozone-Induced Acute Asthma Exacerbation by Suppressing ROS and γδT17 Cells,” Inflammation, 42:1843-1856, 2019.

[0656] Zhou et al., “Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study,” Lancet, 395:1054-1062, 2020.

[0657] Zhao et al., “The role of nuclear factor-erythroid 2 related factor 2 (Nrf-2) in the protection against lung injury,” Am. J. Physiol Lung Cell. Mol. Physiol., 312:L155-162, 2017.

Claims

1. The following compounds or pharmaceutically acceptable salts thereof are intended for use in the preparation of medicaments for the treatment of patients infected with SARS-CoV-2: 。 2. The use according to claim 1, wherein the patient has been identified as having no history of left-sided heart failure or wherein the patient has no evidence of left ventricular dysfunction.

3. The use according to claim 1, wherein the patient does not have cardiovascular disease.

4. The use according to claim 1, wherein the patient has cardiovascular disease.

5. The use according to claim 3 or claim 4, wherein the cardiovascular disease is left-sided cardiomyopathy.

6. The use according to claim 3 or claim 4, wherein the cardiovascular disease is atherosclerosis.

7. The use according to claim 3 or claim 4, wherein the cardiovascular disease is restenosis.

8. The use according to claim 3 or claim 4, wherein the cardiovascular disease is thrombosis.

9. The use according to claim 3 or claim 4, wherein the cardiovascular disease is pulmonary hypertension.

10. The use according to claim 9, wherein the pulmonary hypertension is World Health Organization (WHO) Class I pulmonary hypertension (pulmonary arterial hypertension or PAH).

11. The use according to claim 10, wherein the pulmonary hypertension is pulmonary hypertension associated with connective tissue disease.

12. The use according to claim 10, wherein the pulmonary hypertension is idiopathic pulmonary hypertension.

13. The use according to claim 9, wherein the pulmonary hypertension is WHO Class II pulmonary hypertension.

14. The use according to claim 9, wherein the pulmonary hypertension is WHO Class III pulmonary hypertension.

15. The use according to claim 9, wherein the pulmonary hypertension is WHO Class IV pulmonary hypertension.

16. The use according to claim 9, wherein the pulmonary hypertension is WHO Class V pulmonary hypertension.

17. The use according to claim 1, wherein the patient does not have endothelial dysfunction.

18. The use according to claim 1, wherein the patient has endothelial dysfunction.

19. The use according to claim 1, wherein the patient does not have stage 4 or higher chronic kidney disease.

20. The use according to claim 1, wherein the patient does not have a concentration of less than 45 mL / min / 1.73 m 2 The estimated glomerular filtration rate (eGFR).

21. The use according to claim 1, wherein the patient’s elevated albumin / creatinine ratio (ACR) is not greater than 2000 mg / g.

22. The use according to claim 1, wherein the patient does not have diabetes.

23. The use according to claim 1, wherein the patient has diabetes.

24. The use according to claim 23, wherein the diabetes is type 2 diabetes.

25. The use according to claim 1, wherein the patient does not have diabetes-related complications.

26. The use according to claim 1, wherein the patient has complications related to diabetes.

27. The use according to claim 26, wherein the diabetes-related complication is diabetic nephropathy.

28. The use according to claim 26, wherein the complication is selected from the group consisting of obesity, stroke, peripheral vascular disease, neuropathy, myonecrosis, retinopathy and metabolic syndrome (Syndrome X).

29. The use according to claim 1, wherein the patient does not have insulin resistance.

30. The use according to claim 1, wherein the patient has insulin resistance.

31. The use according to claim 1, wherein the patient does not have fatty liver disease.

32. The use according to claim 1, wherein the patient has fatty liver disease.

33. The use according to claim 1, wherein the patient does not have liver damage.

34. The use according to claim 1, wherein the patient has liver damage.

35. The use according to claim 1, wherein the patient is not overweight.

36. The use according to claim 1, wherein the patient is overweight.

37. The use according to claim 36, wherein the patient is obese.

38. The use according to claim 37, wherein the obesity is Class I.

39. The use according to claim 37, wherein the obesity is Class II.

40. The use according to claim 37, wherein the obesity is Class III.

41. The use according to claim 37, wherein the patient's body mass index (BMI) is from 25 kg / m². 2 Up to 30kg / m 2 .

42. The use according to claim 37, wherein the patient's BMI is from 30 kg / m². 2 Up to 35 kg / m 2 .

43. The use according to claim 37, wherein the patient's BMI is from 35 kg / m². 2 Up to 40 kg / m 2 .

44. The use according to claim 37, wherein the patient's BMI is from 40 kg / m². 2 Up to 80 kg / m 2 .

45. The use according to claim 1, wherein the patient has cancer.

46. ​​The use according to claim 1, wherein the patient does not have cancer.

