WO2022109086A1 - Molécules libérant du monoxyde de carbone et compositions pharmaceutiques et utilisations associées - Google Patents

Molécules libérant du monoxyde de carbone et compositions pharmaceutiques et utilisations associées Download PDF

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Publication number
WO2022109086A1
WO2022109086A1 PCT/US2021/059818 US2021059818W WO2022109086A1 WO 2022109086 A1 WO2022109086 A1 WO 2022109086A1 US 2021059818 W US2021059818 W US 2021059818W WO 2022109086 A1 WO2022109086 A1 WO 2022109086A1
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Prior art keywords
alkyl
pharmaceutical composition
halo
disease
coorn
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PCT/US2021/059818
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English (en)
Inventor
Marta NORTON DE MATOS
Lukas A. KROMER
Patricia M. REIS
João D. SEIXAS
Carlos C. ROMÃO
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Proterris, Inc.
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Publication of WO2022109086A1 publication Critical patent/WO2022109086A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F11/00—Compounds containing elements of Groups 6 or 16 of the Periodic Table
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • CO Carbon monoxide
  • CORM-2 the ones with the more extensive in vivo use are the lipid- soluble CORM-2, [Ru(CO)3Ch]2, and its water-soluble CORM-3 derivative, [RU(CO) 3 C12(H 2 NCH 2 CO)2].
  • the half-lives of CORM-2 and CORM-3 are too short for therapeutic use.
  • the half-life of CO released from CORM-3 is 2.14 ⁇ 0.17 minutes (Fizan et al., Materials, 2019, 12, 1643).
  • the half-life of CORM-2 is about 1 minute in phosphate buffered saline at 37 °C with pH ⁇ 7.4 (Nguyen et al., Macromol. Rapid Comm. 2016, 37, 739-744).
  • the present application provides molybdenum CORM compounds, pharmaceutical compositions thereof, and methods of their use and treatment.
  • the CORM compounds and pharmaceutical compositions comprising the same allow for a sustained or slow release of CO under physiological conditions.
  • the CORMs can avoid large and potentially toxic increases in COHb levels, and in some embodiments have the potential to deliver CO in a significantly local manner to target tissues and/or provide a sustained level of therapeutic CO over time.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (I) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, and a pharmaceutically acceptable carrier: wherein Ri is Ci-6 alkyl, halo, or Ci-6 alkoxy;
  • R2 is H or Ci-6 alkyl; each R3 is independently -(C(Ri2Ri3))kCOORn, halo, Ci-6 alkoxy, or Ci-6 alkyl;
  • R11 is H or Ci-6 alkyl
  • R12 is H or Ci-6 alkyl
  • R13 is H or Ci-6 alkyl; k is 0, 1, or 2; q is 0, 1, 2, 3, or 4; and n is 0, 1, or 2.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, and a pharmaceutically acceptable carrier:
  • Ri is Ci-6 alkyl, halo, or Ci-6 alkoxy
  • R3 is -(C(Ri2Ri3))kCOORn, halo, Ci-6 alkoxy, or Ci-6 alkyl;
  • R11 is H or Ci-6 alkyl
  • R12 is H or Ci-6 alkyl
  • R13 is H or Ci-6 alkyl; and k is 0, 1, or 2.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (III) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof and a pharmaceutically acceptable carrier: wherein Ri is Ci-6 alkyl, halo, or Ci-6 alkoxy;
  • R3 is -(C(Ri2Ri3))kCOORn, halo, Ci-6 alkoxy, or Ci-6 alkyl;
  • R11 is H or Ci-6 alkyl
  • R12 is H or Ci-6 alkyl
  • R13 is H or Ci-6 alkyl; and k is 0, 1, or 2.
  • the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (IV) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof and a pharmaceutically acceptable carrier: wherein Ri is Ci-6 alkyl, halo, or Ci-6 alkoxy;
  • R3 is -(C(Ri2Ri3))kCOORn, halo, Ci-6 alkoxy, or Ci-6 alkyl;
  • R11 is H or Ci-6 alkyl
  • R12 is H or Ci-6 alkyl
  • R13 is H or Ci-6 alkyl; and k is 0, 1, or 2.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof and a pharmaceutically acceptable carrier:
  • Ri is Ci-6 alkyl, halo, or Ci-6 alkoxy
  • R3 is -(C(Ri2Ri3))kCOORn, halo, Ci-6 alkoxy, or Ci-6 alkyl;
  • R11 is H or Ci-6 alkyl
  • R12 is H or Ci-6 alkyl
  • R13 is H or Ci-6 alkyl; and k is 0, 1, or 2.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VI) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof and a pharmaceutically acceptable carrier: each R4 is independently H, Ci-6 alkyl, halo, or Ci-6 alkoxy;
  • R11 is H or Ci-6 alkyl; m is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; and at least four of Xi, X2, X3, X4, X5, and Xe are selected from CH and CH2, and where one or two of Xi, X2, X3, X4, X5, and Xe may be selected from null, O, N, or NH.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is Ci-6 alkyl; R3 is COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is methyl; R3 is COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is methyl; R3 is COORn; and Rn is H or Ci-6 alkyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is methyl; R3 is COORn; and Rn is H, methyl, or ethyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is methyl; and R3 is COOH.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is halo; R3 is COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is halo; R3 is COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is halo; R3 is COORn; and Rn is H or Ci-6 alkyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is halo; R3 is COORn; and Rn is H, methyl, or ethyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is Br; and R3 is COOH.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is - OCH3; R3 is COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is - OCH3; R3 is COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is - OCH3; R3 is COORn; and Rn is H or Ci-6 alkyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is - OCH3; R3 is COORn; and Rn is H, methyl, or ethyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is - OCH3; and R 3 is COOH.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof
  • Ri is H, Ci-6 alkyl, halo, or Ci-6 alkoxy; each R3 is independently -(C(Ri2Ri3))kCOORn, halo, Ci-6 alkoxy, or Ci-6 alkyl;
  • R11 is H or Ci-6 alkyl
  • R12 is H or Ci-6 alkyl
  • R13 is H or Ci-6 alkyl; k is 0, 1, or 2.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is H, Ci-6 alkyl, halo, or Ci-6 alkoxy; each R3 is independently COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • Formula (VII) a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is H, Ci-6 alkyl, halo, or Ci-6 alkoxy; each R3 is independently COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is Ci-6 alkyl; each R3 is independently COORn; and Rn is H or Ci-6 alkyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is methyl; each R3 is independently COORn; and Rn is H or Ci-6 alkyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is halo; each R3 is independently COORn; and Rn is H or Ci-6 alkyl.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is methyl; and each R3 is COOH.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is methyl; and each R3 is COOEt.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is Br; and each R 3 is COOH.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is Br; and each R3 is COOEt.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VIII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof and a pharmaceutically acceptable carrier: each R4 is independently H, Ci-6 alkyl, halo, or Ci-6 alkoxy;
  • Rs is H or Ci-6 alkyl
  • R14 and R15 are independently H, halo, Ci-6 alkoxy, or Ci-6 alkyl;
  • Ri6 is H or CI-6 alkyl; q is 0, 1, 2, 3, or 4.
