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WO2018134190A1 - Co-cristaux d'un composé antitumoral - Google Patents

Co-cristaux d'un composé antitumoral Download PDF

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Publication number
WO2018134190A1
WO2018134190A1 PCT/EP2018/050989 EP2018050989W WO2018134190A1 WO 2018134190 A1 WO2018134190 A1 WO 2018134190A1 EP 2018050989 W EP2018050989 W EP 2018050989W WO 2018134190 A1 WO2018134190 A1 WO 2018134190A1
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WO
WIPO (PCT)
Prior art keywords
dasatinib
crystal
ethoxyphenol
resorcinol
xrpd
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2018/050989
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English (en)
Inventor
Nicolas Tesson
Montserrat Trilla Castano
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Cerbios Pharma SA
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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 WO2018134190A1 publication Critical patent/WO2018134190A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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 new co-crystals of Dasatinib with phenolic compounds having improved properties, processes for their preparation, their use in therapy and pharmaceutical compositions containing them.
  • Dasatinib chemically known as N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2- hydroxyethyl)-1 -piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, has the following formula
  • Sprycel ® It is marketed under the trade name Sprycel ® and it is administered in dosages of 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg.
  • Such compound is an oral dual BCR/ABL and SRC family tyrosine kinase inhibitor approved for use in treatment of chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).
  • CML chronic myelogenous leukemia
  • Ph+ALL Philadelphia chromosome-positive acute lymphoblastic leukemia
  • the marketed pharmaceutical formulations contain Dasatinib monohydrate as active ingredient.
  • Dasatinib free base in monohydrate or in anhydrous form is a compound with a very low solubility
  • Dasatinib free base monohydrate has been reported to have an aqueous solubility of 0.36 ⁇ g/mL and Dasatinib free base in anhydrous form of about 0.9 ⁇ g/mL at 25°C (see Table 1 at page 12 of WO 2013/186726).
  • bioavailability of a drug is influenced by its solubility in water. For this reason a high aqueous solubility positively influences the bioavailability of the drug, whereas a low aqueous solubility negatively impacts on the bioavailability of the drug.
  • the present invention relates to co-crystals of Dasatinib with phenolic compounds selected among resorcinol, vanillyl alcohol, 4-ethoxyphenol, carvacrol and p-cresol.
  • the invention also relates to processes for the preparation of said co-crystals, pharmaceutical compositions containing them and use of these co-crystals as medicaments and in a method of treatment of chronic myelogenous leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia.
  • the co-crystals of Dasatinib with phenolic compounds selected among resorcinol, vanillyl alcohol, 4-ethoxyphenol, carvacrol and p-cresol have been characterized through X-ray diffraction from crystalline powders (XRPD) (X-ray powder diffraction), and/or by nuclear magnetic resonance spectrometer ( 1 H-NMR), and/or by differential scanning calorimetry (DSC) and/or through Karl Fischer (KF).
  • XRPD crystalline powders
  • 1 H-NMR nuclear magnetic resonance spectrometer
  • DSC differential scanning calorimetry
  • Karl Fischer Karl Fischer
  • 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 appreciated from Figure 1.
  • 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 plastic sheet used in the preparation of the samples to be analysed.
  • FIG 2 XRPD spectrum of co-crystal of Dasatinib with resorcinol herein defined as Form 1