47. The use according to claim 45, wherein the cancer is an advanced solid tumor or a malignant lymphoma.

48. The use according to claim 45, wherein the cancer is selected from the group consisting of: breast cancer, prostate cancer, colon cancer, brain cancer, melanoma, pancreatic cancer, ovarian cancer, leukemia, or bone cancer.

49. The use according to claim 48, wherein the cancer is advanced malignant melanoma.

50. The use according to claim 48, wherein the cancer is pancreatic cancer.

51. The use according to claim 1, wherein the patient does not have chronic obstructive pulmonary disease (COPD).

52. The use according to claim 1, wherein the patient has chronic obstructive pulmonary disease (COPD).

53. The use according to claim 1, wherein the patient is a smoker.

54. The use according to claim 1, wherein the patient is not a smoker.

55. The use according to claim 1, wherein the patient has impaired renal function.

56. The use according to claim 1, wherein the patient has elevated levels of at least one kidney disease-related biomarker.

57. The use according to claim 56, wherein the biomarker is serum creatinine.

58. The use according to claim 56, wherein the biomarker is cysteine ​​protease inhibitor C.

59. The use according to claim 56, wherein the biomarker is uric acid.

60. The use according to claim 1, wherein the patient has radiographic infiltration confirmed by imaging prior to treatment.

61. The use according to claim 60, wherein the imaging is a chest X-ray or CT scan.

62. The use according to claim 1, wherein the patient's oxygen saturation at rest is at most 94% before treatment.

63. The use according to claim 1, wherein the patient requires supplemental oxygen prior to treatment.

64. The use according to claim 1, wherein the patient requires non-invasive ventilation prior to treatment.

65. The use according to claim 1, wherein the patient requires mechanical ventilation for up to 2 days prior to treatment.

66. The use according to claim 1, wherein the drug is used to suppress or prevent systemic inflammation in the patient.

67. The use according to claim 66, wherein the drug is used to inhibit or prevent cytokine storm in the patient.

68. The use according to claim 1, wherein the drug is used to inhibit or prevent lung inflammation in the patient.

69. The use according to claim 1, wherein the drug is used to treat or prevent inflammation-induced liver injury in the patient.

70. The use according to claim 1, wherein the drug is used to treat or prevent acute lung injury in the patient.

71. The use according to claim 1, wherein the drug is used to treat or prevent kidney damage in the patient.

72. The use according to claim 1, wherein the drug is used to treat or prevent acute kidney injury in the patient.

73. The use according to claim 1, wherein the drug is used to improve the renal function of the patient.

74. The use according to claim 1, wherein the drug is used to increase the estimated glomerular filtration rate (eGFR) of the patient.

75. The use according to claim 1, wherein the drug is used to treat or prevent acute respiratory distress syndrome in the patient.

76. The use according to claim 1, wherein the drug is used to treat or prevent epileptic seizures in the patient.

77. The use according to claim 1, wherein the drug is used to treat or prevent encephalitis in the patient.

78. The use according to claim 1, wherein the drug is used to reduce the patient's hospital stay.

79. The use according to claim 1, wherein the drug is used to reduce the time spent in the intensive care unit.

80. The use according to claim 1, wherein the drug is used to delay the patient's need for hospitalization.

81. The use according to claim 1, wherein the drug is used to increase the survival probability of the patient.

82. The use according to claim 1, wherein the drug is used to avoid the need for non-invasive mechanical ventilation.

83. The use according to claim 1, wherein the drug is used to avoid the need for invasive mechanical ventilation.

84. The use according to claim 1, wherein the drug is used to prevent respiratory failure.

85. The use according to claim 1, wherein the drug is used to reduce the patient's WHO score.

86. The use according to claim 1, wherein the drug is used to avoid the need for renal replacement therapy.

87. The use according to claim 1, wherein the patient exhibits minor hematuria.

88. The use according to claim 87, wherein the patient presents with hematuria.

89. The use according to claim 1, wherein the patient further exhibits microalbuminuria.

90. The use according to claim 89, wherein the patient exhibits albuminuria.

91. The use according to claim 90, wherein the concentration of albumin in the patient's urine is between 30 µg / mg creatinine and 300 µg / mg creatinine.

