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WO2018134189A1 - Co-cristal d'un composé antitumoral - Google Patents

Co-cristal d'un composé antitumoral Download PDF

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Publication number
WO2018134189A1
WO2018134189A1 PCT/EP2018/050983 EP2018050983W WO2018134189A1 WO 2018134189 A1 WO2018134189 A1 WO 2018134189A1 EP 2018050983 W EP2018050983 W EP 2018050983W WO 2018134189 A1 WO2018134189 A1 WO 2018134189A1
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WO
WIPO (PCT)
Prior art keywords
dasatinib
triethyl citrate
crystal
suspension
room temperature
Prior art date
Application number
PCT/EP2018/050983
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English (en)
Inventor
Nicolas Tesson
Montserrat Trilla Castano
Original Assignee
Cerbios-Pharma Sa
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 Cerbios-Pharma Sa filed Critical Cerbios-Pharma Sa
Publication of WO2018134189A1 publication Critical patent/WO2018134189A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings

Definitions

  • the present invention relates to a new co-crystal of Dasatinib having improved properties than other known crystalline or co-crystalline forms of Dasatinib, processes for its preparation, its use in therapy and pharmaceutical compositions containing it.
  • Dasatinib is the name of the chemical compound N-(2-chloro-6-methylphenyl)-2-[[6- [4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide and has the followin formula
  • Such compound is an anti-cancer drug produced by Bristol-Myers Squibb and it is marketed under the trade name Sprycel ® .
  • Dasatinib is an oral dual BCR/ABL and SRC family tyrosine kinase inhibitor approved for use in the treatment of chronic myelogenous leukemia (CML) after treatment with imatinib and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It is administered in dosages of 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg.
  • CML chronic myelogenous leukemia
  • Ph+ ALL Philadelphia chromosome-positive acute lymphoblastic leukemia
  • the marketed pharmaceutical formulation contains Dasatinib monohydrate as active ingredient.
  • Dasatinib is disclosed in the International patent application WO 00/62778 and in the patent US 6,596,746.
  • Dasatinib Several crystalline forms of Dasatinib are known in the art.
  • compositions containing a co-crystal of an Active Pharmaceutical Ingredient may have more advantageous properties compared with the ones that contain the only API.
  • the invention also relates to processes for the preparation of said co- crystal, pharmaceutical compositions containing it and use of this co-crystal in a method of treatment of chronic myelogenous leukemia or Philadelphia chromosome- positive acute lymphoblastic leukemia.
  • the co-crystals of Dasatinib with triethyl citrate have been characterized through X- ray diffraction from crystalline powders (XRPD) (X-ray powder diffraction), by nuclear magnetic resonance spectrometer ( 1 H-NMR) and by differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction
  • 1 H-NMR nuclear magnetic resonance spectrometer
  • DSC differential scanning calorimetry
  • the samples were mounted on a zero-background silicon holder and allowed to spin during the data collection at 0.25 rev/s. Scanning: 2 ⁇ angle, angular range measurement of 3.0° to 40°, with a step size of 0.013° and a scanning speed of 0.328 s (10.20 s/step).
  • the samples were covered with a plastic sheet before making the XRPD analysis. Such plastic sheet exhibits an amorphous profile, as it can be appreciated from Figure 2.
  • the co-crystals of the present invention are not limited to the ones that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying figures. In fact, a diffraction angle measurement error of about 5% or less should always be taken into account.
  • the 1 H-NMR spectra were recorded in deuterated dimethyl sulfoxide (DMSO-d6) with a Varian Mercury 400 MHz spectrometer, equipped with a broadband probe ATB 1 H/19F/X of 5 mm. Spectra are acquired dissolving 5-10 mg of sample in 0.7 mL of deuterated dimethyl sulfoxide (DMSO-d6).
