Classifications

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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P31/12—Antivirals
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• • A—HUMAN NECESSITIES
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  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• This application relates generally to compositions for treating viral infections and more particularly to methods for treating coronaviral infections and its related diseases and symptoms.
• Coronaviruses are a large family of viruses that typically circulate among animals including camels, cats, and bats. Rarely, these viruses cross-over into a different species.
• SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
• SARS-CoV-2 causes coronavirus disease 2019 (“COVID-19”) in humans, where small droplets and aerosols containing the virus can spread from an infected person to another person in close contact.
• SARS-CoV-2 is closely related to SARS-CoV which emerged in 2002 and caused an outbreak of SARS. SARS was highly lethal but faded after intense public mitigation efforts.
• MERS-CoV emerged in 2012 as another highly lethal coronavirus causing MERS.
• the SARS-CoV-2 virus is a potent inducer of inflammatory cytokines and chemokines, such as IL-1 ⁇ , IL-IRA, IL-2, IL-4, IL-7, IL-8, IL- 9, IL-10, basic FGF, GCSF, GMCSF, IFN ⁇ , IP-10, MCP-1, MIP-1 ⁇ , MIP-1 ⁇ , PDGF, TNF ⁇ , and VEGF (Huang et al., Lancet, 395(10223):497-506 (2020)).
• IL-1 ⁇ IL-1 ⁇
• IL-IRA interleukin-2
• IL-4 interleukin-2
• IL-8 interleukin-8
• IL-10 basic FGF
• GMCSF GMCSF
• IFN ⁇ IFN ⁇
• IP-10 IP-10
• MCP-1, MIP-1 ⁇ , MIP-1 ⁇ , PDGF, TNF ⁇ , and VEGF Huang et al., Lancet, 395(10223):
• COVID-19 The predominant symptoms of COVID-19 include fever, shortness of breath, fatigue, myalgia, cough, and loss of smell and/or taste. Pneumonia is present in most SARS-CoV-2 infected patients. Less common symptoms include sputum production, headache, hemoptysis, nausea, and diarrhea.
• sHLH Secondary hemophagocytic lymphohistiocytosis
• IL-2, IL-7, GCSF, IFN- ⁇ , IP-10, MCP-1, MIP-1 ⁇ , and TNF ⁇ is associated with COVID-19 disease severity.
• a recent retrospective, multicenter study of 150 confirmed COVID-19 cases in Wuhan, China indicated that elevated ferritin and IL-6 are predictors of COVID-19 mortality, suggesting that the mortality might be due to SARS-CoV-2-driven hyper inflammation.
• the SARS-CoV-2 virus and related COVID-19 disease represents a challenging and unique threat to public health. There exists a need for new and improved treatments and compositions for preventing and/or treating the SARS-CoV-2 infection and the resulting COVID-19 disease.
• One aspect of the disclosure is directed to a method of treating a viral infection in a subject in need thereof.
• the method comprises administering orally, to a subject having a viral infection, a therapeutically effective amount of Compound I or a derivative thereof to treat the viral infection
• Another aspect of the disclosure is directed to a method of treating infection induced Cytokine Release Syndrome (CRS) or acute respiratory distress syndrome (ARDS) associated with viral infection in a subject.
• the method comprises administering orally, to a subject having an infection, a therapeutically effective amount of Compound I or a derivative thereof, thereby treating the CRS or ARDS.
• Another aspect of the present disclosure is directed to a method of reducing at least one pro-inflammatory cytokine in the lungs of a subject following viral infection.
• the method comprises administering orally, to a subject having a viral infection, a therapeutically effective amount of Compound I or a derivative thereof, thereby reducing levels of at least on pro- inflammatory cytokine in the lungs of the subject.
• Compound I As described herein the, recitation of “Compound I” throughout this disclosure is intended to encompasses atropisomer compounds (P)-I and (M)-l of Compound I as described herein, where compounds (P)-I and (M)-l are present in any molar ratio from 4: 1 (( (P)-I:(M)-I) to 999:1 or where Compound (P)-I is substantially free from Compound (M)-I, where Compounds (P)-I and (M)-l are in any form (e.g., free base, crystalline form, etc.) as described herein.
• FIG. 1 depicts a PXRD diffractogram obtained from a sample of crystalline form A of (P)-ATI-450.
• FIG. 2 depicts a TGA curve (top curve) and DSC curve (bottom curve) obtained from a sample of crystalline for A of (P)-I.
• FIG. 3 shows modulation of ex vivo lipopolysaccharide (LPS)-stimulated cytokine/chemokine production in whole blood samples from subjects administered ATI-450 (100 mg once daily or 50 mg twice daily). The data is shown as a percent of pre-administration blood level.
• LPS lipopolysaccharide
• FIG. 4A and FIG. 4B illustrate a reduction of at least about 70% of LPS-stimulated GM-CSF, IFN ⁇ , IL-2, and MIP-1 ⁇ release in subjects administered 100 mg ATI-450 once daily (FIG. 4A) and 50 mg ATI-450 twice daily (FIG. 4B).
• FIG. 5A shows a reduction of LPS-stimulated IL-6, IL-8, and MIP-1 ⁇ release in blood samples from subjects administered 100 mg ATI-450 once daily.
• FIG. 5B shows a reduction of LPS-stimulated IL-6, IL-8, MIP-1 ⁇ , G-CSF, IL-1RA, IP-10, and MCP-1 levels in blood samples from subjects administered 50 mg ATI-450 twice daily. No significant reduction in the anti-inflammatory cytokine IL-10 or IL-1RA was not observed.
• FIG. 6 provides data relating to the number of polymorphonuclear neutrophils (PMN) as an indicator of inflammatory response after administration of ATI-450 as compared to vehicle-treated animals.
• PMN polymorphonuclear neutrophils
• MK2 inhibitor is a reference to one or more MK2 inhibitors and equivalents thereof known to those skilled in the art, and so forth.
• compositions and methods of the present disclosure can comprise, consist essentially of, or consist of, the components or steps disclosed.
• the term “about” means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%- 55%.
• administering when used in conjunction with a therapeutic means to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted.
• administering when used in conjunction with a MK2 inhibitor compound, can include, but is not limited to, providing a MK2 inhibitor compound into or onto the target tissue; providing a MK2 inhibitor compound systemically to a patient by, e.g., oral administration whereby the therapeutic reaches the target tissue.
• a derivative thereof refers to a salt thereof, a pharmaceutically acceptable salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof.
• an isotope thereof e.g., tritium, deuterium
• substantially free refers to the absence of isomers within the limits of detection of analytical methods such as nuclear magnetic resonance (NMR), gas chromatography/mass spectroscopy (GC/MS), high performance liquid chromatography (HPLC), or liquid chromatography/mass spectroscopy (LC/MS).
• analytical methods such as nuclear magnetic resonance (NMR), gas chromatography/mass spectroscopy (GC/MS), high performance liquid chromatography (HPLC), or liquid chromatography/mass spectroscopy (LC/MS).
• condition as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “disease”, in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
• combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
• MK2 inhibitor is used herein to refer to a compound that exhibits an IC 50 with respect to mitogen-activated protein kinase-activated protein kinase 2 (“MK2”) activity of no more than about 100 ⁇ M and more typically not more than about 50 ⁇ M, as measured in the MK2 enzyme assays.
• IC 50 is the concentration of inhibitor which reduces the activity of an enzyme (e.g., MK2) to half-maximal level.
• MK2 mitogen-activated protein kinase-activated protein kinase 2
• Compounds disclosed herein have been discovered to exhibit inhibition against MK2. In some embodiments, the compounds will exhibit an IC 50 with respect to MK2 of no more than about 1 nM.
• the compounds will exhibit an IC 50 with respect to MK2 of no more than about 1 ⁇ M. In some embodiments, the compounds will exhibit an IC 50 with respect to MK2 of about 1 ⁇ M to about 50 ⁇ M. In certain embodiments, compounds will exhibit an IC 50 with respect to MK2 of no more than about 10 ⁇ M; in further embodiments, compounds will exhibit an IC 50 with respect to MK2 of no more than about 5 ⁇ M; in yet further embodiments, compounds will exhibit an IC 50 with respect to MK2 of not more than about 1 ⁇ M; in yet further embodiments, compounds will exhibit an IC 50 with respect to MK2 of not more than about 300 nM, as measured in the MK2 assay described herein.
• the term “pharmaceutically acceptable salt” refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal.
• pharmaceutically acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
• the nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
• Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
• Suitable pharmaceutically acceptable acid addition salts of the compounds of embodiments herein may be prepared from an inorganic acid or an organic acid. All of these salts may be prepared by conventional means from the corresponding compound of embodiments herein by treating, e.g., the compound with the appropriate acid or base.
• Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, phosphoric and diphosphoric acid; and organic acids, for example formic, acetic, trifluoroacetic, propionic, succinic, glycolic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, b-hydroxybutyric, malonic, galactic, galacturonic, citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, ace
• Salts derived from pharmaceutically-acceptable inorganic bases suitable for the formulations as described herein include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
• Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, chloroprocaine, diethanolamine, N-methylglucamine, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,
• X- may be an anion of various mineral acids (e.g., chloride, bromide, iodide, sulfate, nitrate, phosphate), or an anion of an organic acid (e.g., acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate, p- toluenesulfonate).
• mineral acids e.g., chloride, bromide, iodide, sulfate, nitrate, phosphate
• organic acid e.g., acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate, p- toluenesulfonate.
