WO2016098070A1 - Forme cristalline de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4-[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine - Google Patents

Forme cristalline de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4-[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine Download PDF

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WO2016098070A1
WO2016098070A1 PCT/IB2015/059779 IB2015059779W WO2016098070A1 WO 2016098070 A1 WO2016098070 A1 WO 2016098070A1 IB 2015059779 W IB2015059779 W IB 2015059779W WO 2016098070 A1 WO2016098070 A1 WO 2016098070A1
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ceritinib
crystalline
phenyl
hydroxide
piperidin
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PCT/IB2015/059779
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English (en)
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Celine GALLAND
Arnaud Grandeury
Jerzy Antoni Budz
Benjamin Martin
Flavien SUSANNE
Michel Aubry
Serbuelent SEVINC
Andrea Decker
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Novartis Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is directed to a new form of 5-Chloro-N2-(2-isopropoxy-5-methyl- 4-piperidin-4-yl-phenyl)-N4- [2-(propane-2-sulfony l)-phenyl] -pyrimidine-2, 4-diamine.
  • the present disclosure also generally relates to a pharmaceutical composition comprising the form, as well of methods for obtaining such form, and methods of using the form as a medicine.
  • Anaplastic lymphoma kinase is a receptor tyrosine kinase (RTK) belonging to the insulin receptor superfamily. Genetic alterations of ALK have been implicated in oncogenesis in hematopoietic and non-hematopoietic tumors. The gene has been found to be rearranged, mutated, or amplified in a series of tumors, including non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • ALK tyrosine kinase inhibitors such as crizotinib, or ceritinib
  • ceritinib has been approved by the US FDA as Zykadia® for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.
  • the approved dosage is a daily dose of 750 mg administered orally, with possible dose reduction in 150 mg increment(s) to 600 mg and 450 mg as needed.
  • the minimum treatment dose is 300 mg.
  • the approved dosage form is a capsule of size 00 containing a 150 mg dose of ceritinib.
  • the present invention provides a new crystalline form of ceritinib, also referred to as Form C.
  • the present invention relates to the compound ceritinib obtained in a distinct crystalline form.
  • the present invention provides a crystalline ceritinib, preferably in substantially pure form, characterized by a X-ray powder diffraction pattern obtained by using Cu K-alpha radiation comprising five or more 2 ⁇ values selected from the group consisting of 5.0 ⁇ 0.2, 9.6 ⁇ 0.2, 10.1 ⁇ 0.2, 12.3 ⁇ 0.2, 13.7 ⁇ 0.2, 14.45 ⁇ 0.2, 15.1 ⁇ 0.2, 15.55 ⁇ 0.2, 17.1 ⁇ 0.2, 18.1 ⁇ 0.2, 19.3 ⁇ 0.2, 20.0 ⁇ 0.2, 20.55 ⁇ 0.2, 21.9 ⁇ 0.2, 24.4 ⁇ 0.2, 25.9 ⁇ 0.2, 27.8 ⁇ 0.2, 28.4 ⁇ 0.2, 28.85 ⁇ 0.2, and 31.7 ⁇ 0.2 at a temperature of about 25°C, substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.
  • the present invention provides the crystalline ceritinib, preferably is in substantially pure form, having a differential scanning calorimetry thermogram substantially the same as that shown in shown in FIG.2, and having a melting point of 162.4° C, as determined by differential scanning calorimetry.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline ceritinib, and a pharmaceutically acceptable carrier.
  • the present invention also provides a method for the preparation of the crystalline ceritinib which comprises steps: (i) providing 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin- 4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in a solvent, preferably isopropanol, to a first reactor at about 20° C; and (ii) providing base solution to a second reactor at about 5° C; followed by (iii) mixing the solutions (i) withand (ii), wherein preferably the ratio of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride to the base is at least 2.
  • the present invention also provides another method for the preparation of the crystalline ceritinib which comprises steps: (i) providing 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin- 4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in a solvent mixture, wherein preferably the solvent mixture is composed of 29.0% of water, 12.0% of Isopropanol and 59.0% of Tetrahydrofuran; (ii) adding 5% Brine solution; (iii) performing extraction using n-heptane; followed by crystallization.
