Classifications

• • 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
  • C07D401/14—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 three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

• the present invention relates to a novel polymorph of 4-methyl-N-[3-(4-methyl-irrridazol- l-yl)-5-(liifluoromemyl)-phenyl]-3-[(4-pyridin-3-yl-pyrimidm benzamide monohydrochloride monohydrate, and to methods for preparing, pharmaceutical compositions comprising, and methods of treatment using said polymorph.
• Background of the invention
• pyrimidin-2-yl)aiTiino] benzamide having formula (I) was first disclosed in WO 2004/005281.
• This compound also known as nilotinib, is a tyrosine kinase inhibitor and is indicated in the treatment of drug-resistant chronic myelogenous leukemia (CML).
• CML chronic myelogenous leukemia
• WO 2004/005281 does not disclose any salts or hydrates of nnotinib.
• WO 2007/015871 is directed to various salts of nilotinib.
• Preferred embodiments include the hydrochloride, monophosphate, diphosphate, sulfate, methane sulfonate, ethane sulfonate, benzene sulfonate and p-toluene sulfonate salts of nilotinib.
• the hydrochloride salt in particular, the application only discloses forms A and B and further specifically discloses the preparation of the nnotinib monohydrochloride monohydrate by adding nHotinib free base to methanol and hydrochloric acid and recovering the hydrochloride salt after seeding.
• nilotinib hydrochloride form A is a hydrated form or an anhydrous form, however it is prepared using very similar solvents and conditions to those used to prepare form B, which is a form of nilotinib monohydrochloride monohydrate.
• the marketed product, Tasigna ® is the monohydrochloride monohydrate salt described above.
• These alternative salts and salt forms must also pass the quality and safety criteria set out by die various health authorities around the world and can themselves be marketed as equally efficacious and often more cost effective alternatives to patient groups and healthcare systems around the world.
• the inventors have succeeded in preparing an alternative novel crystalline form of nilotinib monohydrochloride monohydrate to that disclosed in the prior art.
• this novel form does not require seeding or separate exposure to moisture, thus overcomes any disadvantages that may be present with these techniques.
• nilotinib monohydrochloride monohydrate having an X-ray diffraction pattern comprising major peaks at 5.70, 7.56, 9.82, 15.01, 17.31 and 27.68 ⁇ 0.2 degrees 2-theta.
• a particularly preferred embodiment provides nilotinib monohydrochloride monohydrate having an X- ray diffraction pattern comprising further peaks at 8.60, 11.39, 12.41, 15.78, 18.64, 19.64, 20.27, 20.65, 21.48, 22.31, 22.84, 24.05, 24.40, 25.46, 25.94 and 29.64 ⁇ 0.2 degrees 2-theta.
• nilotinib monohydrochloride monohydrate having an X-ray diffraction pattern substantially as shown in Figure 1.
• nilotinib monohydrochloride monohydrate having a differential scanning calorimetry (DSC) thermogram with endothermic peaks at about 95.8°C ⁇ 0.5°C and about 258.8°C ⁇ 0.5°C.
• DSC differential scanning calorimetry
• the nilotinib monohydrochloride monohydrate has a differential scanning calorimetry thermogram substantially as shown in Figure 2.
• a further alternative embodiment comprises nilotinib monohydrochloride monohydrate having a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 3.
• TGA thermogravimetric analysis
• a second aspect of the invention provides a process for preparing nilotinib monohydrochloride monohydrate according to the first aspect of the invention comprising:
• nilotinib monohydrochloride salt used in step (iv) may be nilotinib monohydrochloride dihydrate.
• the high boiling point solvent used in step (iv) has a boiling point of greater than 80°C, most preferably between 80°C and 150°C.
• particularly preferred high boiling point solvents are selected from xylene, toluene and mixtures thereof.
• the heating in step (iv) is carried out at reflux temperatures, preferably for between about 2-10 hours, most advantageously for between about 3-4 hours.
• step (ii) adding a solution of HQ in an organic solvent to the mixture from step (i) or adding the mixture from step (i) to a solution of HC1 in an organic solvent; separating the resulting nilotinib monohydrochloride salt from the mixture in step heating the separated salt from step (iii) in a high boiling point solvent system; and isolating the resulting nilotinib monohydrochloride monohydrate salt from the solvent system of step (iv).
• the organic solvent system from step (i) comprises N,N- dimethylacetamide, acetone, ethanol, n-butanol, N-methyl pyrrolidine, tetrahydiOfuran or mixtures thereof.
