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WO2025207099A1 - Inhibiteurs de ppar-delta pour prévenir une fibrillation auriculaire post-opératoire - Google Patents

Inhibiteurs de ppar-delta pour prévenir une fibrillation auriculaire post-opératoire

Info

Publication number
WO2025207099A1
WO2025207099A1 PCT/US2024/022032 US2024022032W WO2025207099A1 WO 2025207099 A1 WO2025207099 A1 WO 2025207099A1 US 2024022032 W US2024022032 W US 2024022032W WO 2025207099 A1 WO2025207099 A1 WO 2025207099A1
Authority
WO
WIPO (PCT)
Prior art keywords
ppar5
modulator
compound
alkyl
pharmaceutically acceptable
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/US2024/022032
Other languages
English (en)
Inventor
Olivier VAN TILL
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.)
Astellas Pharma Inc
Astellas Engineered Small Molecules Us Inc
Original Assignee
Astellas Pharma Inc
Astellas Engineered Small Molecules Us Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Astellas Pharma Inc, Astellas Engineered Small Molecules Us Inc filed Critical Astellas Pharma Inc
Priority to PCT/US2024/022032 priority Critical patent/WO2025207099A1/fr
Publication of WO2025207099A1 publication Critical patent/WO2025207099A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the present invention is directed towards methods of reducing likelihood of developing post-operative atrial fibrillation in a human patient.
  • POAF Post-operative atrial fibrillation
  • AF new-onset atrial fibrillation
  • AF onset is 2-4 days postoperatively.
  • Episodes are often self-limiting, but associated adverse consequences of POAF include hemodynamic instability, increased risk of stroke, perioperative mortality, myocardial infarction, acute renal failure, lengthened hospital and intensive care unit stays and greater costs, long-term mortality, and longstanding persistent AF.
  • rhythm control strategy e.g., by electric/direct-current cardioversion
  • an anti coagulation therapy e.g. , with warfarin
  • modulators of peroxisome proliferator-activated receptor delta such as Compound (I), the structure of which is shown below, can significantly reduce likelihood of developing POAF:
  • the reduction rate of POAF risk within 7 postoperative days is 71%, which is higher than the current standard symptomatic preventative treatment for POAF with beta-blockers (48%).
  • the surgery is an open chest cardiac surgery, and in other embodiments, it is a different type of surgery.
  • the PPAR5 modulator e.g., Compound (I)
  • the PPAR5 modulator is given as a single dose.
  • the PPAR5 modulator e.g., Compound (I)
  • the effective amount of the PPAR5 modulator is between 0.1 mg and 0.5 g.
  • Figure 1 shows the POAF probability versus Exposure (Cmax).
  • the lines are a logistic regression, shaded areas: 95% CI, black squares: the proportion of responders grouped by quartiles of exposure metrics and plotted at the median for the groups with the error bars represent 95%CI.
  • the exposure range in each quartile is denoted by the horizontal black line along with the number of subjects in each quartile.
  • Figure 2 shows the POAF probability versus Exposure (AUCinf).
  • the lines are a logistic regression, shaded areas: 95% CI, black squares: the proportion of responders grouped by quartiles of exposure metrics and plotted at the median for the groups with the error bars represent 95%CI.
  • the exposure range in each quartile is denoted by the horizontal black line along with the number of subjects in each quartile.
  • Peroxisome proliferator-activated receptor delta also known as peroxisome proliferator-activated receptor beta (PPAR-P) or as NR1C2 (nuclear receptor subfamily 1, group C, member 2), refers to a nuclear receptor protein that functions as a transcription factor regulating the expression of genes.
  • Ligands of PPAR6 can promote myoblast proliferation after injury, such as injury to skeletal muscle.
  • PPAR6 (OMIM 600409) sequences are publicly available, for example from GenBank® sequence database e.g., accession numbers NP_001165289.1 (human, protein) NP_035275 (mouse, protein), NM_001171818 (human, nucleic acid) and NM_011145 (mouse, nucleic acid)).
  • Compound (I) is believed to have protective effects on kidney cells that are under cellular stress as a result of ischemia, inflammation and oxidative stress following CABG and/or valve surgery.
  • Compound (I) will reduce inflammatory responses and increase oxidative stress systemically, which is expected to reduce the immediate consequences of stress responses following CABG and/or valve surgery.
  • CPB cardio-pulmonary bypass pump
  • PPAR5 modulator refers to substances that modify (e.g., increases or decreases) the activity of PPAR5. Substances can be tested for their PPAR5 agonist activity by, for example, contacting the substance with cells expressing PPAR5, detecting their binding with PPAR5 and then detecting signals that serve as the indicator of the activation of PPAR5.
  • Alkoxy means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl.
  • Ci-C4-alkoxy includes methoxy, ethoxy, propoxy, isopropoxy and butoxy.
  • haloalkyl and haloalkoxy mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • Ci-C4-haloalkyl includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, bromomethyl, fluoroethyl, difluoroethyl, di chloroethyl and chloropropyl
  • Ci-C4-haloalkoxy includes fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, bromomethoxy, fluoroethoxy, difluoroethoxy, di chloroethoxy and chloropropoxy.
  • halogen means fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br), or iodine or iodo (I).
  • aryl examples include phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl and indenyl.
  • Cycloalkyl means a 3-12 membered saturated aliphatic cyclic hydrocarbon radical. It can be monocyclic, bicyclic (e.g., a bridged or fused bicyclic ring), or tricyclic.
  • monocyclic Cs-Ce-cycloalkyl means a radical having from 3 to 6 carbon atoms arranged in a monocyclic ring.
  • Cs-Ce-cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • “5- or 6-membered heterocycle” means a radical having from 5 or 6 ring atoms (including 1 to 3 ring heteroatoms) arranged in a monocyclic ring.
  • Examples of “5- or 6- membered heterocycle” include, but are not limited to, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetra
  • “5-membered heteroaryl” means a monocyclic aromatic ring system having five ring atoms selected from carbon and at least one (typically 1 to 3, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen or sulfur). Typical examples are 5-membered heteroaryl containing 1 or 2 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms such as pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, and the like.
  • a non-hydrogen substituent is in the place of hydrogen on a carbon, sulfur or nitrogen of the substituent.
  • a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of hydrogen on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro substituent
  • difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each nonhydrogen substituent can be identical or different (unless otherwise stated).
  • Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms, as well as racemates and mixtures thereof.
  • the term “geometric isomer” refers to compounds having at least one double bond, wherein the double bond(s) may exist in cis, trans, syn, anti,
  • E Delta-Value
  • Z Zero-Value
  • geometric isomeric purity of the named or depicted geometric isomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight.
  • Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geomeric isomers in the mixture.
  • the term “pharmaceutically acceptable salt” refers to a non-toxic salt form of a compound of this disclosure.
  • Pharmaceutically acceptable salts e.g., of Compound (I) disclosed herein
  • Pharmaceutically acceptable salts include those derived from suitable inorganic and organic acids and bases.
  • Pharmaceutically acceptable salts are well known in the art. Suitable pharmaceutically acceptable salts are, e.g., those disclosed in Berge, S.M., et al. J. Pharma. Sci. 66: 1-19 (1977).
  • compositions include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate
  • Fonadelpar represented by the following structural formula:
  • T3D 959 represented by the following structural formula:
  • the PPAR5 modulator is a compound represented by the or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is hydrogen, halogen, -Ci-C4-alkyl, -Ci-C4-haloalkyl, -CN, -Ci-C4-alkoxy, -Ci-C4-haloalkoxy, or -Cs-Ce-cycloalkyl;
  • R 2 is halogen, -Ci-C4-alkyl, -Ci-C4-haloalkyl, -Ci-C4-haloalkoxy, -S(Ci-C4-alkyl), or furanyl, wherein the furanyl can be optionally substituted with -Ci-C4-alkyl; and the remainder of the variables are as defined for Formula (I) above.
  • R 1 is hydrogen or halogen
  • R 2 is halogen, -Ci-C4-alkyl, -Ci-C4-haloalkyl, -Ci-C4-haloalkoxy, -S(Ci-C4-alkyl), or furanyl, wherein the furanyl can be optionally substituted with -Ci-C4-alkyl
  • each R 20 is independently hydrogen or halogen; and the remainder of the variables are as defined for Formula (I) above.
  • R 1 is hydrogen or fluoro
  • R 2 is Ci-C4-haloalkyl or Ci-C4-haloalkoxy
  • x is 1
  • R 20 is hydrogen
  • R 1 is hydrogen
  • R 2 is trifluoromethyl or trifluoromethoxy
  • x is 1
  • R 20 is hydrogen
  • the PPAR5 modulator is Compound (I), represented by the following structural formula: or a pharmaceutically acceptable salt thereof. In one specific embodiment, the PPAR5 modulator is meglumine salt of Compound (I).
  • the PPAR5 modulator can be used in combination with other agents.
  • an effective amount can be from 0.1 mg to about 50 g per day.
  • administer refers to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Oral and intravenous administration are commonly used.
  • Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergam on; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.
  • the disclosed PPAR5 modulators can be used in combination with other agents known to have beneficial activity with the disclosed PPAR5 modulators.
  • disclosed compounds can be administered alone or in combination with one or more other PPAR5 modulators, such as a thiazolidinedione, including rosiglitazone, pioglitazone, troglitazone, and combinations thereof, or a sulfonylurea agent or a pharmaceutically acceptable salt thereof, such as tolbutamide, tolazamide, glipizide, carbutamide, glisoxepide, glisentide, glibornuride, glibenclamide, gliquidone glimepiride, gliclazide and the pharmaceutically acceptable salts of these compounds, or muraglitazar, farglitazar, naveglitazar, netoglitazone, rivoglitazone, K-l l l, GW-677954, (-)-Halofenate
  • disclosed compounds may be administered in combination with dexamphetamine, amphetamine, mazindole or phentermine; and administered in combination with medicaments having an anti-inflammatory effect.
  • the pharmaceutical compositions provided herein can be administered as a combination therapy with one or more pharmacologically active substances having favorable effects on metabolic disturbances or disorders.
  • the disclosed pharmaceutical compositions may be administered in combination with RXR agonists for treating metabolic and cardiovascular diseases medicaments, which lower blood glucose; antidiabetics, such as insulins and insulin derivatives, including Lantus, Apidra, and other fast-acting insulins, and GLP-1 receptor modulators; active ingredients for treating dyslipidemias; anti-atherosclerotic medicaments; anti-obesity agents; anti-inflammatory active ingredients; active ingredients for treating malignant tumors; anti -thrombotic active ingredients; active ingredients for treating high blood pressure; active ingredients for treating heart failure, and combinations thereof.
  • RXR agonists for treating metabolic and cardiovascular diseases medicaments, which lower blood glucose
  • antidiabetics such as insulins and insulin derivatives, including Lantus, Apidra, and other fast-acting insulins, and GLP-1 receptor modulators
  • active ingredients for treating dyslipidemias anti
  • composition of the invention is formulated to be compatible with its intended route of administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings.
  • Intravenous formulations comprise the pharmaceutically active agent dissolved in a pharmaceutically acceptable solvent or solution, such as sterile water, normal saline solutions, lactated Ringer’s, or other salt solutions such as Ringer’s solution.
  • a pharmaceutically acceptable solvent or solution such as sterile water, normal saline solutions, lactated Ringer’s, or other salt solutions such as Ringer’s solution.
  • the formulation should promote the overall stability of the active ingredient(s), also, the manufacture of the formulation should be cost-effective. All of these factors ultimately determine the overall success and usefulness of an intravenous formulation.
  • An oral formulation typically is prepared as a compressed preparation in, for example, the form of a tablet or pill.
  • a tablet may contain, for example, about 5-10% of the active ingredient (e.g., the PPAR5 modulators); about 80% of fillers, disintegrants, lubricants, glidants, and binders; and 10% of compounds which ensure easy disintegration, disaggregation, and dissolution of the tablet in the stomach or the intestine. Pills can be coated with sugar, varnish, or wax to disguise the taste.
  • the effective amount of the PPAR5 modulator is in an amount equivalent to about 0.1 mg to 500 mg per day.
  • the method may comprise administering the PPAR5 modulator (e.g., Compound (I) disclosed herein) in an amount of about 0.1 mg to about 250 mg per day, an amount of about 0.1 mg to about 125 mg per day, an amount of about 0.1 mg to about 100 mg per day, an amount of about 0.1 mg to about 75 mg per day, an amount of about 0.1 mg to about 50 mg per day, an amount of about 125 mg to about 500 mg per day, an amount of about 250 mg to about 500 mg per day, or a pharmaceutically acceptable salt of the PPAR5 modulator (e.g., Compound (I) disclosed herein) in an amount equivalent to any of the foregoing.
  • the effective amount of the PPAR5 modulator as free base is 100 or less mg per day, or a pharmaceutically acceptable salt thereof is in an amount equivalent to 100 mg or less per day.