  • the pharmaceutical compositions will comprise a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be formulated for local or systemic delivery.
  • the composition is formulated for parenteral delivery (e.g., intravenous delivery) or oral delivery (e.g., enteral delivery).
  • the compositions are formulated for intravenous delivery or other administration routes such as transdermal.
  • the present application provides a method for treating or preventing an inflammatory or immunological disease in a subject in need thereof.
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.
  • Exemplary inflammatory or immunological conditions may affect any organ or tissue, including but not limited to liver, lungs, gastrointestinal tractjoints and/or bones, kidneys, heart, muscle, and skin.
  • Exemplary inflammatory diseases include non-alcoholic steatohepatitis (NASH) and arthritis.
  • NASH non-alcoholic steatohepatitis
  • An exemplary immunological disease is cancer, and may include administration of a compound or composition described herein in connection with an immunotherapy, chemotherapy, or radiotherapy regimen.
  • FIG. 1 illustrates the gradient method used in HPLC for stability and quantification of pyridine-2-carboxaldehyde CO-releasing molecules (PyCa-CORM), wherein water is solvent A and acetonitrile is solvent B.
  • PyCa-CORM pyridine-2-carboxaldehyde CO-releasing molecules
  • FIG. 2 illustrates CO release of PyCa-CORMs with aromatic amines in Hepes 7.4 buffer at room temperature, in the dark at a concentration of 50pM.
  • FIG. 3 illustrates CO release profile of PyCa-CORMs with aromatic amines in sheep blood diluted in Alsever’s solution, at 37°C, at a concentration corresponding to an in vivo dose of 50 mg/kg.
  • FIG. 4 illustrates CO release profile of PyCa-CORMs with aryl amines as determined by incubation with deoxy-Myoglobin at room temperature and a 20pM concentration.
  • FIG. 5 illustrates %COHb and amount of CO in blood (pmol/mg) in systemic circulation in mice treated with aryl derived PyCa-CORMs over time.
  • FIG. 6 illustrates %COHb and amount of CO in blood (pmol/mg) in systemic circulation in mice treated with amino acid derived PyCa-CORMs (ALF 819 and ALF 843) over time, and profiles recorded for both i.v. and i.p administration for ALF843 at 30 mg/kg.
  • FIG. 7 illustrates HPLC chromatograms of selected PyCa-CORMs in 50% NCMe/ftO.
  • FIG. 8 illustrates the clearance curve of ALF843 in mice, showing rapid clearance from plasma in the first 5 minutes to a concentration of 106 pg/mL in the plasma (28% of theoretical Cmax).
  • FIG. 9 illustrate the clearance curve of ALF826 in mice, showing rapid clearance from plasma in the first 5 minutes to a concentration of 89 pg/mL in the plasma (24% of theoretical Cmax) with a terminal half-life of 26.5 minutes.
  • FIG. 10 illustrate a graphic representation of the Arthritic Score along the time of the execution of the K/BxN mouse model with 5 CORMs (ALF821, ALF826, ALF828, ALF843 and ALF844).
  • Dexamethasone (Dexa) was used as positive control.
  • Daily i.p. dose was 30 mg/kg for 36 days. Time points for blood analysis are also marked.
  • FIG. 11 illustrate histological analysis of joints from front and hind paws of the animal treated with ALF826 in the K/BxN mice model for 36 days. Top left is a normal, control histological analysis of a healthy mouse.
  • the present application is based on the discovery that CORMs, including molybdenum carbonyl pyridine carboxaldehyde complex compounds, function as CO-releasing molecules (CORMs) under physiological conditions.
  • CORMs including molybdenum carbonyl pyridine carboxaldehyde complex compounds
  • Compounds and pharmaceutical compositions described herein can provide CO-release kinetics suitable for therapy, including parenteral therapy.
  • the present application provides compounds and pharmaceutical compositions of compounds of the Formulas (I)-(VIII) (described herein).
  • the present application provides a pharmaceutical composition comprising the compounds of the Formulas (I)-(VIII) and the use thereof.
  • H denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
  • alkyl is used, either alone or within other terms such as “haloalkyl” or “alkylamino”, it embraces linear or branched radicals having one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms.
  • alkylenyl or “alkylene” embraces bridging divalent alkyl radicals such as methylenyl or ethylenyl.
  • alkyl radicals can have substituents, for example, wherein one or more carbon atoms in the chain is substituted with a heteroatom selected from halo, oxygen, nitrogen, or sulfur. Such substituted alkyl radicals are described further below.
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • alkoxy embraces linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and Zc/V-butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
  • conjugate means a conjugate made from the CORMs orPyCa-CORMs described herein conjugated (covalently) to another molecule, such as both not limited to a ligand (e.g., GalNac), protein (e.g., albumin, or antibody or antigen-binding fragment), a peptide, an aptamer, a polymer (e.g., PEG) or combinations thereof.
