WO2023194300A1 - Formes solides de vismodégib - Google Patents

Formes solides de vismodégib Download PDF

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Publication number
WO2023194300A1
WO2023194300A1 PCT/EP2023/058668 EP2023058668W WO2023194300A1 WO 2023194300 A1 WO2023194300 A1 WO 2023194300A1 EP 2023058668 W EP2023058668 W EP 2023058668W WO 2023194300 A1 WO2023194300 A1 WO 2023194300A1
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WO
WIPO (PCT)
Prior art keywords
vismodegib
solid form
ppm
theta
degrees
Prior art date
Application number
PCT/EP2023/058668
Other languages
English (en)
Inventor
Michal HEGEDUS
Original Assignee
Synthon B.V.
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 Synthon B.V. filed Critical Synthon B.V.
Publication of WO2023194300A1 publication Critical patent/WO2023194300A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom

Definitions

  • the invention relates to solid forms of Vismodegib and to processes for preparation thereof.
  • This invention relates to solid forms of Vismodegib, compound of formula (1) and processes for preparation thereof,
  • Vismodegib 2-Chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]-4-(methanesulfonyl) benzamide, is a small molecule systemic hedgehog antagonist. Vismodegib was approved for the treatment of patients with advanced basal cell carcinoma for whom surgery is considered inappropriate.
  • Vismodegib was disclosed in W02006028958 application. Solid form of Vismodegib is described in WO2014147504 or WO2014195977 application.
  • An article published as Org. Process Res. Dev. 2016, 20, 1509-1519 described a process for preparation of Vismodegib and a solid form thereof, Form B.
  • the solid Form B prepared according to the process described in the article contains methyl isobutyl ketone, solvent used for preparation of the solid form, on levels 2000 ppm. Such high level might be inacceptable for the product used for a treatment.
  • Prior art there describes no process for preparation of solid Form B containing less than 550 ppm of methyl isobutyl ketone.
  • Solid form of a salt can have improved properties such as solubility, purity or stability that is requested when they are incorporated into a final formulation such as tablets or capsules. There is therefore still a need for solid forms of Vismodegib having improved properties such as a low content of solvent(s).
  • the presented invention relates to a process for preparation of solid form B of Vismodegib.
  • the presented invention also relates to solid form S of Vismodegib and to a process for preparation thereof.
  • the presented invention further relates to solid form M of Vismodegib and to a process for preparation thereof.
  • Solid forms of Vismodegib of the presented invention show excellent crystallinity, purity and stability.
  • Solid forms of Vismodegib of the presented invention preferably the solid Form B of Vismodegib, more preferably the solid Form B prepared according to the presented invention, contain less than 550 ppm, preferably less than 500 ppm or 450 ppm or 400 ppm or 350 ppm or 300 ppm or 250 ppm or 200 ppm of methyl isobutyl ketone.
  • Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Vismodegib, Form S, prepared according to Example 1
  • Figure 2 depicts the DSC pattern of solid form of Vismodegib, Form S, prepared according to Example 1
  • Figure 3 depicts the TGA pattern of solid form of Vismodegib, Form S, prepared according to Example 1
  • Figure 4 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Vismodegib, Form M, prepared according to Example 2
  • Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Vismodegib, Form B, prepared according to Example 3 or 4 or 5
  • the presented invention relates to a solid form of Vismodegib, Form S and to a process for preparation thereof.
  • the presented invention relates to a process for preparation of solid Form B of Vismodegib comprising subjecting solid Form S of Vismodegib to a temperature between 45°C and 65°C and relative humidity between 80% and 100% for between 2 and 21 days to provide solid Form B of Vismodegib.
  • the solid Form B of the presented invention preferably prepared by the process of the presented invention contains less than 550 ppm, preferably less than 500 ppm or 450 ppm or 400 ppm or 350 ppm or 300 ppm or 250 ppm or 200 ppm of methyl tert-butyl ether.
  • the presented invention further relates to a process for preparation of solid Form B of Vismodegib comprising: a. Mixing the solid Form S of Vismodegib with water; b. Stirring the mixture at a temperature between 85°C and 100°C for between 1.5 and 5 hours.
  • the concentration of solid Form S in water can be between 0.08 g/ml and 0.12 g/ml.
  • the mixture is stirred at temperature between 85°C and 100°C for between 1.5 and 5 hours.
  • the mixture is cooled to a temperature between 20°C and 25°C, obtained suspension is filtered off and obtained solid can be optionally dried.
  • the presented invention further relates to a process for preparation of solid Form B of Vismodegib comprising: a. Mixing the solid Form S of Vismodegib with water; b. Stirring the mixture at a temperature between 15°C and 35°C for between 1.5 and 5 hours.
  • the process can be optionally performed under a protective atmosphere for example under nitrogen or argon.
  • concentration of solid Form S in water can be between 8 g/ml and 16 g/ml.
  • the mixture is stirred at temperature between 15°C and 35°C for between 1.5 and 5 hours. Obtained suspension is filtered off and obtained solid can be optionally dried for example at a temperature between 40°C and 60°C for between 2 and 10 hours.
  • the solid Form B obtained by the process contains less than 550 ppm, preferably less than 500 ppm or 450 ppm or 400 ppm or 350 ppm or 300 ppm or 250 ppm or 200 ppm of methyl tert-butyl ether.
  • the solid Form S can be characterized by XRPD pattern having 20 values 17.3°, 20.7° and 21.8° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form S can be also characterized by XRPD pattern having 20 values 10.0°, 11.6°, 17.3°, 19.0°, 20.7° and 21.8° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form S can be also characterized by XRPD pattern depicted in Figure 1.
  • the solid form can be further characterized by DSC pattern depicted in Figure 2.
  • the solid form can be further characterized by TGA pattern depicted in Figure 3.
  • the solid form S can be prepared by a process comprising: a. Dissolving Vismodegib in methyl isobutyl ketone to obtain a mixture; b. Cooling the mixture to a temperature between -5°C and 5°C at the rate of 2-4 °C/min; c. Isolating the solid form.
  • the concentration of Vismodegib in methyl isobutyl ketone can be between 0.03 g/ml and 0.07 g/ml.
  • Vismodegib is dissolved in methyl isobutyl ketone preferably at a temperature between 90°C and 120°C.
  • the mixture is rapidly (at the rate of 2-4 °C/min) cooled to a temperature between -5°C and 5°C.
  • the mixture is then stirred at a temperature between -5°C and 5 °C for between 1 and 5 hours. Obtained suspension was filtered off and obtained solid can be optionally dried in vacuum to provide solid Form S of Vismodegib.
  • the presented invention also relates to a solid form of Vismodegib, Form M and to a process for preparation thereof.
  • the solid Form M can be characterized by XRPD pattern having 20 values 7.5°, 11.3°and 15.1° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form M can be also characterized by XRPD pattern having 20 values 7.5°, 11.3°, 15.1°, 18.2°, 19.1° and 23.3° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid form can be also characterized by XRPD pattern depicted in Figure 4.
  • the solid form M can be prepared by a process comprising: a. Heating the solid Form B of Vismodegib at a rate of 10°C/min to a temperature between 185°C and 187°C; b. Keep at this temperature for between 5 and 10 minutes.
  • the solid forms of presented invention can be used in a pharmaceutical composition for the treatment of conditions treatable by Vismodegib or a salt thereof.
  • Nuclear magnetic resonance spectroscopy was performed using Avance III 400 MHz NMR spectrometer.

