WO2021207271A1

WO2021207271A1 - Organoselenide glutathione peroxidase mimetics for the treatment of inflammatory pulmonary disorders

Info

Publication number: WO2021207271A1
Application number: PCT/US2021/026047
Authority: WO
Inventors: Peter Tam; Eric Tam
Original assignee: Ebvia Inc.
Priority date: 2020-04-10
Filing date: 2021-04-06
Publication date: 2021-10-14

Abstract

A method is provided for treating an inflammatory pulmonary disorder in a subject by administering to the subject a therapeutically effective amount of an organoselenide glutathione peroxidase mimetic in the context of a prescribed dosage regimen, where the organoselenide has both anti-inflammatory and anti-oxidant activity. The method enables the treatment of pulmonary disorders such as ARDS and pulmonary fibrosis, which may or may not be secondary to a viral or bacterial infection of the lungs. A method is also provided for treating a subject infected with an influenza virus or a coronavirus such as SARS CoV-2 by administration of an antiviral organoselenide glutathione peroxidase mimetic. Formulations comprising an organoselenide glutathione peroxidase mimetic such as ebselen with one or more additional active agents are also provided, as are ebselen formulations for pulmonary administration via oral inhalation.

Description

ORGANOSELENIDE GLUTATHIONE PEROXIDASE MIMETICS FOR THE TREATMENT OF INFLAMMATORY PULMONARY DISORDERS

TECHNICAL FIELD

[0001] The present invention relates generally to the treatment of pulmonary disorders, and more particularly relates to the use of glutathione peroxidase mimetics, particularly organoselenides, in treating pulmonary disorders associated with inflammation.

BACKGROUND

[0002] Many pulmonary disorders are serious and life-threatening, yet not uncommon. Acute Respiratory Distress Syndrome (ARDS), for example, is a type of respiratory failure characterized by a rapid onset of widespread inflammation in the lungs, in which symptoms include breathing difficulty (dyspnea), rapid breathing (tachypnea), hyperventilation, and hypoxemia. ARDS affects 3 million people a year globally, with a death rate on the order of 35% to 55%. Treatment involves mechanical ventilation, including airway pressure release ventilation (APRV) and positive end-expiratory pressure (PEEP); extracorporeal membrane oxygenation (ECMO) is sometimes used as well. Despite the seriousness of the condition, there is currently no recommended pharmaceutical therapy for the treatment of ARDS. See Lewis et al. (July 23, 2019), "Pharmaceutical Agents for Adults with Acute Respiratory Distress Syndrome," Cochrane Database Syst Rev. 7: CD004477. The same is true for other serious pulmonary disorders, including pulmonary fibrosis, COPD, lung cancer, emphysema, and others. [0003] Inflammatory pulmonary disorders such as ARDS and pulmonary fibrosis can occur secondary to a viral or bacterial infection of the lungs. At the present time, in the midst of the 2020 Covid-19 pandemic, many people who are hospitalized with the virus (the coronavirus SARS-CoV-2) develop ARDS, and either do not survive or cannot return to normal function after recovery. It is imperative that a straightforward pharmaceutical intervention be developed to treat the many patients suffering from ARDS, particularly, at the present time, the many thousands of hospitalized Covid-19 patients. SUMMARY OF THE INVENTION

[0004] Accordingly, the present invention addresses the above need in the art by providing a method for treating a pulmonary disorder associated with inflammation, such as ARDS. The method involves administering to a subject afflicted with the disorder a therapeutically effective amount of an organoselenide glutathione peroxidase mimetic having anti-inflammatory and anti oxidant activity, wherein administration is carried out within the context of a prescribed dosage regimen.

[0005] In one aspect of the method, the pulmonary disorder is ARDS, pulmonary fibrosis, viral infection of the lungs, bacterial infection of the lungs, lung cancer, lung injury, emphysema, the result of an inhaled lung toxin, or a combination of two or more of the foregoing.

[0006] In another aspect of the invention, the pulmonary disorder is ARDS. When the ARDS or other disorder is secondary to a viral infection of the lungs, the organoselenide selected has antiviral activity as well.

[0007] In another aspect of the invention, the organoselenide glutathione peroxidase mimetic (also referred to herein as "the organoselenide compound" or simply "the organoselenide") is administered to a subject infected with a coronavirus such as SARS-CoV-1, SARS-CoV-2, or MERS-CoV.

[0008] In an additional aspect of the invention, the organoselenide glutathione peroxidase mimetic (also referred to herein as "the organoselenide compound" or simply "the organoselenide") is administered to a subject infected with an influenza virus, e.g., an influenza A virus or influenza B.

[0009] In a further aspect of the invention, the method for treating a subject with an inflammatory pulmonary disorder comprises administering a combination of a therapeutically effective amount of an organoselenide glutathione peroxidase mimetic and an additional active agent such as a corticosteroid, an anti-malarial agent, an antiviral agent, an antibiotic agent, or a combination of two or more of the foregoing. In some embodiments, the organoselenide compound is administered in combination with an additional active agent selected from hydroxychloroquine, remdesivir, maraviroc, ivermectin, azithromycin, molnupiravir, and combinations thereof. [00010] In an additional aspect of the invention, the organoselenide compound is administered orally, parenterally, transdermally, transmucosally, by inhalation, or via an implanted reservoir. In some embodiments, the organoselenide compound is administered by oral inhalation.

[00011] In some embodiments, the organoselenide compound has the molecular structure indicated in Formula (I)

(I)

[00012] wherein:

[00013] A is a monocyclic, bicyclic, or polycyclic aryl group that is optionally heteroatom- containing, optionally substituted with at least one non-hydrogen substituent, or both heteroatom-containing and substituted, and if bicyclic or polycyclic, containing rings that are fused or linked;

[00014] n is zero or 1;

[00015] X is Se or Se(=0);

[00016] Y is O or S; and

[00017] R is a C1-C24 hydrocarbyl group that may be heteroatom-containing and/or substituted with one or more non-hydrogen substituents;

[00018] or is a metabolite or pro-drug thereof.

[00019] In some embodiments, the organoselenide compound is ebselen.

[00020] In other embodiments, the organoselenide compound has the molecular structure indicated in Formula (IA)

wherein A, n, X, Y, and R are as defined above with regard to the structure of Formula (I). [00021] In some embodiments, the organoselenide compound is ebselen diselenide.

[00022] The invention also addresses the above-mentioned need in the art by providing a method for treating a subject suffering from ARDS by administration of a therapeutically effective amount of ebselen, via oral inhalation of a pharmaceutical composition comprising the ebselen in a vehicle suitable for pulmonary administration.

[00023] The invention also addresses the above-mentioned need in the art by providing a method for treating a subject infected with SARS-CoV-2 by administration of a therapeutically effective amount of ebselen, via oral inhalation of a pharmaceutical composition comprising the ebselen in a vehicle suitable for pulmonary administration.

[00024] In some embodiments, the pharmaceutical composition for oral inhalation is aqueous and administered to the patient using a liquid nebulizer.

[00025] In other embodiments, the pharmaceutical composition for oral inhalation is a dry powder formulation and administered to the patient using a dry powder inhaler.

[00026] The invention additionally provides a pharmaceutical formulation comprising a therapeutically effective amount of a combination of (a) ebselen; and (b) at least one additional active agent selected from a corticosteroid, an anti-malarial drug, an antiviral agent, and an antibiotic agent, wherein the therapeutically effective amount is an amount effective to treat a pulmonary disorder associated with inflammation.

[00027] In some embodiments, the additional active agent in the pharmaceutical formulation is at least one of hydroxychloroquine, remdesivir, maraviroc, ivermectin, azithromycin, and molnupiravir.

[00028] The invention also provides a pharmaceutical formulation for administration via oral inhalation, containing a therapeutically effective amount of ebselen in a vehicle suitable for pulmonary administration.

[00029] Additional objects, advantages, and salient features of exemplary embodiments of the invention will become apparent to those skilled in the art from the following description.