  • ligand e.g., GalNac
  • protein e.g., albumin, or antibody or antigen-binding fragment
  • a peptide e.g., an aptamer
  • polymer e.g., PEG
  • Conjugates can be through any point of attachment of Formulas (I)-(VIII), as can be selected by one of skill in the art.
  • a group or atom that replaces a hydrogen atom is also called a substituent.
  • Any particular molecule or group can have one or more substituent depending on the number of hydrogen atoms that can be replaced.
  • the symbol represents a covalent bond and can also be used in a radical group to indicate the point of attachment to another group. In chemical structures, the symbol is used to represent a methyl group in a molecule.
  • therapeutically effective amount means an amount of a compound that ameliorates, attenuates or eliminates one or more symptom of a particular disease or condition, or prevents or delays the onset of one of more symptom of a particular disease or condition.
  • patient and “subject” may be used interchangeably and mean animals, such as dogs, cats, cows, horses, sheep and humans. In some embodiments, patients are mammals (e.g., human).
  • treating include preventative (e.g., prophylactic) and palliative treatment.
  • excipient or “carrier” means any pharmaceutically acceptable additive, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration to a patient.
  • API active pharmaceutical ingredient
  • the present application provides the molybdenum carbonyl pyridine carboxaldehyde CO- releasing molecules (PyCa-CORMs).
  • the CORMs described herein provide for slow and/or sustained release of CO upon administration.
  • the CO release kinetics of compounds described herein allow for release of CO in a more local fashion in target tissue (including in connection with targeting moieties) and/or avoid dangerous increases in CO-Hb levels upon administration.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (I) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is Ci-6 alkyl, halo, or Ci-6 alkoxy;
  • R2 is H or Ci-6 alkyl; each R3 is independently -(C(Ri2Ri3))kCOORn, halo, Ci-6 alkoxy, or Ci-6 alkyl;
  • R11 is H or Ci-6 alkyl
  • R12 is H or Ci-6 alkyl
  • R13 is H or Ci-6 alkyl; k is 0, 1, or 2; q is 0, 1, 2, 3, or 4; and n is 0, 1, or 2.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof,: wherein Ri is Ci-6 alkyl, halo, or Ci-6 alkoxy;
  • R3 is -(C(Ri2Ri3))kCOORn, halo, Ci-6 alkoxy, or Ci-6 alkyl;
  • R11 is H or Ci-6 alkyl
  • R12 is H or Ci-6 alkyl
  • R13 is H or Ci-6 alkyl; and k is 0, 1, or 2.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (III) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is Ci-6 alkyl, halo, or Ci-6 alkoxy;
  • R3 is -(C(Ri2Ri3))kCOORn, halo, Ci-6 alkoxy, or Ci-6 alkyl;
  • R11 is H or Ci-6 alkyl
  • R12 is H or Ci-6 alkyl
  • R13 is H or Ci-6 alkyl; and k is 0, 1, or 2.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VI) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: each R4 is independently H, Ci-6 alkyl, halo, or Ci-6 alkoxy;
  • R11 is H or Ci-6 alkyl; m is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, or 4; and at least four of Xi, X2, X3, X4, X5, and Xe are selected from CH and CH2, and where one or two of Xi, X2, X3, X4, X5, and Xe may be selected from null, O, N, or NH.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is Ci-6 alkyl; R3 is COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is methyl; R3 is COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is methyl; R3 is COORn; and Rn is H or Ci-6 alkyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is methyl; R3 is COORn; and Rn is H, methyl, or ethyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is methyl; and R3 is COOH.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is halo; R3 is COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is halo; R3 is COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is halo; R3 is COORn; and Rn is H or Ci-6 alkyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is halo; R3 is COORn; and Rn is H, methyl, or ethyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is Br; and R3 is COOH.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is - OCH3; R3 is COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is - OCH3; R3 is COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is - OCH3; R3 is COORn; and Rn is H or Ci-6 alkyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is - OCH3; R3 is COORn; and Rn is H, methyl, or ethyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (II), (III), (IV), or (V) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Ri is - OCH 3 ; and R 3 is COOH.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VI) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Xi is N; X4 is O; X2, X3, X5, or Xe is CH2.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VI) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Xi is N; X4 is N; X2, X3, X5, or Xe is CH2; Re is Ci-6 alkyl linked to X4; m is 1.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VI) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: wherein Xi is N; X4 is N; X2, X3, X5, or Xe is CH2; Re is methyl linked to X4; m is 1.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof
  • Ri is H, Ci-6 alkyl, halo, or Ci-6 alkoxy; each R3 is independently -(C(Ri2Ri3))kCOORn, halo, Ci-6 alkoxy, or Ci-6 alkyl;
  • R11 is H or Ci-6 alkyl
  • R12 is H or Ci-6 alkyl
  • R13 is H or Ci-6 alkyl; k is 0, 1, or 2.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is H, Ci-6 alkyl, halo, or Ci-6 alkoxy; each R3 is independently COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is H, Ci-6 alkyl, halo, or Ci-6 alkoxy; each R3 is independently COORn, halo, or Ci-6 alkyl; and Rn is H or Ci-6 alkyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is H, Ci-6 alkyl; each R3 is independently COORn; and Rn is H or Ci-6 alkyl.
  • Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is H, Ci-6 alkyl; each R3 is independently COORn; and Rn is H or Ci-6 alkyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is methyl; each R3 is independently COORn; and Rn is H or Ci-6 alkyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is halo; each R3 is independently COORn; and Rn is H or Ci-6 alkyl.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is methyl; and each R3 is COOH.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is methyl; and each R3 is COOEt.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is Br; and each R 3 is COOH.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, wherein Ri is Br; and each R3 is COOEt.