• X- is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, trifluoroacetate or methanesulfonate.
• solvate is used herein to describe a molecular complex comprising a compound of embodiments herein and an amount of one or more pharmaceutically acceptable solvent molecules.
• hydrate is employed when said solvent is water.
• solvate forms include, but are not limited to, compounds of embodiments herein in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in embodiments herein one solvent molecule can be associated with one molecule of the compounds of embodiments herein, such as a hydrate.
• one solvent molecule can be associated with one molecule of the compound described herein, such as a hydrate. In some embodiments, more than one solvent molecule may be associated with one molecule of the compound described herein, such as a dihydrate. Additionally, in some embodiments herein less than one solvent molecule may be associated with one molecule of the compound described herein, such as a hemihydrate. Furthermore, solvates of embodiments herein are contemplated as solvates of the compound described herein that retain the biological effectiveness of the non-solvate form of the compounds.
• Embodiments herein also includes isotopically-labeled compounds of embodiments herein, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes suitable for inclusion in the compounds of embodiments herein include isotopes of hydrogen, such as 2 H and 3 H carbon, such as 11 C, 13 C and 14 C, chlorine, such as 31 C1, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
• Certain isotopically-labeled compounds of embodiments herein, e.g., those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
• the radioactive isotopes tritium, 3 H, and carbon-14, 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
• Substitution with heavier isotopes such as deuterium, 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
• Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
• PET Positron Emission Topography
• Isotopically-labeled compounds of embodiments herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
• Preferred isotopically-labeled compounds include deuterated derivatives of the compounds of embodiments herein.
• deuterated derivative embraces compounds of embodiments herein where in a particular position at least one hydrogen atom is replaced by deuterium.
• Deuterium (D or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
• Hydrogen deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial.
• a deuterated derivative of a compound of embodiments herein has an isotopic enrichment factor (ratio between the isotopic abundance and the natural abundance of that isotope (the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation).
• the isotopic enrichment factor is at least 5000 (75% deuterium). In some embodiments, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent from the other deuteration sites.
• the term “subject” as used herein and interchangeably with “patient”, includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and farm animals.
• the subject described herein is an animal.
• the subject is a mammal.
• the subject is a human.
• the subject is a non-human animal.
• the subject is a non-human mammal.
• the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
• the subject is a companion animal such as a dog or cat.
• the subject is a livestock animal such as a cow, pig, horse, sheep, or goat.
• the subject is a research animal such as a rodent, dog, or non-human primate.
• the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig.
• the phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.
• terapéuticaally acceptable refers to those compounds, and a derivative thereof, which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
• treat refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results.
• beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total, whether induction of or maintenance of), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease.
• Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Treatment may also be preemptive in nature, i.e., it may include prevention of disease.
• Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen, or may involve prevention of disease progression.
• prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease to a clinically significant or detectable level.
• Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease and prolonging disease-free survival as compared to disease-free survival if not receiving treatment and prolonging disease-free survival as compared to disease-free survival if not receiving treatment.
• Embodiments herein are directed to oral pharmaceutical compositions that inhibit MK2 activity and methods of treatment that involve administering to a subject in need thereof an oral dose of the MK2 inhibitor compound. Some embodiments include methods for the treatment of viral infections in a subject by orally administering the MK2 inhibitor compound described herein. Some embodiments include methods for treating infection induced cytokine release syndrome or acute respiratory distress syndrome in a subject by orally administering the MK2 inhibitor compound described herein.
• compositions disclosed herein possess a specific MK2 inhibitor which prevents p38 MAP Kinase mediated inflammatory signaling, and thus, can be used in the treatment or prophylaxis of a viral infection in which p38 MAP Kinase signaling plays an active role.
• embodiments provide oral pharmaceutical compositions comprising the MK2 inhibitor disclosed herein together with a pharmaceutically acceptable carrier, as well as methods for using the compounds and compositions.
• Certain embodiments provide methods for inhibiting p38 MAP kinase using compounds of embodiments herein.
• use of the specific MK2 inhibitor disclosed herein for use in the manufacture of a medicament for the treatment of a viral infection ameliorated by the inhibition of p38 MAP Kinase.
• the oral pharmaceutical composition disclosed herein comprises a therapeutically effective amount of Compound (I) as shown below.
• Compound I is chemically known as 3-chloro-4-((3,5-difluoropyridin-2- yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]- 2-one and may be prepared according to the methods described in U.S. Patent No. 9,115,089, which is hereby incorporated by reference in its entirety.
• 3-chloro-4-((3,5-difluoropyridin-2- yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]- 2-one is manufactured by and commercially available from Aclaris Therapeutics, Inc. (640 Lee Road, Suite 200, Wayne, PA 19087, USA).
• Atropisomerism refers to a type of isomerism resulting from hindered rotation around a single bond due to steric strain of the substituents. This phenomenon creates stereoisomers which display axial chirality. Atropisomers may be separated (resolved) via supercritical fluid chromatography using a mobile phase of carbon dioxide and ethanol/methanol.
• Compound I encompasses atropisomer compounds (P)-I and (M)-I as depicted above in any molar ratio from 4:1 ((P)-I:(M)-I) to 999:1 or Compound (P)-I substantially free from Compound (M)-I, where Compounds (P)-I and (M)-I are in any form (e.g., free base, crystalline form, etc.) as described herein.
• Compound I of the oral composition as disclosed herein comprises Compound (P)-I and Compound (M)-I in a molar ratio of about 4: 1 ((P)-I:(M)-I) to about 999: 1.
• the molar ratio of (C)-I to (M)-I is about 4.3:1, about 4.6:1, about 4.9:1, about 5.25:1, about 5.7:1, about 6.1:1, about 6.7:1, about 7.3:1, about 8.1:1, about 9:1, about 10:1, about 11.5:1, about 13.3:1, about 15.7:1, about 19:1, about 24:1, about 32.3:1, about 49:1, about 91:1, about 110.1:1, about 124:1, about 141.9:1, about 165.7:1, about 199:1, about 249:1, about 332.3:1, about 399:1, about 499:1, and about 999:1.
• the molar ratio of (P)-I to (M)-I is about 399: 1.
• Compound I of the oral composition as disclosed herein comprises at least 80 mol% of Compound (P)-I.
• the oral composition as disclosed herein comprises at least 81 mol% of Compound (P)-I, at least 82 mol% of Compound (P)-I, at least 83 mol% of Compound (P)-I, at least 84 mol% of Compound (P)-I, at least 85 mol% of Compound (P)-I, at least 86 mol% of Compound (P)-I, at least 87 mol% of Compound (P)-I, at least 88 mol% of Compound (P)-I, at least 89 mol% of Compound (P)- I, at least 90 mol% of Compound (P)-I, at least 91 mol% of Compound (P)-I, at least 92 mol% of Compound (P)-I, at least 93 mol% of Compound (P)-I, at least
• the oral composition as disclosed herein comprises at least 99.75 mol% of Compound (P)-I. In a preferred embodiment the oral composition as disclosed herein comprises at least 99.75 mol% of Compound (P)-l. In any embodiment, Compound I of the oral composition as disclosed herein comprises Compound (P)-I substantially free from Compound (M)-I.
• the oral pharmaceutical composition disclosed herein comprises 10 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 40 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 50 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 60 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 80 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 100 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 120 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 160 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 200 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 240 mg of Compound I.
• the oral pharmaceutical compositions described herein comprise Compound I in an amount of about 5 mg to about 200 mg.
• Compound I is present in the pharmaceutical composition as described herein in an amount of about 5 mg to about 300 mg, about 7.5 mg to about 300 mg, about 10 mg to about 300 mg, about 12.5 mg to about 300 mg, about 15 mg to about 300 mg, about 17.5 mg to about 300 mg, about 20 mg to about 300 mg, about 22.5 mg to about 300 mg, about 25 mg to about 300 mg, about 27.5 mg to about 300 mg, about 30 mg to about 300 mg, about 32.5 mg to about 300 mg, about 35 mg to about 300 mg, about 37.5 mg to about 300 mg, about 40 mg to about 300 mg, about 42.5 mg to about 300 mg, about 45 mg to about 300 mg, about 47.5 mg to about 300 mg, about 50 mg to about 300 mg, about 50 mg to about 290 mg, about 50 mg to about 280 mg, about 50 mg to about 270 mg , about 50 mg to about 260 mg, about 50 mg to
• Compound I is present in the pharmaceutical composition as described herein in an amount of about 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg,
• Compound I is present in the pharmaceutical composition as described herein in an amount of 50 mg, 80 mg, 100 mg, 120 mg, 160 mg, or 240 mg.
• Compound I of the oral composition as disclosed herein comprises a free base. In any embodiment, Compound I of the oral composition as disclosed herein comprises a pharmaceutically acceptable salt.
• Compound I of the oral composition comprises Compound (P)-I and Compound (M)-l as disclosed herein in the free base form. In any embodiment, Compound I of the oral composition comprises Compound (P)-I and Compound (M)-I as disclosed herein in form of pharmaceutically acceptable salts, as described supra.
• Compound I of the oral compositions is a non-solvated form or in a solvated form.
• one solvent molecule can be associated with one molecule of Compound I described herein, such as a hydrate.
• more than one solvent molecule may be associated with one molecule of Compound I as described herein, such as a dihydrate.
• less than one solvent molecule may be associated with one molecule of Compound I described herein, such as a hemihydrate.