  • the DSC thermograms were acquired with a Mettler-Toledo DSC2. The samples were weighted into a 40 ⁇ _ aluminium crucible with a pinhole lid and heated from 25 to 300°C at a rate of 10°C/min under nitrogen (50 mL/min).
  • FIG. 1 XRPD spectrum of the co-crystal of Dasatinib with triethyl citrate.
  • FIG. 2 XRPD spectrum of the plastic sheet used in the preparation of the samples to be analysed.
  • FIG 3 1 H-NMR spectrum of the co-crystal of Dasatinib with triethyl citrate.
  • FIG. 4 DSC thermogram of the co-crystal of Dasatinib with triethyl citrate.
  • FIG. 5 DSC thermogram of Dasatinib anhydrous form N-6.
  • FIG. 6 DSC thermogram of Dasatinib monohydrate.
  • the term "about”, when referred to a value, means the stated value plus or minus 5% while, when referred to a range, means the outmost values plus or minus 5%.
  • the first object of the present invention is a co-crystal of Dasatinib with triethyl citrate, preferably a co-crystal of Dasatinib with triethyl citrate having a molar ratio of
  • Said co-crystal has a DSC thermogram as substantially shown in FIG. 4, having an endothermic peak at about 91 - 97°C and another endothermic peak at about 255 - 265°C.
  • the same co-crystal has a XRPD spectrum as substantially shown in FIG. 1 , wherein the most relevant peaks fall at 4.5, 8.2, 9.1 , 10.4, 10.6, 13.6, 17.7, 19.7, 22.0, 24.7 ⁇ 0.2 ° in 2 ⁇ .
  • the characteristic peaks of the co-crystal of Dasatinib with triethyl citrate in said FIG. 1 , also the amorphous pattern of the plastic sheet used in the preparation of the samples to be analysed is shown. However, given FIG. 2, this latter is easily distinguishable.
  • the co-crystal of Dasatinib and triethyl citrate is a substantially anhydrous product, having a KF of 0.3% w/w.
  • This new co-crystal has in particular an improved solubility, a good thermal stability, it is very stable during storage and does not decompose in accelerated stability tests.
  • the co-crystal of Dasatinib with triethyl citrate has an optimal morphology and structure which positively impacts on the flowability and compressibility properties and therefore on the preparation of oral pharmaceutical formulations.
  • this new co-crystal of Dasatinib with triethyl citrate has improved characteristics making it very advantageous for the use in the pharmaceutical field.
  • a second object of the present invention is a process for the preparation of a co- crystal of Dasatinib with triethyl citrate, as defined above, comprising:
  • Dasatinib used as starting material for forming the suspension at step a) can be any form of Dasatinib known in the art, which is scarcely soluble in methanol, for example crystalline form N-6, which is a substantially anhydrous form, known by US 7 491 725.
  • the amount of Dasatinib in the suspension can be comprised between about 0.05 g/mL and about 0.5 g/mL and it is preferably about 0.5 g/mL.
  • the molar ratio between Dasatinib and triethyl citrate in the suspension can be comprised for example between about 1 :5 and about 1 :40 and it is preferably about
  • the suspension at step b) is stirred at room temperature for at least two hours, more preferably for a time range comprised between 2 and 10 hours, even more preferably for three or four hours.
  • the suspension can be stirred using a mechanical or magnetic stirring, the mechanical stirring is preferred on large scale production to avoid heterogeneity problems, while magnetic stirring is preferred for small scale production.
  • the cocrystallization can be triggered by seeding the suspension at step b) with a co-crystal previously obtained according to the above disclosed process.
  • the recovery of the co-crystal of Dasatinib with triethyl citrate can be carried out according to known techniques to a man skilled in the art, for example through a Buckner filter, a sintered funnel or by centrifugation.
  • the co-crystal of Dasatinib with triethyl citrate is recovered by filtration with a sintered funnel washing the obtained co-crystal with a mixture of heptane/TBME (methyl ie/f-butyl ether).
