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Title:
METHODS AND COMPOSITIONS FOR TREATING AND PREVENTING VIRAL INFECTION
Document Type and Number:
WIPO Patent Application WO/2021/202547
Kind Code:
A1
Abstract:
The present invention relates to methods, compositions, and combinations for preventing and/or treating viral infection, particularly infection with Influenza A or SARS-CoV-2 or a variant thereof. In certain aspects, the methods, compositions, and combinations include a synthetic triterpenoid, such as 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-2-yl)-1H-imidazole ("CDDO-2P-Im") and 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-3-yl)-1H-imidazole ("CDDO-3P-Im"). In certain embodiments, the synthetic triterpenoid prevents or reduces an aberrant inflammatory response caused by a viral infection.

Inventors:
SPORN MICHAEL B (US)
Application Number:
PCT/US2021/024910
Publication Date:
October 07, 2021
Filing Date:
March 30, 2021
Export Citation:
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Assignee:
TRITERPENOID THERAPEUTICS INC (US)
International Classes:
C07J61/00
Attorney, Agent or Firm:
O'CONNOR, Kevin A. (US)
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Claims:
CLAIMS

1. A method for preventing an infection with a virus in a subject in need thereof, the method comprising administering a prophylactically effective amount of a synthetic triterpenoid to the subject.

2. The method of claim 1, wherein the subject is at risk of being exposed to the virus.

3. The method of claim 1, wherein the subject is suspected of being exposed to the virus.

4. The method of any one of claims 1-3, wherein the subject is a human.

5. The method of claim 1, wherein the synthetic triterpenoid is l-[2-Cyano-3,12- dioxooleana- 1,9(1 l)-dien-28-oyl]-4(-pyridin-2-yl)-lH-imidazole (“CDDO-2P-Im”) or l-[2- Cyano-3,12-dioxooleana-l,9(l l)-dien-28-oyl]-4(-pyridin-3-yl)-lH-imidazole (“CDDO-3P-Im”).

6. The method of claim 5, wherein the virus is selected from the group consisting of Influenza A, SARS-CoV-2, and variants thereof.

7. A method for treating an infection with a virus in a host in need thereof, the method comprising administering a therapeutically effective amount of a synthetic triterpenoid to the host.

8. The method of claim 7, wherein the host is a human.

9. The method of any one of claims 7-8, wherein the therapeutically effective amount is an amount to reduce an aberrant inflammatory response caused by viral infection.

10. The method of any one of claims 7-8, wherein the synthetic triterpenoid is l-[2- Cyano-3,12-dioxooleana-l,9(ll)-dien-28-oyl]-4(-pyridin-2-yl)-lH-imidazole (“CDDO-2P-Im”) or l-[2-Cyano-3,12-dioxooleana-l,9(l l)-dien-28-oyl]-4(-pyridin-3-yl)-lH-imidazole (“CDDO- 3P-Im”).

11. The method of claim 10, wherein the virus is selected from the group consisting of Influenza A, SARS-CoV-2, and variants thereof.

12. The method of any one of claims 1-11, wherein the virus belongs to the family Orthomyxoviridae, Coronaviridae, Filoviridae, or Orthocoronavirinae .

13. The method of any one of claims 1-11, wherein the virus is Influenza A.

14. The method of any one of claims 1-11, wherein the virus is SARS-CoV-2 or a variant thereof.

15. The method of any one of claims 2-4, 9, or 12-14, wherein the synthetic triterpenoid is l-[2-Cyano-3,12-dioxooleana-l,9(l l)-dien-28-oyl]-4(-pyridin-2-yl)-lH-imidazole (“CDDO- 2P-Im”) or l-[2-Cyano-3,12-dioxooleana-l,9(l l)-dien-28-oyl]-4(-pyridin-3-yl)-lH-imidazole (“CDDO-3P-Im”)).

16. A method for treating a patient having, or suspected of having, COVID-19, the method comprising administering a therapeutically effective amount of a synthetic triterpenoid to the subject.

17. The method of claim 16, wherein the synthetic triterpenoid is l-[2-Cyano-3,12- dioxooleana- 1,9(1 l)-dien-28-oyl]-4(-pyridin-2-yl)-lH-imidazole (“CDDO-2P-Im”) or l-[2- Cyano-3,12-dioxooleana-l,9(l l)-dien-28-oyl]-4(-pyridin-3-yl)-lH-imidazole (“CDDO-3P-Im”).

18. The method of claim 16, wherein the host is a human.

19. The method of claim 18, wherein the synthetic triterpenoid is l-[2-Cyano-3,12- dioxooleana- 1,9(1 l)-dien-28-oyl]-4(-pyridin-2-yl)-lH-imidazole (“CDDO-2P-Im”) or l-[2- Cyano-3,12-dioxooleana-l,9(l l)-dien-28-oyl]-4(-pyridin-3-yl)-lH-imidazole (“CDDO-3P-Im”).

20. The method of any one of claims 17-19, wherein the therapeutically effective amount is an amount to reduce an aberrant inflammatory response caused by an infection with SARS-CoV-2 or a variant thereof.