BRIEF DESCRIPTION OF THE DRAWINGS [00030] FIG. 1 (prior art; taken from Ninomiya et al. (2011) Coord. Chem. Rev. 255:2968- 2990) illustrates the interconversions of ebselen and its metabolites by reaction with hydroperoxides, thiols, and other compounds.

[00031] FIG. 2 provides the expected weight loss and mortality rate of SARS-CoV-2-infected mice in the experimental study described in Example 1.

DETAILED DESCRIPTION OF THE INVENTION [00032] 1. Definitions and Terminology:

[00033] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the invention pertains. Specific terminology of particular importance to the description of the present invention is defined below.

[00034] In this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, Thus, for example, "an active agent" refers not only to a single active agent but also to a combination of two or more different active agents, "a dosage form" refers to a combination of dosage forms as well as to a single dosage form, and the like.

[00035] When referring to an active agent, whether specified as a particular compound (e.g., ebselen or ebselen selenide) or a compound class (e.g., an organoselenide), the term used to refer to the agent is intended to encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs and derivatives, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, hydrates, crystalline forms, enantiomers, stereoisomers, and other such derivatives, analogs, and related compounds. [00036] The terms "treating" and "treatment" as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, and improvement or remediation of damage. Unless otherwise indicated, the terms "treating” and "treatment” as used herein encompass prevention of symptoms or the occurrence of a pulmonary disorder, such as, but not necessarily, in an individual who may be predisposed to such symptoms or disorders. For example, a person who is asymptomatic but infected with a virus that tends to progress toward a pulmonary disorder such as Acute Respiratory Distress Syndrome (ARDS) or pulmonary fibrosis, may be treated with the compounds and compositions of the invention according to the methods disclosed herein. [00037] The terms "effective amount" and "therapeutically effective amount" of an agent, compound, composition or combination of the invention refer to an amount that is nontoxic and effective for producing a therapeutic effect upon administration to a subject.

[00038] The term "dosage form" denotes any form of a pharmaceutical composition that contains an amount of active agent sufficient to achieve a therapeutic effect with a single administration. When the formulation is an orally administered tablet or capsule, the dosage form is usually one such tablet or capsule. The frequency of administration that will provide the most effective results in an efficient manner without significant adverse effects will vary with the characteristics of the particular active agent, including both its pharmacological characteristics and its physical characteristics.

[00039] The term "controlled release" refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a "controlled release" formulation, administration does not result in immediate release of the drug into an absorption pool. The term is used interchangeably with "nonimmediate release" as defined in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, PA: Mack Publishing Company, 1995). In general, the term "controlled release" as used herein includes sustained release, modified release and delayed release formulations. "Sustained release” (synonymous with "extended release”) refers to a formulation that provides for gradual release of an active agent over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of an agent over an extended time period. "Controlled release” also includes "delayed release," indicating a formulation that, following administration to a patient, provides for a measurable time delay before the active agent is released from the formulation into the patient's body. Controlled release dosage forms herein, however, are generally of the sustained release type.

[00040] By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing and/or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[00041] "Pharmacologically active" (or simply "active") as in a "pharmacologically active" analog, refers to a compound having the same type of pharmacological activity as the parent compound and approximately equivalent or greater in degree.

[00042] As used herein, a "subject" or "individual" or "patient" refers to any subject for whom therapy is desired, and generally refers to the recipient of the therapy to be practiced according to the invention. The subject can be any vertebrate, but will typically be a mammal. If a mammal, the subject is normally human, but may also be a domestic livestock, laboratory subject or pet animal.

[00043] Chemical substituent and compound terminology:

[00044] As used herein, the phrase "having the structure" is not intended to be limiting and is used in the same way that the term "comprising" is commonly used.

[00045] The term "alkyl" as used herein refers to a branched or unbranched saturated hydrocarbon group typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl, and the like. Generally, although again not necessarily, alkyl groups herein contain 1 to about 18 carbon atoms, preferably 1 to about 12 carbon atoms. The term "lower alkyl" intends an alkyl group of 1 to 6 carbon atoms. Preferred lower alkyl substituents contain 1 to 3 carbon atoms, and particularly preferred such substituents contain 1 or 2 carbon atoms (i.e., methyl and ethyl). "Substituted alkyl" refers to alkyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkyl" and "heteroalkyl" refer to alkyl in which at least one carbon atom is replaced with a heteroatom, as described in further detail infra. If not otherwise indicated, the terms "alkyl" and "lower alkyl" include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom- containing alkyl or lower alkyl, respectively.

[00046] The term "alkenyl" as used herein refers to a linear, branched or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, n- propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like. Generally, although again not necessarily, alkenyl groups herein contain 2 to about 18 carbon atoms, preferably 2 to 12 carbon atoms. The term "lower alkenyl" intends an alkenyl group of 2 to 6 carbon atoms, and the specific term "cycloalkenyl" intends a cyclic alkenyl group, preferably having 5 to 8 carbon atoms. The term "substituted alkenyl" refers to alkenyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" refer to alkenyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms "alkenyl" and "lower alkenyl" include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom- containing alkenyl and lower alkenyl, respectively.

[00047] The term "alkynyl" as used herein refers to a linear or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like. Generally, although again not necessarily, alkynyl groups herein contain 2 to about 18 carbon atoms, preferably 2 to 12 carbon atoms. The term "lower alkynyl" intends an alkynyl group of 2 to 6 carbon atoms. The term "substituted alkynyl" refers to alkynyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkynyl" and " heteroalky nyl" refer to alkynyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms "alkynyl" and "lower alkynyl" include linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl and lower alkynyl, respectively. [00048] The term "alkoxy" as used herein intends an alkyl group bound through a single, terminal ether linkage; that is, an "alkoxy" group may be represented as -O-alkyl where alkyl is as defined above. A "lower alkoxy" group intends an alkoxy group containing 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, etc. Preferred lower alkoxy substituents contain 1 to 3 carbon atoms, and particularly preferred such substituents contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy). The terms "alkenyloxy" and "alkynyloxy" are defined in an analogous manner.

[00049] The term "aryl" as used herein, and unless otherwise specified, refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety). Preferred aryl groups contain 5 to 24 carbon atoms, and particularly preferred aryl groups contain 5 to 14 carbon atoms. Exemplary aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like. "Substituted aryl" refers to an aryl moiety substituted with one or more substituent groups, and the terms "heteroatom- containing aryl" and "heteroaryl" refer to aryl substituent, in which at least one carbon atom is replaced with a heteroatom, as will be described in further detail infra. If not otherwise indicated, the term "aryl" includes unsubstituted, substituted, and/or heteroatom-containing aromatic substituents.

[00050] The term "aryloxy" as used herein refers to an aryl group bound through a single, terminal ether linkage, wherein "aryl" is as defined above. An "aryloxy" group may be represented as -O-aryl where aryl is as defined above. Preferred aryloxy groups contain 5 to 24 carbon atoms, and particularly preferred aryloxy groups contain 5 to 14 carbon atoms. Examples of aryloxy groups include, without limitation, phenoxy, o-halo-phenoxy, w-halo-phenoxy, p- halo-phenoxy, o-methoxy -phenoxy, w-methoxy-phenoxy, /i-methoxy-phenoxy, 2,4-dimethoxy- phenoxy, 3,4,5-trimethoxy-phenoxy, and the like.

[00051] The term "alkaryl" refers to an aryl group with an alkyl substituent, and the term "aralkyl" refers to an alkyl group with an aryl substituent, wherein "aryl" and "alkyl" are as defined above. Preferred aralkyl groups contain 6 to 24 carbon atoms, and particularly preferred aralkyl groups contain 6 to 16 carbon atoms. Examples of aralkyl groups include, without limitation, benzyl, 2-phenyl-ethyl, 3 -phenyl -propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4- phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like. Alkaryl groups include, for example, />-methylphenyl, 2,4-dimethylphenyl, p- cyclohexylphenyl, 2,7-dimethylnaphthyl, 7-cyclooctyinaphthyl, 3 -ethyl-cy cl openta- 1,4-diene, and the like. The terms "alkaryloxy" and "aralkyloxy" refer to substituents of the formula -OR wherein R is alkaryl or aralkyl, respectively, as just defined.