• solvates of embodiments herein are contemplated as solvates of Compound I as described herein that retain the biological effectiveness of the non-solvate form of Compound I.
• Compound 1 of the oral composition is a deuterated derivative.
• deuterated derivative embraces compounds of embodiments herein where in a particular position at least one hydrogen atom is replaced by deuterium.
• Deuterium (D or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
• Compound I of the oral composition as disclosed herein comprises Compound (P)-I (free base) in a crystalline form.
• the crystalline form of Compound (P)-I is crystalline Form A as disclosed and characterized herein.
• Compound I or a derivative thereof may be used according to the methods herein in any crystalline or amorphous form.
• Crystalline forms may be characterized by one or more of powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Raman spectroscopy, infrared (IR) spectroscopy, solid- state NMR, and the like.
• the crystalline form A of Compound (P)-I of the oral composition may be characterized by its PXRD pattern.
• the crystalline Form A of Compound (P)-I is characterized by an PXRD pattern having a peak expressed in degrees 2Q at about 9.78 ⁇ 0.2.
• the crystalline Form A of Compound (P)-I is characterized by an PXRD pattern having peaks expressed in degrees 2Q at 9.78 ⁇ 0.2 and 15.51 ⁇ 0.2.
• the crystalline Form A of Compound (P)-I is characterized by an PXRD pattern having peaks expressed in degrees 20 at 9.78 ⁇ 0.2, 15.51 ⁇ 0.2, 19.6 ⁇ 0.2, and 25.92 ⁇ 0.2.
• the crystalline Form A of Compound (P)-I is characterized by an PXRD pattern having peaks expressed in degrees 20 at 9.78 ⁇ 0.2, 15.34 ⁇ 0.2, 15.51 ⁇ 0.2, 19.6 ⁇ 0.2, 20.57 ⁇ 0.2, 21.01 ⁇ 0.2, 25.92 ⁇ 0.2, 29.05 ⁇ 0.2, and 29.48 ⁇ 0.2.
• crystalline form A of (P)-I may be characterized by a PXRD pattern shown in FIG. 1.
• the diffractogram of FIG. 1 was acquired on a PANalytical X'Pert Pro diffractometer using Ni -filtered Cu Ka (45 kV/40 mA) radiation and a step size of 0.02 °2 ⁇ and X'celeratorTM RTMS (Real Time Multi-Strip) detector.
• Configuration on the incidental beam side fixed divergence slit (0.25°), 0.04 rad Soller slits, anti-scatter slit (0.25°), and 10 mm beam mask.
• Configuration on the diffracted beam side fixed divergence slit (0.25°) and 0.04 rad Soller slit. Samples were mounted flat on zero-background Si wafers.
• Crystalline form A of (P)-I may be additionally or alternatively characterized by thermogravimetric analysis (TGA).
• TGA thermogravimetric analysis
• TGA curves were obtained with a TA Instruments Q500 thermogravimetric analyzer under 40 mL/min N 2 purge at 15°C/min in Pt or A1 pans.
• Samples of crystalline form A of (P)-I yielded a TGA curve corresponding substantially to the representative TGA curves (top curve) as depicted in FIG. 2.
• FIG. 2 reveals that, in the sample analyzed, negligible weight loss was observed. Weight loss (0.7%) is observed between 25°C and 256°C by TGA for freebase crystalline form A of (P)-I suggesting that crystalline form A of (P)-I is substantially anhydrous.
• the crystalline form A of (P)-I may additionally or alternatively be characterized by differential scanning calorimetry (DSC).
• DSC differential scanning calorimetry
• the crystalline Form A of Compound (P)-I is characterized by a DSC plot (see FIG. 2) comprising an initial endothermic melting event with an onset temperature of about 188°C, followed by an exothermic recrystallization event at about 196°C, with a final sharp endothermic melting event at about 254°C.
• DSC analyses were conducted with a TA Instruments Q100 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under 40 mL/min N 2 purge. DSC thermograms were obtained at 15°C/min in crimped A1 pans.
• the oral composition of the present disclosure comprises Compound I as disclosed herein formulated by admixture with a pharmaceutically acceptable carrier or excipient.
• the pharmaceutical compositions include the therapeutically effective amount of Compound I and a physiologically acceptable diluent or carrier.
• the pharmaceutical composition further includes one or more additional therapeutic components and/or adjuvants.
• the oral compositions disclosed herein may further comprise pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
• pharmaceutically acceptable diluents fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
• the means and methods for preparation and administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, Banker, G. S., & Rhodes, C. T. (2002). Modern pharmaceutics. New York: Marcel Dekker.; and Goodman, L. S., Brunton, L. L., Chabner, B
• Another aspect of the present disclosure relates a method for treating a viral infection in a subject in need thereof.
• This method comprises orally administering, to a human subject having a viral infection, an oral dose of Compound I, i.e., Compound (P)-I and (M)-I in any molar ratio as described supra and in any form(e.g., free form, crystalline form) as described supra, in an amount that is therapeutically effective to treat the infection.
• Compound I i.e., Compound (P)-I and (M)-I in any molar ratio as described supra and in any form(e.g., free form, crystalline form) as described supra, in an amount that is therapeutically effective to treat the infection.
• Viral infections suitable for treatment in accordance with the methods disclosed herein include any infection caused by or associated with a double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), double-stranded genomic RNA (dsRNA), single-strand positive RNA, and single-strand negative RNA virus.
• the viral infection is an infection that causes or is associated with an excessive or uncontrolled release of proinflammatory cytokines (i.e., a cytokine storm).
• Exemplary viral infections to be treated in accordance with the methods described herein include, without limitation, infection by influenza (e.g., H1N1, H5N1), parainfluenza, paramyxovirus, adenovirus, parvovirus, enterovirus, variola virus, rotavirus, hemorrhagic fever viruses (viruses in the families of Arenaviridae , Bunyaviridae, Filoviridae, Falviviridae, and Togaviridae) hepatitis virus, parechovirus, human T-lymphotrophic virus, Epstein-Barr virus (herpes virus), and coronavirus (SARS-CoV, SARS-CoV-2, MERS-CoV).
• influenza e.g., H1N1, H5N1
• parainfluenza paramyxovirus
• adenovirus adenovirus
• parvovirus enterovirus
• variola virus rotavirus
• hemorrhagic fever viruses
• the viral infection to be treated in accordance with the methods and compositions described herein is a coronavirus.
• coronavirus include both human coronaviridae virus(e.g., SARS-CoV-2, SARS-CoV, MERs-CoV, HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1) and animal coronaviridae viruse(se.g., Feline CoV [serotypes I and II], porcine epidemic diarrhea CoV (PEDV), porcine PRCV, porcine TGEV, Dog CCOC, Rabbit RaCoV, etc.).
• the viral infection is a SARS-associated coronavirus.
• the viral infection is SARS-CoV-2 or a variant thereof.
• influenza virus A e.g., influenza virus A, influenza virus B, influenza virus C, or influenza virus D.
• influenza virus A e.g., H1N1, H5N1, H3N2.
• Another aspect of the present disclosure relates a method for treating infection induced cytokine release syndrome (CRS) or acute respiratory distress syndrome (ARDS) in a subject.
• This method involves administering, to a human subject having an infection, an oral dose of Compound I (i.e., Compound (P)-I and (M)-I in any molar ratio as described supra and in any form(e.g., free form, crystalline form) as described supra, in an amount that is therapeutically effective to treat the infection induced CRS or acute respiratory distress syndrome ARDS.
• Compound I i.e., Compound (P)-I and (M)-I in any molar ratio as described supra and in any form(e.g., free form, crystalline form) as described supra, in an amount that is therapeutically effective to treat the infection induced CRS or acute respiratory distress syndrome ARDS.
• CRS is a systemic inflammatory response that can be triggered by a variety of factors, including infections.
• CRS or cytokine storm involves the excessive or uncontrolled release of proinflammatory cytokines, including interferons, interleukins, chemokines, colony stimulating factors (CSFs), and tumor necrosis factor.
• Inflammation associated with CRS typically begins at a local site and spreads throughout the body via systemic circulation. Infection induced CRS, especially viral or bacterial induced CRS in the lung alveolar environment or in systemic circulation often leads to acute lung injury.
• Acute lung injury is characterized by acute mononuclear/neutrophilic inflammatory response followed by a chronic fibroproliferative phase marked by progressive collagen deposition in the lung.
• Acute respiratory distress syndrome is a severe form of acute lung injury associated with pathogen infection
• the methods of the present disclosure are suitable for treating CRS or ARDS associated with a viral infection, where the viral infection is caused by influenza (e.g., H1N1, H5N1), parainfluenza, paramyxovirus, adenovirus, parvovirus, enterovirus, variola virus, rotavirus, hemorrhagic fever viruses (viruses in the families of Arenaviridae , Bunyaviridae, Filoviridae, Falviviridae, and Togaviridae) hepatitis virus, parechovirus, human T-lymphotrophic virus, Epstein-Barr virus (herpes virus), and coronavirus (SARS-CoV, SARS-CoV-2, MERS-CoV).
• influenza e.g., H1N1, H5N1
• parainfluenza paramyxovirus
• adenovirus adenovirus
• parvovirus enterovirus
• variola virus rotavirus
• the methods of the present disclosure are suitable for treating CRS or ARDS associated with a bacterial(e.g., streptococcal infection, pneumonia), fungal, or parasitic infection.