Description:
METHODS AND COMPOSITIONS FOR TREATING AND PREVENTING VIRAL

INFECTION

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Patent Application No. 63/003,534, which was filed on April 1, 2020, the entire contents of which are incorporated herein by reference.

TECHNICAL FIELD

[0002] The present invention relates to methods and compositions for treating and preventing viral infection, particular infection by viruses of the family Orthomyxoviridae , such as influenzavirus, and viruses of the family Coronaviridae , such as SARS-CoV-2.

BACKGROUND

[0003] Certain viruses containing minus-strand RNA (“(-)RNA”), such as viruses in the family Coronaviridae , Filoviridae, or Orthocoronavirinae cause epidemics of serious human illness.

[0004] The family Filoviridae includes genera Ebolavirus and Marburgvirus . There are at least five distinct species of the genus Ebolavirus , including Bundibugyo virus (“BDBV”), Ebola virus (“EBOV”, formerly designated Zaire ebolavirus), Reston virus (“RESTV”), Sudan virus (“SUDV”), and Tai Forest virus (“TAFV”; formerly known as Cote d’Ivoire ebolavirus).

[0005] Ebola virus disease (EVD), formerly known as Ebola haemorrhagic fever, is a severe, often fatal illness in humans. From 1976 until late 2013/early 2014, sporadic outbreaks had occurred in humans in Central Africa, causing more than 1,800 human infections with a lethality rate up to 90%. The Ebola epidemic that began in early 2014 is the largest in history, affecting multiple countries in West Africa, such as Guinea, Liberia, and Sierra Leone and causing more than 19,000 human infections and more than 7,500 deaths. The virus causing the 2014 West African outbreak belongs to the Zaire species, also known as EBOV.

[0006] The family Orthomyxoviridae includes species such as Influenzavirus A and

Influenzavirus B. There several subtypes of Influenzavirus A, including H1N1, H1N2, H2N2, H3N2, H5N1, H7N9, H7N7, H9N2, H7N2, H7N3, H5N2, AND H10N7.

[0007] Influenza A virus subtype H1N 1 (A/H1N1) is the subtype of influenza A virus that was the most common cause of human influenza (flu) in 2009, and is associated with the 1918 outbreak known as the Spanish flu. A highly pathogenic form of Influenza A virus subtype H5N1 (A/H5N1) is the causative agent of H5N1 flu, commonly known as avian influenza (“bird flu”). [0008] The family Coronaviridae includes genera such as Betacoronavirus. Several distinct species of the genus Betacoronavirus , including Middle East respiratory syndrome-related coronavirus (MERS-CoV), Severe acute respiratory syndrome coronavirus (SARS-CoV), and Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), produce symptoms that are potentially severe in humans. SARS-CoV-2 is the virus responsible for coronavirus disease 2019 (COVID-19) COVID-19 is spreading rapidly across the globe, with no proven effective therapy. [0009] COVID-19 patients requiring ICU admission have high circulating levels of IL-6,

GM-CSF, MCP and MIP1 (CCL2) cytokines compared to those with uncomplicated illnesses. This hyper-inflammation syndrome (aka “cytokine storm”) is a prodromal feature of acute respiratory distress syndrome (ARDS) and multi-organ failure. Bronchoalveolar fluids (BALF) from patients with severe COVID-19 are enriched in CCL2, one of the most potent chemokines driving the recruitment of monocytes into the lung. Of note, cytokine storm is also associated with extensive lung damage in SARS-CoV and MERS-CoV infections, suggesting that innate hyper inflammation is common to respiratory zoonoses. Indeed, much of the human pathology of COVID-19 (and other viruses as well, especially severe influenza) appears to be the result of an exaggerated inflammatory response, terminating with accumulation of large amounts of fluid in the lung which block needed gas exchange.

[0010] At this time, there is no preventive vaccine or post-exposure treatment option available for human use for many of these viruses. Moreover, recent global epidemics underscore the need for preventative and therapeutic treatment options. Therefore, there continues to be a significant need for treatments for viral diseases, particularly viral diseases caused by infection with viruses in the family Orthomyxoviridae, Coronaviridae , Filoviridae, or Orthocoronavirinae .

SUMMARY OF THE INVENTION

[0011] In one aspect, this disclosure provides a method for preventing infection with a virus in a subject in need thereof. The method includes administering a prophylactically effective amount of at least one synthetic triterpenoid to the subject. In certain embodiments, the subject is a human. In some such embodiments, the subject is at risk of being exposed to the virus. In some such embodiments, the subject is suspected of being exposed to the virus. [0012] In one aspect, this disclosure provides a method for treating a host infected with a virus. The method includes administering a therapeutically effective amount of at least one synthetic triterpenoid to the host. In certain embodiments, the host is a human.

[0013] In one aspect, this disclosure provides a composition for treating or preventing a viral infection in a host or subject. The composition comprises at least one synthetic triterpenoid in combination with a pharmaceutically acceptable carrier or excipient. When used to treat or prevent a viral infection, a synthetic triterpenoid can be used in combination with one or more additional therapeutic or prophylactic agents, such as one more anti-viral agents.