  • the present invention also provides the crystalline ceritinib for use as a medicine.
  • the present invention further provides the crystalline ceritinib for use as a medicine for the treatment of proliferative disorders, preferably cancer, more preferably cancers mediated by ALK.
  • the present invention also provides the use of the crystalline ceritinib for the preparation of a medicament for the treatment of proliferative disorders, preferably cancer, more preferably cancers mediated by ALK.
  • the present invention also provides a method for the treatment of proliferative disorders, preferably cancer, more preferably cancers mediated by ALK, comprising administering to a patient in need of such treatment an effective amount of the crystalline ceritinib.
  • Figure 1 depicts the x-ray powder crystal diffraction results of 5-Chloro-N2-(2-isopropoxy-5- methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine Form C.
  • Figure 2 depicts differential scanning calorimetry results of Form C of 5-Chloro-N2-(2- isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine- 2, 4-diamine.
  • Figure 4 depicts first equilibration: 2 mL Ethanol and 200 mg of Form C of 5-Chloro-N2-(2- isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine- 2, 4-diamine.
  • Figure 5 depicts second equilibration: 2 rriL Ethanol and 150 mg of Form C + 150 g Form A of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)- phenyl]-pyrimidine-2, 4-diamine.
  • Figure 6 depicts third equilibration: 2 rriL Isopropanol and 200 mg of Form C of 5-Chloro-N2- (2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]- pyrimidine-2, 4-diamine.
  • Figure 7 depicts fourth equilibration: 2 mL Isopropanol and 150 mg of Form C + 150 g Form A of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)- phenyl]-pyrimidine-2, 4-diamine.
  • Figure 8 depicts IR spectrum of ceritinib form C.
  • ceritinib is a very promising drug, it is a difficult compound to formulate. In water, it exhibits solubility of only 0.02 mg/mL (at 25°C), and together with its low permeability according to the Biopharmaceutics Classification System qualifies for a class IV compound. In addition, physical characteristics of ceritinib cause sticking and picking during tableting or encapsulation of the drug and make it poorly compressible.
  • this polymorphism of the drug molecule can affect the shelf life, solubility, formulation properties, processing properties, and the action of a drug.
  • Different polymorphs in addition, can have different rates of uptake in the body, leading to lower or higher biological activity than desired. In extreme cases, an undesired polymorph can even show toxicity.
  • the present invention provides a new crystalline form of ceritinib, also referred to as Form C.
  • Ceritinib is 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine, in the form of a free base, of formula
  • Ceritinib is an anaplastic lymphoma kinase (ALK) inhibitor.
  • ALK is a member of the insulin receptor super family of receptor tyrosine kinases.
  • Compound I was originally described in WO 2008/073687 Al as Example 7, compound 66.
  • polymorph refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.
  • the crystalline form(s) differ with respect to thermodynamic stability, physical parameters, x-ray structure and methods of preparation.
  • amorphous refers to a disordered solid state.
  • Crystalline ceritinib of the present invention is hydroscopic, and 24-h solubility of crystalline ceritinib is 1.3 at 10°C in ethanol/water 40/40 v/v. The equilibration and competitive
  • Form C is less stable than Form A or Form B.
  • Form C can be advantageously obtained in a fast, continuous precipitation process.
  • Forms A and B in that it gives rise to a different polymorph of the HCl salt.
  • Crystalline ceritinib of the present invention in HCl solution pH 1 gives a different polymorph of the HCl salt compared to the forms A and B in similar conditions.
  • Crystalline ceritinib of the present invention (Form C) is highly crystalline powder with XRPD pattern uniquely different from that of previous polymorphs (Forms A and B).