[00052] The term "acyl" refers to substituents having the formula -(CO)-alkyl, -(CO)-aryl, or - (CO)-aralkyl, and the term "acyloxy" refers to substituents having the formula -0(CO)-alkyl, -0(CO)-aryl, or -0(CO)-aralkyl, wherein "alkyl," "aryl, and "aralkyl" are as defined above. [00053] The term "cyclic" refers to alicyclic or aromatic substituents that may or may not be substituted and/or heteroatom containing, and that may be monocyclic, bicyclic, or polycyclic. [00054] The term "alicyclic" is used in the conventional sense to refer to an aliphatic cyclic moiety, as opposed to an aromatic cyclic moiety, and may be monocyclic, bicyclic, or polycyclic.

[00055] The terms "halo" and "halogen" are used in the conventional sense to refer to a chloro, bromo, fluoro, or iodo substituent.

[00056] The term "heteroatom-containing" as in a "heteroatom-containing alkyl group" (also termed a "heteroalkyl" group) or a "heteroatom-containing aryl group" (also termed a "heteroaryl" group) refers to a molecule, linkage or substituent in which one or more carbon atoms are replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus, silicon, or selenium, typically nitrogen, selenium, oxygen or sulfur, preferably nitrogen or selenium, or both nitrogen and selenium. Similarly, the term "heteroalkyl" refers to an alkyl substituent that is heteroatom-containing, the term "heterocyclic" refers to a cyclic substituent that is heteroatom-containing, the terms "heteroaryl" and heteroaromatic" respectively refer to "aryl" and "aromatic" substituents that are heteroatom-containing, and the like. Examples of heteroalkyl groups include alkoxyaryl, alkyl sulfanyl -substituted alkyl, N-alkylated amino alkyl, and the like. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, etc., and examples of heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, etc. [00057] "Hydrocarbyl" refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, more preferably 1 to about 18 carbon atoms, most preferably about 1 to 12 carbon atoms, including linear, branched, cyclic, saturated, and unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like. "Substituted hydrocarbyl" refers to hydrocarbyl substituted with one or more substituent groups, and the term "heteroatom-containing hydrocarbyl" refers to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, the term "hydrocarbyl" is to be interpreted as including substituted and/or heteroatom-containing hydrocarbyl moieties.

[00058] When a functional group is termed "protected," this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene et al., Protective Groups in Organic Synthesis (New York: Wiley, 1991).

[00059] By "substituted" as in "substituted alkyl," "substituted aryl," and the like, as alluded to in some of the aforementioned definitions, is meant that in the alkyl, aryl, or other moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non hydrogen substituents. Examples of such substituents include, without limitation, additional hydrocarbyl groups, e.g., C1-C24 hydrocarbyl, C1-C12 hydrocarbyl, Ci-Cs hydrocarbyl, and C1-C6 hydrocarbyl; functional groups such as halo, hydroxyl, sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₄ aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl (-CO-alkyl) and C₆-C₂₄ arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄ alkoxycarbonyl (-(CO)-O-alkyl), C₆-C₂₄ aryloxycarbonyl (-(CO)-O-aryl), halocarbonyl (-CO)-X where X is halo), C₂-C₂₄ alkylcarbonato (-O-(CO)-O-alkyl), C₆-C₂₄ arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO-), carbamoyl (-(CO)-NH2), mono-(Ci-C24 alkyl)-substituted carbamoyl (- (CO)-NH(alkyl)), di-(Ci-C24 alkyl)-substituted carbamoyl (-(CO)-N(CI-C24 alkyl)2), mono-(C6- C₂₄ aryl)-substituted carbamoyl (-(CO)-NH-aryl), di-(C₆-C₂₄ aryl)-substituted carbamoyl (-(CO)- N(aryl)₂), di-N-( alkyl), N-(C₆-C₂₄ aryl)-substituted carbamoyl, thiocarbamoyl (-(CS)-NH₂), carbamido (-NH-(CO)-NH₂), cyano (-CºN), isocyano (-N⁺ºC -), cyanato (-0-CºN), isocyanato (-0— N⁺ºC -), isothiocyanato (-S-CºN), azido (-N=N⁺ºN ), formyl (-(CO)-H), thioformyl (- (CS)-H), amino (-NEE), mono-(alkyl)-substituted amino, di-(alkyl)-substituted amino, mono- (C5-C24 aryl)-substituted amino, di-(Cs-C24 aryl)-substituted amino, C2-C24 alkylamido (-NH- (CO)-alkyl), C₆-C₂₄ arylamido (-NH-(CO)-aryl), imino (-CR=NH where R=hydrogen, alkyl, C₅- C₂₄ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, etc.), alkylimino (-CR=N(alkyl), where R=hydrogen, Ci- C₂₄ alkyl, C₅-C₂₄ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, etc.), arylimino (-CR=N(aryl), where R=hydrogen, C1-C24 alkyl, C5-C24 aryl, C6-C24 alkaryl, C6-C24 aralkyl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO₂-OH), sulfonato (-SO₂-O-), C₁-C₂₄ alkylsulfanyl (-S-alkyl; also termed "alkylthio"), arylsulfanyl (-S-aryl; also termed "arylthio"), C₁-C₂₄ alkylsulfmyl (-(SO)-alkyl), C₅- C₂₄ arylsulfmyl (-(SO)-aryl), C₁-C₂₄ alkylsulfonyl (-S0₂-alkyl), C₅-C₂₄ arylsulfonyl (-S0₂-aryl), phosphono (-P(0)(OH)2), phosphonato (-P(0)(0-)2), phosphinato (-P(0)(0-)), phospho (-PO2), and phosphino (-PH₂); and the hydrocarbyl moieties C₁-C₂₄ alkyl (preferably Ci-Cix alkyl, more preferably C₁-C₁₂ alkyl, most preferably C₁-C₆ alkyl), C₂-C₂₄ alkenyl (preferably C₂-C₁₈ alkenyl, more preferably C₂-C₁₂ alkenyl, most preferably C₂-C₆ alkenyl), C₂-C₂₄ alkynyl (preferably C₂- Ci₈ alkynyl, more preferably C₂-C₁₂ alkynyl, most preferably C₂-C₆ alkynyl), C₅-C₂₄ aryl (preferably C5-C14 aryl), C₆-C24 alkaryl (preferably C₆-C18 alkaryl), and C₆-C24 aralkyl (preferably C6-C18 aralkyl).

[00060] In addition, the aforementioned functional groups may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbyl moieties such as those specifically enumerated above. Analogously, the above- mentioned hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties such as those specifically enumerated.

[00061] When the term "substituted" appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group. For example, the phrase "substituted alkyl, alkenyl, and aryl" is to be interpreted as "substituted alkyl, substituted alkenyl, and substituted aryl." Analogously, when the term "heteroatom-containing" appears prior to a list of possible heteroatom-containing groups, it is intended that the term apply to every member of that group. For example, the phrase "heteroatom-containing alkyl, alkenyl, and aryl" is to be interpreted as "heteroatom-containing alkyl, substituted alkenyl, and substituted aryl."

[00062] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase "optionally substituted" means that a non hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non hydrogen substituent is not present.

[00063] 2. The Active Agents :

[00064] In a first aspect of the invention, a method is provided for treating a pulmonary disorder associated with inflammation, wherein the method comprises administering to a subject a therapeutically effective amount of a glutathione peroxidase mimetic comprising an organoselenide having anti-inflammatory and anti-oxidant activity. More specifically, the active agent is a selenium-containing heterocycle, or a ring-opened analog and/or dimer thereof, where the compound has the structure of Formula (I)

in which:

[00065] A is a monocyclic, bicyclic, or polycyclic aryl group that is optionally heteroatom- containing, optionally substituted with at least one non-hydrogen substituent, or both heteroatom-containing and substituted, and if bicyclic or polycyclic, containing rings that are fused or linked;

[00066] n is zero or 1;

[00067] X is Se or Se(=0);

[00068] Y is O or S; and

[00069] R is a C₁-C₂₄ hydrocarbyl group.

