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WO2025133098A2 - Procédés de fabrication de formes cristallines de sels de (s)-n-(3-amino-1-(hydroxyamino)-3-méthyl-1-oxobutan-2-yl)-4-((4-(((2-méthoxyéthyl)amino)méthyl)phényl)éthynyl)benzamide - Google Patents

Procédés de fabrication de formes cristallines de sels de (s)-n-(3-amino-1-(hydroxyamino)-3-méthyl-1-oxobutan-2-yl)-4-((4-(((2-méthoxyéthyl)amino)méthyl)phényl)éthynyl)benzamide Download PDF

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Publication number
WO2025133098A2
WO2025133098A2 PCT/EP2024/087865 EP2024087865W WO2025133098A2 WO 2025133098 A2 WO2025133098 A2 WO 2025133098A2 EP 2024087865 W EP2024087865 W EP 2024087865W WO 2025133098 A2 WO2025133098 A2 WO 2025133098A2
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WO
WIPO (PCT)
Prior art keywords
methyl
amino
phenyl
methoxyethyl
oxobutan
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/EP2024/087865
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English (en)
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WO2025133098A3 (fr
Inventor
Christophe Pierre Alain Chassaing
Daniel Salanta
Thorsten Meyer
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Intervet International BV
Intervet Inc
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Intervet International BV
Intervet Inc
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Publication date
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Publication of WO2025133098A2 publication Critical patent/WO2025133098A2/fr
Publication of WO2025133098A3 publication Critical patent/WO2025133098A3/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • WO20231 18558 discloses the synthesis of (S)-A/-(3-amino-1-(hydroxyamino)-3- methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide dihydrochloride
  • WO20231 18557 discloses injectable pharmaceutical compositions for the treatment of respiratory diseases in animals.
  • Formulations comprising (S)-A/-(3- amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide dihydrochloride are disclosed.
  • the invention concerns processed to make crystalline forms of (S)-/V-(3-amino-1-
  • FIG. 1 is a characteristic X-ray diffraction pattern of the crystalline (S)-/V-(3-amino- 1 -(hydroxyam ino)-3-methyl-1 -oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis tosylate monohydrate salt.
  • FIG. 2 is a carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum of the crystalline (S)-/V-(3-amino-1- (hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis tosylate monohydrate salt. Peaks labeled with asterisks correspond to spinning sidebands.
  • CPMAS cross-polarization magic-angle spinning
  • FIG. 3A is a typical DSC thermogram of (S)-A/-(3-amino-1 -(hydroxyamino)-3- methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis tosylate monohydrate salt.
  • FIG. 3B shows the TGA thermogram of (S)W-(3-amino-1 -(hydroxyam ino)-3- methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis tosylate monohydrate salt.
  • FIG. 6 is a typical DSC thermogram of (S)-4-(hydroxyamino)-3-(4-((4-(((2- methoxyethyl)ammonio)methyl)phenyl)ethynyl)benzamido)-2-methyl-4-oxobutan- 2-aminium propionate.
  • FIG. 7 shows the DVS isotherm plot for the tosylate monohydrate salt.
  • FIG. 8 shows the DVS isotherm plot for the propionate salt.
  • FIG. 9 shows the structure of the (S)-A/-(3-amino-1-(hydroxyamino)-3-methyl-1- oxobutan-2-yl)-4-((4-(((2-methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis tosylate monohydrate salt which might also be named (S)-4-(hydroxyamino)-3-(4-((4-(((2- methoxyethyl)ammonio)methyl)phenyl)ethynyl)benzamido)-2-methyl-4-oxobutan- 2-aminium 4-methylbenzenesulfonate hydrate according to Chem Draw® version 21.0.0.28 or, (S)-4-(hydroxyamino)-3-(4-((4-(((2- methoxyethyl)ammonio)methyl)phenyl)ethynyl)benzamido)-2-methyl-4-oxobutan
  • FIG. 10 shows the structure of the (S)-N-(3-amino-1 -(hydroxyamino)-3-methyl-1 - oxobutan-2-yl)-4-((4-(((2-methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis propionate salt which might also be named (S)-4-(hydroxyamino)-3-(4-((4-(((2- methoxyethyl)ammonio)methyl)phenyl)ethynyl)benzamido)-2-methyl-4-oxobutan- 2-aminium propionate according to ChemDraw® version 21 .0.0.28 or, (S)-4-(hydroxyamino)-3-(4-((4-(((2- methoxyethyl)ammonio)methyl)phenyl)ethynyl)benzamido)-2-methyl-4-oxobutan- 2-aminium propionate or
  • FIG. 11 shows the PXRD of bis-tosylate anhydrate.
  • FIG. 12 shows the DSC of bis-tosylate anhydrate.
  • FIG. 14 shows the PXRD of the free base (S)-A/-(3-amino-1-(hydroxyamino)-3- methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide.
  • FIG. 15 shows the TGA of the free base (S)-/V-(3-amino-1-(hydroxyamino)-3- methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide.
  • FIG. 16 shows of the DSC of the free base(S)-A/-(3-amino-1-(hydroxyamino)-3- methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide.