  • XRPD X-ray powder diffraction
  • the present invention relates to the crystalline ceritinib characterized by a X-ray powder diffraction (XRPD) pattern obtained by using Cu K-alpha radiation comprising five or more 2 ⁇ values selected from the group consisting of 5.0 ⁇ 0.2, 9.6 ⁇ 0.2, 10.1 ⁇ 0.2, 12.3 ⁇ 0.2, 13.7 ⁇ 0.2, 14.45 ⁇ 0.2, 15.1 ⁇ 0.2, 15.55 ⁇ 0.2, 17.1 ⁇ 0.2, 18.1 ⁇ 0.2, 19.3 ⁇ 0.2, 20.0 ⁇ 0.2, 20.55 ⁇ 0.2, 21.9 ⁇ 0.2, 24.4 ⁇ 0.2, 25.9 ⁇ 0.2, 27.8 ⁇ 0.2, 28.4 ⁇ 0.2, 28.85 ⁇ 0.2, and 31.7 ⁇ 0.2 at a temperature of about 25°C.
  • the XRPD pattern is summarized in FIG. 1.
  • the crystalline ceritinib is characterized by a XRPD pattern obtained by using Cu K-alpha radiation comprising eight or more 2 ⁇ values selected from the group consisting of 5.0 ⁇ 0.2, 9.6 ⁇ 0.2, 10.1 ⁇ 0.2, 12.3 ⁇ 0.2, 13.7 ⁇ 0.2, 14.45 ⁇ 0.2, 15.1 ⁇ 0.2, 15.55 ⁇ 0.2, 17.1 ⁇ 0.2, 18.1 ⁇ 0.2, 19.3 ⁇ 0.2, 20.0 ⁇ 0.2, 20.55 ⁇ 0.2, 21.9 ⁇ 0.2, 24.4 ⁇ 0.2, 25.9 ⁇ 0.2, 27.8 ⁇ 0.2, 28.4 ⁇ 0.2, 28.85 ⁇ 0.2, and 31.7 ⁇ 0.2 at a temperature of about 25°C.
  • the crystalline ceritinib is characterized by XRPD pattern obtained by using Cu K-alpha radiation comprising twelve or more 2 ⁇ values selected from the group consisting of 5.0 ⁇ 0.2, 9.6 ⁇ 0.2, 10.1 ⁇ 0.2, 12.3 ⁇ 0.2, 13.7 ⁇ 0.2, 14.45 ⁇ 0.2, 15.1 ⁇ 0.2, 15.55 ⁇ 0.2, 17.1 ⁇ 0.2, 18.1 ⁇ 0.2, 19.3 ⁇ 0.2, 20.0 ⁇ 0.2, 20.55 ⁇ 0.2, 21.9 ⁇ 0.2, 24.4 ⁇ 0.2, 25.9 ⁇ 0.2, 27.8 ⁇ 0.2, 28.4 ⁇ 0.2, 28.85 ⁇ 0.2, and 31.7 ⁇ 0.2 at a temperature of about 25°C.
  • the crystalline ceritinib is characterized by XRPD pattern obtained by using Cu K-alpha radiation comprising all 2 ⁇ values selected from the group consisting of 5.0 ⁇ 0.2, 9.6 ⁇ 0.2, 10.1 ⁇ 0.2, 12.3 ⁇ 0.2, 13.7 ⁇ 0.2, 14.45 ⁇ 0.2, 15.1 ⁇ 0.2, 15.55 ⁇ 0.2, 17.1 ⁇ 0.2, 18.1 ⁇ 0.2, 19.3 ⁇ 0.2, 20.0 ⁇ 0.2, 20.55 ⁇ 0.2, 21.9 ⁇ 0.2, 24.4 ⁇ 0.2, 25.9 ⁇ 0.2, 27.8 ⁇ 0.2, 28.4 ⁇ 0.2, 28.85 ⁇ 0.2, and 31.7 ⁇ 0.2 at a temperature of about 25°C.
  • the present invention relates to the crystalline ceritinib having a X-ray diffraction spectrum, obtained by using Cu K-alpha radiation at a temperature of about 25°C, substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.
  • the present invention relates to the HC1 salt of the new crystalline form disclosed herein.
  • substantially the same with reference to X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account.
  • peak positions (2 ⁇ ) will show some inter-apparatus variability, typically as much as 0.2°.
  • relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only.
  • the present invention relates to the crystalline ceritinib exhibiting the following thermal parameters: melting point, Tm (onset) 162.4° C as determined by differential scanning calorimetry at a scanning rate of 10° C/min (as shown in FIG. 2).