[00070] As explained in the preceding section, the compound may also be in the form of a prodrug, metabolite, analog, and the like, with prodrugs and metabolites of particular interest.

For those compounds that can exist as individual enantiomers or diastereomers, the compound may be isomerically pure or a mixture of isomers.

[00071] As also explained in the preceding section, the hydrocarbyl groups herein, including, but not limited to, R of Formula (I), may be heteroatom-containing and/or substituted with one or more non-hydrogen substituents. Any heteroatoms present are typically selected from nitrogen, selenium, oxygen or sulfur, and are preferably nitrogen or selenium, or both nitrogen and selenium. When R is substituted, the one or more non-hydrogen substituents are typically halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C24 aryloxy, C2- C24 alkylcarbonyl, C6-C24 arylcarbonyl, C2-C24 alkylcarbonyloxy, C6-C24 arylcarbonyloxy, halocarbonyl, C₂-C₂₄ alkylcarbonato, C₆-C₂₄ arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(Ci-C24 alkyl)-substituted carbamoyl, di-(Ci-C24 alkyl)-substituted carbamoyl, mono-(C6- C₂₄ aryl)-substituted carbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono-(Ci-C₂₄ alkyl)-substituted amino, di-(Ci-C24 alkyl)-substituted amino, mono-(C5-C24 aryl)-substituted amino, di-(Cs-C24 aryl)-substituted amino, C₂-C₂₄ alkylamido, C₆-C₂₄ arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylthio, C5-C24 arylthio, C1-C24 alkylsulfmyl, C5-C24 arylsulfmyl, C₁-C₂₄ alkylsulfonyl, C₅-C₂₄ arylsulfonyl, phosphono, phosphonato, phosphinato, phosphono, phosphino, C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C5-C24 aryl, C6-C24 alkaryl, and C₆-C₂₄ aralkyl, and, where the substituents permit, any two substituents can be taken together to form a cyclic structure selected from a five-membered ring and a six-membered ring, optionally fused to an additional five-membered or six-membered ring, wherein the rings are aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and have zero to 4 non-hydrogen substituents and zero to 3 heteroatoms.

[00072] The integer 'h' in the structure of Formula 1 will typically be zero, such that the compound has the structure of Formula (II)

[00073] In some embodiments, Y is O and A is phenyl or a monocyclic, N-heteroaryl group such as pyrrolyl, imdazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, any of which may be substituted with one or more non-hydrogen substituents. When Y is O and A is optionally substituted phenyl or optionally substituted pyridinyl (with one carbon atom between the N-heteroatom and the Se atom), it will be appreciated that the compound of Formula (II) then has the structure of Formula (III)

when X is Se and wherein R is as defined above with regard to the structures of Formulae (I) and (II), and Z is N or CH. R¹, R², and R³ are independently selected from:

[00074] H (i.e., hydrido);

[00075] Halo, typically F or Cl;

[00076] C1-C12 alkyl, including C1-C6 alkyl, either unsubstituted or substituted with at least one non-hydrogen substituent, such as a halogen atom (typically F or Cl) or a C1-C6 alkoxy group, e.g., C1-C4 alkoxy ; [00077] C1-C12 alkoxy, including C1-C6 alkoxy, either unsubstituted or substituted with at least one halogen atom, again, typically F or Cl; and

[00078] C5-C12 aryl, e.g., phenyl, either unsubstituted or substituted with one to three non hydrogen substituents, generally, although not necessarily, selected from halo and C1-C6 alkyl. [00079] In some embodiments, R¹, R², and R³ are H, such that the compound of Formula (III) then has the structure of Formula (IV) (when Z is CH) or Formula (V) (when Z is N):

wherein R is as defined previously.

[00080] A compound having the structure of Formula (V) may be converted to the quaternary ammonium salt using conventional means, e.g., reaction with methyl iodide to produce the iodide salt. Reaction may be carried out to provide ammonium halides, carbonates, glycolates, and the like, as will be appreciated by those of ordinary skill in the art. Administration of compound (V) as the quaternary ammonium salt may enhance bioavailability as well as compatibility with aqueous formulations.

[00081] In some embodiments, R groups suitable with respect to any of the above structures (I) through (V) include, without limitation,

[00082] (a) C1-C24 alkyl, including C1-C12 alkyl and C1-C6 alkyl, such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-hexyl, cyclopropyl, cyclohexyl, adamantyl, n- dodecanyl, and n-octadecyl;

[00083] (b) C₅-C₁₂ aryl, e.g., phenyl;

[00084] (c) C₃-C₁₂ heteroaryl, including C₃-C₅ heteroaryl, particularly monocyclic N- heteroaryl such as pyrrolyl, imdazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and

[00085] (d) substituted analogs of (a), (b), and (c), in which there are 1-5, more typically 1 or

2, substituents independently selected from halo, lower alkyl, primary amino, lower alkyl secondary amino, lower alkyl tertiary amino, hydroxyl, nitro, C1-C6 acyloxy, and C1-C6 alkoxy carbonyl.

[00086] Accordingly, two other groups of compounds having the structure of Formula (III) have the structure of Formula (VI) and Formula (VII)

(VI)

in which:

[00087] Z, R¹, and R² are as defined above;

[00088] m is zero or 1;

[00089] R⁴ is lower alkyl;

[00090] R⁵ and R⁶ are independently selected from H, halo, lower alkyl, primary amino, lower alkyl secondary amino, lower alkyl tertiary amino, hydroxyl, nitro, C2-C6 acyloxy, and C1-C6 alkoxy carbonyl;

[00091] one or two of Q¹, Q², Q³, Q⁴, and Q⁵ are N and the remaining three or four of Q¹, Q², Q³, Q⁴, and Q⁵ are CR⁷, where R⁷ is H, halo, hydroxyl, lower alkyl, lower alkoxy, lower alkyl primary amino, or nitro.

[00092] A related group of compounds has the structure of Formula (VIII)

in which Z, R¹, R², R⁴, and m are as defined previously, and R⁸ is lower alkyl. In some embodiments, R¹ and R² are both H.

[00093] Additional compounds are Se-Se dimers of the above structures. Dimers of the structures of Formulae (I) through (VIII) (when X in Formulae (I), (II), and (III) is Se) have the corresponding structures represented by Formulae (IA) through (VIIIA) below:

[00094]

[00095] The molecular structures of specific and representative organoselenides useful in conjunction with the present invention are provided in Table 1, along with the molecular formula, molecular weight, and reference citation describing synthesis or analysis of the compound: TABLE 1

[00096] An active agent of particular interest herein is ebselen, Compound 1 in Table 1. Also included are the metabolites of ebselen and other ebselen derivatives illustrated in FIG. 1 (prior art; taken from Ninomiya et al. (2011) Coord. Chem. Rev. 255:2968-2990), which illustrates the interconversions of ebselen and its metabolites by reaction with hydroperoxides, thiols, and other compounds.

[00097] The active agents can be obtained commercially or synthesized using methods described in the literature or known to those of ordinary skill in the art. The references cited in Table 1 provide syntheses for the compounds listed as well as analogs thereof. [00098] 3. Active Agent Combinations:

[00099] Two or more of the active agents can be administered in combination, administered separately or in a single dosage form. In some cases, synergy can be seen with respect to therapeutic efficacy. In some cases, synergy can be seen with respect to a reduction in side effects observed with any one of the active agents co-administered. In some cases, the synergy allows for a reduction in the dosage of one or more active agents being co-administered. [000100] The active agent can also be co-administered with a different type of active agent, i.e., an active agent other than an organoselenide glutathione peroxidase mimetic that may serve the same purpose - treatment of a pulmonary disorder associated with inflammation, or treatment of a viral infection - or it may serve a different purpose. Other types of agents include, without limitation:

[000101] Other anti-inflammatory agents, e.g., corticosteroids such as beclomethasone, budesonide, flunisolide, fluticasone, and salmeterol;

[000102] Antimalarial drugs such as chloroquine, hydroxychloroquine, quinacrine, amodiaquine, and primaquine;

[000103] Antiviral agents such as remdesivir, BCX4430, and other nucleotide analogs; maraviroc, leronlimab, aplaviroc, vicriviroc, and other CCR5 antagonists; favipiravir, pimodivir, baloxavir, sofosbuvir, ivermectin, and other viral polymerase inhibitors; and antiviral ribonucleoside analogs and prodrugs thereof, such as molnupiravir; and [000104] Antibiotic agents such as the macrolide antibiotics azithromycin and clarithromycin; fluoroquinolone antibiotics such as levofloxacin or moxafloxacin, or a combination of a macrolide antibiotic with a beta-lactam such as amoxicillin; or tetracycline.