  • FIG 3 DSC thermogram of Dasatinib with resorcinol herein defined as Form 1.
  • FIG. 4 XRPD spectrum of co-crystal of Dasatinib with resorcinol herein defined as Form 2.
  • FIG 5 1 H-NMR spectrum of co-crystal of Dasatinib with resorcinol herein defined as Form 2.
  • FIG 6 DSC thermogram of co-crystal of Dasatinib with resorcinol herein defined as Form 2.
  • FIG 7 XRPD spectrum of co-crystal of Dasatinib with vanillyl alcohol.
  • FIG 8 XRPD spectrum of co-crystal of Dasatinib with 4-ethoxyphenol.
  • Fig 9 1 H-NMR spectrum of co-crystal of Dasatinib with 4-ethoxyphenol.
  • FIG 10 DSC thermogram of co-crystal of Dasatinib with 4-ethoxyphenol.
  • FIG 1 1 XRPD spectrum of co-crystal of Dasatinib with carvacrol.
  • FIG 12 1 H-NMR spectrum of co-crystal of Dasatinib with carvacrol.
  • FIG 13 DSC thermogram of co-crystal of Dasatinib with carvacrol.
  • FIG 14 XRPD of co-crystal of Dasatinib with p-cresol.
  • 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 a phenolic compound selected among resorcinol, vanillyl alcohol, 4-ethoxyphenol, carvacrol and p-cresol.
  • FIG. 2 In addition to the characteristic peaks of the co-crystal of Dasatinib with resorcinol, in FIG. 2 (Form 1 ) and in FIG. 4 (Form 2), also the amorphous pattern of the plastic sheet used in the preparation of the samples to be analysed is shown. However, given FIG. 1 , the latter is easily distinguishable.
  • the co-crystal of Dasatinib with vanillyl alcohol according to the present invention has a molar ratio Dasatinib:vanillyl alcohol comprised between 1 :1 and 1 :2. It is preferably characterized by a XRPD, as reported in FIG 7, wherein the most relevant peaks fall at 5.3, 8.1 , 13.2, 15.5, 17.4, 21.3, 25.3, 26.2, 26.6 ⁇ 0.2° in 2 ⁇ .
  • FIG. 7 also the amorphous pattern of the plastic sheet used in the preparation of the samples to be analysed is shown. However, given FIG. 1 , the latter is easily distinguishable.
  • the co-crystal of Dasatinib with 4-ethoxyphenol has a molar ratio Dasatinib:4-ethoxyphenol of about 1 :1. It is preferably characterized by a XRPD, as reported in FIG 8, wherein the most relevant peaks fall at 5.7, 9.0, 16.6, 17.3, 18.9, 19.8, 23.4, 25.3, 26.4, 27.2 ⁇ 0.2° in 2 ⁇ and it has preferably a DSC thermogram as substantially reported in FIG. 10 showing multiple endothermic peaks, wherein the endothermic peak representing the fusion of the co- crystal is at 200 - 207°C.
  • the co-crystal of Dasatinib with carvacrol has a molar ratio Dasatinib:carvacrol of about 2:1. It is preferably characterized by a XRPD as reported in FIG. 1 1 wherein the most relevant peaks fall at 5.9, 1 1 .8, 15.2, 16.6, 17.7, 18.3, 21.1 , 21 .5, 23.0, 24.0 ⁇ 0.2° in 2 ⁇ and it has preferably a DSC thermogram as substantially reported in FIG. 13 with two endothermic peaks wherein the endothermic peak representing the fusion of the co-crystal is at 215 - 223°C.
  • FIG. 1 1 In addition to the characteristic peaks of the co-crystal of Dasatinib with carvacrol, in said FIG. 1 1 , also the amorphous pattern of the plastic sheet used in the preparation of the samples to be analysed is shown. However, given FIG. 1 , the latter is easily distinguishable.
  • the co-crystal of Dasatinib with p-cresol has a molar ratio Dasatinib:p-cresol of about 1 :1. It is preferably characterized by a XRPD as reported in FIG. 14 wherein the most relevant peaks fall at 5.5, 10.8, 15.7, 17.2, 23.7 ⁇ 0.2° in 2 ⁇ .
  • co-crystals of Dasatinib with phenolic compounds selected among resorcinol, vanillyl alcohol, 4-ethoxyphenol, carvacrol and p-cresol have improved properties compared to the crystalline and co-crystalline forms known in the art.
  • a second object of the present invention are processes for the preparation of the co- crystals of Dasatinib with phenolic compounds as reported above.