  • the present invention relates to the crystalline ceritinib having a differential scanning calorimetry thermogram which is substantially the same as that shown in shown in FIG.2.
  • the crystalline form C of ceritinib can have infrared absorption spectra as depicted in Figure 8.
  • the infrared absorption bands can be at 3416, 3310, 2798, 1065, 1022, 1009, 942, 885, 863, 769 and 678 (in units of wavenumbers, cm "1 ).
  • the most significant differences observed between the spectra of forms C compared to forms A and B were in the range of 4000- 3000 cm "1 and 800-600 cm "1
  • the crystalline ceritinib is in
  • substantially pure form As used herein, the term "substantially pure" with reference to a particular polymorphic form means that the polymorphic form includes less than 10%, preferably less than 5%, more preferably less than 3%, most preferably less than 1% by weight of any other physical forms of the compound.
  • the remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation.
  • the crystalline ceritinib may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight % of material comprises other form(s) of ceritinib and/or reaction impurities and/or processing impurities.
  • the presence of reaction impurities and/or processing impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance
  • crystalline ceritinib has less than 1.0 % by weight total impurities, in another embodiment of the above mentioned aspects, crystalline ceritinib has less than 0.5 % by weight total impurities. In a further embodiment of the above mentioned aspects, crystalline ceritinib has less than 0.1 % by weight total impurities.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline ceritinib of the present invention, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes generally recognized as safe (GRAS) solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, buffering agents (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, and the like), and the like and combinations thereof, as would be known to those skilled in the art (see, for example,
  • the present invention relates to a method for the preparation of a crystalline ceritinib. Considering the challenge to crystallize ceritinib in a continuous production mode, preferably in a single step continuous mode, the reactive precipitation is one of the selected processes of the present invention.
  • continuous production also called “continuous process” or “continuous flow process” refers to a flow production method used to manufacture, produce, or process materials without interruption.
  • continuous production In continuous production mode the materials being processed are continuously in motion, undergoing chemical reactions or subject to mechanical or heat treatment. Continuous processing is contrasted with batch production.
  • batch production' is a technique used in manufacturing, in which the object in question is created stage by stage over a series of workstations, and different batches of products are made. Batch crystallization is widely used in pharmaceutical processing.
  • use of continuous crystallization due to employment of continuous crystallizers allows more flexibility in control of temperature, supersaturation, nucleation, crystal growth and all the other process parameters that influence crystal size distribution.
  • continuous production can avoid scale-up difficulties, and improve quality while maintaining or reducing manufacturing costs.
  • reactive precipitation refers to precipitation which occurs through the mixing of solutions which react together (e.g. acid plus base solutions).
  • continuous reactive precipitation refers to reactive precipitation which occurs continuously due to a continuous flow of reactive solutions. Compared to a batch reactive crystallization, continuous reactive precipitation results in a very high uniform supersaturation conditions, so that the end result is formation of small particles with a narrow size distribution.
  • the present invention relates to a method for the preparation of a crystalline ceritinib which comprises steps: (i) providing 5-Chloro-N2-(2-isopropoxy-5-methyl- 4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in a solvent to a first reactor at about 15°C to about 25° C, preferably at about 20° C; and (ii) providing base solution to a second reactor at about 0°C to about 10°C, preferably at about 5° C; followed by (iii) mixing the solutions (i) and (ii), preferably wherein the ratio of 5- Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)- phenyl]-pyrimidine-2, 4-diamine dihydrochlor
  • the present invention relates to a method, suitable for a continuous production mode, for the preparation of a crystalline ceritinib which comprises steps: (i) providing 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2- sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in a solvent to a first reactor at about 15°C to about 25° C, preferably at about 20° C; and (ii) providing base solution to a second reactor at about 0°C to about 10°C, preferably at about 5° C; followed by (iii) mixing the solutions (i) and (ii), preferably wherein the ratio of 5-Chloro-N2-(2-isopropoxy-5-methyl-4- piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyr
  • dihydrochloride to the base is at least 2.