[000105] The invention encompasses the co-administration of the organoselenide glutathione peroxidase mimetic and other active agents as well, which are already known or are discovered hereinafter, for the indications disclosed herein.

[000106] 4. Methods of Use:

[000107] A. Pulmonary disorders associated with inflammation:

[000108] In some embodiments, a pulmonary disorder associated with inflammation is treated by administering to a subject a therapeutically effective amount of a glutathione peroxidase mimetic having anti-inflammatory and anti-oxidant activity. The glutathione peroxidase comprises an organoselenide as described in the preceding section, and administration is carried out within the context of a predetermined dosage regimen, which may be a single, e.g., bolus, dose, or a dose regularly administered throughout an ongoing treatment period, such as a daily dose, a twice-weekly dose, a weekly dose, or the like. Modes of administration are described in further detail infra.

[000109] Inflammation is a complex biological response of tissue to harmful stimuli, such as oxidative stress, irritants, pathogens, and damaged cells. It is a protective attempt by an organism to remove an injurious stimulus and initiate the healing process for injured tissue. The inflammatory response involves the production and release of inflammatory modulators that function to both destroy damaged cells and heal injured tissue. In order to perform this function, however, various inflammatory modulators either directly produce and/or signal the release of agents that produce reactive oxygen species for the purpose of destroying invading agents and/or injured cells. The inflammatory response, therefore, involves a balance between the destruction of damaged cells and the healing of injured tissue, since an imbalance can lead to oxidative stress and the onset of various inflammatory disease pathologies.

[000110] Pulmonary disorders associated with inflammation that can be treated according to the present method include, without limitation, acute respiratory distress syndrome (ARDS); pulmonary fibrosis; viral infection of the lungs; bacterial infection of the lungs; lung cancer; lung injury; presence of an inhaled lung toxin; and emphysema. A pulmonary disorder "associated with" inflammation is intended to mean that pulmonary inflammation is present along with the stated disorder, and may be either a result of or a cause of the disorder. It should be noted that the aforementioned pulmonary disorders are not necessarily independent of each other. For example, a viral or bacterial infection of the lungs can lead to ARDS, although a subject may suffer from ARDS in the absence of a viral or bacterial pulmonary infection. As another example, ARDS can lead to pulmonary fibrosis, but not all pulmonary fibrosis is caused by ARDS. COPD, another inflammatory pulmonary condition, is typically caused by cigarette smoking or exposure to dust or fumes, not an infection. The present method effectively treats any of the above-noted pulmonary disorders, whether they are manifesting as a single disorder or as a combination of disorders, and, in the latter case, whether the combination of co-occurring disorders are unrelated or are related as cause and effect. [000111] ARDS: While the pathophysiology of ARDS is not completely known, ARDS is believed to result from a pulmonary or extrapulmonary event that cause the release of inflammatory modulators, promoting neutrophil accumulation in the microcirculation of the lung. Neutrophils damage the vascular endothelium and alveolar epithelium, leading to pulmonary edema, hyaline membrane formation, decreased lung compliance, and difficult air exchange. Most cases of ARDS are associated with pneumonia or sepsis. See Sagui et al. (2012) 85(4): 352-358, who also report that the in-hospital mortality rate related to ARDS is on the order of about 35% to 55%. Accordingly, it is of critical importance to treat patients suffering from ARDS as quickly and effectively as possible.

[000112] The active agents herein can treat subjects suffering from ARDS regardless of cause or the presence of an associated disorder, insofar as the compounds are both anti-inflammatory and anti-oxidant. In some embodiments, the subject has a viral infection of the lungs, and the viral infection has led to ARDS. In such a case, the active agent administered serves as both an anti inflammatory agent and as an antiviral agent, operating via at least one distinct mechanism.

Viral infections of the lungs that can be treated using the present methods include, without limitation, coronaviruses and influenza viruses. Representative coronaviruses that can be treated according to the method of the invention include SARS-CoV-1, SARS-CoV-2, and MERS-CoV. Representative influenza viruses include influenza A of any subtype, such as the HI, H3, and H5 subtypes, e.g., H1N1 (swine flu), H3N2 (many seasonal flus), and H5N1 (avian or bird flu), as well as influenza B.

[000113] In other embodiments, the active agent as specified earlier herein is used in the treatment of a viral infection in a subject, where a pulmonary disorder associated with inflammation may or may not be present. The method of treatment involves administration of a therapeutically effective amount of a glutathione peroxidase mimetic comprising an organoselenide as described in the preceding section, and administration is carried out within the context of a predetermined dosage regimen, which, as before, may be a single, e.g., bolus, dose, or a dose regularly administered throughout an ongoing dosage period. Viruses that can be treated include coronaviruses such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV, and influenza viruses including influenza A viruses, e.g., of the HI, H3, or H5 subtypes, and influenza B. [000114] 5. Formulations, Dosage Forms, and Modes of Administration [000115] Pharmaceutical formulations suitable for use in conjunction with the present invention include compositions wherein the active agent is contained in a "therapeutically effective" amount, i.e., in an amount effective to achieve its intended purpose. Determination of a therapeutically effective amount for any particular active agent is within the capability of those skilled in the art. Generally, the toxicity and therapeutic efficacy of a compound or composition described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., procedures used for determining the maximum tolerated dose (MTD), the ED50, which is the effective dose to achieve 50% of maximal response, and the therapeutic index (TI), which is the ratio of the MTD to the ED50. Obviously, compounds and compositions with high TIs are the more preferred compounds and compositions herein, and preferred dosage regimens are those that maintain plasma or tissue levels of the active agents at or above a minimum concentration to maintain the desired therapeutic effect. Dosage will, of course, also depend on a number of factors, including the particular compound or composition, the site of intended delivery, the route of administration, and other pertinent factors known to the prescribing physician.

[000116] Administration of an active agent herein may be carried out using any appropriate mode of administration. Thus, administration can be, for example, oral, parenteral, transdermal, transmucosal (including rectal and vaginal), sublingual, by inhalation, or via an implanted reservoir in a dosage form. The term "parenteral" as used herein is intended to include subcutaneous, intravenous, and intramuscular injection.

[000117] Depending on the intended mode of administration, the pharmaceutical formulation containing the active agent may be a solid, semi-solid or liquid, such as, for example, a tablet, a capsule, a caplet, a liquid, a suspension, an emulsion, a suppository, granules, pellets, beads, a powder, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. Suitable pharmaceutical compositions and dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts and literature, e.g., in Remington: The Science and Practice of Pharmacy (Easton, Pa.: Mack Publishing Co., 1995). For those compounds that are orally active, oral dosage forms are generally preferred, and include tablets, capsules, caplets, solutions, suspensions and syrups, and may also comprise a plurality of granules, beads, powders, or pellets that may or may not be encapsulated. Preferred oral dosage forms are tablets and capsules. [000118] Tablets may be manufactured using standard tablet processing procedures and equipment. Direct compression and granulation techniques are preferred. In addition to the active agent, tablets will generally contain inactive, pharmaceutically acceptable carrier materials such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, coloring agents, and the like. [000119] Capsules are also preferred oral dosage forms for those active agents that are orally active, in which case the active agent-containing composition may be encapsulated in the form of a liquid or solid (including particulates such as granules, beads, powders or pellets). Suitable capsules may be either hard or soft, and are generally made of gelatin, starch, or a cellulosic material, with gelatin capsules preferred. Two-piece hard gelatin capsules are preferably sealed, such as with gelatin bands or the like. See, for example, Remington: The Science and Practice of Pharmacy, cited supra , which describes materials and methods for preparing encapsulated pharmaceuticals.