  • the present application provides a molybdenum carbonyl pyridine carboxaldehyde complex of Formula (VIII) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof: each R4 is independently H, Ci-6 alkyl, halo, or Ci-6 alkoxy;
  • Rs is H or Ci-6 alkyl
  • R14 and R15 are independently H, halo, Ci-6 alkoxy, or Ci-6 alkyl; Ri6 is H or C I-6 alkyl; q is 0, 1, 2, 3, or 4.
  • the CORM compound is selected from Table 1.
  • the CORMs described herein have a CO-releasing kinetic profile desirable for therapeutic use, including in some embodiments for parenteral administration.
  • the CORM compositions described herein will release CO in blood, serum or plasma (ex vivo) for at least about 30 minutes, or at least about 60 minutes, or at least about 90 minutes, or at least about 120 minutes or at least about 180 minutes.
  • the CORMs described herein have a half-life (ex vivo) in blood, serum, or plasma of at least about 10 minutes, or at least about 20 minutes, or at least about 30 minutes. In various embodiments, the half-life of the compounds in plasma or serum is not more than about two hours, or not more than about one hour.
  • the CORM has a half-life in a mouse model of about 10 to about 120 minutes, or about 15 to about 120 minutes, or about 20 to about 120 minutes, or about 30 to about 120 minutes, or about 10 to about 90 minutes, or about 10 to about 60 minutes, or about 10 to about 30 minutes.
  • the half-life in a mouse model is from about 15 to about 60 minutes or from about 15 to about 45 minutes.
  • the CORMs described herein have the ability to release CO under physiological conditions in a sustained fashion, thereby avoiding a sharp increase in COHb.
  • CO-Hb levels will typically be under about 5% (e.g., about 3%). However, for smokers, COHb levels can be as high as about 10%. COHb levels around 20% are generally considered toxic and dangerous.
  • COHb levels upon administration of the compositions described herein, COHb levels will not rise by more than about 7% from the baseline level, and in various embodiments, will not rise by more than about 5%, or more than about 3%, or more than about 2%, from the baseline level.
  • the compositions described herein allow for release of CO in a target tissue, for example, by accumulating the CORM in target tissue.
  • the target tissue is a tissue with inflammation or an undesirable immunological environment or reaction.
  • the CORM will accumulate in target tissue (e.g., liver, lungs, kidneys, muscle joints, and/or skin) without the aid of a targeting moiety.
  • a targeting moiety or ligand is employed with the composition or compound (e.g., in the form of a particle or conjugate) to drive accumulation in selected tissues.
  • targeted tissues or organs include liver, lung, kidney, gastrointestinal tract, bone, joints, heart, brain, skin, muscle, lymph nodes, spleen, bladder, and pancreas.
  • targeted tissue is tumor tissue.
  • the CORM will accumulate in tumor tissue at least in part due to the enhanced permeability and retention (EPR) effect.
  • EPR enhanced permeability and retention
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a molybdenum carbonyl pyridine carboxaldehyde complex of Formulas (I) to (VIII) (described above) or a pharmaceutically acceptable salt, ester, conjugate, amide, solvate, or hydrate thereof, or combination thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be formulated for local or systemic delivery.
  • the composition is formulated for parenteral delivery (e.g., intravenous delivery) or oral delivery (e.g., enteral delivery).
  • the pharmaceutically acceptable carrier includes any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • General considerations in formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980); and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).
  • the pharmaceutical composition can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound of the present application (the “active ingredient”) into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient, which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and/or any additional ingredients in a pharmaceutical composition of the disclosure can vary depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 90% (w/w) active ingredient, such as about 1% to about 50%, or about 1% to about 40%, or about 1% to about 20%, or about 1% to about 10% (w/w) active ingredient (e.g., CORM).
  • the composition comprises the active ingredient from about 5% to about 50%, or from about 5% to about 40%, or about 5% to about 30%, or about 5% to about 20% (w/w).
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils.
  • Excipients/carriers such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.
  • cross-linked poly(vinyl-pyrrolidone) crospovidone
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g.
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • Cremophor polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Pol oxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
  • polyoxyethylene ethers e.g. polyoxyethylene lauryl ether [Brij 30]
  • poly(vinyl-pyrrolidone) diethylene glycol monolaurate
  • triethanolamine oleate sodium oleate
  • potassium oleate ethyl oleate
  • oleic acid ethyl la
  • Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g.
  • acacia sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and/or combinations thereof.
  • exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, NeoIone, Kathon, and Euxyl.
  • the preservative is an anti-oxidant.
  • the preservative is a chelating agent.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, com, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buck
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyl dodecanol, oleyl alcohol, silicone oil, and combinations thereof.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
  • sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable carrier or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostea
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active ingredients can be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound of the instant disclosure may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as can be required.
  • the present application contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.
  • Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the disclosure can be a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles, which may comprise the active ingredient (CORM), and which have a diameter in the low nanometer range.
  • CORM active ingredient
  • Such compositions are conveniently in the form of dry powders for administration, and may optionally employ a propellant.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • compositions of the disclosure formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • the formulation is useful for intranasal delivery.
  • An exemplary formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • compositions may be formulated in a dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the dosage regimen will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, of the subject; route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • kits e.g., pharmaceutical packs.
  • the kits provided may comprise a pharmaceutical composition or compound and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound.
  • the pharmaceutical composition or compound provided in the container and the second container are combined to form one unit dosage form.
  • a single container may comprise one or more compartments for containing a pharmaceutical composition or compound, and/or a pharmaceutically acceptable carrier for suspension or dilution.
  • a single container can be appropriate for modification such that the container may receive a physical modification so as to allow combination of compartments and/or components of individual compartments.
  • a foil or plastic bag may comprise two or more compartments separated by a perforated seal which can be broken so as to allow combination of contents of two individual compartments once the signal to break the seal is generated.
  • a kit may thus comprise such multi-compartment containers providing a pharmaceutical composition or compound and one or more pharmaceutically acceptable carriers.
  • instructions for use are additionally provided in such kits of the disclosure.
  • Such instructions may provide, generally, for example, instructions for dosage and administration.