  • FIG. 17 shows the PXRD of the HCI salt (S)-/V-(3-amino-1-(hydroxyamino)-3- methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide dihydrochloride.
  • FIG. 18 shows the TGA of the HCI salt (S)-/V-(3-amino-1-(hydroxyamino)-3-methyl- 1-oxobutan-2-yl)-4-((4-(((2-methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide dihydrochloride.
  • FIG. 19 shows the DSC of the HCI salt (S)-/V-(3-amino-1 -(hydroxyamino)-3- methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide dihydrochloride.
  • the salt When selecting a salt for incorporation into a pharmaceutical product, the salt’s stability in both the solid state and in the formulation must be considered. Furthermore, the salt’s toxicity, bioavailability and efficacy must be evaluated. Both the bis tosylate mono hydrate salt and bis propionate salt were more stable than the hydrochloride salt and the parent free base in long term stability studies at ambient and accelerated conditions. Furthermore, the bis tosylate mono hydrate salt was more stable than the bis propionate salt. The bis tosylate mono hydrate salt is the most stable salt identified. This was unexpected.
  • Scheme 1 is a process to prepare (S)-N-(3-amino-1-(hydroxyamino)-3-methyl-1- oxobutan-2-yl)-4-((4-(((2-methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis tosylate monohydrate salt.
  • Bovine respiratory disease is the most common and costly disease affecting beef cattle in the world.
  • Bovine respiratory disease has a multifactorial etiology and develops as a result of complex interactions between environmental factors, host factors, and pathogens.
  • Environmental factors e.g., weaning, transport, commingling, crowding, inclement weather, dust, and inadequate ventilation
  • certain environmental factors e.g., crowding and inadequate ventilation
  • the infection is usually a sum of three codependent factors: Stress, an underlying viral infection, and a new bacterial infection.
  • the diagnosis of the disease is complex since there are multiple possible causes.
  • SRD swine respiratory disease
  • XRPD X- ray powder diffraction
  • CPMAS carbon-13 cross-polarization magic-angle spinning
  • NMR nuclear magnetic resonance
  • DSC differential scanning calorimetry
  • substantially purified refers to a crystalline form of the compound that is at least 90% pure. In an alternate embodiment, “substantially purified” refers to a crystalline form of the compound that is at least 95%, 99%, or 99.9% pure.
  • An embodiment of the invention is a crystalline form of (S)-/V-(3-amino-1- (hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis tosylate monohydrate salt having at least one of the following characteristics: an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of d-spacing [A] ( ⁇ 0.2) selected from the group consisting of 14.07, 10.96, 9.46, 7.37, 6.07, 5.48, 5.23, 4.92, 4.55, 4.26 and 3.82 or in terms of °29( ⁇ 0.2) selected from the group consisting of 6.28, 8.07, 9.35, 12.00, 14.60, 16.16, 16.94, 18.05, 19.51 , 20.84 and 23.28; a carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR
  • Another embodiment of the invention is the crystalline form having carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum substantially as shown in Figure 2.
  • CPMAS carbon-13 cross-polarization magic-angle spinning
  • NMR nuclear magnetic resonance
  • Another embodiment of the invention is the crystalline form having a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 3.
  • Another embodiment of the invention is the crystalline form having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 68.6 °C+/-5°C and an exotherm greater than 200 °C.
  • An embodiment of the invention is a crystalline form of (S)-/V-(3-amino-1- (hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis tosylate monohydrate salt having an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °20( ⁇ 0.2) selected from the group consisting of 6.28, 8.07 and 9.35.
  • XRPD X-ray powder diffraction
  • An embodiment of the invention is a crystalline form of (S)-/V-(3-amino-1- (hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis tosylate monohydrate salt having an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °20( ⁇ 0.2) selected from the group consisting of 12.00, 14.60, 16.16 and 16.94.
  • XRPD X-ray powder diffraction
  • An embodiment of the invention is a crystalline form of (S)-/V-(3-amino-1- (hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis tosylate monohydrate salt having an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °20( ⁇ 0.2) selected from the group consisting of 18.05, 19.51 , 20.84 and 23.28.
  • XRPD X-ray powder diffraction
  • Another embodiment of the invention is a pharmaceutical composition comprising any of the above crystalline forms and a pharmaceutical excipient.
  • Another embodiment of the invention is the pharmaceutical composition, wherein the crystalline form is substantially purified.