[0014] In some embodiments of any aspects disclosed herein, the synthetic triterpenoid is an analog or derivative of l-[2-Cyano-3,12-dioxooleana-l,9(l l-dien-28-oyl) (CDDO-Im) or a pharmaceutically acceptable salt thereof and, in particular, a pyridyl analog such as CDDO-2P-Im or CDDO-3P-Im. In some such embodiments, the synthetic triterpenoid is l-[2-Cyano-3,12- dioxooleana- 1,9(1 l)-dien-28-oyl]-4(-pyridin-2-yl)-lH-imidazole (CDDO-2P-Im) or a pharmaceutically acceptable salt thereof. In some embodiments of any aspects disclosed herein, the synthetic triterpenoid is administered orally.

[0015] In some embodiments of any aspects disclosed herein, the virus belongs to the family Orthomyxoviridae, Coronaviridae, Filoviridae, or Orthocoronavirinae . In some such embodiments, the virus is Influenza A. In some such embodiments, the virus is SARS-CoV-2 or a variant thereof.

BRIEF DESCRIPTION OF THE DRAWINGS [0016] FIG. 1 depicts a Western blot. CDDO-Im, CDDO-2P-Im, and CDDO-3P-Im inhibit

Caspase 1 activation. LPS primed BMDM were treated with different doses of CDDO-Im, CDDO- 2P-Im, or CDDO-3P-Im for 15 min before ATP (5 mM) was added for 45 min. Medium supernatant (SUP) and cell extracts (Lys) were analyzed by immunoblotting.

[0017] FIG. 2 is a set of bar graphs. CDDO-Im, CDDO-2P-Im (right panel), and CDDO-

3P-Im (left panel) inhibit IL-Ib production by NLRP3 inflammasome activation. LPS primed- BMDM were treated with different doses of CDDO-Im, CDDO-2P-Im, or CDDO-3P-Im for 15 min before ATP (5 mM) was added for 45 min. Supernatant were analyzed by ELISA for IL-Ib. [0018] FIG. 3 is a bar graph. CDDO-Im, CDDO-2P-Im, and CDDO-3P-Im inhibit mono sodium urate (MSU)-induced peritonitis. Peritoneal cavity IL-Ib levels expressed as mean and SEM (n = 6). [0019] FIG. 4 is a bar graph. CDDO-Me, CDDO-Im, CDDO-2P-Im, and CDDO-3P-Im inhibit expression of CCL2 in human macrophages at picomolar concentrations.

[0020] FIG. 5 is a set of line graphs showing dose response curves for CDDO-2P-Im and oseltamivir in cytotoxicity, CPE inhibition, and plaque reduction assays.

DETAILED DESCRIPTION

[0021] This detailed description is intended only to acquaint others skilled in the art with the present invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples are intended for purposes of illustration only. This invention, therefore, is not limited to the embodiments described in this patent application, and may be variously modified.

[0022] A. DEFINITIONS

[0023] As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:

[0024] The term “about” as used herein, means approximately, and in most cases within

10% of the stated value.

[0025] The term “pharmaceutically acceptable” is used adjectivally to mean that the modified noun is appropriate for use as a pharmaceutical product for human use or as a part of a pharmaceutical product for human use.

[0026] The terms “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a condition, disorder, or disease and/or the attendant symptoms thereof.

[0027] B. METHODS OF PREVENTION AND TREATMENT

[0028] In one aspect, this disclosure provides a method for preventing infection with a virus in a subject in need thereof. The method comprises administering a synthetic triterpenoid to a subject in need thereof. In some embodiments, the virus belongs to the family Orthomyxoviridae, Coronaviridae, Filoviridae , or Orthocoronavirinae . In some embodiments, the virus is Influenza

A. In some embodiments, the virus is SARS-CoV-2. In some such embodiments, the virus is a SARS-CoV-2 variant, such as B.1.1.7 (also classified as 20I/501Y.V1), B.1.351 (also classified as 20H/501Y.V2), P.l (also classified as 20J/501Y.V3), B.1.427 (also classified as 20C/S:452R),

B.1.429 (also classified as 20C/S:452R), B.1.525 (also classified as 20C), or B.1.526 (also classified as 20C). In some such embodiments, the virus is a SARS-CoV-2 variant having a mutation at K417, L452, E484, and/or N501.

[0029] In some embodiments, the synthetic triterpenoid is l-[2-Cyano-3,12-dioxooleana-

1,9(1 l)-dien-28-oyl]-4(-pyridin-2-yl)-lH-imidazole. In some embodiments, the synthetic triterpenoid is administered orally. In some embodiments, the subject is a human. In some such embodiments, the subject is at risk of being exposed to the virus. In some such embodiments, the subject is suspected of being exposed to the virus.

