WO2018185664A1 - Solvates d'éluxadoline - Google Patents

Solvates d'éluxadoline Download PDF

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Publication number
WO2018185664A1
WO2018185664A1 PCT/IB2018/052304 IB2018052304W WO2018185664A1 WO 2018185664 A1 WO2018185664 A1 WO 2018185664A1 IB 2018052304 W IB2018052304 W IB 2018052304W WO 2018185664 A1 WO2018185664 A1 WO 2018185664A1
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WO
WIPO (PCT)
Prior art keywords
crystalline form
eluxadoline
peaks
spacings
depicted
Prior art date
Application number
PCT/IB2018/052304
Other languages
English (en)
Inventor
Anu Arya
Chandra Has Khanduri
Original Assignee
Sun Pharmaceutical Industries Limited
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 Sun Pharmaceutical Industries Limited filed Critical Sun Pharmaceutical Industries Limited
Publication of WO2018185664A1 publication Critical patent/WO2018185664A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine

Definitions

  • the present invention relates to solvates of eluxadoline, processes for their preparation, pharmaceutical compositions comprising these solvates, and their use for the treatment of irritable bowel syndrome with diarrhea (IBS-D).
  • IBS-D irritable bowel syndrome with diarrhea
  • Eluxadoline chemically is 5-[[[(25)-2-amino-3-[4-(aminocarbonyl)-2,6- dimethylphenyl] - 1 -oxopropyl] [( IS)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl]amino]methyl]-2- methoxybenzoic acid, represented by Formula I.
  • Eluxadoline is a mu-opioid receptor agonist, indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D).
  • PCT Publication No. WO 2009/009480 purportedly discloses Form a and Form ⁇ crystals of eluxadoline and processes thereof.
  • PCT Publication No. WO 2017/015606 purportedly discloses amorphous Form, crystalline Forms I, II, III and IV and a process for the preparation of Form a crystal of eluxadoline.
  • WO 2017/015606 purportedly discloses amorphous Form, crystalline Forms I, II, III and IV and a process for the preparation of Form a crystal of eluxadoline.
  • the present invention relates to solvates of eluxadoline, processes for their preparation, pharmaceutical compositions comprising these solvates, and their use for the treatment of irritable bowel syndrome with diarrhea (IBS-D).
  • IBS-D irritable bowel syndrome with diarrhea
  • solvates of eluxadoline of the present invention exhibit good thermodynamic stability, solubility, and bioavailability.
  • Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of methanol solvate of eluxadoline designated as crystalline Form S 1.
  • XRPD X-Ray Powder Diffraction
  • FIG. 2 depicts a Differential Scanning Calorimetry (DSC) thermogram of methanol solvate of eluxadoline designated as crystalline Form SI .
  • DSC Differential Scanning Calorimetry
  • Figure 3 depicts an XRPD pattern of isopropyl alcohol solvate of eluxadoline designated as crystalline Form S2.
  • Figure 4 depicts a DSC thermogram of isopropyl alcohol solvate of eluxadoline designated as crystalline Form S2.
  • Figure 5 depicts an XRPD pattern of n-butanol solvate of eluxadoline designated as crystalline Form S3.
  • Figure 6 depicts a DSC thermogram of n-butanol solvate of eluxadoline designated as crystalline Form S3.
  • Figure 7 depicts an XRPD pattern of n-pentanol solvate of eluxadoline designated as crystalline Form S4.
  • Figure 8 depicts a DSC thermogram of n-pentanol solvate of eluxadoline designated as crystalline Form S4.
  • Figure 9 depicts an XRPD pattern of diisopropyl ether solvate of eluxadoline designated as crystalline Form S5.
  • Figure 10 depicts a DSC thermogram of diisopropyl ether solvate of eluxadoline designated as crystalline Form S5.
  • contacting refers to dissolving, slurring, stirring, suspending, or combinations thereof.
  • solvate refers to an aggregate of eluxadoline of Formula I with one or more molecules of a solvent, wherein the solvent is present in a stoichiometric or in a non-stoichiometric amount.
  • solvents include methanol, isopropyl alcohol, n-butanol, n-pentanol, diisopropyl ether, dimethyl digol, ethanol, acetone, amyl alcohol, isopropyl acetate, ethyl acetate, 2-ethoxy ethanol, and 1,2- dimethoxy benzene.
  • a first aspect of the present invention provides solvates of eluxadoline.
  • the solvates of eluxadoline are methanol, isopropyl alcohol, n- butanol, n-pentanol, diisopropyl ether, dimethyl digol, ethanol, acetone, amyl alcohol, isopropyl acetate, ethyl acetate, 2-ethoxy ethanol, and 1,2-dimethoxy benzene.
  • the solvates of eluxadoline are in a crystalline form or in an amorphous form.
  • a second aspect of the present invention provides methanol solvate of eluxadoline designated as crystalline Form S 1.