  • instructions may further provide additional detail relating to specialized instructions for particular containers and/or systems for administration.
  • instructions may provide specialized instructions for use in conjunction and/or in combination with an additional therapeutic agent.
  • the composition comprises the CORM described herein encapsulated in a particle, such as a microparticle or nanoparticle.
  • the particle chemistry can be selected for sustained release of the CORM, or release of the CORM in certain environments to affect local release. Encapsulation within non-toxic host molecules is one way to achieve sustained release of the active drug in vivo. This strategy minimizes unwanted effects that can result from a sharp increase in concentration and/or availability of potentially toxic drugs.
  • the conjugates, particles, and micelles described herein can extend the half-life of the CORMs or PyCa-CORMs in circulation and improve delivery and/or accumulation to the target tissue (e.g. as described in Yin et al., Journal of Controlled Release 2014, 187 (C), 14-21).
  • the particles can include the CORM or PyCa-CORM in a core surrounded by a coating including, without limitation, an enteric coating.
  • the CORM or PyCa-CORM may also be dispersed throughout the particles.
  • the CORM or PyCa-CORM may also be adsorbed within the particles.
  • the particles may be of any order release kinetics, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, and any combination thereof.
  • the particles can include, in addition to the CORM or PyCa-CORM, any material routinely used in the pharmaceutical and medical fields, including erodible, non- erodible, biodegradable, or non-biodegradable materials or combinations thereof.
  • the particles may be microcapsules containing the CORM or PyCa-CORM in solution or in a semi-solid state.
  • the particles can be of virtually any shape.
  • particles comprising the CORM with an enteric coating can be used for enteral delivery to the gastrointestinal tract.
  • Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering CORMs or PyCa-CORMs.
  • Such polymers may be natural or synthetic polymers.
  • the polymer is selected for the desired release profile for delivery to the GI.
  • Bioadhesive polymers of particular interest include bioerodible hydrogels as described in H.S. Sawhney, C.P. Pathak and J. A. Hubell in Macromolecules, 1993, 26: 581-587.
  • polyhyaluronic acid casein, gelatin, glutin, polyanhydride, polyacrylic acid, alginate, chitosan, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), and poly (octadecyl acrylate).
  • the nanoparticle or microparticle comprises a polymeric matrix that comprises two or more polymers, and can be selected for parenteral delivery.
  • the polymeric matrix may comprise polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, or polyamines, or combinations thereof.
  • At least one polymer is a polyalkylene glycol, such as polyethylene glycol.
  • at least one polymer is a polyester, such as poly(lactic-co-glycolic acid) (PLGA).
  • the polymeric matrix comprises a copolymer of two or more polymers, such as a copolymer of a polyalkylene glycol and a polyester, e.g., a copolymer of PLGA and polyethylene glycol (PEG).
  • the polymeric matrix comprises a lipid-terminated polyalkylene glycol and a polyester, such as lipid-terminated PEG, and PLGA.
  • the lipid can be 1,2 distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), or salts thereof.
  • DSPE 1,2 distearoyl-sn-glycero-3-phosphoethanolamine
  • the lipid of the lipid-terminated PEG can self-assemble with PLGA.
  • that particles are nanoparticles, and the nanoparticles may be about 40 nm to about 500 nm in size (mean diameter). In other embodiments, the nanoparticles are about 40 nm to about 250 nm in size. In still another embodiment, the nanoparticles are about 40 nm to about 150 nm in size. In another embodiment, the nanoparticle is about 40 to about 100 nm in size. In still other embodiments, the particles are microparticles, which may be in the range of 500 nm to about 2 pm in size.
  • the CORMs or PyCa-CORMs described herein are conjugated to a ligand, protein (e.g., albumin), peptide, vitamin, or polymer (including PEG) to improve half-life and tissue selectivity.
  • the conjugated CORMs or PyCa-CORMs enable local carbon monoxide delivery, targeting specific tissues in need thereof.
  • polymeric conjugates (including with polymers described above) can reduce clearance of the CORMs from circulation, thereby increasing half-life and accumulation in target tissue.
  • the conjugate comprises a ligand having binding affinity for target tissue.
  • ligands include antibodies or antigen-binding fragments or other ligands, such as GalNac.
  • GalNac ligands can be useful for targeting hepatocytes.
  • Other targeting moieties that may be employed include nucleic acid aptamers, growth factors, hormones, cytokines, interleukins, antibodies, integrins, fibronectin receptors, and p-glycoprotein receptors.
  • the nanoparticle or microparticle is covalently bound to the targeting moiety via a maleimide functional group at the free terminus of PEG.
  • the CORMs or PyCa-CORMs described herein are conjugated to a hydrophilic polymer at one end and a hydrophobic polymer at the other end.
  • Such conjugates form micelles, enabling the delivery to the CORMs or PyCa-CORMs described herein to the tissues in need thereof.
  • the hydrophilic polymer is polyethylene glycol) (PEG).
  • the hydrophobic polymer is poly (n-butylacrylamide).
  • the hydrophilic polymer is selected from the group consisting of polyurethane, copolyester, polyesteramide block copolymer, poly etheramide block copolymer, polyetheresteramide block copolymer, and poly etherester block copolymer, and combinations thereof.
  • the hydrophobic polymer is selected from the group consisting of a polyolefin, a styrene polymer, a halogenated hydrocarbon polymer, a vinyl polymer, an acrylic polymer, an acrylate polymer, a methacrylic polymer, a methacrylate polymer, a polyester, an anhydride polymer, a polyacrylamide, a cyclo-olefin polymer, a polysiloxane, a polycarbonate, and combinations thereof.
  • the nanoparticle or microparticle comprising a CORM or PyCa- CORM as described herein further comprises a targeting moiety.
  • the targeting moiety is covalently attached to the nanoparticle or microparticle.
  • the targeting moiety is covalently attached to the outer surface of the nanoparticle or microparticle.
  • the present application is based at least in part on the discovery that compounds and pharmaceutical compositions described herein release an effective amount of carbon monoxide (CO) once administered with a therapeutically desirable release profile.