• the oral composition suitable for administration to a subject in accordance with the methods described herein comprises a therapeutically effective amount of Compound I (i.e., in a molar ratio of Compound (P)-I: Compound (M)-I) of 4:1 to 999:1, in any form as described herein) or an oral pharmaceutical composition comprising the same.
• Compound I i.e., in a molar ratio of Compound (P)-I: Compound (M)-I
• an oral pharmaceutical composition comprising the same.
• the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the viral infection being treated.
• administration of a therapeutically effective amount of Compound I or an oral composition comprising the same is effective to cause at least partial remission of the symptoms that characterize the viral infection. In some embodiments, administration of a therapeutically effective amount of Compound I or an oral composition comprising the same is effective to cause full remission of the symptoms that characterize the viral infection.
• Such treatment is effective to inhibit progression of one or more of respiratory distress, low blood oxygen levels, and inflammatory response
• administration of a therapeutically effective amount of Compound I or an oral composition comprising the same is effective to cause inhibition of p38 MAP kinase-mediated inflammatory signaling. In any embodiments, administration of a therapeutically effective amount of Compound I or an oral composition comprising the same is effective to cause inhibition of MK2 inflammatory signaling.
• administration of a therapeutically effective amount of Compound I or an oral composition comprising the same is effective to cause a reduction in the in vivo serum levels of one or more inflammatory cytokines, including, but not limited to TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, IFN ⁇ , IL-17, IL-18, IL-1 ⁇ , and IL-IRA as compared to the in vivo serum levels of the corresponding cytokines prior to treatment the composition described herein.
• inflammatory cytokines including, but not limited to TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, IFN ⁇ , IL-17, IL-18, IL-1 ⁇ , and IL-IRA
• the oral compositions of embodiments herein may be administered at a first dose to prevent progression, at a second dose to induce remission, and/or a third dose to prevent the disease and/or maintain remission of the disease.
• Such doses may be the same dose, a lower dose, or a higher dose.
• the dose may be administered more frequently, less frequently or at the same frequency.
• the dose may be administered in combination with another therapy, a therapeutic, an adjuvant, or the like.
• a subject can be any mammal or non-mammal.
• subjects include a primate, a human, a dog, a cat, a mouse, a rat, a cow, a horse, and a pig.
• the subject is a human.
• the terms “subject,” “individual” or “patient” are used interchangeably herein and include human and non-human animals.
• Non-human animals include all vertebrates, for example, mammals and non-mammals, such as non-human primates, sheep, dogs, rats, cats, cows, horses, chickens, amphibians, and reptiles. Examples of mammals include non-human primates, sheep, dogs, cats, cows, and horses.
• the various methods of treating a viral infection comprising administering to a subject a therapeutically effective amount of Compound I, as disclosed herein, are suitable for treating humans having a viral infection or disease and may be symptomatic or asymptomatic.
• Compound I i.e., Compound (P)-I and (M)-I in any molar ratio as described supra and in any form ( e.g ., free form, crystalline form) as described supra , or an oral pharmaceutical composition comprising the same is administered in an amount effective to treat a viral infection or infection induced CRS or ARDS in a subject in need thereof.
• Subjects in need of such therapy are disclosed above.
• the subject is one infected with a coronavirus, e.g., SARS-CoV and SARS-CoV-2.
• a therapeutically effective amount comprises 5 mg/day to 300 mg/day of Compound I.
• the dosage to be administered to a particular subject will depend on the characteristics of the subject being treated, e.g., the particular subject treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and can be easily determined by one of skill in the art (e.g., by the clinician).
• 10 mg/day of Compound I is administered to a subject with an infection.
• 40 mg/day of Compound I is administered to a subject with an infection.
• 50 mg/day of Compound I is administered to the subject to a subject with an infection.
• 60 mg/day of Compound I is administered to a subject with an infection.
• 80 mg/day of Compound I is administered to a subject with an infection.
• 100 mg/day of Compound I is administered to a subject with an infection.
• 120 mg/day of Compound I is administered to a subject with an infection.
• 160 mg/day of Compound I is administered to a subject with an infection.
• 200 mg/day of Compound I is administered to a subject with an infection.
• 240 mg/day of Compound I is administered to a subject with an infection.
• the therapeutically effective amount of Compound I is 5 mg/day to 300 mg/day, about 7.5 mg/day to about mg/day, about 10 mg/day to about 300 mg/day, about 12.5 mg/day to about 300 mg/day, about 15 mg/day to about 300 mg/day, about 17.5 mg/day to about 300 mg/day, about 20 mg/day to about 300 mg/day, about 22.5 mg/day to about 300 mg/day, about 25 mg/day to about 300 mg/day, about 27.5 mg/day to about 300 mg/day, about 30 mg/day to about 300 mg/day, about 32.5 mg/day to about 300 mg/day, about 35 mg/day to about 300 mg/day, about 37.5 mg/day to about 300 mg/day, about 40 mg/day to about 300 mg/day, about 42.5 mg/day to about 300 mg/day, about 45 mg/day to about 300 mg/day, about 47.5 mg/day to about 300 mg/day, about 50 mg/day to about 300 mg/day, about 50 mg/day to about 300 mg/
• the therapeutically effective amount of Compound I comprises 5 mg/day, 7.5 mg/day, 10 mg/day, 12.5 mg/day, 15 mg/day 17.5 mg/day, 20 mg/day,
• the therapeutically effective amount of Compound I comprises 100 mg/day, 160 mg/day, or 240 mg/day.
• the oral dose of Compound I that is administered to the subj ect in accordance with the methods disclosed herein comprises Compound (P)-I and Compound (M)-I in a molar ratio of about 4:1 ( (P)-I:(M)-l),
• the molar ratio of (P)-I to (M)-I is about 4.3:1, about 4.6:1, about 4.9:1, about 5.25:1, about 5.7:1, about 6.1:1, about 6.7:1, about 7.3:1, about 8.1:1, about 9:1, about 10:1, about 11.5:1, about 13.3:1, about 15.7:1, about 19:1, about 24:1, about 32.3:1, about 49:1, about 91:1, about 110.1:1, about 124:1, about 141.9:1, about 165.7:1, about 199:1, about249:1, about 332.3:1, about 399:1, about 499:1, and about 999: 1.
• the oral dose of Compound I that is administered to the subj ect in accordance with the methods disclosed herein comprises Compound (P)-I substantially free from Compound (M)-I.
• the oral dose of Compound I that is administered to the subj ect in accordance with the methods disclosed herein comprises at least 80 mol% of Compound (P)-I.
• the oral composition as disclosed herein comprises at least 81 mol% of Compound (P)-I, at least 82 mol% of Compound (P)-I, at least 83 mol% of Compound (P)- I, at least 84 mol% of Compound (P)-I, at least 85 mol% of Compound (P)-I, at least 86 mol% of Compound (P)-I, at least 87 mol% of Compound (P)-I, at least 88 mol% of Compound (P)- I, at least 89 mol% of Compound (P)-I, at least 90 mol% of Compound (P)-I, at least 91 mol% of Compound (P)-I, at least 92 mol% of Compound (P)-I, at least 90 mol% of Compound (P
• a subject having a viral infection is administered orally 5 mg/day to 300 mg/day of Compound I.
• the subject having a viral infection is administered an oral composition comprising Compound I once a day.
• the subject having a viral infection is administered a composition comprising Compound I twice a day.
• the subject having a viral infection is administered an oral composition comprising 10 mg, 30 mg, 50 mg, 80 mg, 100 mg, 120 mg, 160 mg, 200 mg, or 240 mg of Compound I once daily.
• a subject having a viral infection is administered orally 5 mg/day to 300 mg/day of Compound I.
• the subject having a coronaviral infection is administered an oral composition comprising Compound I once a day.
• the subject having a coronaviral infection is administered a composition comprising Compound I twice a day.
• the subject having a coronaviral infection is administered an oral composition comprising 10 mg, 30 mg, 50 mg, 80 mg, 100 mg, 120 mg, 160 mg, 200 mg, or 240 mg of Compound I once daily.
• a subject having a viral infection is administered orally 5 mg/day to 300 mg/day of Compound I.
• the subject having a SARS- CoV infection is administered an oral composition comprising Compound I once a day. In some embodiments, the subject having a SARS-CoV infection is administered a composition comprising Compound I twice a day. In some embodiments, the subject having a SARS-CoV infection is administered an oral composition comprising 10 mg, 30 mg, 50 mg, 80 mg, 100 mg, 120 mg, 160 mg, 200 mg, or 240 mg of Compound I once daily.
• a subject having infection induced CRS or ARDS is administered orally 5 mg/day to 300 mg/day of Compound I.
• the subject having an infection induced CRS or ARDS is administered an oral composition comprising Compound I once a day.
• the subject having a corona virus infection is administered a composition comprising Compound I twice a day.
• the subject having a corona virus infection is administered an oral composition comprising 10 mg, 30 mg, 50 mg, 80 mg, 100 mg, 120 mg, 160 mg, 200 mg, or 240 mg of Compound I once daily.
• the subject having a viral infection or infection induced CRS or ARDS is administered an oral composition comprising 100 mg of Compound I once daily.
• the subject having a viral infection or infection induced CRS or ARDS is administered an oral composition comprising 160 mg of Compound I once daily.
• the subject having a viral infection or infection induced CRS or ARDS is administered an oral composition comprising 200 mg of Compound I once daily.
• the subject having a viral infection or infection induced CRS or ARDS is administered an oral composition comprising 240 mg of Compound I once daily.