[000120] Oral dosage forms, whether tablets, capsules, caplets, or particulates, may, if desired, be formulated so as to provide for gradual, sustained release of the active agent over an extended time period. Generally, as will be appreciated by those of ordinary skill in the art, sustained release dosage forms are formulated by dispersing the active agent within a matrix of a gradually hydrolyzable material such as a hydrophilic polymer, or by coating a solid, drug-containing dosage form with such a material. Hydrophilic polymers useful for providing a sustained release coating or matrix include, by way of example: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, acrylic acid alkyl esters, methacrylic acid alkyl esters, and the like, e.g. copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate; and vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, and ethylene-vinyl acetate copolymer.

[000121] Preparations according to this invention for parenteral administration include sterile aqueous and nonaqueous solutions, suspensions, and emulsions. Injectable aqueous solutions contain the active agent in water-soluble form. Examples of nonaqueous solvents or vehicles include fatty oils, such as olive oil and com oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, low molecular weight alcohols such as propylene glycol, synthetic hydrophilic polymers such as polyethylene glycol, liposomes, and the like. Parenteral formulations may also contain adjuvants such as solubilizers, preservatives, wetting agents, emulsifiers, dispersants, and stabilizers, and aqueous suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and dextran. Injectable formulations are rendered sterile by incorporation of a sterilizing agent, filtration through a bacteria-retaining filter, irradiation, or heat. They can also be manufactured using a sterile injectable medium. The active agent may also be in dried, e.g., lyophilized, form that may be rehydrated with a suitable vehicle immediately prior to administration via injection.

[000122] The active agent may also be administered through the skin using conventional transdermal drug delivery systems, wherein the active agent is contained within a laminated structure that serves as a drug delivery device to be affixed to the skin. In such a structure, the drug composition is contained in a layer, or "reservoir," underlying an upper backing layer. The laminated structure may contain a single reservoir, or it may contain multiple reservoirs. In one embodiment, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Alternatively, the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form. Transdermal drug delivery systems may in addition contain a skin permeation enhancer.

[000123] In addition, the active agent may also be formulated in a depot preparation for controlled release of the active agent, preferably sustained release over an extended time period. These sustained release dosage forms are generally administered by implantation (e.g., subcutaneously or intramuscularly or by intramuscular injection).

[000124] Other modes of administration are suitable as well. For example, administration may be rectal or vaginal, preferably using a suppository that contains, in addition to the active agent, excipients such as a suppository wax. Formulations for nasal or sublingual administration are also prepared with standard excipients well known in the art.

[000125] The active agent may also be formulated for inhalation, e.g., as a solution in saline, as a dry powder, or as an aerosol. For the treatment of pulmonary disorders and diseases, pulmonary drug delivery is optimal. The large surface of the lung, the rapid onset of drug action with high bioavailability, targeted delivery, and numerous other advantages make pulmonary delivery preferred for the treatment of pulmonary disorders such as ARDS, pulmonary fibrosis, and others, including those mentioned herein. Formulations for aerosol delivery to the lungs may be solutions, suspensions, emulsions, powders, or semi-solid preparations.

[000126] Pulmonary delivery can be achieved via the intranasal route, but oral inhalative administration of an aerosolized liquid formulation, including intratracheal instillation and intratracheal inhalation, is preferred. Liposome aerosols are also envisioned herein; see, e.g., Schreier et al. (1994) J. Liposome Res. 4(1): 229-238. Several types of nebulizers are available for administering a liquid formulation via oral inhalation, namely jet nebulizers, ultrasonic nebulizers, vibrating mesh nebulizers, and jet nebulizers driven by compressed air. See, e.g.,

Patil et al. (2012) Lung India 29(1): 44-49. For patients who are connected to a ventilator system for breathing assistance, a suitable aerosol drug delivery system is described in U.S. Patent No. 10,471,083. Liquid formulations containing the organoselenide compound herein may be aqueous solutions, formulated from an aqueous vehicle in which the organoselenide is dissolved, and containing excipients such as antioxidants, solvents (e.g., ethanol, glycols), a propellant, and the like. The formulations may also be suspensions, with the organoselenide micronized and suspended in a liquid carrier, and including dispersing agent(s), propellant, and other excipients as deemed necessary.

[000127] A pharmaceutical formulation for delivery to the lungs via oral inhalation can also be a dry powder formulation, such as may comprise nanoparticle-sized solid particles containing the organoselenide compound and suitable dry powder excipients, for example, lactose monohydrate, magnesium stearate, mannitol, and the like. Small particle size is essential to ensure efficient targeted delivery to the lungs. A dry powder inhaler can be used to deliver individual doses of a powdered drug formulation, e.g., the Spinhaler (Fisons Pharmaceuticals, Rochester, NY) or Rotohaler (Glaxo-Smith-Kline). Suitable dry powder composition components and inhaler types are described, inter alia , by de Boer (2017) Expert Opin Drug Deliv. 14(4): 499-512, and U.S. Patent Publication No. 2009/00004279 to Hofmann et al., and reference may be had thereto for information regarding dry powder formulation, components, and inhalers that can be used in a pulmonary delivery method herein.

[000128] Experimental: Evaluation of Ebselen in the Treatment of ARDS [000129] Ebselen, an anti-inflammatory, anti-oxidant organoselenide compound useful in conjunction with the present invention, has been found to potently inhibit lipid peroxidation through a glutathione peroxidase-like action; see Muller et al. (1984) Biochem. Pharmacol. 33:3235-3239. Ebselen and analogs thereof have also been found to have antimicrobial activity against a number of pathogenic microorganisms (_< Staphylococcus aureas, Staphylococcus simulans, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Candida albicansm, and Aspergillus niger), and virucidal activity in vitro against human herpes virus type 1 (HHV-1), encephalomy carditis virus (EMCV), and vesicular stomatitis virus (VSV); (Pietka- Ottlik (2008) Chem. Pharm. Bull. 56(10): 1423-1427; Pietka-Ottlik et al. (2010) Molecules 15:8214-8228). Administration of ebselen to humans has been carried out in several contexts and found to be safe and effective, with regard to patients afflicted with Clostridium difficile infection (U.S. Patent No. 10,172,829 to Bender et al.; Bender et al. (23 September 2015)

Science and Translational Medicine 7(306):306ral48); in individuals who have noise-induced hearing loss (Kil et al. (2017) The Lancet 390(10098): P969-979); in people who have suffered a middle cerebral artery occlusion (Ogawa et al. (1999) Cerebrovasc. Dis. 9: 112-118); and in patients who have suffered an aneurysmal subarachnoid hemorrhage (Saito et al. (1998) Neurosurgery 42(2): 269-277).

[000130] Ebselen can be readily evaluated for its potential in treating patients with inflammatory pulmonary conditions, particularly ARDS, and for its potential as an antiviral agent against SARS-CoV-2 infection.

[000131] A dosage form containing a specific dose or concentration of ebselen is prepared using standard pharmaceutical formulation methodologies. Examples of ebselen formulations are provided in the literature: see U.S. Patent No. 10,172,829 to Bender et al., Example 5; U.S.

Patent No. 6,815,434 to Kil et al., Example 3; and other references cited herein. Subjects with pulmonary inflammation, as observed with ARDS, are given an ebselen dose in the range of 150 mg to 600 mg twice daily. The efficacy of treatment is evaluated as follows: (1) chest X-ray or CT scan to identify increases or decreases in pulmonary infiltrates; (2) identifying an increase or decrease in the ratio of partial arterial oxygen pressure to fraction of inspired oxygen (PaO/FiCh); and (3) auscultation and determining breathing rate. With regard to (2), normal PaO/FiCh levels are 300-500 mmHg, while in hypoxemic ARDS patients, PaO/FiCh levels are below 300 mmHg or even 200 mmHg. A substantial fraction of the treated ARDS patients exhibit improvement with respect to ease of breathing, pulmonary inflammation, and PaO/FiCh level.

