WO2019134970A1 - Nouveaux sels d'un inhibiteur de bcl-2, formes cristallines associées, leur procédé de préparation et compositions pharmaceutiques les contenant - Google Patents

Nouveaux sels d'un inhibiteur de bcl-2, formes cristallines associées, leur procédé de préparation et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO2019134970A1
WO2019134970A1 PCT/EP2019/050161 EP2019050161W WO2019134970A1 WO 2019134970 A1 WO2019134970 A1 WO 2019134970A1 EP 2019050161 W EP2019050161 W EP 2019050161W WO 2019134970 A1 WO2019134970 A1 WO 2019134970A1
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WIPO (PCT)
Prior art keywords
compound
crystalline form
ppm
tosylate salt
expressed
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PCT/EP2019/050161
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English (en)
Inventor
Michael Lynch
Julie Linol
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Les Laboratoires Servier
Vernalis (R&D) Limited
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Publication of WO2019134970A1 publication Critical patent/WO2019134970A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the invention relates to novel salts of A/-(4-hydroxyphenyl)-3- ⁇ 6-[((35)-3-(4- morpholinylmethyl)-3,4-dihydro-2(l/-/)-isoquinolinyl)carbonyl]-l,3-benzodioxol-5-yl ⁇ -/V- phenyl-5, 6, 7, 8-tetrahydro-l-indolizine carboxamide, referred to herein as 'Compound A', or polymorphs or solvates thereof, methods for preparing the same as well as pharmaceutical compositions thereof.
  • the invention relates to the para- toluenesulfonate salt of Compound A, referred to herein as the tosylate salt of Compound A.
  • the invention also relates to the use of such compositions for the treatment of cancer, diseases of the immune system and auto-immune diseases.
  • the present invention relates to Compound A salts of formula (la) :
  • HA is selected from the following list: fumaric acid, maleic acid, malonic acid, para-toluenesulfonic acid and sulfuric acid, as well as a method for preparing the same, pharmaceutical compositions containing the same, and uses thereof.
  • the invention relates also to the hemifumarate salt of Compound A of formula (lb):
  • HA is fumaric acid, as well as a method for preparing the same, pharmaceutical compositions containing the same and uses thereof.
  • the present invention relates to the tosylate salt of Compound A of formula (II):
  • the present invention also relates to novel crystalline forms of the salts of Compound A of formulas (la) and (lb), or solvates thereof, methods for preparing the same, as well as pharmaceutical compositions containing the same, and uses thereof.
  • the crystalline forms of the salts according to the invention enable to prepare pharmaceutical formulations having a consistent and reproducible composition and having good characteristics of stability.
  • the crystalline form I of the tosylate salt of Compound A is especially robust.
  • Figure 1 shows the X-ray powder diffraction pattern (XPRD) of the crystalline form I of Compound A, tosylate salt.
  • Figure 2 shows the solid-state 13 C NMR spectrum of the crystalline form I of Compound A, tosylate salt.
  • the term 'pharmaceutical composition for oral administration means for example a tablet, a dragee, a granule, a sublingual tablet, a capsule or a lozenge, in particular a tablet. Such tablet may optionally be film-coated.
  • the useful dosage varies according to the sex, age and weight of the patient, the administration route, the nature of the cancer and any associated treatments; the useful dosage ranges from 50 mg to 1500 mg of Compound A per day expressed in terms of the free base.
  • alcohols means Ci-C 6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol, 2-pentanol, 3-pentanol, isopentanol, hexanol.
  • ketones means a C 3 -C 6 ketone such as acetone, methyl ethyl ketone, 2- pentanone, 3-pentanone, 3-methyl-2-butanone, 2-hexanone, 3-hexanone, ethyl isopropyl ketone, methyl isopropyl ketone, 2,2-dimethyl-3-butanone.
  • 'Cancer' means a class of disease in which a group of cells display uncontrolled growth. Cancer types include haematological cancer (lymphoma and leukemia) and solid tumors including carcinoma, sarcoma, or blastoma. 'Cancer' includes cancer of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the oesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer.
  • the crystalline form I of the tosylate salt of Compound A according to E2 characterized in that it has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°): 5.26; 6.11; 7.62; 9.64; 11.04; 13.14; 16.27; 16.99; 17.30; 19.35; 19.93; 21.24; 21.62; 22.10; 24.78.
  • Pharmaceutical composition comprising as active ingredient the tosylate salt of Compound A according to El in association with one or more pharmaceutically acceptable excipients.
  • composition comprising as active ingredient the crystalline form I of the tosylate salt of Compound A according to any one of E2 to E5 in association with one or more pharmaceutically acceptable excipients.