  • Crystalline Form S 1 is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at d-spacings of about 12.2, 4.6, 4.5, 3.9, and 3.6 A, and further characterized by additional peaks at d-spacings of about 7.6, 7.3, 5.9, 4.3, and 4.1 A.
  • XRPD X-ray powder diffraction
  • Table 1 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S 1.
  • Crystalline Form SI is characterized by a differential scanning calorimetry (DSC) thermogram having endothermic peaks at about 77.9°C and 197.2°C.
  • DSC differential scanning calorimetry
  • Crystalline Form S 1 is also characterized by an XRPD pattern substantially as depicted in Figure 1, or a DSC thermogram substantially as depicted in Figure 2.
  • a third aspect of the present invention provides isopropyl alcohol solvate of eluxadoline designated as crystalline Form S2.
  • Crystalline Form S2 is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 6.9, 4.9, 3.8, and 3.6 A, and further characterized by additional peaks at d-spacings of about 9.9, 6.4, 5.6, 4.6, and 4.2 A.
  • Table 2 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S2.
  • Crystalline Form S2 is characterized by a DSC thermogram having endothermic peaks at about 80.4°C, 101.1°C, and 168.9°C.
  • Crystalline Form S2 is also characterized by an XRPD pattern substantially as depicted in Figure 3, or a DSC thermogram substantially as depicted in Figure 4.
  • a fourth aspect of the present invention provides n-butanol solvate of eluxadoline designated as crystalline Form S3.
  • Crystalline Form S3 is characterized by an XRPD pattern having peaks at d-spacings of about 13.8, 6.9, 4.9, 3.8, and 2.8, A, and further characterized by additional peaks at d-spacings of about 6.4, 5.7, 4.2, 4.0, and 3.7 A.
  • Table 3 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S3.
  • Crystalline Form S3 is characterized by a DSC thermogram having endothermic peaks at about 87.1°C and 178.8°C.
  • Crystalline Form S3 is also characterized by an XRPD pattern substantially as depicted in Figure 5, or a DSC thermogram substantially as depicted in Figure 6.
  • a fifth aspect of the present invention provides n-pentanol solvate of eluxadoline designated as crystalline Form S4.
  • Crystalline Form S4 is characterized by an XRPD pattern having peaks at d-spacings of about 14.1, 6.9, 5.7, 4.9, and 3.8 A, and further characterized by additional peaks at d-spacings of about 12.0, 8.9, 8.1, 4.6, and 4.2 A.
  • Table 4 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S4.
  • Crystalline Form S4 is characterized by a DSC thermogram having endothermic peaks at about 73.9°C and 186.5°C.
  • Crystalline Form S4 is also characterized by an XRPD pattern substantially as depicted in Figure 7, or a DSC thermogram substantially as depicted in Figure 8.
  • a sixth aspect of the present invention provides diisopropyl ether solvate of eluxadoline designated as crystalline Form S5.
  • Crystalline Form S5 is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 6.8, 4.9, 3.8, and 3.6 A, and further characterized by additional peaks at d-spacings of about 9.8, 6.4, 5.9, 5.6, and 4.2 A.
  • Table 5 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S5.
  • Crystalline Form S5 is characterized by a DSC thermogram having endothermic peaks at about 63.3°C and 185.2°C.
  • Crystalline Form S5 is also characterized by an XRPD pattern substantially as depicted in Figure 9, or a DSC thermogram substantially as depicted in Figure 10.
  • a seventh aspect of the present invention provides a process for the preparation of solvates of eluxadoline, comprising contacting eluxadoline with a first solvent and optionally with a second solvent.
  • Eluxadoline may be prepared by any method known in the art, for example, the method described in U.S. Patent No. 7,741,356.
  • the first solvent and second solvent are selected from the group consisting of methanol, isopropyl alcohol, n-butanol, n-pentanol, diisopropyl ether, dimethyl digol, ethanol, acetone, amyl alcohol, isopropyl acetate, ethyl acetate, 2-ethoxy ethanol, 1,2- dimethoxy benzene, water or a mixture thereof.
  • the first solvent and second solvent is methanol.
  • the first solvent and second solvent are isopropyl alcohol.
  • the first and second solvent are n-butanol.
  • the first solvent is n-pentanol and the second solvent is diisopropyl ether.
  • the first solvent is methanol and the second solvent is diisopropyl ether.
  • Eluxadoline is contacted with a solvent for about one hour to about 5 days. In an embodiment, the eluxadoline is contacted with the solvent for about 2 hours to about 4 days. In another embodiment, the eluxadoline is contacted with the solvent for about 5 hours to about 3 days. In another embodiment, the eluxadoline is contacted with the solvent for about 8 hours to about 4 days. In another embodiment, the eluxadoline is contacted with the solvent for about 15 hours to about 2 days.