  • the resultant co-crystal of Dasatinib and triethyl citrate can be dried, preferably at reduced pressure, according to known methods.
  • Dasatinib co-crystal with triethyl citrate can be prepared by:
  • Dasatinib used as starting material in the three suspension preparation methods and crystallization reported above can be for example Dasatinib in crystalline form N-6, known by US 7 491 725.
  • the suspension of Dasatinib and triethyl citrate in acetonitrile can be carried out using a large excess of triethyl citrate in respect of Dasatinib, in particular a molar ratio Dasatinib:triethyl citrate comprised between about 1 :20 and about 1 :40; preferably of about 1 :40 and the concentration of Dasatinib in acetonitrile is 0.025 - 0.05 g/mL.
  • the suspension of Dasatinib and triethyl citrate in heptane can be carried out using a slight excess of triethyl citrate in respect of Dasatinib, in particular a molar ratio Dasatinib:triethyl citrate comprised between about 1 :2 and about 1 :10; preferably of about 1 :3 and the concentration of Dasatinib in heptane is about 0.1 g/mL.
  • the suspension of Dasatinib and triethyl citrate, using triethyl citrate as solvent, can be carried out using a large excess of triethyl citrate in respect of Dasatinib, in particular a molar ratio Dasatinib:triethyl citrate of about 1 :80.
  • the crystallization method in methanol can be carried out using a large excess of triethyl citrate in respect of Dasatinib, in particular a molar ratio Dasatinib:triethyl citrate of about 1 :40.
  • the co-crystal of Dasatinib with triethyl citrate can also be prepared through wet grinding in a solvent selected from water, dimethyl sulfoxide, methanol, isopropanol, tetrahydrofuran, dimethylformamide, and chloroform using a molar ratio Dasatinib:triethyl citrate of 1 :1.
  • the co-crystal of Dasatinib with triethyl citrate can also be prepared through dry grinding using a molar ratio Dasatinib:triethyl citrate from 3:1 to 1 :3, preferably from 1 :1 to 1 :3.
  • said co-crystal can also be prepared through slow evaporation from methanol using a molar ratio Dasatinib:triethyl citrate from 3:1 to 1 :3, preferably from 1 :1 to 1 :3.
  • Dasatinib used in the processes disclosed above can be, for example, Dasatinib in crystalline anhydrous form N-6, known by US 7 491 725.
  • the co-crystal of Dasatinib with triethyl citrate has been surprisingly found to be a stable solid from a crystallinity point of view, as proven for example by the results of the tests disclosed here below.
  • the co-crystal of Dasatinib with triethyl citrate is very stable and maintains its crystalline form, also after four months.
  • Dasatinib monohydrate which is the form present in the marketed formulation, is of 0.36 g/mL (as reported in WO 2013/186726, in Table 1 at page 12).
  • the co-crystal of Dasatinib with triethyl citrate is 4 - 5 times more soluble than Dasatinib in monohydrate form.
  • the co-crystal of Dasatinib with triethyl citrate is much more soluble than Dasatinib in anhydrous form.
  • the DSC thermogram of the co-crystal of Dasatinib with triethyl citrate shows a peak at 91 - 97°C and another endothermic peak at 255 - 265°C, as it can be appreciated from the DSC thermogram in FIG. 4.
  • the melting point of the co-crystal of Dasatinib with triethyl citrate is much lower than the melting point of Dasatinib in anhydrous form N-6 or Dasatinib in monohydrate form as it can be appreciated by making a comparison of the DSC thermograms at FIG. 4, 5 and 6.
  • FIG. 5 shows that Dasatinib in anhydrous form N-6 has a melting point of about 285°C and
  • FIG. 6 shows that Dasatinib monohydrate has two thermal events: the first is the dehydration event with an onset at about 1 14°C leading to Dasatinib in anhydrous form and then, the melting of this anhydrous form with an onset at about 286°C.