[0030] In one aspect, this disclosure provides a method for treating a host infected with a virus. The method includes administering a therapeutically effective amount of at least one synthetic triterpenoid to the host. In some embodiments, the virus belongs to the family Orthomyxoviridae, Coronaviridae, Filoviridae, or Orthocoronavirinae . In some embodiments, the virus is Influenza A. In some embodiments, the virus is SARS-CoV-2 or a SARS-CoV-2 variant. In some embodiments, the synthetic triterpenoid is l-[2-Cyano-3,12-dioxooleana-l,9(l l)-dien-28- oyl]-4(-pyridin-2-yl)-lH-imidazole. In some embodiments, the synthetic triterpenoid is administered orally. In some embodiments, the host is a human. In some such embodiments, the host is in the early stages of a disease caused by the virus.

[0031] In one aspect, this disclosure provides a method for treating a patient diagnosed with, or suspected of suffering from, a disease caused by a virus, such as COVID-19. The method includes administering a therapeutically effective amount of at least one synthetic triterpenoid to the patient. In some embodiments, the synthetic triterpenoid is l-[2-Cyano-3,12-dioxooleana- 1,9(1 l)-dien-28-oyl]-4(-pyridin-2-yl)-lH-imidazole. In some embodiments, the synthetic triterpenoid is administered orally. In some embodiments, the patient is a human. In some such embodiments, the patient is confirmed to be positive for SARS-CoV-2 or a SARS-CoV-2 variant. In other such embodiments, the patient is suspected to be positive for SARS-CoV-2 or a SARS- CoV-2 variant. SARS-CoV-2 variants include, but are not limited to, B.l.1.7 (also classified as 201/501 Y. VI), B.1.351 (also classified as 20H/501Y.V2), P.l (also classified as 20J/501Y.V3), B.1.427 (also classified as 20C/S:452R), B.1.429 (also classified as 20C/S:452R), B.1.525 (also classified as 20C), or B.1.526 (also classified as 20C).

[0032] In certain embodiments, an initial diagnosis or clinical impression of viral infection is established. Such diagnosis or clinical impression may be reached on the basis of a physical examination, a patient history, and/or one or more laboratory tests. In certain embodiments, a diagnosis or clinical impression that the patient is infected with a virus is reached in the absence of a laboratory test. In certain embodiments, a diagnosis or clinical impression that the patient is infected with a virus is based, at least in part, on the results of a laboratory test. In certain embodiments, a healthcare provider requests the results of a laboratory test to detect or quantify a virus in a patient sample. In certain embodiments, the laboratory test is an immunoassay, such as an enzyme-linked immunosorbent assay (ELISA) or Western blot. In certain embodiments, the laboratory test detects and/or quantifies a viral antigen. For example, a viral antigen may be detected and/or quantified by ELISA. In certain embodiments, the laboratory test detects and/or quantifies a virus-specific immunoglobulin, such as immunoglobulin M (IgM) or G (IgG). For example, a virus-specific IgM or IgG may be detected and/or quantified by ELISA or Western blot. In certain embodiments, the laboratory test detects and/or quantifies a viral genome or portion thereof. For example, a viral genome or portion thereof may be detected and/or quantified by reverse transcription-polymerase chain reaction (RT-PCR). In certain embodiments, the laboratory test is a viral load test. For example, viral load may be determined by PCR, branched- chain DNA, or nucleic acid sequence based amplification (NASBA). In certain embodiments, the patient sample is a blood sample, such as a serum sample. In certain embodiments, the patient sample is a saliva sample.

[0033] In one aspect, this disclosure provides a method for treating or preventing macrophage activation syndrome in a patient in need thereof. In certain embodiments, macrophage activation syndrome is caused by a viral infection, such as infection with an influenza virus ( e.g ., Influenza A) or a betacoronavirus (e.g., SARS-CoV-2 or variants thereof). The method includes administering an effective amount of at least one synthetic triterpenoid to the patient. In some embodiments, the synthetic triterpenoid is l-[2-Cyano-3,12-dioxooleana-l,9(l l)-dien-28-oyl]-4(- pyridin-2-yl)-lH-imidazole. In some embodiments, the synthetic triterpenoid is administered orally. In some embodiments, the patient is a human. In some such embodiments, the patient is confirmed to be infected with a virus such as Influenza A, SARS-CoV-2, or a SARS-CoV-2 variant.

[0034] C. COMPOUNDS, COMPOSITIONS, AND COMBINATIONS

[0035] CDDO-Im is a synthetic triterpenoid. US Patent No. 6,974,801 and WO

2004/064723, each of which are incorporated herein by reference in their entirety, describe l-(2- cyano-3,12-dioxooleana-l,9(l l)-dien-28-oyl) imidazole (CDDO-Im), which has the chemical structure:

[0036] US Patent No. 9,896,475, which is incorporated herein by reference in its entirety, describes analogs and derivatives of CDDO-Im, including pyridyl analogs of CDDO-Im, which are more stable in human plasma and achieve a higher concentration in target tissues such as liver, pancreas, kidney and lungs.