  • CO carbon monoxide
  • the present application provides a method for treating or preventing an inflammatory or immunological disease in a subject in need thereof.
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.
  • the targeted tissue or organ includes liver, lung, kidney, gastrointestinal tract, bone, joints, heart, brain, skin, muscle, lymph nodes, spleen, bladder, prostate, and pancreas.
  • targeted tissue is tumor tissue.
  • the subject in need of treatment has an inflammatory heart disease, such as endocarditis, myocarditis, pericarditis, or combinations thereof.
  • the subject in need of treatment has an inflammatory liver disease, which may be selected from fatty liver disease, liver fibrosis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), cirrhosis of the liver, alcoholic steatohepatitis (ASH), alcoholic liver diseases (ALD), HCV-associated cirrhosis, viral hepatitis, drug induced liver injury, and hepatocellular necrosis.
  • NASH nonalcoholic steatohepatitis
  • NAFLD nonalcoholic fatty liver disease
  • ASH alcoholic steatohepatitis
  • ALD alcoholic liver diseases
  • HCV-associated cirrhosis viral hepatitis
  • drug induced liver injury and hepatocellular necrosis.
  • the subject in need of treatment has an inflammatory kidney disease, which may be selected from glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), interstitial nephritis, IgA nephropathy (Berger's disease), pyelonephritis, lupus nephritis, goodpasture's syndrome, Wegener's granulomatosis, chronic kidney disease, and acute kidney injury.
  • the subject in need of treatment is a transplant recipient (e.g., kidney, liver, or lung transplant recipient), having or at risk of graft versus host disease or transplant rejection or transplant failure.
  • the subject in need of treatment has an inflammatory lung disease, such as a condition selected from asthma, chronic obstructive pulmonary disease (COPD), interstitial lung tissue fibrosis (e.g., IPF), sarcoidosis, allergic pneumonitis (HP), chronic allergic pneumonitis, acute lung injury, viral pneumonia (e.g., COVID-19), and bronchiolitis obliterans with organizing pneumonitis (BOOP).
  • COPD chronic obstructive pulmonary disease
  • IPF interstitial lung tissue fibrosis
  • HP allergic pneumonitis
  • chronic allergic pneumonitis acute lung injury
  • viral pneumonia e.g., COVID-19
  • BOOP bronchiolitis obliterans with organizing pneumonitis
  • the subject in need of treatment has an inflammatory pancreas disease, which may be selected from acute pancreatitis, chronic pancreatitis, and hereditary pancreatitis.
  • the subject in need of treatment has an inflammatory disease of the bones or joints, such as arthritis, rheumatoid arthritis, juvenile idiopathic arthritis, osteoarthritis, and psoriatic arthritis.
  • the inflammatory disease is rheumatoid arthritis.
  • inflammatory diseases include, but are not limited to, inflammation associated with arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter's arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, cardiovascular disease, chronic prostatitis, conjunctivitis, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, type 2 diabetes mellitus), a skin condition (e.g., psoriasis, eczema, burns,
  • the present application provides a method for treating or preventing compartment syndrome in a subject in need thereof.
  • the method comprises administering to the subject transdermally, intravenously or via local injection of a therapeutically effective amount of a pharmaceutical composition described herein.
  • the composition can be delivered by local injection to the site or areas surrounding an injury.
  • compartment syndrome is acute or chronic compartment syndrome.
  • the present application provides a method for promoting wound healing in a subject in need thereof.
  • the method comprises administering to the subject via topical or intradermal administration to a wound of a therapeutically effective amount of a pharmaceutical composition described herein.
  • the wound is a chronic wound (e.g., diabetic ulcer or amputation wound) or a burn (e.g., 2nd or 3rd degree bum).
  • the composition is applied to the area of a skin graft and/or a donor site.
  • the present application provides a method for treating or preventing an inflammatory skin condition in a subject in need thereof.
  • the method comprises administering to the subject via topical or intradermal administration of a therapeutically effective amount of a pharmaceutical composition described herein.
  • exemplary skin conditions include psoriasis, allergic reaction, autoimmune condition, rash, hives, eczema, pruritus, and dermatitis.
  • the subject to be treated has a cancer, which may be a solid tumor or hematological malignancy.
  • the target tissue is a solid tumor (which may be a primary tumor or may comprise tumor metastases).
  • the cancer is selected from bladder cancer, head and neck cancer, pancreatic cancer, colon carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, lymphoma, prostate cancer, colorectal cancer, ovarian cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer, kidney cancer, liver cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, glioblastoma multiforme, nonsmall-cell lung cancer, hepatocellular carcinoma, small-cell lung cancer, melanoma
  • the compounds and compositions described herein may provide immunological benefits to potentiate cancer immunotherapy, or in some embodiments, chemotherapy or radiation therapy.
  • the compounds or compositions described herein are administered with an immune checkpoint inhibitor, such as an immune checkpoint inhibitor therapy that provides for PD-1 blockade and/or targets CTLA-4.
  • the checkpoint inhibitor is selected from ipilimumab, tremelimumab, nivolumab, averumab, durvalumab, atezolizumab, penbrolizumab and any combination thereof.
  • therapy with the CORM or compositions thereof is initiated at least one week prior to immune checkpoint inhibitor therapy.
  • the subject to be treated is receiving a therapeutically effective amount of an immunotherapy, such as an immunotherapy selected from checkpoint blockade, adoptive cell therapy, CAR-T cell therapy, marrow-infiltrating lymphocytes, A2aR blockade, KIR blockade, vaccines (e.g., tumor vaccines), passive immunotherapy antibodies, and combinations thereof.
  • an immunotherapy such as an immunotherapy selected from checkpoint blockade, adoptive cell therapy, CAR-T cell therapy, marrow-infiltrating lymphocytes, A2aR blockade, KIR blockade, vaccines (e.g., tumor vaccines), passive immunotherapy antibodies, and combinations thereof.