• Further solvents that may be utilised comprise methanol, methanol- ater, acetonitrile, isopropyl alcohol and dimethyl formamide or mixtures thereof.
• the organic solvent system from step (i) does not comprise methanol.
• step (ii) a solution of HCl in an organic solvent is added to the mixture from step (i).
• the solution of HCl used in step (ii) is prepared by passing HCl gas through an organic solvent.
• the organic solvent used in preparing the solution of HCl used in step (ii) is selected from the group comprising a Q_ 4 alcohol, ethyl acetate, tetrahydrofuran and acetonitrile or mixtures thereof.
• the Q_ 4 alcohol is one or more of methanol, ethanol, isopropanol and n-butanol.
• an anti-solvent is added to the mixture from step (ii) to aid precipitation of the desired nilotinib monohydrochloride salt, most preferably the solvent/ anti-solvent combination is as defined in the Table below:
• NMP N-methyl pyrrolidine
• nilotinib monohydrochloride salt separated in step (iii) is nilotinib monohydrochloride dihydrate.
• the high boiling point solvent used in step (iv) has a boiling point of greater than 80°C, most preferably between 80°C and 150°C.
• particularly preferred high boiling point solvents are selected from xylene and/ or toluene.
• a third aspect of the invention provides nilotinib monohydrochloride monohydrate according to the first aspect of the invention or prepared by a process according to the second aspect of the invention, having a chemical purity as determined by HPLC of greater than 95%, preferably greater than 99%, most preferably greater than 99.5%.
• a fourdi aspect of the invention provides nilotinib monohydrochloride monohydrate according to the first or third aspects of the invention or prepared by a process according to the second aspect of the invention, having a polymorphic purity as determined by X-ray crystallography of greater than 95%, preferably greater than 99%, most preferably greater than 99.5%.
• the nilotinib monohydrochloride monohydrate according to the first, third or fourth aspects of the invention or prepared by a process according to the second aspect of the invention is suitable for use in medicine, preferably for die treatment of cancer, more preferably for the treatment of chronic myelogenous leukaemia (CML), more preferably for the treatment of adults with chronic phase or accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia (CML) with resistance or intolerance to prior therapy including imatinib.
• CML chronic myelogenous leukaemia
• CML chronic myelogenous leukaemia
• a fifth aspect of the invention provides the use of nilotinib monohydrochloride monohydrate according to the first, third or fourth aspects of the invention or prepared by a process according to the second aspect of the invention, for the manufacture of a medicament for the treatment cancer, preferably for the treatment of chronic myelogenous leukaemia (CML), more preferably for the treatment of adults with chronic phase or accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia (CML) with resistance or intolerance to prior therapy including imatinib.
• CML chronic myelogenous leukaemia
• CML chronic myelogenous leukaemia
• a sixth aspect of the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising nilotinib monohydrochloride monohydrate according to the first, third or fourth aspects of the invention or prepared by a process according to the second aspect of the invention, and at least one pharmaceutically acceptable excipient.
• the pharmaceutical composition is suitable for use in the treatment of cancer, preferably for use in the treatment of chronic myelogenous leukaemia (CML), most preferably for use in the treatment of adults with chronic phase or accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia (CML) with resistance or intolerance to prior therapy including imatinib.
• CML chronic myelogenous leukaemia
• CML chronic myelogenous leukaemia
• a seventh aspect of the invention provides a method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of nilotinib monohydrochloride monohydrate according to the first, third or fourth aspects of the invention or prepared by a process according to the second aspect of the invention, or a therapeutically effective amount of a pharmaceutical composition according to the sixth aspect of the invention.
• the patient is a mammal, preferably a human.
• the method is for treating chronic myelogenous leukaemia (CML), more preferably for treating adults with chronic phase or accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia (CML) with resistance or intolerance to prior therapy including imatinib.
• CML chronic myelogenous leukaemia
• CML chronic myelogenous leukaemia
• CML chronic myelogenous leukaemia
• Figure 1 is a representative X-ray powder diffraction pattern of nilotinib monohydrochloride monohydrate according to the invention.
• Figure 2 is a representative differential scanning calorimetry thermogram of nilotinib monohydrochloride monohydrate according to the invention.
• Figure 3 is a representative fhermogravimetry curve of riilotinib monohydrochloride monohydrate according to the invention.