  • a co-crystal of Dasatinib with resorcinol having a molar ratio Dasatinib:resorcinol 1 :2, herein defined as Form 1 can be prepared through a process comprising:
  • Dasatinib used as starting material can be, for example, crystalline anhydrous form N-6 known by US 7 491 725.
  • a co-crystal of Dasatinib with resorcinol having a molar ratio Dasatinib:resorcinol 1 :2, herein defined as Form 2, can be prepared through a process comprising the slow evaporation from a methanol solution containing Dasatinib:resorcinol in a molar ratio 1 :2 or 1 :3 at room temperature for a range of time between 2 and 6 days, using an amount of Dasatinib to methanol of 0.025 g/mL.
  • Dasatinib used as starting material can be, for example, crystalline anhydrous form N-6 known by US 7 491 725.
  • a co-crystal of Dasatinib with vanillyl alcohol can be prepared through a process comprising the slow evaporation from a methanol solution containing Dasatinib:vanillyl alcohol in a molar ratio comprised between 1 :1 and 1 :3 at room temperature for a range of time between 2 and 6 days, using an amount of Dasatinib to methanol of 0.025 g/mL.
  • Dasatinib used as starting material can be for example crystalline anhydrous form N-6 known by US 7 491 725.
  • a co-crystal of Dasatinib with 4-ethoxyphenol can be prepared through:
  • a co-crystal of Dasatinib with 4-ethoxyphenol is prepared through suspension of Dasatinib and 4-ethoxyphenol in water at 50°C.
  • the formation of the co-crystal of Dasatinib with 4-ethoxyphenol can be triggered adding to the suspension seeds of the co-crystal of Dasatinib with 4- ethoxyphenol previously obtained according to the processes disclosed above.
  • Dasatinib used as starting material can be, for example, crystalline anhydrous form N-6 known by US 7 491 725.
  • a co-crystal of Dasatinib with carvacrol can be prepared through:
  • Dasatinib and carvacrol in methanol at 50°C using a molar ratio Dasatinib:carvacrol of 1 :8 and an amount of Dasatinib to methanol of 0.4 g/mL.
  • a process for preparing a co-crystal of Dasatinib with carvacrol, Dasatinib used as starting material can be, for example, crystalline anhydrous form N-6 known by US 7 491 725.
  • the co-crystal of Dasatinib with carvacrol is obtained through suspension in methanol at 50°C.
  • the formation of the co-crystal of Dasatinib with carvacrol can be triggered adding to the slurry seeds of the co-crystal of Dasatinib with carvacrol previously obtained according to the processes disclosed above.
  • a co-crystal of Dasatinib with p-cresol can be prepared through wet grinding in a solvent selected from water and tetrahydrofuran using a molar ratio Dasatinib:p- cresol of 1 :1.
  • Dasatinib used as starting material can be, for example, crystalline anhydrous form N-6 known by US 7 491 725.
  • the co-crystals of Dasatinib with 4-ethoxyphenol and with carvacrol are very stable, also for long time and even under thermal stress conditions.
  • the co-crystal of Dasatinib with 4-ethoxyphenol and carvacrol have been stored at 40°C ( ⁇ 2°C)/75 ⁇ 5% RH, according to the accelerated stability conditions of the ICH guidelines, in open vials and the results are the following:
  • a further object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a co-crystal of Dasatinib with a phenolic compound, as defined above, as active ingredient and at least a pharmaceutically acceptable excipient and/or carrier.
  • composition comprising a co-crystal of Dasatinib with the phenolic compounds, as defined above, also comprising imatinib as further active ingredient.
  • compositions can be prepared in a pharmaceutical dosage form according to the known techniques.
  • the dosages of active ingredient present in such compositions can be the ones commercially used in therapy for Dasatinib.