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  • Animal Behavior & Ethology (AREA)
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  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne un procédé de réduction de la probabilité de développer une fibrillation auriculaire post-opératoire chez un patient chirurgical présentant un risque de développer une fibrillation auriculaire post-opératoire, comprenant l'administration au patient d'une quantité efficace d'un modulateur de PPARδ. Dans certains modes de réalisation, le modulateur de PPARδ est le composé (I), représenté par la formule structurale suivante (I) ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2024/022032 2024-03-28 2024-03-28 Inhibiteurs de ppar-delta pour prévenir une fibrillation auriculaire post-opératoire Pending WO2025207099A1 (fr)

Priority Applications (1)

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PCT/US2024/022032 WO2025207099A1 (fr) 2024-03-28 2024-03-28 Inhibiteurs de ppar-delta pour prévenir une fibrillation auriculaire post-opératoire

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PCT/US2024/022032 WO2025207099A1 (fr) 2024-03-28 2024-03-28 Inhibiteurs de ppar-delta pour prévenir une fibrillation auriculaire post-opératoire

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US9695137B2 (en) 2013-03-14 2017-07-04 The University Of Toledo Analogs of peroxisome proliferator activated receptor (PPAR) agonists, and methods of using the same
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EP4015623A1 (fr) 2020-12-17 2022-06-22 Universite De Montpellier Pré-traitement de csm avec un agoniste bêta/delta ppar pour le traitement des lésions d'ischémie-reperfusion
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