[0037] Particular synthetic triterpenoids described herein include compounds having the structure of Formula I and pharmaceutically acceptable salts thereof:

Formula I wherein one or more of R 1 , R 2 or R 3 is independently a heteroaryl group (preferably a pyridyl group), cycloalkyl group, heterocyclyl group, carboxamide group, nitrile group, haloalkyl group, or acyl group, each of which may be substituted or unsubstituted where appropriate, and the remaining R groups are hydrogen. In a particular embodiment, R 2 is a substituted or unsubstituted aryl group, heteroaryl group, cycloalkyl group or heterocyclyl group, and R 1 and R 3 are hydrogen. [0038] In certain embodiments, R 2 is a substituted or unsubstituted heteroaryl group

(preferably a pyridyl group) and R 1 and R 3 are hydrogen. In some such embodiments, the heteroaryl group (preferably a pyridyl group) is unsubstituted. In other such embodiments, the heteroaryl group (preferably a pyridyl group) is substituted with one or more substituents selected from the group consisting of halogen, Ci-6-alkyl, Ci-6-haloalkyl, and a carboxamide, each of which is optionally substituted.

[0039] The term “heteroaryl” refers to a five- or six-membered aromatic ring structure, wherein at least one of the aromatic ring atoms is nitrogen, oxygen or sulfur, and wherein the monovalent group is composed of carbon, hydrogen, aromatic nitrogen, aromatic oxygen or aromatic sulfur. Non-limiting examples of aryl groups include acridinyl, furanyl, imidazoimidazolyl, imidazopyrazolyl, imidazopyridinyl, imidazopyrimidinyl, indolyl, indazolinyl, methylpyridyl, oxazolyl, phenylimidazolyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, tetrahydroquinolinyl, thienyl, triazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrroloimidazolyl, and chromenyl, wherein the point of attachment is one of the aromatic atoms. In particular embodiments, the heteroaryl is a pyridyl group. In some such embodiments, the pyridyl group is unsubstituted. In other such embodiments, the pyridyl group is substituted.

[0040] “Cycloalkyl” means a non-aromatic mono- or multicyclic ring system including about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1- decalinyl, norbornyl, adamantyl and the like.

[0041] “Heterocyclyl” or “heterocycloalkyl” means a non-aromatic saturated monocyclic or multicyclic ring system including about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N- oxide, S-oxide or S,S-di oxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4- dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. Non-limiting examples of suitable bicyclic heterocyclyl rings include decahydro-isoquinoline, decahydro- [2,6]naphthyridine, and the like.

[0042] As used herein, a “carboxamide” or “carboxamide group” refers to a -C(=0)NH2 group.

[0043] The term “nitrile” or “nitrile group” is intended to refer to a -CºN group.

[0044] As used herein, “alkyl” or “alkyl group” includes linear or branched saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Ci- 6 alkyl, for example, includes Ci, C2, C3, C4, C5, and Ce alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, sec- pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, n-hexyl, and 2-methylpentyl. In particular embodiments, an alkyl of this invention is a Ci- 6 alkyl, C1-5 alkyl, Ci-4 alkyl, C1-3 alkyl, or C1-2 alkyl.

[0045] The term “haloalkyl group” refers to a linear or branched alkyl group substituted by one or more halogen atoms, the same or different, optionally selected from fluorine, chlorine, bromine, and iodine. Examples of this group include fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2, 2,3,3- tetrafluoropropyl, 2,2, 3 ,3 , 3 -pentafluoropropyl .

[0046] “Acyl,” as used herein alone or as part of another group, refers to a -C(=0)R radical, where R is, e.g ., an aryl, alkyl, alkenyl, alkynyl, cycloalkyl, or haloalkyl group. When the R group contains a halogen, the group is termed a “haloacyl” group. An example is a trifluoroacetyl group. [0047] The term “aryl” refers to a monovalent group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a five- or six-membered aromatic ring structure wherein the ring atoms are all carbon, and wherein the monovalent group is composed of carbon and hydrogen. Non-limiting examples of aryl groups include phenyl, methylphenyl, (dimethyl)phenyl, -ethylphenyl, propylphenyl, -C6H4CH(CH 3 )2, -C6H4CH(CH2)2, methylethylphenyl, vinylphenyl, naphthyl, and the monovalent group derived from biphenyl. In particular embodiments, the aryl is a phenyl group.

[0048] As used herein, “alkenyl” or “alkenyl group” refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The radical may be in either the cis or trans conformation about the double bond(s). Examples of alkenyl include, but are not limited to, ethenyl, propenyls, such as prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl, prop-2en-2-yl, cycloprop- 1-en-l-yl; cycloprop-2-en-l-yl; butenyls such as but-1- en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-lyl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta- 1,3-dienl-yl, beta-l,3-dien-2-yl, cy cl obut- 1-en-l-yl, cyclobut-l-en3-yl, cyclobuta-l,3-dien-l-yl.

[0049] As used herein, an “alkynyl” or “alkynyl group” refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyls, propargyl, and the like.

[0050] Any of the groups described herein may be unsubstituted or optionally substituted.