Abstract

La présente invention concerne des formes solides de vismodégib, un composé de formule (1) et des procédés de préparation de ceux-ci.
PCT/EP2023/058668 2022-04-05 2023-04-03 Formes solides de vismodégib WO2023194300A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22166755.3 2022-04-05
EP22166755 2022-04-05

Publications (1)

Publication Number Publication Date
WO2023194300A1 true WO2023194300A1 (fr) 2023-10-12

Family

ID=81328350

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/058668 WO2023194300A1 (fr) 2022-04-05 2023-04-03 Formes solides de vismodégib

Country Status (1)

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WO (1) WO2023194300A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006028958A2 (fr) 2004-09-02 2006-03-16 Genentech, Inc. Inhibiteurs pyridyles de la signalisation hedgehog
WO2014147504A2 (fr) 2013-03-22 2014-09-25 Shilpa Medicare Limited Procédé de préparation de formes solides de 2-chloro-n-(4-chloro-3-(pyridin-2-ylphényl)-4-méthylsulfonylbenzamide
WO2014195977A2 (fr) 2013-06-05 2014-12-11 Hetero Research Foundation Nouveaux polymorphes de vismodegib
WO2015169269A1 (fr) * 2014-05-05 2015-11-12 Zentiva, K.S. Sels de 2-chloro-n- (4-chloro -3- (pyridin -2-yl)phényl)-4- (méthylsulfonyl)benzamide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006028958A2 (fr) 2004-09-02 2006-03-16 Genentech, Inc. Inhibiteurs pyridyles de la signalisation hedgehog
WO2014147504A2 (fr) 2013-03-22 2014-09-25 Shilpa Medicare Limited Procédé de préparation de formes solides de 2-chloro-n-(4-chloro-3-(pyridin-2-ylphényl)-4-méthylsulfonylbenzamide
WO2014195977A2 (fr) 2013-06-05 2014-12-11 Hetero Research Foundation Nouveaux polymorphes de vismodegib
WO2015169269A1 (fr) * 2014-05-05 2015-11-12 Zentiva, K.S. Sels de 2-chloro-n- (4-chloro -3- (pyridin -2-yl)phényl)-4- (méthylsulfonyl)benzamide

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
MINO R CAIRA ED - MONTCHAMP JEAN-LUC: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY; [TOPICS IN CURRENT CHEMISTRY], SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP008166276, ISSN: 0340-1022, [retrieved on 19990226], DOI: 10.1007/3-540-69178-2_5 *
ORG. PROCESS RES. DEV., vol. 20, 2016, pages 1509 - 1519
REMY ANGELAUD ET AL: "Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 20, no. 8, 27 July 2016 (2016-07-27), US, pages 1509 - 1519, XP055471748, ISSN: 1083-6160, DOI: 10.1021/acs.oprd.6b00208 *
REMY ANGELAUD ET AL: "Supporting Information: Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib", ORGANIC PROCESS RESEARCH AND DEVELOPMENT 2016, 20, 27 July 2016 (2016-07-27), US, pages S1 - S43, XP055471761, Retrieved from the Internet <URL:https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00208/suppl_file/op6b00208_si_001.pdf> [retrieved on 20180502] *

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