  • a further object of the invention is a co-crystal of Dasatinib with a phenolic compound, 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 a co-crystal of Dasatinib with a phenolic compound, as defined above.
  • CML chronic myelogenous leukemia
  • Ph+ALL Philadelphia chromosome-positive acute lymphoblastic leukemia
  • EXAMPLE 1 Preparation of the co-crystal of Dasatinib and resorcinol (molar ratio 1 :2) Form 1 by heating.
  • DSC pinhole lid
  • EXAMPLE 2 Preparation of the co-crystal of Dasatinib and resorcinol (molar ratio 1 :2) Form 2 by slow evaporation in MeOH (methanol).
  • EXAMPLE 4 Preparation of the co-crystal of Dasatinib with 4-ethoxyphenol by suspending in water.
  • Dasatinib form N-6 (5.02 g, 10.29 mmol)
  • 4-ethoxyphenol (2.84 g, 20.56 mmol, 2.0 equivalents) water (100 mL, 20 volumes) was added.
  • the suspension was heated at 50°C overnight.
  • the solid was filtered with a sintered funnel (porosity 3), washed with water at 50°C (3 x 10 mL, 3 x 2 volumes) and dried under vacuum (approximately 1 mbar, room temperature) to give the co-crystal of Dasatinib with 4-ethoxyphenol (6.26 g, 97% yield) as a white solid.
  • the co-crystal of Dasatinib with 4-ethoxyphenol has a XRPD as reported in FIG. 8 wherein the most relevant peaks fall at 5.7, 9.0, 16.6, 17.3, 18.9, 19.8, 23.4, 25.3, 26.4, 27.2 ⁇ 0.2° in 2 ⁇ .
  • the co-crystal of Dasatinib with 4-ethoxyphenol has a DSC thermogram as substantially reported in FIG. 10 showing multiple endothermic peaks, wherein the endothermic peak representing the fusion of the co-crystal is at 200 - 207°C.
  • the solid was filtered with a sintered funnel (porosity 3), washed with a mixture heptane/methyl tert-butyl ether (8:2, 2 x 10 mL, 2 x 2 volumes) and dried under vacuum (approximately 1 mbar, room temperature) to give the co-crystal of Dasatinib with carvacrol (5.22 g, 90% yield) as a white solid.
  • the co-crystal of Dasatinib with carvacrol has a XRPD as reported in FIG. 1 1 wherein the most relevant peaks fall at 5.9, 1 1.8, 15.2, 16.6, 17.7, 18.3, 21 .1 , 21.5, 23.0, 24.0 ⁇ 0.2° in 2 ⁇ .
  • the co-crystal of Dasatinib with carvacrol has a DSC thermogram as substantially reported in FIG. 13, with two endothermic peaks, wherein the endothermic peak representing the fusion of the co-crystal is at 215 - 223°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne des co-cristaux de Dasatinib avec des composés phénoliques choisis parmi le résorcinol, l'alcool vanillique, le 4-éthoxyphénol, le carvacrol et le p-crésol, des procédés pour leur préparation, des compositions pharmaceutiques les contenant et leur utilisation dans le traitement de la leucémie myéloïde chronique (LMC) et de la leucémie lymphoblastique aiguë à chromosome Philadelphie positif (Ph + ALL).
PCT/EP2018/050989 2017-01-20 2018-01-16 Co-cristaux d'un composé antitumoral Ceased WO2018134190A1 (fr)

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IT102017000006157A IT201700006157A1 (it) 2017-01-20 2017-01-20 Co-cristalli di un composto antitumorale
IT102017000006157 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)

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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
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

Patent Citations (7)

* 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
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

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Title
PETER A WOOD ET AL: "Knowledge-based approaches to co-crystal design", CRYSTENGCOMM, ROYAL SOCIETY OF CHEMISTRY, CAMBRIDGE, GB, vol. 16, 1 January 2014 (2014-01-01), 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
US12064430B2 (en) 2018-06-15 2024-08-20 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
US12064428B2 (en) 2018-06-15 2024-08-20 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof

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