92. The use according to claim 90, wherein the concentration of albumin in the patient's urine is greater than 300 µg / mg creatinine.

93. The use according to claim 1, wherein the patient further exhibits proteinuria.

94. The use according to claim 90, wherein the patient exhibits significant proteinuria.

95. The use according to claim 94, wherein the patient's urine exhibits the presence of multiple proteins.

96. The use according to claim 94, wherein the patient’s urine exhibits a protein / creatinine ratio greater than 0.2 mg / g.

97. The use according to claim 96, wherein the patient’s urine exhibits a protein / creatinine ratio greater than 1.0 mg / g.

98. The use according to claim 1, wherein the patient has a concentration of less than 45 mL / min / 1.73 m 2 eGFR.

99. The use according to claim 98, wherein the patient exhibits an ACR of less than 2000 mg / g.

100. The use according to claim 1, wherein the patient is less than 75 years old.

101. The use according to claim 100, wherein the patient is less than 70 years old.

102. The use according to claim 101, wherein the patient is less than 60 years old.

103. The use according to claim 102, wherein the patient is less than 40 years old.

104. The use according to claim 103, wherein the patient is less than 30 years old.

105. The use according to claim 104, wherein the patient is less than 25 years old.

106. The use according to claim 1, wherein the patient does not have at least one of the following characteristics: (A) Cardiovascular diseases; (B) Elevated baseline B-type natriuretic peptide (BNP) levels; (C) Estimated glomerular filtration rate (eGFR) < 45 mL / min / 1.73 m 2 ;and (D) Elevated albumin / creatinine ratio (ACR) > 2000 mg / g.

107. The use according to claim 106, wherein the patient does not have two of the features.

108. The use according to claim 106, wherein the patient does not have three of the said features.

109. The use according to claim 108, wherein the patient does not have any of the features.

110. The use according to claim 1, wherein the patient was not intubated for three days or longer during treatment.

111. The use according to claim 1, wherein the patient is not mechanically ventilated for three days or longer during treatment.

112. The use according to claim 1, wherein the patient does not require invasive mechanical ventilation for three days or longer during treatment.

113. The use according to claim 1, wherein the patient was not intubated for three days or longer during treatment.

114. The use according to claim 1, wherein it is unknown that the patient has an impaired left ventricular ejection fraction.

115. The use according to claim 114, wherein it is unknown that the patient has a left ventricular ejection fraction (LVEF) of less than 40%.

116. The use according to claim 1, wherein the patient has not previously been hospitalized for heart failure.

117. The use according to claim 1, wherein the patient has not previously experienced cardiac arrest.

118. The use according to claim 1, wherein the patient has not previously experienced shock.

119. The use according to claim 1, wherein the patient does not have an uncontrolled bacterial infection.

120. The use according to claim 1, wherein the patient does not have an uncontrolled fungal infection.

121. The use according to claim 1, wherein the patient does not have any other uncontrolled viral infection other than SARS-CoV-2 infection.

122. The use according to claim 1, wherein the patient does not have a history of cirrhosis, chronic active hepatitis, or severe liver disease.

123. The use according to claim 1, wherein the patient does not have an estimated glomerular filtration rate (eGFR) <15 mL / min / 1.73 m 2 Medical history.

124. The use according to claim 1, wherein the patient does not have a history of needing dialysis.

125. The use according to claim 1, wherein the patient's ALT level or AST level is not more than 5 times higher than ULN.

126. The use according to claim 1, wherein the patient is a person.

127. The use according to claim 1, wherein the patient is male.

128. The use according to claim 1, wherein the patient is female.

129. The use according to claim 1, wherein at least a portion of the compound exists as a crystalline form having a CuKα X-ray diffraction pattern with prominent diffraction peaks at 8.8, 12.9, 13.4, 14.2, and 17.4°2θ.