• Figure 4 is a comparison of the X-ray powder diffraction patterns of the prior art forms A and B of nilotinib monohydrochloride monohydrate as disclosed in WO 2007/015871. Detailed description of the invention
• Alternative crystalline forms are desirable for a number of reasons. Preparing novel salt forms is always desirable, as it widens the repertoire available to the medicinal chemist or the pharmaceutical formulator. Cancer medication is traditionally very expensive. Any means by which the cost of such medication can be reduced is particularly advantageous to individuals and to health care providers. Providing alternative but equally efficacious salts and polymorphs thereof that may be formulated into significantly cheaper drug products is a particularly advantageous and desirable goal. A further advantage may be that the novel alternative crystalline form according to the invention may have improved dissolution, bioavailability and/or processability over the prior art forms. Preparing such alternative salts or salt forms is not necessarily routine.
• nilotinib monohydrochloride monohydrate having an X-ray diffraction pattern comprising major peaks at 5.70, 7.56, 9.82, 15.01, 17.31 and 27.68 ⁇ 0.2 degrees 2-theta.
• a particularly preferred embodiment provides nilotinib monohydrochloride monohydrate having an X- ray diffraction pattern comprising further peaks at 8.60, 11.39, 12.41, 15.78, 18.64, 19.64, 20.27, 20.65, 21.48, 22.31, 22.84, 24.05, 24.40, 25.46, 25.94 and 29.64 ⁇ 0.2 degrees 2-theta.
• nilotinib monohydrochloride monohydrate having an X-ray diffraction pattern substantially as shown in Figure 1.
• nilotinib monohydrochloride monohydrate having a differential scanning calorimetry thermogram substantially as shown in Figure 2.
• a further alternative embodiment comprises nilotinib monohydrochloride monohydrate having a thermogravimetric analysis thermogram substantially as shown in Figure 3.
• a second aspect according to the invention provides a process for preparing nilotinib monohydrochloride monohydrate according to the first aspect of the invention comprising: (i) mixing nilotinib free base in an organic solvent system;
• step (ii) adding a solution of HC1 in an organic solvent to the mixture from step (i);
• the term "mixing" is meant to include any addition of nilotinib free base to an organic solvent system, this may include dissolving or suspending all or any proportion of the n otinib free base in the solvent system.
• the addition of the nilotinib free base to the solvent system may be a suspension or the free base may be dissolved completely or partially in the solvent system.
• the organic solvent system comprises N,N- dimethylacetamide, acetone, ethanol, n-butanol, N-methyl pyrrolidine, tetrahydrofuran or mixtures thereof.
• Further solvents that may be utilised comprise methanol, methanol-water, acetonitrile, isopropyl alcohol and dimethyl formamide or mixtures thereof.
• the organic solvent system from step (i) does not comprise methanol.
• the inventors have found that addition of a solution of HC1 in an organic solvent to the reaction mixture obtained in step (i), or vice versa, results in a nilotinib monohydrochloride salt.
• the solution of HC1 used in step (ii) is prepared by passing HC1 gas through the organic solvent.
• the organic solvent used in preparing the solution of HC1 used in step (ii) is selected from the group comprising a C 1 alcohol, ethyl acetate, acetonitrile, tetrahydrofuran or mixtures thereof.
• the C alcohol is one or more of methanol, ethanol, isopropanol and n-butanol.
• the resultant nilotinib monohydrochloride salt in step (iii) is separated from the reaction mixture preferably by precipitation.
• an anti-solvent is added to the mixture from step (ii) in order to aid precipitation of the resultant nilotinib monohydrochloride salt.
• An anti-solvent can be added to a solvent system in order to reduce the solubility of a solute, in this case the nilotinib monohydrochloride salt, causing the solute to precipitate out of solution.
• NMP N-methyl pyrrolidine
• Table 1 also shows approximate advantageous mixing times. Of course the sldlled person will realise, these times are not limiting and may be varied within the scope of die invention. Further, it is within the skillset of one of ordinary skill in the art to determine suitable amounts of solvent to be used, as well as suitable reaction temperatures.
• the reaction mixture in step (ii) is stirred until the precipitate forms.
• the precipitate may form spontaneously or the reaction mixture may be cooled to facilitate the formation of the desired precipitate.
• the inventors have found that stirring the reaction mixture to form the precipitate is particularly advantageous. In this regard the stirring times shown in Table 1 are particularly advantageous.
• the formation of the desired precipitate may cause the reaction mixture to become increasingly viscous.
• additional solvent may be added to loosen the mixture.
• Most preferably the same solvent system utilised in step (i) is added to loosen the mixture.
• the addition of solvent may cause the nilotinib monohydrochloiide salt to redissolve.
• additional anti-solvent may be added to cause the desired nilotinib monohydrochloride salt to precipitate from the solution. It is currently believed that the nilotinib monohydrochloride salt separated in step (iii) is nilotinib monohydrochloride dihydrate.