  • An embodiment of the invention is a crystalline form of the (S)-N-(3-amino-1- (hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis propionate salt having at least one of the following characteristics: an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °20( ⁇ 0.2) selected from the group consisting of 3.57, 7.16, 7.59, 10.74, 11.14, 11.32, 12.76, 13.87, 14.35, 14.69, 15.60, 16.15, 18.22, 18.58, 18.94, 22.40 and 22.80 or in terms of d-spacing [A] ( ⁇ 0.2) selected from the group consisting of 24.73, 12.34, 11.65, 8.24, 7.95, 7.75, 6.94, 6.39, 6.17, 6.03, 5.68, 5.49, 4.93, 4.
  • Another embodiment of the invention is the crystalline form having an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 4.
  • XRPD X-ray powder diffraction
  • Another embodiment of the invention is the crystalline form having carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum substantially as shown in Figure 5.
  • CPMAS carbon-13 cross-polarization magic-angle spinning
  • NMR nuclear magnetic resonance
  • Another embodiment of the invention is the crystalline form having a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 6.
  • DSC differential scanning calorimetry
  • An embodiment of the invention is a crystalline form of (S)-N-(3-amino-1- (hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis propionate salt having an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °20( ⁇ O.2) selected from the group consisting of 3.57, 7.16 and 7.59.
  • XRPD X-ray powder diffraction
  • An embodiment of the invention is a crystalline form of (S)-N-(3-amino-1- (hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis propionate salt having an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °20( ⁇ O.2) selected from the group consisting of 10.74, 11.14, 11.32, 12.76, 13.87, 14.35 and 14.69.
  • XRPD X-ray powder diffraction
  • An embodiment of the invention is a crystalline form of (S)-N-(3-amino-1- (hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis propionate salt having an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °20( ⁇ 0.2) selected from the group consisting of 15.60, 16.15, 18.22, 18.58, 18.94, 22.40 and 22.80.
  • XRPD X-ray powder diffraction
  • the reducing agent is NaBH4.
  • reaction of step b) further comprises a palladium catalyst.
  • the palladium catalyst is Pd(PPh3)4.
  • step c) the product of step c) is isolated as the HCI salt.
  • the solvent is dimethyl sulfoxide (DMSO) or cyclopentyl methyl ether (CPME).
  • reaction of step e) further comprises water (H2O).
  • the 2-propanol is substantially free of water.
  • An embodiment of the invention is a method of preparing (S)-A/-(3-amino-1- (hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis tosylate monohydrate salt comprising reacting S)-/V-(3-amino-1 -(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-
  • reaction further comprises a solvent.
  • the solvent is isopropanol.
  • reaction further comprises water (H2O).
  • An embodiment of the invention is a method of preparing the (S)-N-(3-amino-1- (hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((4-(((2- methoxyethyl)amino)methyl)phenyl)ethynyl)benzamide bis propionate salt comprising reacting S)-/V-(3-amino-1 -(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-
  • An embodiment of the invention is a method of preparing 4-(4-(((2- methoxyethyl)amino)methyl)phenyl)-2-methylbut-3-yn-2-ol comprising a) reacting 4-bromobenzaldehyde with 2-methoxyethylamine to yield /V-(4- bromobenzyl)-2-methoxyethan-1 -amine b) reacting A/-(4-bromobenzyl)-2-methoxyethan-1 -amine with 2-methyl-3-butyn-2- ol to yield 4-(4-(((2-methoxyethyl)amino)methyl)phenyl)-2-methylbut-3-yn-2-ol.
  • A acetonitrile with 0.05 % (vol./vol.) formic acid.
  • ESI/MS positive and negative ions scan: 100-650 m/z;
  • Binary pump G4220A included degasser
  • Hygroscopicity was evaluated by dynamic vapor sorption (DVS).
  • the water sorption-desorption isotherms were obtained using a DVS system (Surface Measurement Systems, DVS Adventure). At 25°C, one RH cycle was performed for the sample. In the cycle, RH was raised by 10% per step, from 0% or 30% to 90% and then back to 0% or 30%RH. A rate of change in mass per time unit (dm/dt) of 0.002 wt%/min was set as the equilibrium criteria. Once the criteria was met, the system would hold the set parameters for 10 minutes. The maximum equilibration time was 180 minutes.
  • Figure 7 shows the DVS isotherm plot for the tosylate monohydrate salt.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des procédés de fabrication de formes cristallines de sels de (S)-N-(3-amino-1-(hydroxyamino)-3-méthyl-1-oxobutan-2-yl)-4-((4-(((2- méthoxyéthyl)amino)méthyl)phényl) éthynyl)benzamide.
PCT/EP2024/087865 2023-12-21 2024-12-20 Procédés de fabrication de formes cristallines de sels de (s)-n-(3-amino-1-(hydroxyamino)-3-méthyl-1-oxobutan-2-yl)-4-((4-(((2-méthoxyéthyl)amino)méthyl)phényl)éthynyl)benzamide Pending WO2025133098A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23218942.3 2023-12-21
EP23218942 2023-12-21

