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WO2018185711A1 - Solvates d'éluxadoline - Google Patents

Solvates d'éluxadoline Download PDF

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Publication number
WO2018185711A1
WO2018185711A1 PCT/IB2018/052380 IB2018052380W WO2018185711A1 WO 2018185711 A1 WO2018185711 A1 WO 2018185711A1 IB 2018052380 W IB2018052380 W IB 2018052380W WO 2018185711 A1 WO2018185711 A1 WO 2018185711A1
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WO
WIPO (PCT)
Prior art keywords
crystalline form
eluxadoline
peaks
spacings
depicted
Prior art date
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Ceased
Application number
PCT/IB2018/052380
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English (en)
Inventor
Anu Arya
Chandra Has Khanduri
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.)
Sun Pharmaceutical Industries Ltd
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Sun Pharmaceutical Industries Ltd
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Filing date
Publication date
Application filed by Sun Pharmaceutical Industries Ltd filed Critical Sun Pharmaceutical Industries Ltd
Publication of WO2018185711A1 publication Critical patent/WO2018185711A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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] [(15)- 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. WO2009/009480 purportedly discloses Form a and Form ⁇ crystals of eluxadoline and processes thereof.
  • PCT Publication No. WO2017/015606 purportedly discloses amorphous Form, crystalline Forms I, II, III and IV, and a process for the preparation of Form a crystal of eluxadoline.
  • WO2017/015606 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 XRPD pattern of dimethyl digol solvate of eluxadoline designated as crystalline Form S6.
  • Figure 2 depicts a DSC thermogram of dimethyl digol solvate of eluxadoline designated as crystalline Form S6.
  • Figure 3 depicts an XRPD pattern of ethanol solvate of eluxadoline designated as crystalline Form S7.
  • Figure 4 depicts a DSC thermogram of ethanol solvate of eluxadoline designated as crystalline Form S7.
  • Figure 5 depicts an XRPD pattern of isopropyl acetate solvate of eluxadoline designated as crystalline Form S8.
  • Figure 6 depicts a DSC thermogram of isopropyl acetate solvate of eluxadoline designated as crystalline Form S8.
  • Figure 7 depicts an XRPD pattern of amyl alcohol solvate of eluxadoline designated as crystalline Form S9.
  • Figure 8 depicts a DSC thermogram of amyl alcohol solvate of eluxadoline designated as crystalline Form S9.
  • Figure 9 depicts an XRPD pattern of acetone solvate of eluxadoline designated as crystalline Form S10.
  • Figure 10 depicts a DSC thermogram of acetone solvate of eluxadoline designated as crystalline Form S 10.
  • 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 dimethyl digol solvate of eluxadoline designated as crystalline Form S6.
  • Crystalline Form S6 is characterized by an XRPD pattern having peaks at d-spacings of about 13.9, 6.9, 4.9, 3.8, and 2.8 A, and further characterized by additional peaks at d-spacings of about 5.7, 4.2, 4.1, 4.0, and 3.7 A.
  • Table 1 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S6.
  • Crystalline Form S6 is characterized by a DSC thermogram having endothermic peaks at about 67.3°C, 143.3°C, 187.8°C, and 199.5°C.
  • Crystalline Form S6 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 ethanol solvate of eluxadoline designated as crystalline Form S7.
  • Crystalline Form S7 is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 6.9, 4.9, 3.8, and 2.8 A, and further characterized by additional peaks at d-spacings of about 9.9, 6.4, 5.7, 4.2, and 3.7 A.
  • Table 2 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S7.
  • Crystalline Form S7 is characterized by a DSC thermogram having endothermic peaks at about 65.3 °C, 184.5°C, 195.2°C, and 202.5°C. Crystalline Form S7 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 isopropyl acetate solvate of eluxadoline designated as crystalline Form S8.
  • Crystalline Form S8 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, 4.2, 3.9, and 2.8 A.
  • Table 3 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S8.
  • Crystalline Form S8 is characterized by a DSC thermogram having endothermic peaks at about 62.6°C and 191.7°C.
  • Crystalline Form S8 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 amyl alcohol solvate of eluxadoline designated as crystalline Form S9.
  • Crystalline Form S9 is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 4.9, 3.8, 3.6, and 2.8 A, and further characterized by additional peaks at d-spacings of about 6.8, 6.4, 5.9, 5.7, and 4.2 A.