  • the co-crystal of Dasatinib with triethyl citrate has a melting point much lower than Dasatinib in anhydrous or monohydrate forms.
  • crystalline forms having a stronger crystal lattice have higher melting point and lower solubility in water.
  • anhydrous crystalline form N-6 is very stable, but scarcely soluble in water, the same for Dasatinib in monohydrate form.
  • the co-crystal of Dasatinib with triethyl citrate is proven to have improved properties compared to the crystalline and co-crystalline forms of Dasatinib known in the art.
  • a further object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising the co-crystal of Dasatinib with triethyl citrate, as defined above, as active ingredient and at least a pharmaceutically acceptable excipient and/or carrier.
  • composition comprising the co-crystal of Dasatinib with triethyl citrate further comprising imatinib as further active ingredient.
  • compositions can be prepared in a pharmaceutical dosage form according to known techniques.
  • the dosages of active ingredient present in such composition can be the ones commercially used in therapy for Dasatinib.
  • a further object of the invention is a co-crystal of Dasatinib with triethyl citrate, as defined above, for use as a medicament, preferably as oral dual BCR/ABL and SRC family tyrosine kinase inhibitor; more preferably for the treatment of chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
  • CML chronic myelogenous leukemia
  • Ph+ ALL Philadelphia chromosome-positive acute lymphoblastic leukemia
  • a further object of the invention is a method of treatment of a human being, in need of an oral dual BCR/ABL and SRC family tyrosine kinase inhibitor in a method of treatment of chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), comprising administering to said human being a therapeutically effective amount of the co- crystal of Dasatinib with triethyl citrate, as defined above.
  • CML chronic myelogenous leukemia
  • Ph+ ALL Philadelphia chromosome-positive acute lymphoblastic leukemia
  • Form N-6 anhydrous crystalline form known by US 7 491 725
  • IPA Isopropyl alcohol
  • EXAMPLE 1 Preparation of the co-crystal of Dasatinib and triethyl citrate from a suspension in methanol.
  • the solid was filtered with a sintered funnel (porosity 3), analysed by XRPD, washed with a mixture heptane/TBME (8:2, 2 x 10 mL, 2 x 2 volumes) and dried under vacuum (approximately 1 mbar, RT) overnight.
  • a co-crystal of Dasatinib with triethyl citrate was obtained as a white solid but an excess of triethyl citrate was still observed by 1 H-NMR (1 :1 .7, Dasatinib:triethyl citrate).
  • the solid (8.59 g) was suspended in a mixture heptane/TBME (8:2, 60 mL, 12 volumes) and it was stirred at RT for 1 hour.
  • the solid was filtered with a sintered funnel (porosity 3), washed with the mixture heptane/TBME (8:2, 2 x 10 mL, 2 x 2 volumes) and dried under vacuum (approximately 1 mbar, RT) overnight affording pure co-crystal of Dasatinib with triethyl citrate (6.76 g, 86% yield) with 1 :1 molar ratio (Dasatinib:triethyl citrate).
  • the co-crystal of Dasatinib with triethyl citrate has a DSC thermogram as reported in FIG. 4, having an endothermic peak at about 91 - 97°C and another endothermic peak at about 255 - 265°C.
  • the co-crystal of Dasatinib with triethyl citrate has a XRPD, as reported in Figure 1 , wherein the most relevant peaks fall at 4.5, 8.2, 9.1 , 10.4, 10.6, 13.6, 17.7, 19.7, 22.0, 24.7 ⁇ 0.2° in 2 ⁇ .
  • EXAMPLE 2 Preparation of the co-crystal of Dasatinib and triethyl citrate by wet grinding in IPA.