  • the present invention relates to a method, suitable for a continuous production mode, for the preparation of a crystalline ceritinib, which comprises steps:
  • dihydrochloride to the base is at least 2.
  • slurry means a compound suspension, which is a heterogeneous mixture of the compound and a solvent at a given temperature.
  • the solvent is isopropanol.
  • Suitable solvents for this purpose include, for example, the aforementioned nonpolar solvents and polar solvents, including protic polar solvents such as alcohols, and aprotic polar solvents such as ketones.
  • the ratio of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl- phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride to the base is at least 2.
  • step (iii) The amount of the base solution of the step (ii) used in step (iii) depends on the base used and may vary, however the amount of base must be sufficient to convert 5-Chloro-N2- (2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]- pyrimidine-2, 4-diamine dihydrochloride to 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4- yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine.
  • the base solution is aqueous alkali hydroxide selected from the list consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, and caesium hydroxide.
  • the base solution is aqueous potassium hydroxide.
  • the base solution is aqueous sodium hydroxide.
  • the base solution is aqueous alkali hydroxide, and 5-Chloro-N2-(2-isopropoxy-5- methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride of the step (i) mixed with at least two equivalents of the base of the step (ii).
  • the base solution is aqueous alkaline earth hydroxide selected from the list consisting of beryllium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, and radium hydroxide.
  • the base solution is magnesium hydroxide or calcium hydroxide.
  • the base solution is aqueous alkaline earth hydroxide, and 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)- N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride of the step (i) mixed with at least one equivalent of the base of the step (ii).
  • sodium hydroxide is a preferred base
  • other strong bases such as hydroxides of alkali or alkaline earth metals, or other weak bases, such as N3 ⁇ 4, CH 3 NH 2 , C 5 H 5 N may be used.
  • the amount of base must be sufficient to convert 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin- 4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride to 5- Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)- phenyl]-pyrimidine-2, 4-diamine.
  • the present invention relates to a method, suitable for a continuous production mode, for the preparation of a crystalline ceritinib, which comprises steps:
  • a roughton mixer is the most adapted equipment.
  • mixing is done using a roughton mixer.
  • Different flow speeds are suitable for the method of invention, preferably from 50 to 400 mL/min.
  • the above described method for the preparation of a crystalline ceritinib is suitable for a continuous production mode.
  • This continuous crystallization technique has many advantages. Most notably a significant reduction in equipment footprint can be realized for higher volume products.
  • this method for the preparation of a crystalline ceritinib is carried out in one step instead of two steps (recrystallization and dry milling), because the grains produced are already smaller, and thus it provides an additional significant manufacturing advantage.
  • the above describe method for the preparation of the crystalline ceritinib is preferred due to its suitability in a continuous production, other methods are also possible.
  • Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent.
  • Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, and addition of antisolvents (counters olvents) to the solvent mixture.
  • High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs.
  • the present invention relates to a method for the preparation of the crystalline ceritinib which comprises steps:
  • the solvent mixture is composed of about 29.0% of water, about 12.0% of isopropanol and about 59.0% of tetrahydrofuran. In a further embodiment, the solvent mixture has a pH of approximately 1.
  • the term "about” or “approximately” shall have the meaning of within 10%, more preferably within 5%, of a given value or range.
  • the Brine solution is sodium chloride solution. However, other salt solutions can also be used.
  • the concentration of Brine solution can be at least 5%.
  • the reaction mixture of step (i) is diluted with 5% Brine solution.
  • the extraction using n-heptane is six-step extraction. While in a preferred embodiment, the extraction is performed using Heptane as it provides the most efficient extraction, other solvents also can be used.
  • particle precipitation is performed by adding ethanol, and adjusting pH to 13 by stirring in NaOH.
  • the isolated solids obtained in any of the above described methods for the preparation of the crystalline ceritinib may be analyzed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD), or the like, to assure formation of the preferred crystalline form of the product.
  • the resulting crystalline form is typically produced in an amount of greater than about 70 weight % isolated yield, preferably greater than 90 weight % isolated yield, based on the weight of the compound originally employed in the crystallization procedure.
  • the product may be comilled or passed through a mesh screen to delump the product, if necessary.