  • E8 Pharmaceutical composition according to E6 or E7 for use in the treatment of cancers, auto-immune diseases and diseases of the immune system.
  • composition according to E8 wherein the cancer is selected from the bladder, brain, breast and uterus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the oesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small- cell lung cancer, prostate cancer and small-cell lung cancer.
  • DMSO dimethyl sulfoxide
  • the crystalline form I of the hemifumarate salt of Compound A according to E20 characterized in that it has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°): 3.91; 7.84; 8.51; 9.17; 10.68; 13.27; 14.11; 14.53; 14.78; 17.45; 19.34; 20.73; 21.31; 23.04; 23.11; 23.84.
  • E23 The crystalline form I of the malonate salt of Compound A according to E22, characterized in that it has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°): 3.84; 7.70; 8.97; 11.06; 11.27; 11.62; 13.70; 15.26; 16.38; 17.64; 18.81; 19.07; 19.33; 19.86; 20.14; 22.26; 22.46; 22.73; 23.19; 23.86; 27.15.
  • the crystalline form I of the hydrogensulfate salt of Compound A according to E24 characterized in that it has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°): 5.30; 6.17; 7.70; 11.17; 11.49; 12.48; 13.29; 15.58; 16.47; 17.01; 17.18; 17.53; 20.03; 20.74; 21.91; 22.43; 22.67; 24.92; 25.12; 27.73.
  • E27 The crystalline form I of the maleate salt of Compound A according to E26, characterized in that it has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°): 3.75; 7.60; 9.13; 10.04; 11.14, 14.27, 17.19, 19.93, 20.56, 24.61.
  • composition comprising as active ingredient a crystalline form according to any one of E18 to E27 in association with one or more pharmaceutically acceptable excipients.
  • composition according to E28 for use in the treatment of cancers, auto-immune diseases and diseases of the immune system.
  • E30 Pharmaceutical composition according to E29, wherein the cancer is selected from the bladder, brain, breast and uterus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the oesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small- cell lung cancer, prostate cancer and small-cell lung cancer.
  • crystalline form I of the tosylate salt of Compound A has the advantage of making it possible to prepare pharmaceutical formulations having a consistent and reproducible composition and having good characteristics of stability. More especially, only one crystalline form was observed in the range of solvents and temperatures used for the screening, showing a limited polymorphism of the tosylate salt in the tested conditions. Furthermore, the crystalline form I of the tosylate salt of Compound A thereby obtained is sufficiently stable to allow its storage for an extended period without particular conditions for temperature, light, humidity or oxygen levels.
  • Example 1 Process for obtaining crystalline form I of the tosylate salt of Compound A
  • Example 2 Process for obtaining crystalline form I of the tosylate salt of Compound A (seeding)
  • Example 3 Crystalline form I of the tosylate salt of Compound A (X-ray powder diffraction diagram)
  • Measurement mode continuous from 3° to 55° (Bragg's angle 2 theta) in increments of 0.017°
  • the form I of the tosylate salt of Compound A was also characterised by solid-state Nuclear Magnetic Resonance spectroscopy ( Figure 2).
  • the solid-state 13 C NMR spectrum of the batch was recorded at ambient temperature using a Bruker SB Avance III 500 spectrometer with a 4-mm CP/MAS SB VTN type probe under the following conditions:
  • tosylate salt crystalline form I can be defined by the presence of the following peaks in the NMR spectrum (expressed in ppm ⁇ 0.2 ppm):
  • the hygroscopicity of the crystalline form I of Compound A, tosylate salt was assessed using the dynamic vapour sorption (DVS) technique.
  • 5 to 10 mg of the drug substance test sample were accurately weighed into a DVS sample pan working at 25°C under controlled humidity.
  • the mass of the sample was recorded whilst drying under 0 per cent RH (relative humidity) and during two subsequent cycles of increasing and decreasing linear variations of relative humidity in the range 0-90 per cent RH at a rate of 10 per cent per hour.
  • the relative humidity was maintained constant when it reached either 0 or 90 per cent RH until the mass variation was less than 0.002 per cent per minute within a limit of time of 6 h.
  • the DVS profile shows that water sorption and desorption are perfectly reversible.
  • the crystalline form I of the tosylate salt of Compound A can be considered as being slightly hygroscopic according to the European Pharmacopoeia (Ph. Eur.).