  • Eluxadoline is contacted with a solvent at a temperature of about 20°C to about
  • the eluxadoline is contacted with the solvent at a temperature of about 25°C to about 60°C. In another embodiment, the eluxadoline is contacted with the solvent at a temperature of about 35°C to about 55°C. In an embodiment, the eluxadoline is contacted with the solvent at a temperature of about 50°C to about 55°C.
  • the solvates of eluxadoline may be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the solvates of eluxadoline may be dried by drying under reduced pressure, by air drying, suck drying, or vacuum tray drying.
  • An eighth aspect of the present invention provides a process for the preparation of eluxadoline comprising drying a solvate of eluxadoline.
  • the solvates of eluxadoline are methanol, isopropyl alcohol, n- butanol, n-pentanol, diisopropyl ether, dimethyl digol, ethanol, acetone, amyl alcohol, isopropyl acetate, ethyl acetate, 2-ethoxy ethanol, and 1,2-dimethoxy benzene.
  • the solvate of eluxadoline is dried for about one hour to about 7 hours. In an embodiment, the solvate of eluxadoline is dried for about 2 hours to about 6 hours. In another embodiment, the solvate of eluxadoline is dried for about 3 hours to about 5 hours. In another embodiment, the solvate of eluxadoline is dried for about 3.5 hours to about 4 hours.
  • the solvate of eluxadoline is dried at a temperature of about 40°C to about 80°C. In an embodiment, the solvate of eluxadoline is dried at a temperature of about 50°C to about 70°C. In another embodiment, the solvate of eluxadoline is dried at a temperature of about 55°C to about 65°C.
  • Eluxadoline may be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. Eluxadoline may be dried by drying under reduced pressure, by air drying, suck drying, or vacuum tray drying.
  • a ninth aspect of the present invention provides a pharmaceutical composition comprising solvates of eluxadoline, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the solvates of eluxadoline are methanol, isopropyl alcohol, n- butanol, n-pentanol, diisopropyl ether, dimethyl digol, ethanol, acetone, amyl alcohol, isopropyl acetate, ethyl acetate, 2-ethoxy ethanol, and 1,2-dimethoxy benzene.
  • a tenth aspect of the present invention provides a method for treating irritable bowel syndrome with diarrhea (IBS-D) comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising solvates of eluxadoline.
  • the solvates of eluxadoline are methanol, isopropyl alcohol, n- butanol, n-pentanol, diisopropyl ether, dimethyl digol, ethanol, acetone, amyl alcohol, isopropyl acetate, ethyl acetate, 2-ethoxy ethanol, and 1,2-dimethoxy benzene.
  • XRPD of the sample was determined by using a PANalytical ® instrument; Model X'pert PRO; Detector: X'celerator ® .
  • NMR of the sample was determined using a Bruker ® instrument, Model Avance III 400, using 5 mm PABBO probe.
  • Eluxadoline (1 g) was dissolved in methanol (40 mL) to obtain a solution. The solution was stirred at 60°C for 6 hours to obtain a solid mass. The solid mass was collected by filtration and then dried at 25°C to 30°C under vacuum for 2 hours to obtain the title compound.
  • Eluxadoline (1 g) in isopropyl alcohol (40 mL) was stirred at 65°C for 2 hours and then at 25°C to 30°C for 2 hours to obtain a solid mass.
  • the solid mass was collected by filtration and then dried at 25 °C to 30°C under vacuum for 4 hours to obtain the title compound.
  • Eluxadoline 300 mg was dissolved in n-butanol (12 mL) at 60°C to obtain a solution. The solution was stirred at 60°C for 2 hours and then at 25°C to 30°C overnight to obtain a solid mass. The solid mass so obtained was collected by filtration and then dried at 25°C to 30°C under vacuum for 2 hours to obtain the title compound.
  • Eluxadoline 300 mg was dissolved in n-pentanol (10 mL) at 60°C to obtain a solution. The solution was stirred at 60°C for 2 hours and then at 25°C to 30°C overnight to obtain a solid mass. Diisopropyl ether (15 mL) was added to the solution and stirring was continued at 25°C to 30°C for 5 hours to obtain a solid mass. The solid mass was collected by filtration and then dried at 25°C to 30°C under vacuum for 2 hours to obtain the title compound.
  • Eluxadoline 500 mg was dissolved in methanol (2.5 mL) to obtain a solution. The solution was stirred at 25°C to 30°C for 4.5 hours. Diisopropyl ether (15 mL) was added and the mixture was further stirred at 25 °C to 30°C overnight to obtain a solid mass. The solid mass was collected by filtration and then dried initially at 25 °C under vacuum for 2 hours and further dried at 70°C for 4 hours to obtain the title compound.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