  • Table 4 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form S9.
  • Crystalline Form S9 is characterized by a DSC thermogram having endothermic peaks at about 64.5°C, 141.9°C, 182.3°C, and 199.8°C.
  • Crystalline Form S9 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 acetone solvate of eluxadoline designated as crystalline Form SIO.
  • Crystalline Form SIO is characterized by an XRPD pattern having peaks at d-spacings of about 14.0, 13.8, 6.8, 4.9, and 3.8 A, and further characterized by additional peaks at d-spacings of about 6.7, 4.6, 4.2, 4.1, and 3.7 A.
  • Table 5 provides the d-spacing values (A), the corresponding 2 ⁇ values, and the relative intensity of crystalline Form SIO.
  • Crystalline Form S10 is characterized by a DSC thermogram having endothermic peaks at about 89.3°C, 170.6°C, and 195.9°C. Crystalline Form S10 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 is dimethyl digol and second solvent is diisopropyl ether.
  • the first solvent is ethanol and second solvent is diisopropyl ether.
  • the first and second solvents are isopropyl acetate.
  • the first solvent and the second solvent are amyl alcohol.
  • the first solvent is acetone 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 65°C. In an embodiment, 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.
  • IBS-D irritable bowel syndrome with diarrhea
  • 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. While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
  • NMR of the samples was determined using a Bruker ® instrument, Model Avance III 400, using 5 mm PABBO probe.
  • Eluxadoline (240 mg) was dissolved in dimethyl digol (2.3 mL) and water (0.75 mL) to obtain a solution. The solution was left at 25°C to 30°C for 3 days to 4 days for slow crystallization. Diisopropyl ether (10 mL) was added to the solution. The solid mass was collected by filtration and then dried initially at 25°C under vacuum for 2 hours and further dried at 40°C for 4 hours to obtain the title compound.
  • Eluxadoline 300 mg was dissolved in ethanol (1.5 mL) and water (0.5 mL) to obtain a solution. The solution was stirred at 25°C to 30°C for 4 hours. Diisopropyl ether (25 mL) was added to the solution and then 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 45 °C for 6 hours to obtain the title compound. Yield: 265 mg
  • Eluxadoline 300 mg was dissolved in isopropyl acetate (30 mL) to obtain a slurry. The slurry was stirred at 60°C for 7 hours. The solid mass was collected by filtration and then dried initially at 25 °C under vacuum for 4 hours and further dried at 55°C for 8 hours to obtain the title compound.
  • Eluxadoline 150 mg was dissolved in amyl alcohol (1.5 mL) and water (0.5 mL) to obtain a solution. The solution was stirred overnight at 25°C to 30°C. The solid mass was collected by filtration and then dried initially at 25 °C under vacuum for 2 hours and further dried at 55°C for 10 hours to obtain the title compound.
  • Eluxadoline 200 mg was partially dissolved in acetone (10 mL) to obtain a slurry. The slurry was stirred at 55°C for 7 hours. Diisopropyl ether (15 mL) was added and further stirred overnight at 25 °C to 30°C. The solid mass was collected by filtration and then dried initially at 25 °C under vacuum for 2 hours and further dried at 45 °C for 4 hours to obtain the title compound. Yield: 185 mg

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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 du côlon irritable avec diarrhée (SII-D).
PCT/IB2018/052380 2017-04-05 2018-04-05 Solvates d'éluxadoline Ceased WO2018185711A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201711012314 2017-04-05
IN201711012314 2017-04-05

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WO2018185711A1 true WO2018185711A1 (fr) 2018-10-11

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Cited By (3)

* 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
WO2020039333A1 (fr) * 2018-08-20 2020-02-27 Allergan Holdings Unlimited Company Polymorphes 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
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 (2)

* 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
WO2018047131A1 (fr) * 2016-09-09 2018-03-15 Sun Pharmaceutical Industries Limited Éluxadoline amorphe

Patent Citations (2)

* 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
WO2018047131A1 (fr) * 2016-09-09 2018-03-15 Sun Pharmaceutical Industries Limited Éluxadoline amorphe

Cited By (3)

* 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
WO2020039333A1 (fr) * 2018-08-20 2020-02-27 Allergan Holdings Unlimited Company Polymorphes 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
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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