WO2025199042A1 - Méthodes de traitement de la tuberculose grave - Google Patents

Méthodes de traitement de la tuberculose grave

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Publication number
WO2025199042A1
WO2025199042A1 PCT/US2025/020253 US2025020253W WO2025199042A1 WO 2025199042 A1 WO2025199042 A1 WO 2025199042A1 US 2025020253 W US2025020253 W US 2025020253W WO 2025199042 A1 WO2025199042 A1 WO 2025199042A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
6alkyl
neutrophil extracellular
extracellular trap
formation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/020253
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English (en)
Inventor
Elizabeth GOLD
Alan Diercks
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Seattle Childrens Hospital
Original Assignee
Seattle Childrens Hospital
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Filing date
Publication date
Application filed by Seattle Childrens Hospital filed Critical Seattle Childrens Hospital
Publication of WO2025199042A1 publication Critical patent/WO2025199042A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • neutrophils are the predominant cell type infected with Mtb in the airway (PMID 19749004) and neutrophils are detected in inflammatory TB lesions (PMID 24047412). NETs have been identified in necrotic lesions of patients with non-resolving pulmonary TB (PMID 33149141).
  • a method for treating tuberculosis in an animal comprising inhibiting the formation of a neutrophil extracellular trap in the animal is provided.
  • a method for treating severe tuberculosis in an animal comprising inhibiting the formation of a neutrophil extracellular trap in the animal.
  • a compound that inhibits the formation of a neutrophil extracellular trap for the treatment of severe tuberculosis is provided.
  • the use of a compound that inhibits the formation of a neutrophil extracellular trap to prepare a medicament for the treatment of severe tuberculosis in an animal is provided.
  • a method comprising, inhibiting the formation of a neutrophil extracellular trap to treat severe tuberculosis is provided.
  • FIG. 1 shows a plot of bacterial burden measured by colony forming units (CFU) in wild-type (B6) or Apoe -/- mice on a high-cholesterol diet infected with the H37Rv strain of Mycobacterium tuberculosis (Mtb) for 28 days. Mice were either left untreated or treated daily with GSK484 starting at day 7 post-infection (PI).
  • CFU colony forming units
  • FIG. 1 Figure 2 shows bacterial burden measured by CFU in B6 mice on standard chow diet infected with the H37Rv strain of Mycobacterium tuberculosis (Mtb) for 28 days. Mice were either left untreated or treated daily with GSK484 starting at day 7 post-infection (PI).
  • Figure 4 shows data from Example 3.
  • severe tuberculosis includes: pulmonary tuberculosis with cavitary lesions, necrotic granulomas, and/or alveolar hemorrhage; disseminated tuberculosis including TB meningitis and pericarditis; infection with any drug a resistant strain; tuberculosis in patients with a high bacterial burden at the time of diagnosis; and tuberculosis in patients with underlying pulmonary co-morbidities.
  • the term “high bacterial burden” includes patients whose sputum counts of acid-fast bacilli score 3+ on the International Union against Tuberculosis and Long Disease (IUATLD) or WHO scales.
  • Compounds that Inhibit Neutrophil Extracellular Trap Formation includes any agent that inhibits neutrophil extracellular trap formation in an animal.
  • compounds that inhibits neutrophil extracellular trap formation include: DNase I, sivelestat, PAD4 inhibitors, Cl-amidine, BB-Cl-amidine, GSK484, dipyridamole, hydroxychloroquine, statins, and metformin.
  • Compounds that inhibit neutrophil extracellular trap formation also include the anti-NET compounds discussed in International Patent Application Publication Number WO2016/118476.
  • the anti-NET compound is selected from the group consisting of: DNase; a histone-degrading enzyme; an inhibitor of chromatin decondensation; an antibody against a component of a NET; a protease inhibitor, an elastase inhibitor; and a PAD4 inhibitor.
  • the PAD4 inhibitor is selected from the group consisting of: Cl-amidine and F-amidine.
  • the inhibitors are selective PAD4 inhibitors that are reversible, e.g. including but not limited to GSK484 and GSK199 (Nat. Chem. Biology, in Press).
  • the PAD4 inhibitor is a tetrazole analog, e.g., as described in Subramanian et al., Design, synthesis and biological evaluation of tetrazole analogs of Cl-amidine as protein arginine deiminase inhibitors J. Med. Chem., DOI: 10.1021/jm501636x Publication Date (Web): January 5, 2015.
  • the tetrazole analog is biphenyl tetrazole tert-butyl clamidine (BTT-Cl-amidine) that exhibits enhanced cell killing in a PAD4 expressing cells also blocks the formation of neutrophil extracellular trap.
  • the PAD4 inhibitor is a peptidomimetic compound, e.g. including but not limited to 1,2,3-triazole peptidomimetic based derivatives incorporating beta-phenylalanine and guanidine scaffolds, e.g., as described in Trabocchi et al. Peptidomimetics as protein arginine deiminase 4 (PAD4) inhibitors, J. Enzyme Inhib. Med.
  • the anti-NET compound is an inhibitor of NET release from cells, e.g. Cl-amidine blocks NET release from NZM neutrophils in vitro, other inhibitors of NET release are known to those of skill in the art.
  • the PAD4 inhibitor is BB-Cl-amidine (Knight et al.
  • the PAD4 inhibitor is YW3-56, as described in Wang et al., (2012) J. Biol. Chem 287(31):25941-53.
  • Compounds that inhibit neutrophil extracellular trap formation also include the PAD4 inhibitors discussed in United States Application Publication Number WO2021/0188810.
  • compounds that inhibit neutrophil extracellular trap formation include the compounds of formula (I): and salts described therein, wherein: Ring A is:
  • Ring A is optionally substituted with 1-4 groups selected from fluorine, -CN, -OR, and C1-6 aliphatic optionally substituted with 1-3 fluorine atoms
  • Ring B is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • R 1 is hydrogen, -Cy, or C 1-6 aliphatic optionally substituted with -Cy and optionally further substituted with 1-4 groups selected from fluorine, -CN, and -OR
  • each -Cy is independently a 6-membered aryl ring containing 0-2 nitrogen atoms, or a 4- 7 membered saturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein -Cy is optionally substituted with 1-4 groups selected from fluorine, -CN, and -OR
  • R2 is hydrogen, -CN, -OR, -Cy, or C 1-10
  • compounds that inhibit neutrophil extracellular trap formation also include the PAD4 inhibitors discussed in International Patent Application Publication Number WO 2016/185279.
  • the PAD4 inhibitor is GSK484: or a salt (e.g., the hydrochloride salt) thereof.
  • a salt of a compound of formula (I) can be useful as an intermediate for isolating or purifying a compound of formula (I).
  • administration of a compound of formula (I) as a pharmaceutically acceptable acid or base salt may be appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, - ketoglutarate, and -glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the compounds can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • a mammalian host such as a human patient
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, 00819.006WO1/SCRI.563WO optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • sterile powders for the preparation of sterile injectable solutions the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • Useful dosages of the compounds of formula (I) can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of 00819.006WO1/SCRI.563WO administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • Example 2 Treatment with the anti-NETosis drug GSK484 had no effect on bacterial burden in these mice ( Figure 2.).
  • Example 2. To explore the potential clinical efficacy of blocking NET formation, Apoe -/- HC mice were infected with about 50 CFU of H37Rv and treated with GSK484 daily starting at day 7 or day 14 PI until a pre-specified endpoint of 40 days PI. Treatment with GSK484 significantly decreased mortality compared to controls ( Figure 3).
  • Example 3 To determine the generalizability of the findings from Example 2, the effect of blocking NET formation in a different mouse strain / bacterial strain combination was evaluated.
  • C3HeB/FeJ (C3H) mice are highly susceptible to Mtb and the pathology in these mice has been shown to be driven, at least in part, by excess neutrophil recruitment, particularly when infected with the hypervirulent SA161 strain of Mtb (Mishra BB, et al., J Exp Med. 2018 Apr 2;215(4):1035–45; and Gern BH, et al., BioRxiv Prepr Serv Biol. 2024 Apr 15;2024.04.12.589315).
  • SA161-infected C3H mice with GSK484 decreased the bacterial burden by approximately 8-fold (Figure 4).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des méthodes de traitement de la tuberculose.
PCT/US2025/020253 2024-03-18 2025-03-17 Méthodes de traitement de la tuberculose grave Pending WO2025199042A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463566580P 2024-03-18 2024-03-18
US63/566,580 2024-03-18