  • the present invention relates to the crystalline ceritinib for use as a medicine.
  • the present invention relates to the crystalline ceritinib for use in the treatment of proliferative disorders. In one embodiment, the present invention relates to the use of the crystalline ceritinib for the preparation of a medicament for the treatment of proliferative disorders.
  • the present invention relates to a method for the treatment of proliferative disorders, comprising administering to a patient in need of such treatment an effective amount of the crystalline ceritinib.
  • proliferative disorder is a cancer. In a further embodiment, the proliferative disorder is mediated by ALK. In another embodiment, the proliferative disorder is a cancer mediated by ALK.
  • disorders mediated by ALK are in particular disorders characterized by amplification of ALK, or somatic mutation of ALK, in particular activation mutations in the fill-length receptor that result in ligand-independent constitutive activation, or rearrangement of ALK, in particular through genetic aberrations involving translocation of the kinase domain with multiple fusion partners.
  • the medicament is useful in treating diseases which respond to inhibition of anaplastic lymphoma kinase activity, focal adhesion kinase (FAK), zeta-chain-associated protein kinase 70 (ZAP-70) insulin-like growth factor (IGF-1R and combinations thereof.
  • FAK focal adhesion kinase
  • ZAP-70 zeta-chain-associated protein kinase 70
  • IGF-1R insulin-like growth factor
  • the diseases are selected from benign or malignant tumor; a cancer selected from anaplastic large cell lymphoma; non-Hodgkin's lymphoma; an inflammatory myofibrolastic tumor; a neuroblastoma; sarcoma; lung; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden disease); pancreas; gastrointestinal cancer; colon; rectum; colon carcinoma; colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary; multiple myeloma; esophagus; a leukaemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; my
  • the present invention relates to the crystalline ceritinib for use as a medicine for the treatment of cancers selected from anaplastic large cell lymphoma; non- Hodgkin's lymphoma; an inflammatory myofibrolastic tumor; a neuroblastoma; sarcoma; lung; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden disease); pancreas; gastrointestinal cancer; colon; rectum; colon carcinoma; colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma;
  • glioblastoma endometrial; melanoma; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary; multiple myeloma; esophagus; a leukaemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; a carcinoma of the brain; oral cavity and pharynx; larynx; small intestine; and melanoma.
  • the present invention relates to the crystalline ceritinib for use as a medicine for the treatment of disorders mediated by ALK, in particular neuroblastoma, anaplastic thyroid cancer or non-small cell lung carcinoma (NSCLC).
  • the present invention relates to the crystalline ceritinib for use as a medicine for the treatment of NSCLC refractory to crizotinib.
  • treating or “treatment” is defined herein to refer to a treatment relieving, reducing or alleviating at least one symptom in a subject or affecting a delay of progression of a disorder.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer.
  • subject or "patient” as used herein includes animals, which are capable of suffering from or afflicted with disorders mediated by anaplastic lymphoma kinase.
  • subjects include mammals, e.g., humans, dogs, horses, cats, mice, rats and transgenic non-human animals.
  • the subject is a human, e.g., a human suffering from a cancer.
  • terapéuticaally effective amount is intended to mean the amount of the inventive crystalline form that, when administered to a subject in need thereof, is sufficient to effect treatment for disorder conditions alleviated by the inhibition of protein kinase activity.
  • the amount of a given compound of the invention that will be therapeutically effective will vary depending upon factors such as the disorder condition and the severity thereof, the identity of the subject in need thereof, etc., which amount may be routinely determined by artisans of ordinary skill in the art.
  • more than 80%, more preferably at least 85%, still more preferably at least 90%, and most preferably at least 95%, of the crystalline form administered is of one of the inventive forms.
  • illustrative modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal.
  • Administration of the crystalline form may be accomplished by administration of a pharmaceutical composition of this invention or via any other effective means.
  • the present invention relates to the crystalline ceritinib for use as an intermediate for preparing crystalline or amorphous forms of ceritinib that are useful as medicine.
  • the present invention relates to the crystalline ceritinib for use as an intermediate for preparing crystalline or amorphous forms of ceritinib that are useful for treatment of proliferative disorders, in particular cancers, in particular disorders mediated by ALK, in particular disorders characterized by amplification of ALK, or somatic mutation of ALK, or rearrangement of ALK.