[000132] The antiviral activity of ebselen can be assessed, for example in Covid-19 patients, by taking nasal and pharyngeal swab samples over a 14-day period, throughout twice-daily administration of 150 mg to 600 mg ebselen, to quantify viral load and changes in viral load.

PCR assays, immunoassays and other known techniques can be used to quantify viral load. Further detail on appropriate methodologies can be found in Gautret et al. (July 2020), "Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial," International Journal of Antimicrobial Agents 56(1): 105949.

EXAMPLE 1

[000133] Evaluation of ebselen in aged mice infected with mouse-adapted SARS-CoV-2: [000134] The purpose of this study was to evaluate the efficacy of ebselen administration in ameliorating the effects of SARS-CoV-2 infection in mice, as measured by mortality, weight loss, viral titer, and lung histopathology. This study assesses the therapeutic effect of the administration of ebselen in an infection of aged BALB/c mice with mouse-adapted SARS-CoV- 2 MA10.

[000135] The expected weight loss and mortality rate of infected aged mice in this aged-mouse model are illustrated in FIG. 2. The expected weight loss and mortality rate of infected aged mice in this aged-mouse model are illustrated in FIG. 2.

[000136] Study Design:

[000137] The study has four groups comprised of two control groups (one infected and one uninfected) and two treatment groups (one with ebselen treatment starting 2 days prior to infection and the other with ebselen treatment starting after the day of infection).

[000138] Drug administration for prophylaxis and treatment: [000139] Prophylaxis: 25 mg/kg, 50 mg/kg, 100 mg/kg, 150 mg/kg, or 200 mg/kg administered 1, 2, 3, or 4 times daily starting 2 days before inoculation through day 7.

[000140] Treatment: 25 mg/kg, 50 mg/kg, 100 mg/kg, 150 mg/kg, or 200 mg/kg is administered 1, 2, 3, or 4 times daily, with subsequent doses administered at least daily. Dosing is administered as close to the same times of day as possible.

[000141] Formulation:

[000142] Ebselen is freshly formulated in a solvent mixture that includes polyethylene glycol (PEG) 400, propylene glycol (PG), and methyl cellulose for a 5 mg/ml, lOmg/ml , 15 mg/ml, or 20 mg/ml solution for PO administration.

[000143] The solution is prepared immediately before dosing.

[000144] Study Procedures:

[000145] Female mice (age 11-12 months) are housed in ventilated cages (4 per cage) in a Biosafety Level (BSL) 3 facility and are acclimated for 7 days prior to challenge. The challenge involves intranasal instillation of 50 mΐ containing 10³ plaque-forming units (PFU) of SARS- CoV-2-MA10 (described in Leist et al. (2020) Cell 183: 1070-1085) under ketamine-xylazine anesthesia. The following sampling schedule is implemented:

[000146] (1) Once daily clinical monitoring, including recording of body weight (max. 30% weight loss allowed for pilot studies), with twice daily wellness checks once mice drop below 20% weight loss. This monitoring schedule begins on the day of virus challenge and extends until the experimental endpoint or weight loss/body condition score-mandated euthanasia, whichever comes first.

[000147] (2) Lungs are then harvested for titering, cytokine, and RNA analyses. Lung lobes taken for titer are weighed. The same lobe is taken from all animals.

[000148] (3) Lung tissue and serum are collected for profiling of fibrin production and coagulation factors (i.e., D-dimer, von Willebrand factor (VWF), and p-selectin).

[000149] Tissues collected for histopathology are processed to obtain standard hematoxylin and eosin (H&E)-stained sections that are evaluated by a board-certified veterinary pathologist. EXAMPLE 2

[000150] Evaluation of ebselen efficacy against influenza A and influenza B [000151] In cell-based assays conducted with Vero 76 cells plated as a monolayer on a microtiter plate, ebselen was shown to effectively inhibit viral replication to a degree comparable to that of ribavirin against different strains of influenza A and influenza B. Table 3 shows the effective concentrations to inhibit 50% of viral replication (EC50) with respect to influenza A H1N1, influenza A H3N2, influenza A H5N1, and influenza B:

TABLE 3: EC50 (mM) obtained for influenza strains:

[000152] Protocol for the cell-based assay, from Reed et al (1938), "A Simple Method of Estimating Fifty Percent Endpoints," Am J Hyg 27: 493-98:

[000153] Confluent or near-confluent cell culture monolayers of Vero 76 cells are prepared in 96-well disposable microplates the day before testing. Cells are maintained in MEM supplemented with 2% FBS supplemented with 50-pg/ml gentamicin. Compounds are dissolved in DMSO, saline or the diluent requested by the submitter. Less soluble compounds are vortexed, heated, and sonicated, and if they still do not go into solution are tested as colloidal suspensions. The test compound is prepared at four serial logio concentrations, usually 0.1, 1.0, 10, and 100 pg/ml or mM (per sponsor preference). Lower concentrations are used when insufficient compound is supplied. Five microwells are used per dilution: three for infected cultures and two for uninfected toxicity cultures. Controls for the experiment consist of six microwells that are infected and not treated (virus controls) and six that are untreated and uninfected (cell controls) on every plate. A known active drug is tested in parallel as a positive control drug using the same method as is applied for test compounds. The positive control is tested with every test run.

[000154] Growth media is removed from the cells and the test compound is applied in 0.1 ml volume to wells at 2X concentration. Virus, normally at ~60 CCID50 (50% cell culture infectious dose) in 0.1 ml volume is added to the wells designated for virus infection. Medium devoid of virus is placed in toxicity control wells and cell control wells. Plates are incubated at 37 °C with 5% CO2 until marked CPE (>80% CPE for most virus strains) is observed in virus control wells. The plates are then stained with 0.011% neutral red for approximately two hours at 37°C in a 5% CO2 incubator. The neutral red medium is removed by complete aspiration, and the cells may be rinsed IX with phosphate buffered solution (PBS) to remove residual dye. The PBS is completely removed, and the incorporated neutral red is eluted with 50% Sorensen’s citrate buffer/50% ethanol for at least 30 minutes. Neutral red dye penetrates into living cells, thus, the more intense the red color, the larger the number of viable cells present in the wells. The dye content in each well is quantified using a spectrophotometer at 540 nm wavelength. The dye content in each set of wells is converted to a percentage of dye present in untreated control wells using a Microsoft Excel computer-based spreadsheet and normalized based on the virus control. The 50% effective (EC50, virus-inhibitory) concentrations and 50% cytotoxic (CC50, cell- inhibitory) concentrations are then calculated by regression analysis. The quotient of CC50 divided by EC50 gives the selectivity index (SI) value. Compounds showing SI values >10 are considered active.

[000155] Reduction of virus yield (Secondary VYR assay):

[000156] Active compounds are further tested in a confirmatory assay. This assay is set up similar to the methodology described above only eight half-logio concentrations of inhibitor are tested for antiviral activity and cytotoxicity. After sufficient virus replication occurs (3 days for SARS-CoV-2), a sample of supernatant is taken from each infected well (three replicate wells are pooled) and tested immediately or held frozen at -80 °C for later virus titer determination. After maximum CPE is observed, the viable plates are stained with neutral red dye. The incorporated dye content is quantified as described above to generate the EC50 and CC50 values. [000157] The VYR test is a direct determination of how much the test compound inhibits virus replication. Virus yielded in the presence of test compound is titrated and compared to virus titers from the untreated virus controls. Titration of the viral samples (collected as described in the paragraph above) is performed by endpoint dilution (Reed and Muench). Serial 1/10 dilutions of virus are made and plated into 4 replicate wells containing fresh cell monolayers of Vero 76 cells. Plates are then incubated, and cells are scored for presence or absence of virus after distinct CPE is observed, and the CCID50 calculated using the Reed-Muench method (24). The 90% (one logio) effective concentration (EC90) is calculated by regression analysis by plotting the logio of the inhibitor concentration versus logio of virus produced at each concentration. Dividing EC90 by the CC50 gives the SI value for this test.