When modifying a particular group, “substituted” means that the group the term modifies may, but does not have to, be substituted. Substitutions include the replacement of an available hydrogen with an alkyl, alkenyl, alkynyl, aryl, haloalkyl, haloacyl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, alkoxyalkoxy, acyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyl sulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, or heterocyclyl.

[0051] Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to the atom.

[0052] In some embodiments of any aspects disclosed herein, a synthetic triterpenoid has the structure of Formula II and pharmaceutically acceptable salts thereof:

Formula II wherein one of Y 1 , Y 2 , or Y 3 , is N and the remaining Y groups are each CH. In a particular embodiment, Y 1 is N and Y 2 and Y 3 are CH. In another particular embodiment, Y 2 is N and Y 1 and Y 3 are CH. In another particular embodiment, Y 3 is N and Y 1 and Y 2 are CH.

[0053] A particularly preferred synthetic triterpenoid is l-[2-Cyano-3,12-dioxooleana-

1,9(1 l)-dien-28-oyl]-4(-pyridin-2-yl)-lH-imidazole (CDDO-2P-Im), which is depicted structurally as:

[0054] Another particularly preferred synthetic triterpenoid is l-[2-Cyano-3,12- dioxooleana- 1,9(1 l)-dien-28-oyl]-4(-pyridin-3-yl)-lH-imidazole (CDDO-3P-Im), which is depicted structurally as:

[0055] In some embodiments of any aspects disclosed herein, a synthetic triterpenoid may be present in a pharmaceutical composition in the form of acid or base addition salts. Acid addition salts may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Suitable base addition salts include salts formed with organic and inorganic cations such as those chosen from the alkali and alkaline earth metals (for example, lithium, sodium, potassium, magnesium, barium and calcium), as well as the ammonium ion and substituted derivatives thereof (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like). Thus, the term “pharmaceutically acceptable salt” is intended to encompass any and all acceptable salt forms.

[0056] Pharmaceutical compositions disclosed herein comprise a synthetic triterpenoid, preferably CDDO-2P-Im or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is an oral dosage form, preferably a solid oral dosage form (e.g., a tablet). In some such embodiments, the solid oral dosage form may comprise pharmaceutically acceptable excipients such as excipients that function as binders, glidants, lubricants, and fillers. Thus, a solid oral dosage form comprising a synthetic triterpenoid, further optionally comprises one or more conventional pharmaceutically acceptable excipients.

[0057] A synthetic triterpenoid, preferably CDDO-2P-Im or a pharmaceutically acceptable salt thereof, may be administered in a single or divided dose to provide a total daily dose. The total daily dose of a synthetic triterpenoid (administered in single or divided doses) may typically be from about 0.1 to about 5000 mg, or from about 1 to about 500 mg, or from about 1 to about 100 mg, or from about 5 to about 50 mg.

[0058] Factors affecting the preferred dosage amount and frequency include the type, age, weight, sex, diet, and condition of the patient; the severity of the pathological condition; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular compound or salt used; whether a drug delivery system is utilized; and the specific drug combination, if any. Thus, the dosage regimen actually employed can vary widely, and therefore, can derive from those set forth herein.

[0059] 1. PROPHYLACTIC USE

[0060] In one aspect, this disclosure provides a synthetic triterpenoid, such as CDDO-2P-

Im, CDDO-3P-Im, or a pharmaceutically acceptable salt thereof, for use as a single agent or in combination with one or more additional therapeutic agents (e.g., anti -viral agents) in a method for preventing infection with a virus, such as Influenza A, SARS-CoV-2, or a SARS-CoV-2 variant. In such aspects, a prophylactically effective amount of the synthetic triterpenoid is administered to a subject to prevent viral infection. In some embodiments, the synthetic triterpenoid is CDDO-2P-Im or a pharmaceutically acceptable salt thereof.

[0061] Without wishing to be bound by theory, it is believed that a synthetic triterpenoid, such as CDDO-2P-Im can block virus (e.g, Influenza A and/or SARS-CoV-2) binding to host cell receptors and thereby disrupt the membrane fusion that is required for viral uptake into host cells. [0062] In some embodiments, CDDO-2P-Im or a pharmaceutically acceptable salt thereof is co-administered with one or more additional therapeutic agents.

[0063] In combination therapy, CDDO-2P-Im or a pharmaceutically acceptable salt thereof may be administered at any suitable frequency and may be administered substantially simultaneous with, or independent from, one or more additional therapeutic agents. In some embodiments, CDDO-2P-Im or a pharmaceutically acceptable salt thereof is administered at least once daily (e.g, once per day).

[0064] CDDO-2P-Im or a pharmaceutically acceptable salt thereof and the one or more additional therapeutic agents may be co-administered to the subject from the same pharmaceutical composition or from separate pharmaceutical compositions. CDDO-2P-Im or a pharmaceutically acceptable salt thereof and the one or more additional therapeutic agents may be co-administered in a substantially simultaneous manner (e.g, within about 5 min of each other), in a sequential manner, or both. It is contemplated, for example, that such combination therapies may include administering one therapeutic agent multiple times between the administrations of the other. The time period between the administration of each agent may range from a few seconds (or less) to several hours or days, and will depend on, for example, the properties of each composition and active ingredient (e.g, potency, solubility, bioavailability, half-life, and kinetic profile), as well as the condition of the patient.