Publications (2)

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WO2025133098A2 true WO2025133098A2 (fr) 2025-06-26
WO2025133098A3 WO2025133098A3 (fr) 2025-08-07

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PCT/EP2024/087865 Pending WO2025133098A2 (fr) 2023-12-21 2024-12-20 Procédés de fabrication de formes cristallines de sels de (s)-n-(3-amino-1-(hydroxyamino)-3-méthyl-1-oxobutan-2-yl)-4-((4-(((2-méthoxyéthyl)amino)méthyl)phényl)éthynyl)benzamide

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023118557A1 (fr) 2021-12-24 2023-06-29 Intervet International B.V. Composition pharmaceutique injectable pour le traitement de maladies respiratoires chez des animaux
WO2023118558A1 (fr) 2021-12-24 2023-06-29 Intervet International B.V. Procédé de préparation de dérivés d'hydroxylamine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013170030A1 (fr) * 2012-05-09 2013-11-14 Achaogen, Inc. Agents antibactériens
US11406617B2 (en) * 2016-12-23 2022-08-09 Intervet Inc. Compounds for the treatment of bovine or swine respiratory disease

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023118557A1 (fr) 2021-12-24 2023-06-29 Intervet International B.V. Composition pharmaceutique injectable pour le traitement de maladies respiratoires chez des animaux
WO2023118558A1 (fr) 2021-12-24 2023-06-29 Intervet International B.V. Procédé de préparation de dérivés d'hydroxylamine

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