Publications (1)

Publication Number Publication Date
WO2025199042A1 true WO2025199042A1 (fr) 2025-09-25

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WO (1) WO2025199042A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170166592A1 (en) * 2015-12-09 2017-06-15 Padlock Therapeutics, Inc. Aza-benzimidazole inhibitors of pad4

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170166592A1 (en) * 2015-12-09 2017-06-15 Padlock Therapeutics, Inc. Aza-benzimidazole inhibitors of pad4

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem 6 January 2015 (2015-01-06), PUBCHEM: "((3S,4R)-3-Amino-4-hydroxypiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone hydrochloride C27H32ClN5O3 CID 86340151 - PubChem", XP093360632, Database accession no. CID86340151 *
LIU DONG, MAI DAT, JAHN ANA N., MURRAY TARA A., AITCHISON JOHN D., GERN BENJAMIN H., URDAHL KEVIN B., ADEREM ALAN, DIERCKS ALAN H.: "APOE protects against severe infection with Mycobacterium tuberculosis by restraining production of neutrophil extracellular traps", PLOS PATHOGENS, PUBLIC LIBRARY OF SCIENCE, US, vol. 21, no. 6, 16 June 2025 (2025-06-16), US , pages e1013267, XP093360637, ISSN: 1553-7374, DOI: 10.1371/journal.ppat.1013267 *
NAKAMURA KOTA, NAKAYAMA HITOSHI, SASAKI SHINICHI, TAKAHASHI KAZUHISA, IWABUCHI KAZUHISA: "Mycobacterium avium-intracellulare complex promote release of pro-inflammatory enzymes matrix metalloproteinases by inducing neutrophil extracellular trap formation", SCIENTIFIC REPORTS, NATURE PUBLISHING GROUP, US, vol. 12, no. 1, US , XP093360623, ISSN: 2045-2322, DOI: 10.1038/s41598-022-09017-y *
TIBERI SIMON, TORRICO MARCELA MUÑOZ, RAHMAN ANANNA, KRUTIKOV MARIA, VISCA DINA, SILVA DENISE ROSSATO, KUNST HEINKE, MIGLIORI GIOVA: "Managing severe tuberculosis and its sequelae: from intensive care to surgery and rehabilitation", JORNAL BRASILEIRO DE PNEUMOLOGIA, vol. 45, no. 2, XP093360624, ISSN: 1806-3713, DOI: 10.1590/1806-3713/e20180324 *

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