• the separated solid from step (iii) is then heated in an organic solvent system comprised of high boiling point solvent(s).
• the high boiling point solvent(s) has a temperature greater than 80°C, most advantageously between 80°C and 150°C.
• the inventors have found a solvent system comprising xylene and/ or toluene to be a particularly advantageous high boiling point solvent system.
• the heating in step (iv) is carried out at reflux temperatures, preferably for between about 2-10 hours, most advantageously for between about 3-4 hours.
• die separated solid from step (iii) may be in the form of a wet cake or may be dried by any suitable means for example by vacuum drying.
• the desired nilotinib monohydrochloride monohydrate salt may then be obtained in step (v) by any of a number of suitable means.
• the heated mixture is preferably allowed to cool to obtain the desired nilotinib monohydrochloride monohydrate salt.
• the salt may then be further isolated by filtration and in particularly preferred embodiments is further dried.
• the filtered nilotinib monohydrochloride monohydrate according to the invention is dried under conditions of reduced pressure. The inventors have found that drying under vacuum or near vacuum until a constant weight is achieved is particularly preferred.
• the filtered nilotinib monohydrochloride monohydrate salt is dried in a vacuum oven, preferably in conditions that do not cause dissociation or degradation of the nilotinib monohydrochloride monohydrate salt.
• the inventors have found drying between about 55-65°C, most preferably between about 60-65°C, to be particularly advantageous. Further preferred embodiments provide drying in a vacuum oven at between about 500-600 mmHg pressure and further embodiments still provide drying for between about 5-20 hours, most preferably for about 10-15 hours.
• a third aspect of the invention provides nilotinib monohydrochloride monohydrate according to the first aspect of the invention or prepared by a process according to the second aspect of the invention, having a chemical purity as determined by HPLC of greater than 95%, preferably greater than 99%, most preferably greater than 99.5%.
• a fourth aspect of the invention provides nilotinib monohydrochloride monohydrate according to the first or third aspects of the invention or prepared by a process according to the second aspect of the invention, having a polymorphic purity as determined by X-ray crystallography of greater than 95%, preferably greater than 99%, most preferably greater than 99.5%.
• a pharmaceutical composition comprising a therapeutically effective amount of nilotinib monohydrochloride monohydrate according to the first, diird or fourth aspects or prepared by a process according to the second aspect of the present invention, and at least one pharmaceutically acceptable excipient.
• the pharmaceutical composition is preferably suitable for use in the treatment of cancer, preferably for use in the treatment of chronic myelogenous leukaemia (CIVIL), most preferably for use in the treatment of adults with chronic phase or accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia (CML) with resistance or intolerance to prior therapy including imatinib.
• CIVIL chronic myelogenous leukaemia
• CML Philadelphia chromosome positive chronic myelogenous leukaemia
• Example 1 illustrate specific embodiments of the present invention. They are not intended to limit the scope of the present invention in any way.
• Example 1
• Nilotinib free base (2 g, 3.76 mmol) was completely dissolved or suspended in acetone (30 ml, 15 volumes). Hydrogen chloride gas in e hanol (3.76 mmol) at 24-30°C was added and die reaction mixture stirred for 5 hours until a precipitate formed. The precipitated solid was then filtered through a Buchner funnel and washed with acetone. The wet solid was transferred to another flask and refluxed with xylene (40 ml, 20 volumes) for 3-4 hours.
• the precipitated solid was filtered dirough a Buchner funnel, dried for 10-15 minutes and subjected to drying in a vacuum oven at 60-65°C for 15 hours at approximately 600 mmHg pressure to yield a light yellow coloured solid.
• the dried solid was subjected to XRPD, KF, HCl content and chloride content analyses, con&ming that the obtained solid was nilotinib monohydrochloride monohydrate according to the invention.
• Table 2 The same procedure was followed using the solvent system, anti-solvent where indicated, HCl source and stirring time as shown for examples 2-10 in Table 2.
• the reaction solvent and anti-solvent amounts given in Table 2 are relative to 1 gram of nilotinib free base.
• nilotinib monohydrochloride monohydrate prepared according to examples 2-10 was >98.5%.
• the nilotinib monohydrochloride monohydrate was also polymorphically pure; XRPDs confirmed the absence of other polymorphic forms.

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• 2011
  • 2011-02-25 IN IN35KO2010 patent/IN2010KO00035A/en unknown
  • 2011-02-25 WO PCT/IB2011/050822 patent/WO2011086541A1/en active Application Filing

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