• the subject having a viral infection or infection induced CRS or ARDS is administered an oral composition comprising 50 mg of Compound I twice daily.
• the subject having a viral infection or infection induced CRS or ARDS is administered an oral composition comprising 80 mg of Compound I twice daily.
• the subject having a viral infection or infection induced CRS or ARDS is administered an oral composition comprising 100 mg of Compound I twice daily.
• the subject having a viral infection or infection induced CRS or ARDS is administered an oral composition comprising 120 mg of Compound I twice daily.
• the dosage administered is a therapeutically effective amount of the composition sufficient to result in amelioration of a symptom or symptoms, and can vary depending upon known factors such as the pharmacodynamic characteristics of the active ingredient and its mode of administration; age, sex, health and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment and the effect desired.
• the oral composition of embodiments herein can be administered to the subject once (e.g., as a single dose or application). In some embodiments, the oral composition of embodiments herein is administered at least once daily, such as at least two, three or four times daily. In some embodiments, the oral composition of embodiments herein may be administered daily, twice daily, three times daily, weekly, twice weekly, every two weeks, every three weeks, monthly, as needed, or as otherwise directed by a physician. The oral composition of embodiments herein may be administered at any interval to achieve the therapeutically desired effect, e.g., induction or maintenance of remission, prevention or relief of a symptom or symptoms.
• the oral composition of embodiments herein may be administered to a subject for a period of 1, 2, 3, 4, 5, 6 days, about a week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about two months, about three months, about four months, about five months, about six months, or a range of any two of these values.
• treatment may be continued for at least a week, a month, a year, or as otherwise directed by a physician.
• treatment may extend over multiple years, the duration of disease, or the lifetime of the subject.
• the oral composition of embodiments herein can be administered once or twice daily to a subject in need thereof for a period of about two to about twenty-eight days, or from about seven to about ten days.
• the oral composition of embodiments herein can also be administered once, twice, or three times daily to a subject for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 times per year, or a combination thereof.
• the oral composition described herein is administered before, after, or with a meal. In some embodiments the oral composition described herein is administered before, after, or with a high fat meal. In some embodiments, the oral composition described herein is administered before, after, or with a standardized high fat meal. In some embodiments, the high-fat meal is a high-calorie, high-fat meal. In some embodiments, the high fat meal follows the FDA guidance on a high-fat meal. In some embodiments, the high- calorie, high-fat meal follows the FDA guidance on a high-fat and high-calorie meal. In some embodiments, the high-fat meal comprises a fat content of about 50% or greater of total caloric content of the meal. See U.S.
• the high- calorie, high-fat meal comprises a fat content of at least 50% of total caloric content of the meal and a total of about 800 to about 1000 kilocalorie content.
• the oral composition described herein is administered following an overnight fast.
• the overnight fast is at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, or at least about 10 hours.
• the oral composition described herein may be administered following a high-fat meal, high-calorie meal following an overnight fast of at least 10 hours.
• a method of treating a viral infection in a subject by administering a therapeutically effective amount of Compound I to the subject may further comprise administering to the subject an antiviral agent, for example, as part of a combination therapy.
• combination therapy refers to an administration regime comprising the administration of two or more active agents to treat a viral infection, as disclosed herein.
• certain embodiments provide methods for treating a viral infection in a human or animal subject in need of such treatment comprising administering to said subject an amount of an oral composition comprising Compound I as disclosed herein in an amount of 5 mg/day to 300 mg/day to reduce or prevent the viral infection or symptoms thereof in the subject, in combination with at least one additional antiviral agent.
• antiviral agents include, but are not limited to, oseltamivir (e.g., TAMIFLUTM), zanamivir (e.g., RELENZATM), amantadine, rimantadine, remdesivir, chloroquine, ritonavir, lopinavir, ribavirin, penciclovir, nitazoxanide, nafamostat, favipiravir, ivermectin, corticosteroids, and any combination thereof.
• oseltamivir e.g., TAMIFLUTM
• zanamivir e.g., RELENZATM
• amantadine rimantadine
• remdesivir remdesivir
• chloroquine ritonavir
• lopinavir lopinavir
• ribavirin ribavirin
• penciclovir nitazoxan
• Administration of Compound I in a combination therapy may comprise administering Compound I and substantially simultaneously administering an antiviral agent.
• Substantially simultaneous administration may comprise administration of a pharmaceutical formulation comprising both Compound I and the antiviral agent, for example, in a single dosage presentation (e.g., a capsule).
• substantially simultaneous administration may comprise separate administration of separate dosage presentation - one comprising Compound I and one comprising an antiviral agent - within a short period of time, such as within 1 minute, 10 minutes, or 1 hour.
• Combination therapy may alternatively encompass administration of Compound I and an antiviral agent sequentially to the patient, for example, where administration of Compound I is separated from administration from the antiviral agent by about 1 hour to about 24 hours, about 1 to about 7 days, or by 1 or more weeks.
• a combination therapy regimen will provide therapeutic effect in treating a viral infection.
• Compound I may be administered as part of a combination therapy with another immunomodulatory drug.
• certain embodiments provide methods for treating a viral infection in a human or animal subject in need of such treatment comprising administering to said subject an amount of an oral composition comprising Compound I as disclosed herein in an amount of 5 mg/day to 300 mg/day to reduce or prevent the viral infection or symptoms thereof in the subject, in combination with at least one additional immunomodulatory agent.
• Suitable immunomodulatory drugs include, but are not limited to, interleukin-6 inhibitors including, but not limited to, baricitinib (e.g., OLUMIANT®), tocilizumab (e.g., ACTEMRATM); CD20 blockers including, but not limited to, rituximab (e.g., RITUXANTM); Tumor Necrosis Factor (TNF) blockers including, but not limited to, etanercept (e.g., ENBRELTM), infliximab (e.g., REMICADETM) and adalimumab (e.g., HUMIRATM); interleukin-1 receptor antagonists including, but not limited to, anakinra (e.g., KINERETTM); interleukin- 17 inhibitors including, but not limited to, AIN457; Janus kinase inhibitors including, but not limited to, tofacitinib; and syk inhibitors including, but not
• a therapeutically effective amount of Compound I may be administered to a subject by any route sufficient to achieve therapeutic systemic circulation levels, for example, orally, intranasally, rectally, topically, transmucosally, intravenously, or other parenteral routes of administration such as subcutaneous, intravenous injection (IV), intramuscular injection (IM), intrathecal injection (IT), or intraperitoneal injection (IP).
• IV subcutaneous, intravenous injection
• IM intramuscular injection
• IT intrathecal injection
• IP intraperitoneal injection
• a therapeutically effective amount of Compound I may be administered in a single dose or in multiple doses at pre- determined intervals over time that when added together provides the therapeutically effective amount.
• a reduction may quantitative or qualitative.
• a quantitative reduction may be at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, and in an ideal situation, about 100% reduction of an adverse quantifiable state related to the viral infection.
• a qualitative reduction may be a reduction based on a subject-reported scale (e.g., from 1 to 10) or a subject- reported decrease in adverse symptoms related to the viral infection that are unable to be quantified.
• the methods of treating a viral infection for example, a SARS-Coactivated virus
• a viral infection for example, a SARS-Coactivated virus
• CoV-2 infection in a subject in need thereof comprising administering a therapeutically effective amount of Compound I will result in improvement in negative symptoms related to the viral infection.
• administration of Compound I may decrease Time to Clinical Improvement (TTCI).
• TTCI is defined as the time (in days) from initiation of treatment until a decline of at least two categories on a six-category ordinal scale of clinical status.
• the six-category ordinal scale are (6) Death; (5) ICU, requiring ECMO and/or IMV (invasive mechanical ventilation); (4) ICU/hospitalization, requiring NIV (non-invasive mechanical ventilation)/HFNC (high -flow nasal cannula therapy); (3) hospitalization, requiring supplemental oxygen (but not NIV/HFNC); (2) hospitalization, not requiring supplemental oxygen; and (1) hospital discharge.
• administration of a therapeutically effective amount of Compound I to a subject in need thereof may result in one or more of the following: (i) An earlier hospital discharge; (ii) A reduction in NEWS (National Early Warning Score); (iii) Reduced duration on mechanical ventilation; (iv) Reduced duration on extracorporeal membrane oxygenation (ECMO); (v) Reduced duration on supplemental oxygenation; (vi) An earlier negative SARS-CoV-2 RT-PCR test in upper and lower respiratory tract specimens; (vii) A reduction in SARS-CoV-2 viral load in upper and lower respiratory tract specimens as assessed by area under viral load curve; (viii) Reduced frequency of serious adverse events; (ix) Reduced need for endotracheal intubation; (x) Improvement in pulmonary function (PEFR); (xi) Decreased white blood cell and differential count; (xii) Reduced levels of high- sensitivity C-reactive protein (hsCRP); (xiii) Prevention or delay of ARDS; and (x
• administration of the pharmaceutical composition disclosed herein to a subject in need thereof reduces at least one pro-inflammatory cytokine in the lung or any other affected organ of a subject following viral infection.
• a method of reducing at least one pro-inflammatory cytokine in the lung of a subject having an infection, e.g., a viral infection comprises administering to subject in need thereof a pharmaceutical composition comprising an effective amount of Compound I.
• pro-inflammatory cytokines are selected from IL-1 ⁇ , IL-1 ⁇ , IL-2, IL-4, IL- 6, IL-7, IL-8, IL-10, IL-12, IL-17, IFN ⁇ , IFN- ⁇ , TNF- ⁇ , IP-10, MCP-1, MIP-1, RANTES, GM- CSF, and combinations thereof.