[000158] Given that ebselen has been demonstrated to be a potent inhibitor of viral replication against various strains of influenza A and influenza B, and SARS-CoV-2, and because of its anti inflammatory properties, it could be administered empirically to patients with “flu-like” symptoms and may obviate the need for differential diagnosis.

Claims

CLAIMS:

1. A method for treating an inflammatory pulmonary disorder in a subject, comprising administering to the subject, within the context of a prescribed dosage regimen, a therapeutically effective amount of an organoselenide glutathione peroxidase mimetic having anti-inflammatory and anti -oxidant activity.

2. The method of claim 1, wherein the pulmonary disorder is selected from: acute respiratory distress syndrome (ARDS); pulmonary fibrosis; viral infection of the lungs; bacterial infection of the lungs; lung cancer; lung injury; presence of an inhaled lung toxin; emphysema, and combinations of any of the foregoing.

3. The method of claim 2, wherein the pulmonary disorder is ARDS.

4. The method of claim 2, wherein the pulmonary disorder is pulmonary fibrosis.

5. The method of claim 2, wherein the pulmonary disorder is a viral infection of the lungs.

6. The method of claim 3, wherein the ARDS is secondary to a viral infection of the lungs.

7. The method of claim 5, wherein the infection is a coronavirus infection.

8. The method of claim 6, wherein the infection is a coronavirus infection.

9. The method of claim 7, wherein the coronavirus infection is caused by the virus SARS-CoV-1, SARS-CoV-2, orMERS-CoV.

10. The method of claim 9, wherein the virus is SARS-CoV-2.

11. The method of claim 5, wherein the infection is an influenza A infection or influenza B infection.

12. The method of claim 11, wherein the infection is an influenza A infection selected from H1N1, H3N2, and H5N1.

13. The method of claim 5, wherein the subject is exhibiting symptoms of respiratory distress and the organoselenide is administered to the subject within one to five days of viral diagnosis.

14. The method of claim 1, wherein an additional active agent is co-administered with the organoselenide.

15. The method of claim 1, wherein the organoselenide is administered in a pharmaceutical composition that additionally comprises at least one excipient.

16. The method of claim 15, wherein the pharmaceutical composition further comprises an additional active agent selected from: a corticosteroid; an anti-malarial agent; an antiviral agent; an antibiotic agent, and combinations thereof.

17. The method of claim 16, wherein the additional active agent is selected from hydroxychloroquine, remdesivir, maraviroc, ivermectin, azithromycin, and molnupiravir.

18. The method of claim 15, wherein the composition is administered to the subject orally, parenterally, transdermally, transmucosally, by inhalation, or via an implanted reservoir.

19. The method of claim 18, wherein the composition is administered to the subject via oral inhalation.

20. The method of claim 19, wherein the composition comprises an aqueous formulation and is administered to the subject using a liquid nebulizer.

21. The method of claim 19, wherein the composition is in dry powder form and is administered to the subject using a dry powder inhaler.

22. The method of claim 15, wherein the composition is administered to the subject at least once daily.

23. The method of claim 15, wherein the composition comprises a controlled release dosage form.

24. The method of claim 1, wherein the organoselenide has the structure of formula (I)

A is a monocyclic, bicyclic, or polycyclic aryl group that is optionally heteroatom- containing, optionally substituted with at least one non-hydrogen substituent, or both heteroatom-containing and substituted, and if bicyclic or polycyclic, containing rings that are fused or linked; n is zero or 1;

X is Se or Se(=0);

Y is O or S; and

R is a C1-C24 hydrocarbyl group that may be heteroatom-containing and/or substituted with one or more non-hydrogen substituents; or is a metabolite or pro-drug thereof.

25. The method of claim 24, wherein n is zero, such that the organoselenide compound has the structure of formula (II)

26. The method of claim 25, wherein A is phenyl or a monocyclic N-heteroaryl group;

Y is O;

X is Se; and

R is C1-C18 alkyl, C1-C18 alicyclic; C5-C12 aryl, or C3-C12 heteroaryl, wherein A and R are independently either unsubstituted or substituted with one to three non-hydrogen substituents.

27. The method of claim 26, wherein A is phenyl or 5-pyridyl, either unsubstituted or substituted with one to three substituents, such that the compound has the structure of Formula

wherein Z is CH or N, and R¹, R², and R³ are selected from H, halo, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, and C5-C12 aryl.

28. The method of claim 27, wherein R¹, R², and R³ are selected from H, halo, and C₁-C₄ alkyl.

29. The method of claim 28, wherein R is C₁-C₁₂ alkyl, C₁-C₁₂ alicyclic, C₅-C₆ aryl, or C₃-C₅ N-heteroaryl, either unsubstituted or substituted with one or two substituents selected from halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, primary amino, carboxyl, C₂-C₄ acyl, C₂-C₄ acyloxy, carboxyl, C₂-C₄ alkoxy carbonyl, primary amino, C₂-C₄ amido, nitro, and hydroxyl.

30. The method of claim 29, wherein Z is CH, R is phenyl, and R¹, R², and R³ are H, such that the organoselenide compound is ebselen.

31. The method of claim 1, wherein the organoselenide compound has the structure of formula (IA)

wherein:

X is Se or Se(=0);

Y is O or S; and

32. The method of claim 31, wherein n is zero, such that the organoselenide compound has the structure of formula (IIA)

33. The method of claim 32, wherein:

A is phenyl or a monocyclic N-heteroaryl group;

Y is O;

X is Se; and

34. The method of claim 33, wherein A is phenyl or 5-pyridyl, either unsubstituted or substituted with one to three substituents, such that the compound has the structure of Formula (IIIA)

35. The method of claim 34, wherein R¹, R², and R³ are selected from H, halo, and C₁-C₄ alkyl.

36. The method of claim 35, wherein R is C1-C12 alkyl, C1-C12 alicyclic, C5-C6 aryl, or C3-C5 N-heteroaryl, either unsubstituted or substituted with one or two substituents selected from halo, C1-C4 alkyl, C1-C4 alkoxy, primary amino, carboxyl, C2-C4 acyl, C2-C4 acyloxy, carboxyl, C2-C4 alkoxy carbonyl, primary amino, C2-C4 amido, nitro, and hydroxyl.

37. The method of claim 36, wherein Z is CH, R is phenyl, and R¹, R², and R³ are H, such that the organoselenide compound is ebselen diselenide.

38. A method for treating an inflammatory pulmonary disorder in a subject, comprising administering to the subject a therapeutically effective amount of ebselen via oral inhalation of a pharmaceutical composition comprising the ebselen.

39. The method of claim 38, wherein the inflammatory pulmonary disorder comprises

ARDS.

40. The method of claim 39, wherein the ARDS is secondary to infection with SARS-

CoV-2.

41. A method for treating a subject infected with SARS-CoV-2, comprising administering to the subject a therapeutically effective amount of ebselen via oral inhalation of a pharmaceutical composition comprising the ebselen.

42. A pharmaceutical formulation comprising a therapeutically effective amount of a combination of (a) ebselen; and (b) at least one additional active agent selected from a corticosteroid, an anti-malarial drug, an antiviral agent, and an antibiotic agent, wherein the therapeutically effective amount is an amount effective to treat a pulmonary disorder associated with inflammation.

43. A pharmaceutical formulation comprising a therapeutically effective amount of a combination of ebselen and at least one of hydroxychloroquine, remdesivir, maraviroc, ivermectin, azithromycin, and molnupiravir, wherein the therapeutically effective amount is an amount effective to treat a pulmonary disorder associated with inflammation.

44. A pharmaceutical formulation for administration via inhalation, comprising a therapeutically effective amount of ebselen in a vehicle suitable for pulmonary administration.

45. The pharmaceutical formulation of claim 44, wherein the vehicle is aqueous.