  • the present invention relates to the crystalline ceritinib for use as an intermediate for preparing crystalline or amorphous forms of ceritinib that are useful for treatment of cancers mediated by ALK.
  • ATR-FTIR PerkinElmer Spectrum BX II; "Golden Gate” diamond ATR cell (from Graseby- Specac Ltd., U.K.), DTGS detector, 12-20 scans, 4000-600 cm “1 range, 4 cm “1 resolution.
  • DSC PerkinElmer DSC 7; hermetically closed gold crucible or an aluminum crucible with a pinhole in the lid, variable heating rates (from 2-20 K/min) and temperature ranges (see the figures for details).
  • the multiscan experiments involve either quench cooling at -500°C/min to - 50°C or cooling at -10°C/min between heating scans. Heating rate Sample pan Melting onset / Melting enthalpy /
  • XRPD Bruker D8 Advance; LynxEye detector; Cu- ⁇ radiation; standard measurement conditions: Bragg -Brentano reflection, 40 kV and 40 mA tube power, 0.02°2 ⁇ step size, 37 s step time, 2.5-50.0°2 ⁇ scanning range; sample holder: 0.1 -mm deep silicon single crystal; standard sample preparation: slight pressure was applied to get a flat surface; the sample was rotated during the measurement.
  • Tetrahydrofuran The solvent mixture had a pH of approximately 1.
  • a six-step extraction was performed at 20°C: first a 5% Brine solution was added, followed by a six step extraction with heptane. 5 % Brine solution was prepared by diluting 92.6 g of sodium chloride solution (27%) diluted with 407.4 g of demineralized water. A clear, colorless 5% Brine solution was obtained.
  • the solution was transferred into a separating funnel, and 400 ml (269.9 g) of n-heptane was added. The mixture was shaken well for 30 seconds. After approximately 2min, 2 phases were separated. The upper phase represented an organic phase, and was a clear, colorless solution. The upper phase was discarded. The lower phase represented an aqueous phase, and was a dark-brown, clear solution. The lower phase was separated, and 400 ml (269.9 g) of n- heptane was again added to it. This procedure was repeated six times (see Table 2). After the last separation, the retained aqueous phase was a brown, clear solution.

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Abstract

La présente invention concerne une nouvelle forme de la 5-chloro-N2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-N4-[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine. La présente invention concerne également, de manière générale, une composition pharmaceutique comprenant ladite forme, ainsi que des méthodes pour obtenir ladite forme, et des méthodes d'utilisation de ladite forme en tant que médicament.
PCT/IB2015/059779 2014-12-19 2015-12-18 Forme cristalline de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4-[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine WO2016098070A1 (fr)

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EP2651918B1 (fr) 2010-12-17 2017-07-12 Novartis AG Formes cristallines de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine
WO2017152858A1 (fr) * 2016-03-11 2017-09-14 苏州晶云药物科技有限公司 Forme cristalline de céritinib et procédé pour sa préparation
WO2021083555A1 (fr) 2019-10-28 2021-05-06 Universitetet I Oslo Inhibiteurs d'alk pour le traitement du cancer alk-négatif et de maladies médiées par des cellules plasmatiques

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2651918B1 (fr) 2010-12-17 2017-07-12 Novartis AG Formes cristallines de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine
EP3121171B1 (fr) 2010-12-17 2018-08-15 Novartis Ag Formes cristallines de la 5-chloro-n2-(2-isopropoxy-5-méthyl-4-pipéridin-4-yl-phényl)-n4[2-(propane-2-sulfonyl)-phényl]-pyrimidine-2,4-diamine
WO2017152858A1 (fr) * 2016-03-11 2017-09-14 苏州晶云药物科技有限公司 Forme cristalline de céritinib et procédé pour sa préparation
WO2021083555A1 (fr) 2019-10-28 2021-05-06 Universitetet I Oslo Inhibiteurs d'alk pour le traitement du cancer alk-négatif et de maladies médiées par des cellules plasmatiques

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