• one or more cytokines selected from IL-1 ⁇ , IL-1RA, IL-6, IL-7, IL-8, IL-9, IL-10, bFGF, GCSF, GMCSF, IFN ⁇ , IP-10, MCP-1, MIP-1 ⁇ , MIP-1 ⁇ , PDGF, VEGF, TNF ⁇ , ferritin, CRP, and ESR are reduced with treatment. Any of the above-described pharmaceutical compositions can be used in this method.
• the viral infection can comprise infection by influenza (e.g., H1N1, H5N1), parainfluenza, paramyxovirus, adenovirus, parvovirus, enterovirus, variola virus, rotavirus, hemorrhagic fever viruses (viruses in the families of Arenaviridae , Bunyaviridae, Filoviridae, Falviviridae, and Togaviridae) hepatitis virus, parechovirus, human T-lymphotrophic virus, Epstein-Barr virus (herpes virus), and coronavirus (SARS-CoV, SARS-CoV-2, MERS-CoV).
• influenza e.g., H1N1, H5N1
• parainfluenza paramyxovirus
• adenovirus adenovirus
• parvovirus enterovirus
• variola virus rotavirus
• hemorrhagic fever viruses viruses in the families of Arenaviridae , Bunyavi
• a method of treating a subject having infection induced CRS or ARDS comprises administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises at least an effective amount of Compound I.
• the infection induced CRS or ARDS can be cause by a viral infection, bacterial infection, or fungal infection.
• the CRS or ARDS treated herein is induced by a viral infection with influenza (e.g., H1N1, H5N1), parainfluenza, paramyxovirus, adenovirus, parvovirus, enterovirus, variola virus, rotavirus, hemorrhagic fever viruses (viruses in the families of Arenaviridae , Bunyaviridae , Filoviridae , Falviviridae , and Togaviridae) hepatitis virus, parechovirus, human T-lymphotrophic virus, Epstein-Barr virus (herpes virus), or coronavirus (SARS-CoV, SARS-CoV-2, MERS-CoV).
• CRS or ARDS in a subject having SARS-CoV-2 is treated according to the methods and composition comprising Compound I as described herein.
• Embodiment 1 is a method of treating a viral infection in a subject, the method comprising: administering orally, to a subject having a viral infection, a therapeutically effective amount of Compound I , or a derivative thereof to treat the viral infection.
• Embodiment 2 is a method of treating infection induced cytokine release syndrome (CRS) or acute respiratory distress syndrome (ARDS) in a subject, the method comprising: administering orally, to a subject having an infection, a therapeutically effective amount of Compound I or a derivative thereof to treat the infection induced CRS or ARDS.
• CRS infection induced cytokine release syndrome
• ARDS acute respiratory distress syndrome
• Embodiment 3 is the method of Embodiment 2, wherein the infection is a viral infection, a bacterial infection, a fungal infection, or a parasitic infection.
• Embodiment 4 is the method of any one of Embodiments 1-3, wherein the infection is a viral infection, and the viral infection comprises infection by influenza, parainfluenza, paramyxovirus, adenovirus, parvovirus, variola virus, enterovirus, rotavirus, a hemorrhagic fever virus, hepatitis virus, parechovirus, human T-lymphotrophic virus, Epstein-Barr virus, or coronavirus.
• influenza parainfluenza
• paramyxovirus adenovirus
• parvovirus variola virus
• enterovirus rotavirus
• a hemorrhagic fever virus hepatitis virus
• parechovirus human T-lymphotrophic virus
• Epstein-Barr virus or coronavirus.
• Embodiment 5 is the method of Embodiment 4, wherein the subject has a coronavirus infection selected from SARS-CoV-2, SARS-CoV, MERS-CoV, and HCoV- NL63, HCoV-229E, HCoV-OC43, and HCoV-HKUl.
• a coronavirus infection selected from SARS-CoV-2, SARS-CoV, MERS-CoV, and HCoV- NL63, HCoV-229E, HCoV-OC43, and HCoV-HKUl.
• Embodiment 6 is the method of Embodiment 5, wherein the viral infection comprises infection by SARS-CoV-2 or a variant thereof.
• Embodiment 7 is the method of any one of Embodiments 1-6, wherein 50 mg/day of Compound I is administered to said subject.
• Embodiment 8 is the method of any one of Embodiments 1-6, wherein 100 mg/day of Compound I is administered to said subject.
• Embodiment 9 is the method of any one of Embodiments 1-6, wherein 160 mg/day of Compound I is administered to said subject.
• Embodiment 10 is the method of any one of Embodiments 1-6, wherein 200 mg/day of Compound I is administered to said subject.
• Embodiment 11 is the method of any one of Embodiments 1-6, wherein 240 mg/day of Compound I is administered to said subject.
• Embodiment 12 is the method of any one of Embodiments 1-11, wherein Compound I is administered once a day.
• Embodiment 13 is the method of any one of Embodiments 1-11, wherein Compound I is administered twice a day.
• Embodiment 14 is the method of any one of Embodiments 1-6 wherein 50 mg of Compound I is administered to the subject twice daily.
• Embodiment 15 is the method of any one of Embodiments 1-6, wherein 50 mg of Compound I is administered to a subject infected with a coronavirus twice daily.
• Embodiment 16 is the method of any one of Embodiments 1-6, wherein 80 mg of Compound I is administered to the subject twice daily.
• Embodiment 17 is the method of any one of Embodiments 1-6, wherein 100 mg of Compound I is administered to the subject twice daily.
• Embodiment 18 is the method of any one of Embodiments 1-6, wherein 120 mg of Compound I is administered to the subject twice daily.
• Embodiment 19 is the method of any one of Embodiments 1-18, wherein Compound I is deuterated.
• Embodiment 20 is the method of any one of Embodiments claims 1-19, wherein Compound I comprises the Compound (P)-I (P)-I, and the Compound (M)-I (M)-I, in a molar ratio of (P)-I to (M)-I of about 4:1.
• Embodiment 21 is the method of Embodiment 20, wherein the molar ratio of (P)-I to (M)-I is about 9:1.
• Embodiment 22 is the method of Embodiment 20, wherein the molar ratio of (P)- I to (M)-I is about 99: 1.
• Embodiment 23 is the method of Embodiment 20, wherein the molar ratio of (P)- I to (M)-I is about 199:1.
• Embodiment 24 is the method of Embodiment 20, wherein the molar ratio of (P)- I to (M)-I is about 399: 1.
• Embodiment 25 is the method of Embodiment 20, wherein the molar ratio of (P)- I to (M)-I is about 999: 1.
• Embodiment 26 is the method of any one of claims 1-19, wherein Compound I comprises the Compound (P)-I substantially free of Compound (M)-I.
• Embodiment 27 is the method of any one of Embodiments claims 1-19, wherein Compound I comprises at least 80 mol% of Compound (P)-I
• Embodiment 28 is the method of Embodiment 27, wherein Compound I comprises at least 90 mol% of Compound (P)-I.
• Embodiment 29 is the method of Embodiment 28, wherein Compound I comprises at least 95 mol% of Compound (P)-I.
• Embodiment 30 is the method of Embodiment 29, wherein Compound I comprises at least 99 mol% of Compound (P)-I.
• Embodiment 31 is the method of any one of Embodiments 1-30, wherein Compound (P)-I is a free base.
• Embodiment 32 is the method of any one of Embodiments 1-30, wherein Compound (P)-I is a pharmaceutically acceptable salt.
• Embodiment 33 is the method of any one of Embodiments 1-30, wherein Compound (P)-I is crystalline form.
• Embodiment 34 is the method of Embodiment 33, wherein the crystalline form of Compound (P)-I is crystalline Form A characterized by an PXRD pattern having a peak expressed in degrees 20 at about 9.78 ⁇ 0.2.
• Embodiment 35 is the method of Embodiment 33, wherein the crystalline form of Compound (P)-I is the crystalline Form A characterized by an PXRD pattern having peaks expressed in degrees 20 at 9.78 ⁇ 0.2 and 15.51 ⁇ 0.2.
• Embodiment 36 is the method of Embodiment 33, wherein the crystalline form of Compound (P)-I is the crystalline Form A characterized by an PXRD pattern having peaks expressed in degrees 20 at 9.78 ⁇ 0.2, 15.51 ⁇ 0.2, 19.6 ⁇ 0.2, and 25.92 ⁇ 0.2.
• Embodiment 37 is the method of Embodiment 33, wherein the crystalline form of Compound (P)-I is the crystalline Form A characterized by an PXRD pattern having peaks expressed in degrees 20 at 9.78 ⁇ 0.2, 15.34 ⁇ 0.2, 15.51 ⁇ 0.2, 19.6 ⁇ 0.2, 20.57 ⁇ 0.2, 21.01 ⁇ 0.2, 25.92 ⁇ 0.2, 29.05 ⁇ 0.2, and 29.48 ⁇ 0.2,
• Embodiment 38 is the method of any one of Embodiments 1-37, wherein the method further comprises administering at least one additional antiviral agent to the subject.
• Embodiment 39 is the method of any one of embodiments 1-37, wherein the method further comprises administering at least one additional immunomodulatory agent to the subject.
• Embodiment 40 is the method of any one of Embodiments 1-39, wherein Compound 1 is formulated as a solid dosage form selected from a tablet, a capsule, a lozenge, a sachet, a powder, granules, and orally dispersible film.