  • the subject in need of treatment is receiving cancer chemotherapy.
  • exemplary chemotherapy may comprise an agent selected from antimetabolites, platinum-based drugs, alkylating agents, tyrosine kinase inhibitors, anthracycline antibiotics, vinca alkloid, proteasome inhibitors, and topoisomerase inhibitors (among others).
  • the chemotherapy comprises 5-fluorouracil, etoposide, cisplatin, paclitaxel, carboplatin, and combinations thereof.
  • the subject in need of treatment may receive a therapeutically effective amount of radiation, such as whole body radiation therapy, external beam radiation therapy, and internal beam radiation therapy.
  • the compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous, intramuscular, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intrava
  • the CORMs or PyCa-CORMs or the pharmaceutical compositions as described herein can be administered to a subject in need thereof in any suitable dose.
  • the therapeutically effective dose is in a range of about 1 to about 50 mg/kg, or about 10 to about 50 mg/kg, about 10 to about 40 mg/kg, or about 10 to about 30 mg/kg, or about 15 to about 40 mg/kg, or about 20 to about 40 mg/kg.
  • the COHb concentration of the subject after administration remains less than about 15%, or less than about 12%.
  • the COHb levels in the patient do not rise more than about 7% or more than about 5% from their baseline levels.
  • the dosage can vary depending on the needs of the patient, the particular formulation being administered, and other factors.
  • the dose administered to the patient should be sufficient to produce a beneficial therapeutic response in the patient.
  • the size of the dose will also be determined by the presence, nature and extent of any adverse side effects associated with the administration of the drug in a particular patient.
  • the total dose can be divided and administered in portions over an appropriate period to address the need for carbon monoxide.
  • Administration of the CORMs or PyCa-CORMs or the pharmaceutical compositions as described herein can occur for a period that varies depending on the nature of the need for the particular carbon monoxide, its severity, and the overall condition of the patient. Administration can be, for example, about twice a day, about daily, several times per week, or about weekly. After treatment, the patient can be monitored for changes in the patient's condition and relief of symptoms of the need for carbon monoxide. The dose of carbon monoxide releasing compound can be increased in situations where the patient is not significantly responsive to a particular dose level, or if the need for carbon monoxide disappears or if unacceptable side effects are observed at a particular dose, the dose can be reduced.
  • the ligand was prepared as follows: A methanolic transparent solution ofN- aminomorpholine (12 mmol; 1.157 ml) was treated by dropwise addition of 1 equivalent of pyridine-2-aldehyde (12 mmol; 1.152 ml). The yellow solution was treated with a few drops of acetic acid and stirred overnight under air. The solvent was evaporated to give an orange oil which upon long drying in vacuum became whitish and solidified. This compound was found pure by 1 H NMR (CDCh) and used for the synthesis of ALF529. A transparent solution of Mo(CO)e (1.89 mmol; 500 mg) in THF (125 ml) was treated with trimethyl A-oxide (4 mmol; 300 mg) added in portions.
  • ALF552 (100 mg) were added to a dry schlenk tube to which methanol carefully dried and previously bubbled with N2 for at least i an hour was added.
  • the purple solution was treated with an excess of sodium methoxide (3 or 4 spatula tips) and the mixture was stirred. After 30 minutes the initial suspension became a transparent solution but TLC (50% AcOEt in MeOH) indicated some starting material. The reaction was left stirring under nitrogen overnight. The next day TLC indicated total consumption of starting material and a single, polar and red spot was observed.
  • Dowex two small spatulas was added to the mixture until the pH became neutral. The suspension was filtered and washed. The solvent is evaporated giving a dark red oily material which is analytically pure. Yield 70%.
  • the gas samples were injected into sealed vials containing air (8 ml) for dilution.
  • the entire gas volume of the vials (8 ml) was transferred with carrier gas to the RCP-GC and analyzed for CO.
  • the GC-RCP chromatograph(Peak Performer RCP, Peak Laboratories LLC, Mountain View, CA) had been calibrated with gas containing a known amount of CO.
  • the calibration curve had been established starting with gas from a cylinder which contained synthetic air with 30 ppm CO (Linde, Cat. No. 14960013) and preparing dilutions in 8-ml vials as described above (Vreman, H. J. et al. Current Protocols in Toxicology 1999,9.2.1-9.2.10).
  • the release of CO from the [Mo(CO)4(pyridine-imine)] complexes was determined in triplicates spectrophotometrically by measuring the conversion of deoxy-myoglobin (deoxy -Mb) to carbonmonoxy myoglobin (CO-Mb) as previously reported with small variations. 10 pl of a freshly prepared 2 mM solution of the complex in DMSO was added to 990 pl of the horse skeletal myoglobin solution in buffer previously reduced to deoxy -Mb by sodium dithionite. The final concentration was 20 pM of complex and changes in the Mb spectra were recorded between 500 and 600 nm over time at 23°C.
  • the CO release was determined by measuring the CO-haemoglobin levels with a whole blood oximeter (Avoximeter® 4000, Instrumentation Laboratory).
  • the Avoximeter provides the total amount of hemoglobin (g dl' 1 ) in the sample and the percentage of O2-Hb, CO- Hb and Met-Hb thereof.
  • the oximeter has an accuracy of ⁇ 0.3 g dl' 1 in the total amount of hemoglobin and ⁇ 2% of the %COHb value measured (Bailey et al., Journal of Clinical Monitoring, 1997, 13, 191-198).
  • mice were injected in the tail vein with a 30 mg/kg dose dissolved in 4.5% DMSO/ 9% Cremophor/saline. Blood was taken from the tail vein of the mice according to the following protocol. At 5 min and 60 min post injection blood was taken from mouse 1; at 10 and 90 min blood was taken from mouse 2; at 20 and 150 min blood was taken from mouse 3; at 30 and 240 min blood was taken from mouse 4. The value of %COHb was measured with the Avoximeter 4000 for each blood sample.
  • Example 17 Methods of quantification of CORMs in vitro and in vivo.