[0065] 2. THERAPEUTIC USE

[0066] In one aspect, this disclosure provides a synthetic triterpenoid, such as CDDO-2P-

Im, CDDO-3P-Im, or a pharmaceutically acceptable salt thereof, for use as a single agent or in combination with one or more additional therapeutic agents (e.g, anti -viral agents) in a method for treating a viral infection or a disease or condition caused by a viral infection. In such aspects, a therapeutically effective amount of the synthetic triterpenoid is administered to a subject to treat the viral infection and/or the disease or condition caused by the viral infection. In some embodiments, the disease or condition is caused by infection with Influenza A. In other embodiments, the disease or condition is caused by infection with SARS-CoV-2 or a variant thereof. For example, the disease or condition may be COVID-19. In some embodiments, the synthetic triterpenoid is CDDO-2P-Im or a pharmaceutically acceptable salt thereof.

[0067] Without wishing to be bound by theory, it is believed that a synthetic triterpenoid can block the overwhelming (and inappropriate if it is too strong) host-mediated inflammatory response caused by the virus after infection.

[0068] In some embodiments, CDDO-2P-Im or a pharmaceutically acceptable salt thereof is co-administered with one or more additional therapeutic agents.

[0069] In combination therapy, CDDO-2P-Im or a pharmaceutically acceptable salt thereof may be administered at any suitable frequency and may be administered substantially simultaneous with, or independent from, one or more additional therapeutic agents. In some embodiments, CDDO-2P-Im or a pharmaceutically acceptable salt thereof is administered at least once daily ( e.g ., once per day).

[0070] CDDO-2P-Im or a pharmaceutically acceptable salt thereof and the one or more additional therapeutic agents may be co-administered to the subject from the same pharmaceutical composition or from separate pharmaceutical compositions. CDDO-2P-Im or a pharmaceutically acceptable salt thereof and the one or more additional therapeutic agents may be co-administered in a substantially simultaneous manner (e.g., within about 5 min of each other), in a sequential manner, or both. It is contemplated, for example, that such combination therapies may include administering one therapeutic agent multiple times between the administrations of the other. The time period between the administration of each agent may range from a few seconds (or less) to several hours or days, and will depend on, for example, the properties of each composition and active ingredient (e.g, potency, solubility, bioavailability, half-life, and kinetic profile), as well as the condition of the patient.

[0071] D. EXAMPLES

[0072] Example 1 : Anti-Inflammatory Effects

[0073] Example 1.1.

[0074] The effects of the pyridyl derivatives of CDDO-IM, (specifically, CDDO-2P-Im and CDDO-3P-Im) on NLRP3 inflammasome activation were tested in mouse BMDMs. Cells were first primed with LPS for 4 hours, then pretreated with specific doses of either CDDO-Im, CDDO-2P-IM or CDDO-3P-Im (30-1000nM) for 15 min before ATP was added for another 45 min. CDDO-Im and its pyridyl derivatives inhibited the amount of caspase-plO (an auto-processed fragment of caspase-1) released into cell culture supernatants in a dose-dependent manner as measured by Western blot (Figure 1). This brief exposure to the selected synthetic triterpenoids also prevented secretion of the caspase-1 dependent cytokine IL-Ib into media, as measured by ELISA (see Figure 2). The effect on caspase-1 activation is specific for the NLRP3 inflammasome as the AIM2 inflammasome activation by poly(dA:dT) was not inhibited by the synthetic CDDO- Im derivatives (data not shown).

[0075] Example 1.2.

[0076] Mice received intraperitoneal (i.p.) injections of mono-sodium urate (MSU) crystals (1 mg/mouse) in the presence or absence of CDDO-Im, CDDO-2P-Im, or CDDO-3P-Im. Due to its particulate material, MSU crystals are potent activators of the NOD-like receptor NLRP3. Four to sixteen hours later a peritoneal lavage was conducted to collect supernatant from the peritoneal cavity. As shown in Figure 3, CDDO-Im, CDDO-2P-Im, and CDDO-3P-Im inhibit MSU-induced peritonitis.

[0077] Data presented herein show that CDDO-2P-Im potently inhibits inflammasome activity, which is believed to be, among other things, a cause of major pain in MM.

[0078] Example 1.3.

[0079] The CC chemokine, CCL2 (previously named MCP-1), has been implicated in tumor immune evasion through recruitment of immunosuppressive regulatory T cells and/or myeloid-derived suppressor cells. Macrophages and microglia within the glioma microenvironment produce CCL2 and in clinical specimens of GBM, elevated levels of CCL2 expression correlated with reduced overall survival of patients. See Chang et ak, Cancer Res. 76(19):5671-5682 (2016).