  • Example 6 Process for obtaining crystalline form I of the fumarate salt of Compound A
  • Example 7 Crystalline form I of the fumarate salt of Compound A (X-ray powder diffraction diagram)
  • K alpha-2 wavelength 1.54443 A
  • K alpha-2/K alpha-1 ratio 0.5
  • Measurement mode continuous from 3° to 55° (Bragg's angle 2 theta) in increments of 0.017°
  • Example 8 Process for obtaining crystalline form I of the hemifumarate salt of Compound A
  • Example 9 Crystalline form I of the hemifumarate salt of Compound A (X-ray powder diffraction diagram)
  • Measurement mode continuous from 3° to 55° (Bragg's angle 2 theta) in increments of 0.017°
  • the X-ray powder diffraction diagram of form I of the hemifumarate salt of Compound A obtained according to the process of Example 8 is expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°) and interplanar distance (expressed in A).
  • the significant lines have been collated in the following table:
  • Example 10 Process for obtaining crystalline form I of the malonate salt of Compound A
  • Example 11 Crystalline form I of the malonate salt of Compound A (X-ray powder diffraction diagram)
  • K alpha-1 wavelength 1.54060 A
  • K alpha-2 wavelength 1.54443 A
  • Measurement mode continuous from 3° to 55° (Bragg's angle 2 theta) in increments of 0.017°
  • the X-ray powder diffraction diagram of the form I of the malonate salt of Compound A obtained according to the process of Example 10 is expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°) and interplanar distance (expressed in A).
  • the significant lines have been collated in the following table:
  • Example 12 Process for obtaining crystalline form I of the hydrogensulfate salt of Compound A
  • Example 13 Crystalline form I of the hydrogensulfate salt of Compound A (X-ray powder diffraction diagram)
  • Measurement mode continuous from 3° to 55° (Bragg's angle 2 theta) in increments of 0.017°
  • the X-ray powder diffraction diagram of the form I of the hydrogensulfate salt of Compound A obtained according to the process of Example 12 is expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°) and interplanar distance (expressed in A).
  • the significant lines have been collated in the following table:
  • Example 14 Process for obtaining crystalline form I of the maleate salt of Compound A
  • Aproximately 750 pi of ethyl acetate was added to about 70 mg of Compound A (free base) to form a slurry. Approximately 750 mI of EtOAc was added to 1.2 equivalent of maleic acid. The acid solution was then added to the Compound A slurry. The slurry was stirred at 60°C for 1 hour then allowed to slowly return to room temperature with stirring. The solid was characterised by the X-ray powder as set out in Example 15.
  • Example 15 Crystalline form I of the maleate salt of Compound A (X-ray powder diffraction diagram)
  • Measurement mode continuous from 6.4° to 30° (Bragg's angle 2 theta) in increments of 0.033°,
  • Measurement time per step 1.0 s.
  • the X-ray powder diffraction diagram of the form I of the maleate salt of Compound A obtained according to the process of Example 14 is expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°) and interplanar distance (expressed in A).
  • the significant lines have been collated in the following table:
  • the drug substance content was determined by LC (% m/m)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux sels et formes cristallines associées du composé A : le sel étant choisi dans la liste suivante : fumarate, hémifumarate, maléate, malonate, tosylate, hydrogénosulfate, caractérisé par leur diagramme de diffraction des rayons X sur poudre, leur procédé de préparation et des compositions pharmaceutiques les contenant.
PCT/EP2019/050161 2018-01-05 2019-01-04 Nouveaux sels d'un inhibiteur de bcl-2, formes cristallines associées, leur procédé de préparation et compositions pharmaceutiques les contenant WO2019134970A1 (fr)

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EP18150419.2 2018-01-05
EP18150419 2018-01-05

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013110890A1 (fr) 2012-01-24 2013-08-01 Les Laboratoires Servier Nouveaux derives d'indolizine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2019008126A1 (fr) * 2017-07-06 2019-01-10 Les Laboratoires Servier Nouvelle forme cristalline d'inhibiteur bcl-2, procédé pour sa préparation et compositions pharmaceutiques la contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013110890A1 (fr) 2012-01-24 2013-08-01 Les Laboratoires Servier Nouveaux derives d'indolizine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2019008126A1 (fr) * 2017-07-06 2019-01-10 Les Laboratoires Servier Nouvelle forme cristalline d'inhibiteur bcl-2, procédé pour sa préparation et compositions pharmaceutiques la contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YERRAM CHANDRAMOULI ET AL: "Review on Cocrystal as an Approach with Newer Implications in Pharmaceutical Field in Intemational", INTERNATIONAL JOURNAL OF MEDICINAL CHEMISTRY & ANALYSIS, IN, vol. 2, no. 2, 2012, pages 91 - 100, XP008184747, ISSN: 2249-7595 *

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