130. The use according to claim 129, wherein the CuKα X-ray diffraction pattern is substantially as shown in Figure 1A or Figure 1B.

131. The use according to claim 1, wherein at least a portion of said compound exists as an amorphous form having a CuKα X-ray diffraction pattern containing a peak at 13.5°2θ and a glass transition temperature (T0) substantially as shown in Figure 1C. g ).

132. The use according to claim 131, wherein the T g The value is in the range of 120℃ to 135℃.

133. The use according to claim 132, wherein the T g The value is in the range of 125℃ to 130℃.

134. The use according to claim 1, wherein at least a portion of the compound exists as a crystalline form having a CuKα X-ray diffraction pattern with prominent diffraction peaks at 6.2, 12.4, 15.4, 18.6, and 24.9°2θ.

135. The use according to claim 134, wherein the crystalline form is further characterized by 1, 2, 3, 4 or 5 additional diffraction peaks selected from a set of the following members: 8.6, 13.3, 13.7, 17.1 and 21.7°2θ.

136. The use according to claim 1, wherein at least a portion of the compound exists as a crystalline form having a CuKα X-ray diffraction pattern with prominent diffraction peaks at 3.6, 7.1, 10.8, 12.4, and 16.5°2θ.

137. The use according to claim 136, wherein the crystalline form is further characterized by 1, 2, 3, 4 or 5 additional diffraction peaks selected from a set of the following members: 12.9, 13.9, 14.8, 18.6 and 20.6°2θ.

138. The use according to claim 136 or 137, wherein the crystalline form is further characterized by having a crystal size of 2949, 1671, 1618, and 1464 ± 4 cm⁻¹. -1 The Raman spectrum of the peak at that point.

139. The use according to claim 1, wherein the daily dose is from 2.5 mg to 30 mg of the compound.

140. The use according to claim 139, wherein the daily dose is 2.5 mg of the compound.

141. The use according to claim 139, wherein the daily dose is 5 mg of the compound.

142. The use according to claim 139, wherein the daily dose is 10 mg of the compound.

143. The use according to claim 139, wherein the daily dose is 15 mg of the compound.

144. The use according to claim 139, wherein the daily dose is 20 mg of the compound.

145. The use according to claim 139, wherein the daily dose is 30 mg of the compound.

146. The use according to claim 1, wherein the compound is administered to the patient in a pharmaceutically effective amount, said pharmaceutically effective amount being a daily dose of 0.01-100 mg compound / kg body weight.

147. The use according to claim 146, wherein the daily dose is 0.05-30 mg compound / kg body weight.

148. The use according to claim 147, wherein the daily dose is 0.1-10 mg compound / kg body weight.

149. The use according to claim 148, wherein the daily dose is 0.1-5 mg compound / kg body weight.

150. The use according to claim 149, wherein the daily dose is 0.1-2.5 mg compound / kg body weight.

151. The use according to claim 1, wherein the compound is administered to the patient as a single dose daily.

152. The use according to claim 1, wherein the compound is administered to the patient daily as two or more doses.

153. The use according to claim 1, wherein the compound is administered orally, intravenously, or intravenously.

154. The use according to claim 1, wherein the compound is formulated into hard or soft capsules or tablets.

155. The use according to claim 1, wherein the compound is formulated into a solid dispersion comprising (i) the compound and (ii) an excipient.

156. The use according to claim 155, wherein the excipient is a methacrylate-ethyl acrylate copolymer.

157. The use according to claim 156, wherein the copolymer comprises methacrylic acid and ethyl acrylate in a 1:1 ratio.

158. The use according to claim 1, wherein the drug is prepared for administration to the patient by means of further comprising a second therapy.

159. The use according to claim 158, wherein the second therapy comprises administering a therapeutically effective amount of the second drug or convalescent plasma to the patient.

160. The use according to claim 159, wherein the second drug is an antiplatelet drug, an anticoagulant, an antiviral drug, or a corticosteroid.

161. The use according to claim 159, wherein the second drug is remdesivir or tocilizumab.

162. The use according to claim 160, wherein the second drug is human type I IFN.

Images