La présente invention concerne des solvates d'éluxadoline, des procédés pour leur préparation, des compositions pharmaceutiques comprenant ces solvates, et leur utilisation pour le traitement du syndrome de l'intestin irritable avec diarrhée (SII-D).
PCT/IB2018/052304 2017-04-03 2018-04-03 Solvates d'éluxadoline WO2018185664A1 (fr)

Applications Claiming Priority (2)

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IN201711011993 2017-04-03
IN201711011993 2017-04-03

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WO2018185664A1 true WO2018185664A1 (fr) 2018-10-11

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10314819B2 (en) 2015-07-23 2019-06-11 Teva Pharmaceuticals International Gmbh Solid state forms of Eluxadoline
WO2021198780A1 (fr) * 2020-03-30 2021-10-07 Allergan Holdings Unlimited Company Formes de l'acide 5-({[2-amino-3-(4-carbamoyl-2,6-diméthyl-phényl)-propionyl]-[1-(4-phényl-1h-imidazol-2-yl)-éthyl]-amino}-méthyl)-2-méthoxy-benzoïque

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017015606A1 (fr) * 2015-07-23 2017-01-26 Teva Pharmaceuticals International Gmbh Formes à l'état solide d'éluxadoline
WO2017153471A1 (fr) * 2016-03-11 2017-09-14 Euticals S.P.A. Nouvelles formes cristallines de solvate stables d'eluxadoline
WO2018046028A1 (fr) * 2016-09-07 2018-03-15 Zentiva, K.S. Formes à l'état solide d'éluxadoline
WO2018047131A1 (fr) * 2016-09-09 2018-03-15 Sun Pharmaceutical Industries Limited Éluxadoline amorphe

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017015606A1 (fr) * 2015-07-23 2017-01-26 Teva Pharmaceuticals International Gmbh Formes à l'état solide d'éluxadoline
WO2017153471A1 (fr) * 2016-03-11 2017-09-14 Euticals S.P.A. Nouvelles formes cristallines de solvate stables d'eluxadoline
WO2018046028A1 (fr) * 2016-09-07 2018-03-15 Zentiva, K.S. Formes à l'état solide d'éluxadoline
WO2018047131A1 (fr) * 2016-09-09 2018-03-15 Sun Pharmaceutical Industries Limited Éluxadoline amorphe

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10314819B2 (en) 2015-07-23 2019-06-11 Teva Pharmaceuticals International Gmbh Solid state forms of Eluxadoline
WO2021198780A1 (fr) * 2020-03-30 2021-10-07 Allergan Holdings Unlimited Company Formes de l'acide 5-({[2-amino-3-(4-carbamoyl-2,6-diméthyl-phényl)-propionyl]-[1-(4-phényl-1h-imidazol-2-yl)-éthyl]-amino}-méthyl)-2-méthoxy-benzoïque

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