  • the solid was filtered with a sintered funnel (porosity 4), washed with heptane (0.1 mL) and dried under vacuum (approximately 1 mbar, RT) overnight affording the co-crystal of Dasatinib with triethyl citrate with a Dasatinib:triethyl citrate molar ratio of 1 :1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention concerne un co-cristal de Dasatinib avec du citrate de triéthyle, des procédés pour sa préparation, des compositions pharmaceutiques de celui-ci et son utilisation dans le traitement de la leucémie myéloïde chronique (LMC) et de la leucémie aiguë lymphoïde chromosome Philadelphie positive (LAL Ph+).
PCT/EP2018/050983 2017-01-20 2018-01-16 Co-cristal d'un composé antitumoral WO2018134189A1 (fr)

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IT102017000006145A IT201700006145A1 (it) 2017-01-20 2017-01-20 Co-cristallo di un composto antitumorale
IT102017000006145 2017-01-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10940149B1 (en) 2018-06-15 2021-03-09 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000062778A1 (fr) 1999-04-15 2000-10-26 Bristol-Myers Squibb Co. Inhibiteurs cycliques de proteine tyrosine kinase
WO2005077945A2 (fr) 2004-02-06 2005-08-25 Bristol-Myers Squibb Company Procede de preparation de carboxamides 2-aminothiazole-5-aromatiques utiles comme inhibiteurs de kinases
US20060004067A1 (en) 2004-02-06 2006-01-05 Bang-Chi Chen Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
WO2010081443A2 (fr) 2009-01-13 2010-07-22 Zentiva, K.S. Formes galéniques d'inhibiteurs de tyrosine kinase
WO2013186726A2 (fr) 2012-06-15 2013-12-19 Basf Se Cristaux à plusieurs composants comprenant du dasatinib et des agents de formation de cocristaux choisis
WO2016001025A1 (fr) * 2014-06-30 2016-01-07 Basf Se Cristaux multi-composants de dasatinib avec du menthol ou de la vanilline

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000062778A1 (fr) 1999-04-15 2000-10-26 Bristol-Myers Squibb Co. Inhibiteurs cycliques de proteine tyrosine kinase
US6596746B1 (en) 1999-04-15 2003-07-22 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
WO2005077945A2 (fr) 2004-02-06 2005-08-25 Bristol-Myers Squibb Company Procede de preparation de carboxamides 2-aminothiazole-5-aromatiques utiles comme inhibiteurs de kinases
US20060004067A1 (en) 2004-02-06 2006-01-05 Bang-Chi Chen Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
US7491725B2 (en) 2004-02-06 2009-02-17 Bristol-Myers Squibb Company Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
WO2010081443A2 (fr) 2009-01-13 2010-07-22 Zentiva, K.S. Formes galéniques d'inhibiteurs de tyrosine kinase
WO2013186726A2 (fr) 2012-06-15 2013-12-19 Basf Se Cristaux à plusieurs composants comprenant du dasatinib et des agents de formation de cocristaux choisis
WO2016001025A1 (fr) * 2014-06-30 2016-01-07 Basf Se Cristaux multi-composants de dasatinib avec du menthol ou de la vanilline

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PETER A. WOOD ET AL.: "Knowledge-based approaches to co-crystal design", CRYSTENGCOMM, vol. 16, 2014, ROYAL SOCIETY OF CHEMISTRY, CAMBRIDGE, pages 5839 - 5848, XP002773478, ISSN: 1466-8033 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10940149B1 (en) 2018-06-15 2021-03-09 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
US11007195B2 (en) 2018-06-15 2021-05-18 Handa Oncology, Llc Kinase inhibitor salts, and compositions thereof
US11052088B2 (en) 2018-06-15 2021-07-06 Handa Oncology, Llc Kinase inhibitor salts, and compositions thereof
US11160805B2 (en) 2018-06-15 2021-11-02 Handa Onocology, Llc Kinase inhibitor salts and compositions thereof
US12064428B2 (en) 2018-06-15 2024-08-20 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
US12064430B2 (en) 2018-06-15 2024-08-20 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof

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