• Embodiment 41 is the method of any one of Embodiments 1-40, wherein said administering is carried out under conditions effective to significantly reduce in vivo serum levels of one or more inflammatory cytokines.
• Embodiment 42 is the method of Embodiment 41, wherein the one or more inflammatory cytokines is selected from the group consisting of TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, IFN ⁇ , IL-17, IL-18, IL-1 ⁇ , and IL-1RA.
• Compound I exists as a P atropisomer and a M atropisomer.
• ATI-450 refers to the aforementioned compound containing about 99.75 mol% of the P atropisomer and about 0.25 mol% of the M atropisomer, i.e., in a ratio of (P)-I to (M)-I of 399:1.
• EXAMPLE 1 p38 Inhibitory Potency and p38/MK2 Substrate Selectivity.
• the ability of Compound (P)-I and (M)-l to inhibit activated phospho-p38 ⁇ was evaluated using a p38 ⁇ /MK2 and a p38 ⁇ /PRAK cascade assay format.
• the kinase activity of p38 ⁇ was determined by its ability to phosphorylate GST-MK2 or GST-PRAK.
• Activation of MK2 or PRAK by p38 ⁇ was quantitated by measuring the phosphorylation of a fluorescently-labeled, MK2/PRAK specific peptide substrate, Hsp27 peptide.
• the phosphorylation of the Hsp27 peptide was quantified using IMAP technology (Molecular Devices, Sunnyvale CA).
• Kinase reactions were carried out in a 384-well plate (Greiner, 781280) in 20 mM HEPES pH 7.5, 10 mM MgCl 2 , 0.01% Triton X-100, 0.01% BSA, 1 mM DTT, and 2% DMSO.
• the concentration of inhibitor in the assays was varied between 0.02 nM to 30,000 nM, while the Hsp27 peptide substrate and MgATP were held constant at 1 ⁇ M and 10 ⁇ M, respectively.
• Activated p38 ⁇ was added to a final concentration of 30 pM for reactions with non-phosphorylated 1 nM GST-MK2 in the cascade reaction.
• the concentration of non-activated GST-PRAK was held constant at 10 nM while p38 ⁇ was added to a final concentration of 200 pM.
• Kinase reactions were incubated at room temperature and quenched after 120 minutes by the addition of IMAP Binding Solution. Under these conditions, approximately 20% of the substrate Hsp27 peptide was phosphorylated. Reactions were initiated by the addition of activated p38 ⁇ except for preincubation experiments, where reactions were initiated by the addition of Hsp27 peptide and MgATP.
• Pre-incubation of p38 ⁇ with inhibitor or p38 ⁇ with non-activated GST-MK2 or non- activated GST-PRAK and inhibitor were performed at 2X final assay concentrations at room temperature 240 minutes prior to adding ATP and Hsp27 peptide to initiate catalysis.
• the inhibitory potency of Compounds (P)-I and (M)-l was quantitated from dose-response IC 50 values or K i values from p38 ⁇ /MK2 cascade assays while the substrate selectivity was calculated as a ratio of p38 ⁇ /PRAK:p38 ⁇ /MK2 IC 50 values.
• EXAMPLE 2 Cytokine regulation in human monocytes.
• the p38 pathway has been shown to be critical for the biosynthesis of a number of pro-inflammatory cytokines including TNF ⁇ , IL-1 ⁇ and IL-6. Therefore, inhibition of the p38 MAP Kinase pathway will lower the inflammatory response by decreasing biosynthesis of pro-inflammatory cytokines.
• This study shows the amount of Compound (P)-I and Compound (M)-I necessary to inhibit biosynthesis of TNF ⁇ , IL-6, and IL-1 ⁇ (pro-inflammatory cytokines) by half, demonstrating the effectiveness of each compound in helping to lower inflammation, an effect which helps treat many diseases, including viral infections (e.g., Covid-19 infection) and infection relate CRS and ARDS.
• Differentiated U937 cells human peripheral blood mononuclear cells (hPBMC)
• hPBMC human peripheral blood mononuclear cells
• the cells were pretreated for 60 minutes in the presence or absence of Compound (P)-I and Compound (M)-I and then stimulated with LPS (0.1 ⁇ g/mL) for 4 hours.
• Culture media was then collected for determination of TNFa, IL-6 or IL-1 ⁇ levels by ELISA.
• Cytokine concentrations were extrapolated from recombinant protein standard curves using a four- parameter logistic model and solving for IC 50 after iterating to the best least-squares fit.
• EXAMPLE 3 Phosphoprotein analysis in human monocytes.
• This study shows the effectiveness and selectivity of Compound (P)-I in inhibiting the JNK pathway.
• the JNK pathway leads to increased inflammation by boosting production of inflammatory cytokines. Inhibition of this pathway will lead to less inflammation and therefore will treat many diseases, including viral infections, including those caused by SARS- CoV-2.
• Evaluation of the impact of Compound (P)-I on p38 and JNK pathway regulation was carried out using phospho-HSP27 and phosphor-JNK for the two pathways, respectively.
• Evaluation of the potency and efficacy of Compound (P)-I to impact phosphoprotein levels was carried out using the human U937 cell line.
• the U937 human pre-monocytic cell line was obtained from the American Type Culture Collection (Rockville, MD).
• the cells were washed on day two by centrifuging and re-suspended in fresh media without PMA.
• Adherent cells were harvested on day three by scraping, centrifuged and re-suspended in fresh media at a density of 1 million per milliliter.
• the PMA-differentiated U937 cells were then distributed into each well of a 96-well flat bottom tissue culture plate (100 mL/well) and the 100,000 cells/well were allowed to recover, incubated, overnight.
• fresh media 50 mL/well
• Compound (P)-I 25 mL/well, concentration response
• the cells were stimulated with LPS (100 ng/mL) in a final assay volume of 100 mL. After 30 minutes, complete lysis buffer (50 mL/well MSD Tris lysis buffer, supplemented with protease inhibitors and phosphatase inhibitors) was added and the plate was placed on a shaker at 4°C for 30 minutes before being stored frozen at -20°C. The cellular lysate (25 mL/well) was thawed and transferred from the assay plate to Meso Scale detection plates for determination of phospho-Hsp27/total Hsp27 or phospho-TNK/total INK. [0172] Compound (P)-I was tested in accordance with the above described assay, yielding IC 50 and EC 50 values described in Table 3 below:
• EXAMPLE 4 Endotoxin-induced cytokine production from human whole blood.
• HWB Human whole blood
• vacutainer collection tubes containing sodium heparin (10 mL, 158 USP units) were collected and rocked gently before being distributed into each well of a 96-well round bottom tissue culture plate (180 mL/well).
• Compound (P)-I (10 mL/well, concentration response) was added and mixed gently for 15-20 seconds using a disposable 96 polypropylene pin tool before the plates were incubated at 37°C/5% CO 2 for 1 hour.
• the HWB was stimulated with LPS (100 ng/mL) in a final assay volume of 200 mL.
• the plates were spun at 240xg for 5 minutes to pellet the red cells.
• the plasma was carefully transferred to another 96-well round bottom plate and diluted 2-fold with assay media (DMEM containing 10% fetal bovine serum (FBS) plus antibiotics). Finally, the diluted plasma (25 mL/well) were transferred to Meso Scale detection plates for determination of IL-1, IL-6 or TNFa.
• EXAMPLE 5 An Open-label Assessment of the Safety and Efficacy of ATI-450 in the Treatment of COVID-19-related Cytokine Release Syndrome.
• ATI-450 is a small molecule inhibitor of MK2 that inhibits production of multiple cytokines such as TNF ⁇ , IL-1 ⁇ , IL-6 and IL-8.
• cytokines such as TNF ⁇ , IL-1 ⁇ , IL-6 and IL-8.
• ATI-450 was well tolerated by test subjects and exhibit a good PK/PD profile.
• Demonstration of the efficacy and safety of ATI-450 in treating viral infections, for example, of the SARS-CoV-2 virus represents a pathway to improvement in clinical symptoms in such patients infected with the SARS-CoV-2 virus and therefore a reduction in healthcare utilization, for example, preventing a subject’s progression to critical care.
• ATI-450 The safety, tolerability, and pharmacodynamics (PD) effect of ATI-450 was tested in subjects having symptoms related to COVID-19-related CRS. After a 2-day screening period, subjects were administered ATI-450 as part of a 14-day treatment period after which the subject was monitored for a 2-week follow-up period. Subjects were orally administered one tablet comprising 50 mg of ATI-450 twice daily. Subjects undergoing treatment are identified as:
• a primary objective of this study is to assess the efficacy of ATI-450 in patients with COVID-19 related cytokine release syndrome. This objective will be assessed determining the proportion of subjects with normalization of fever and oxygen saturation through day 14 of treatment. This is a composite outcome measure that requires (i) a temperature of less than 36.6°C (armpit) or less than 37.2°C (oral) sustained for at least 72 hours and (ii) peripheral capillary oxygen saturation (Sp02) greater than 94% for at least 72 hours.
• This objective will also be assessed by determining the following secondary endpoints: Change of oxygen saturation greater than three percentage points or greater than 10% or decrease in FiO 2 need or reduction of at least 30% in pulmonary consolidations evidenced by HR CT-scan; need for endo-tracheal intubation; all-cause mortality; length of hospital stay (days); entry into ICR for critical care management; Improvement in pulmonary function (PEFR); proportion of participants with normalization of fever through day 14; Change from baseline in white blood cell and differential count; Time to SARS-CoV-2 RT- PCR negativity in oropharyngeal or nasal testing; Change from baseline in high-sensitivity C- reactive protein (hsCRP); Development of new ARDS.