[0080] Human peripheral blood monocytes were isolated using CD 14 magnetic beads and differentiated with 20 ng/ml M-CSF for with 5 days and pretreated or not with 300 nM CDDO- Me; 500 pM CDDO-Im; 500 pM CDDO-2p-Im; 500 pM CDDO-3p-Im for 16 hours, followed by stimulation with 10 ng/ml LPS for an additional 24 hours. Total RNA was extracted and analyzed by RT-qPCR (Taqman) for cytokine expression.

[0081] As shown in Figure 4, CDDO-imidazolides, including CDDO-2P-Im, suppress production of CCL2 by human peripheral blood monocytes at picomolar concentrations. [0082] These data demonstrating potent suppression of CCL2 production by human peripheral blood monocytes further support the clinical application of CDDO-2P-Im.

[0083] The data presented in Example 1 support the potential for synthetic triterpenoids, such as CDDO-2P-Im, to treat aberrant inflammatory responses, including those caused by viral infection.

[0084] Example 2: Anti-Viral Activity

[0085] CDDO-2P-Im was evaluated for efficacy against Influenza virus A using cytopathic effect (CPE) inhibition assay and plaque reduction assay. Cytotoxicity was assessed in parallel. [0086] Antiviral efficacy of CDDO-2P-Im was tested against Influenza virus A H1N1

(Califomia/2009) and Influenza virus A H3N2 (Hong Kong/1968). CDDO-2P-Im was dissolved in basal medium supplemented with 0.2% BSA to provide a 10 mM stock solution.

[0087] Cytotoxicity Assay. Cells were seeded in black 96-well culture plates and incubated overnight. Ten semi-log serial dilutions of CDDO-2P-Im starting at 2 mM were prepared in basal medium containing 0.2% BSA. Culture medium was removed from the cells. CDDO-2P-Im dilutions were added to cells in duplicate and incubated for one hour. Basal medium supplemented with 0.2% BSA was added to cells. Cells were incubated for four days. Cell viability was determined using CellTiter-Glo kit. 50% of cytotoxicity concentration (CCso) was calculated using XLfit dose response model.

[0088] CPE inhibition assay. MDCK cells were used for the CPE inhibition assay. Cells were seeded in 96-well culture plates and incubated overnight. Ten semi-log serial dilutions of CDDO-2P-Im starting at 2 pM were prepared in basal medium containing 0.2% BSA. Culture medium was removed from the cells. CDDO-2P-Im dilutions were added to cells in duplicate and incubated for one hour. Virus at multiplicity of infection of 0.001 prepared in basal medium containing 0.2% BSA was added to cells and incubated for one hour. Basal medium supplemented with 0.2% BSA was added to cells. Cells were incubated for four days. Cells were fixed and stained with crystal violet. Optical density was read and used to calculate 50 percent inhibition concentration (ICso) Using XLfit dose response model.

[0089] Plaque reduction assay. Vero cells were used for the plaque reduction assay. Cells were seeded in 24-well culture plates and incubated overnight. Ten semi-log serial dilutions of CDDO-2P-Im starting at 2 pM were prepared in basal medium containing 0.2% BAS.

[0090] Culture medium was remove from the cells. CDDO-2P-Im dilutions were added to cells in duplicate and incubated for one hour. Virus at 400 plaque forming units (PFUs) prepared in prepared in basal medium containing 0.2% BSA was added to cells and incubated for one hour. Prior to adding 0.8% methylcellulose overlay to cells, CDDO-2P-Im dilutions were added to corresponding cells to bring to 1 x final concentration in the overlay. Cells were incubated for four days. Viral plaques were visualized using a INFV A nucleoprotein specific antibody and a colorimetric substrate. Viral plaque counts were used to calculate 50 percent inhibition concentration (ICso) using XLfit dose response model.

[0091] Oseltamivir (TAMIFLU®) was used as a control. The starting test concentration for CDDO-2P-Im was 2 mM, for oseltamivir 10 pM.

[0092] Dose response curves are shown in Figure 5. Data are presented in Table 1. Values were expressed in pM.

[0093] CDDO-2P-Im blocked the cytopathic effect (CPE) of Influenza Viruses H3N2 and

H1N1 in MDCK cell cultures.

[0094] Figure 5, first panel shows 60 % inhibition of CPE in H3N2 at 50 nanoMolar

CDDO-2P-Im and 30 % inhibition of H1N1 CPE at 50 nanoMolar CDDO-2P-Im. There was no general cytotoxicity of 2P-Im at these concentrations (demonstrated in uninfected cells, marked “CC50”, shown as Blue line on graph).

[0095] CDDO-2P-Im had relatively high toxicity to the control cells, which may have been due to performance of the assay in serum-free media and/or an effect of CDDO-2P-Im on the luciferase enzyme which is used to measure cell viability in this assay.

[0096] Figure 5, third panel shows inhibition of CPE by oseltamavir. The data in Table 1 show that CDDO-2P-Im is more than lOOx more potent than oseltamivir in the CPE assay in H3N2 cells.

[0097] Table 1. a Extrapolated from the dose response curve. b Not calculable.