  • mice Six mice were injected i.v. with 30 mg/kg of PyCa-CORM in 4.5%DMSO/9%Cremophor/Saline. Blood was collected through retroorbital bleeding into heparin-coated tubes at 1, 5, 15, 30, 45, and 60 minutes after dosing. Each mouse was bled once. Plasma was collected by centrifugation at 17,000 x g and 4°C for 5 minutes. The plasma was transferred to fresh tubes and treated with 1 ml of acetone to precipitate proteins. The samples were then centrifuged using the same conditions as described above. Supernatants were transferred to new tubes and evaporated to dryness under a gentle stream of nitrogen gas. The linear range of calibration curve and the dose administered made dilutions unnecessary. The resulting pellets were re-suspended in the original volume of 50% acetonitrile/water solution and analyzed by HPLC using the gradient described above and the appropriate calibration curves.
  • Example 18 Method to determine cytotoxicity
  • Cell survival was determined using the colorimetric MTT assay, which involves the metabolization of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), a yellow tetrazole, into the purple formazan crystals.
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
  • the culture medium was removed and replaced by a fresh medium supplemented with 1 mg mL-1 MTT.
  • the cells were incubated for 1 h at 37 °C, 5% CO2.
  • the formazan crystals produced were solubilized with DMSO and the absorbance of the final solution was determined at 550 nm (BioRad microplate reader). Toxicity is indicated by a reduced purple color compared to the control.
  • the data in Table 2 display three types of CO release profiles in vivo corresponding to three different ligand structures.
  • ALF523 is a very stable compound in circulation which barely raises COHb levels above basal levels.
  • Figure 5 shows the time evolution of the systemic COHb levels for four different arylamine derivatives. All of them result in COHb ⁇ 10% up to 4h post administration.
  • the figure also reports the amount of CO per milligram of fresh blood contained in the blood sample that provided the COHb reading at the same time point.
  • the total CO measured by GC-RCP corresponds to that contained in COHb plus CO contained in intact CORM still present in the blood sample. Both curves are largely parallel.
  • the alanine derivatives ALF819 and ALF843 performed in essentially the same manner either as the ester or the carboxylic acid, respectively.
  • the impact of the mode (i.p. vs. i.v. ) is also displayed in Figure 6 using ALF843.
  • the initially different COHb values become leveled after 10 minutes post-administration.
  • the half-life of the CORMs can be determined by any of the methods that enable the quantification of the CO released over time. In the case of compounds like the ones described here, which have four CO ligands per molecule, the half-life is taken as the time needed for the release of 0.5 equivalents of CO, to the headspace or to the scavenger which is being used to quantify CO release (Zhang, et al., Dalton Transactions, 2009, 4351-4358).
  • half-life values depend on the medium used for their determination.
  • the deoxy-myoglobin assay reveals a small dependence of the half-life with pH. At pH 6.4 most, but not all half-lives of the compounds tested are slightly shorter than those measured at physiologic pH 7.4.
  • the ti/2 values determined by this method are clearly shorter than those obtained in Hepes at pH 7.4.
  • Such acceleration of the initial decomposition rate can be most likely due to the scavenging of CO by deoxy -Mb.
  • the ti/2 values measured in sheep blood are comparable to those measured in the Mb assay although somewhat longer.
  • the plasma clearance curve for ALF843 in mice at the dose of 30 mg/kg is shown in Figure 8.
  • the plasma clearance curve for ALF826 at the dose of 30 mg/kg is shown in Figure 9.
  • a set of CORMs were selected for testing in an animal model of chronic arthritis, the K/BxN mouse model. This model also enables the study of the anti-inflammatory properties of the 5 selected compounds in vivo.
  • the molecules tested were ALF821, ALF826, ALF828, ALF843 and ALF844.
  • Dexamethasone was used as a positive control in all experiments. The experiments were performed through the administration of each molecule in a daily dose of 30mg/Kg intraperitoneally, in groups of 5 mice. The administration of each molecule was maintained for a period of 36 days, and then the treatment was stopped for an additional period of 24 days after which all animals were sacrificed. This pause in the administration of CORMs allowed the study of the arthritis relapse.
  • ALF826 also shows high drug efficiency.

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Abstract

L'invention concerne des molécules de libération de monoxyde de carbone (CORM) et leurs compositions pharmaceutiques. L'invention concerne également leur procédé de préparation et leur utilisation dans le traitement de maladies inflammatoires ou immunologiques.
PCT/US2021/059818 2020-11-18 2021-11-18 Molécules libérant du monoxyde de carbone et compositions pharmaceutiques et utilisations associées WO2022109086A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040067261A1 (en) * 2002-02-04 2004-04-08 Werner Haas Method for treating a mammal by administration of a compound having the ability to release CO, compounds having the ability to release CO and pharmaceutical compositions thereof
US20070207993A1 (en) * 2005-12-20 2007-09-06 Alfama - Investigacao E Desenvolvimetno De Productos Farmaceuticos Lda Molybdenum carbonyl complexes for treating rheumatoid arthritis and other inflammatory diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040067261A1 (en) * 2002-02-04 2004-04-08 Werner Haas Method for treating a mammal by administration of a compound having the ability to release CO, compounds having the ability to release CO and pharmaceutical compositions thereof
US20070207993A1 (en) * 2005-12-20 2007-09-06 Alfama - Investigacao E Desenvolvimetno De Productos Farmaceuticos Lda Molybdenum carbonyl complexes for treating rheumatoid arthritis and other inflammatory diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ALI RAZAK BIN, BLANDAMER MICHAEL J., BURGESS JOHN: "Kinetics of solvolysis and cyanide attack at 2-benzoylpyridine-iminemolybdenum(0) tetracarbonyl and related compounds", TRANSITION METAL CHEMISTRY, CHAPMAN & HALL, GB, vol. 15, no. 5, 1 October 1990 (1990-10-01), GB , pages 388 - 393, XP055939872, ISSN: 0340-4285, DOI: 10.1007/BF01177468 *

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