• HR CT-scan Change of oxygen saturation greater than three percentage points or greater than 10% or decrease in FiO 2 need or reduction of at least 30% in pulmonary consolidations evidenced by HR CT-scan
• need for endo-tracheal intubation all-cause mortality
• length of hospital stay (days) entry into ICR for critical care
• Exploratory endpoints include an assessment of the pharmacodynamics of ATI- 450 in patient with COVID-19 related cytokine release syndrome. This endpoint will be assessed by determining: change from baseline in serum cytokines IL-1 ⁇ , IL-10, sIL-2R, IL-6, IL-8, IFN ⁇ , IL-17, IL-18, IL-10, IL-1 ⁇ , IL-IRA and TNF- ⁇ ; change from baseline in proportion of CD4+ CD3/CD8+CD3 T cells; mean change from pre-dose in ex vivo stimulated cytokine levels (e.g., TNF- ⁇ , IL- ⁇ , IL-6, IL-8 IFN ⁇ , IL-17, IL-18, IL-10, IL-1RA- and IL-1 ⁇ ); ex vivo stimulated phosphoprotein modulation.
• ex vivo stimulated cytokine levels e.g., TNF- ⁇ , IL- ⁇ , IL-6, IL-8 IFN ⁇ , IL-17,
• EXAMPLE 6 Effect of Oral ATI-450 on Plasma Cytokine and Chemokine Profile.
• TLR4 ex vivo lipopolysaccharide
• Cohort 1 Single-ascending dose (SAD) subjects were administered a single oral dose of 100 mg of ATI-450 in the morning after fasting overnight. Blood samples were collected pre-administration and 1-hour post-administration from 2 subjects administered a placebo and 6 subjects administered ATI-450; and
• Cohort 2 Multiple-ascending dose (MAD) subjects were administered a twice daily oral dose of 50 mg ATI-450 for seven days. Blood samples were collected pre- administration on day 1 and 4-hour post-administration on day 7 from 2 subjects administered a placebo and 8 subjects administered ATI-450.
• MAD Multiple-ascending dose
• FIG. 3 depicts lipopolysaccharide-stimulated cytokine/chemokine production as a percent of pre-administration blood concentrations in samples obtained from both Cohort 1 and Cohort 2. Absolute values (in pg/mL) and increase (fold) stimulation of each chemokine/cytokine analyzed in samples from Cohorts 1 and 2 are reported in Table 5 below.
• Table 5 illustrates that chemokines/cytokine expression was induced to varying levels under human whole blood assay conditions. Cytokine production, rank order, and fold stimulations are comparable across samples collected from Cohort 1 and Cohort 2 when comparisons were performed by heat map analysis.
• FIGs. 4A and 4B illustrates that inflammatory cytokines/chemokines GM-CSF, IFN ⁇ , IL-2, and MIP-1 ⁇ were inhibited by ATI-450 by at least about 70% across both cohorts compared to placebo-administered subjects.
• Anti-inflammatory mediators such as IL-10 and IL-1RA were inhibited by ATI-450 but to a lesser extent (about 30%) as shown in FIG. 5A (Cohort 1) and FIG. 5B (Cohort 2).
• EXAMPLE 7 ATI-450 Blocks Lung Neutrophilia in a Rat Model of Pulmonary
• ATI-450 The ability of ATI-450 to suppress pulmonary inflammation was investigated in Sprague-Dawley rats orally administered 1 mg/kg or 10 mg/kg of ATI-450.
• animals were placed in an aerosol chamber containing 60 ⁇ g/mL lipopolysaccharide (LPS) for 40 minutes and then removed to room air.
• LPS lipopolysaccharide
• lungs of the animals were lavaged with cold D-PBS/EDTA solution and the total number of polymorphonuclear neutrophils (PMN) in the solution were counted as an indicator of the inflammatory response.
• FIG. 6 illustrates collected the data, demonstrating that total lung PMNs were significantly reduced in the rats administered ATI-450 when compared to vehicle- treated animals. This suggests that ATI-450 may effectively inhibit lung neutrophilia in vivo.
• Inflammation and inflammatory diseases, conditions, and disorders propagate primarily through the MAPK signal pathway.
• Activation of p38 ⁇ is important for regulating inflammation.
• Aberrant p38 ⁇ activation is associated in the pathobiology of diseases such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease and tissue fibrosis.
• the MAPKAPK2 (MK2) protein is one downstream target of p38 ⁇ and is responsible for the transcriptional production of pro-inflammatory cytokines, including the same cytokines observed as elevated in COVID-19-related inflammation.
• Other severe viral illnesses ⁇ i.e., Dengue fever, influenza, cytomegalovirus
• COVID-19-mediated inflammatory cytokine production may likewise signal through the p38 ⁇ MK2 axis.
• MK2 pathway blockade may suppress inflammation.
• Racemic 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2- hydroxypropan-2-yl)pyrimidin-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (250 mg, 0.49 mmol) may be prepared according to the methods described in U.S. Patent No. 9,115,089, which is hereby incorporated by reference in its entirety.
• Racemic 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2- hydroxypropan-2-yl)pyrimidin-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (250 mg, 0.49 mmol) was separated using supercritical fluid chromatography (Thar 80, preparative SFC, ChiralCel OD-H, 250 x 30 mm ID column) with a mobile phase of carbon dioxide and ethanol.
• the separation method used an isocratic method of 40% ethanol with a flow rate of 50 mL/min and a cycle time of 10 min.
• the crystal-form screening study involved a total of 48 neat and binary solvent systems which addressed the moderate solubility of the input material and provided a diverse set of polarities, dielectric constants, dipole moments, and hydrogen-bond donor/acceptor attributes.
• Water-containing solvents with a variety of water activities (a » ) 1 were also included to probe for the formation of hydrates. Temperatures ranging between 40°C to -20°C.
• PXRD data consists of experimentally determined values of the two-theta position, the intensity values of multiple crystallographic reflections, also known as Bragg reflections, and their peak shape.
• the PXRD data may be analyzed computational, including by the method of Rietveld refinement.
• a detailed description of Rietveld refinement of X-ray powder diffraction data is provided in Pecharsky, Vitalij K.; Zavalij, Peter Y. (2009) Fundamentals of powder diffraction and structural characterization of materials (2nd ed.). New York: Springer. ISBN 978-0-387- 09579-0. OCLC 314182615, which is herein incorporated by reference.
• PXRD data may be collected at various temperatures or pressures in order to facilitate Rietveld refinement.
• the experimental PXRD data including 2-theta values, d- spacing, Bragg reflections and intensity values may be compared to a simulated PXRD pattern derived from the single crystal structure determination which represents an idealized pure powder, using a computational method such as described in Macrae, Clare F., et al. “Mercury 4.0: from visualization to analysis, design and prediction.” Journal of Applied Crystallography vol. 53, 226-235. 1 Feb. 2020, doi:10.1107/S1600576719014092.
• an X-ray powder diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed in the data collection. It is generally accepted that the peak shape, intensity values and two-theta positions derived from an X-ray powder diffraction pattern can fluctuate depending upon the type of instrument used, the measurement conditions and the method of computational analysis performed. It should be further understood that that the two- theta values and their relative intensities may also vary and accordingly, the exact order of intensity values should not be taken into account.
• the experimental error for diffraction angle measurements for a conventional X-ray powder diffraction pattern is typically about 5% or less. Assessment of the extent of measurement error should be taken into account when describing the position of the two-theta diffraction peaks. Consequently, it is to be understood that the crystal forms described in this invention are not limited to the crystal forms that provide X-ray powder diffraction patterns completely identical to the X-ray powder diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X-ray powder diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention.
• Crystalline Form A of Compound (P)-I is anhydrous and was obtained from crystallization conditions described in Example 4 utilizing various organic solvents and organic/water solvent systems.
• X-Ray Powder Diffraction (PXRD) diffractograms were acquired on PANalytical X’Pert Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation and a step size of 0.02° 2 ⁇ and X'celeratorTM RTMS (Real Time Multi-Strip) detector.
• Configuration on the incidental beam side fixed divergence slit (0.25°), 0.04 rad Soller slits, anti-scatter slit (0.25°), and 10 mm beam mask.
• Configuration on the diffracted beam side fixed divergence slit (0.25°) and 0.04 rad Sober slit. Samples were mounted flat on zero-background Si wafers.
• DSC Differential Scanning Calorimetry
• thermograms were obtained with a TA Instruments Q500 thermogravimetric analyzer under 40 mL/min N2 purge at 15°C/min in Pt or A1 pans.
• DSC analysis indicates crystalline Form A of Compound (P)-I exhibits a melting/racemization event at 187.92 °C, followed by a recrystallization event at 195.8 °C, and finally a sharp endotherm at 253.5 °C (melt of racemate). Negligible weight loss (0.7%) is observed between 25-256 °C by TGA.
• DSC and TGS thermograms are shown in FIG. 2
• EXAMPLE 12 Formulations of ATI-450 Tablets.
• compositions of the tablets comprising ATI-450 and tablets comprising placebo used in the Examples herein are provided in Table 9 below.
• the excipients used in the drug tables and their function are provided in Table 10 below.

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